ABSTRACTS-SPEACKERS
SUNDAY, JUNE 17 10:00 AM–11:30 AM
SYMPOSIUM 1–4
The Contribution of Peripheral Effectors in the Dysregulation of
Neuronalpathways in Addiction: From the Gut-Immune-Brain Axis to Liver
Metabolism
Organizer: Philipp Mews
Chair: Drew Kiraly
1 abuse. One limitation of currently published experimental manipulations is that they do not provide
MANIPULATIONS OF THE GUT MICROBIOME AFFECT THE DEVELOPMENT AND
PERSISTENCE OF ADDICTION-LIKE BEHAVIORS
E.G. Peck1, A. Godino1, N.L. Mervosh2, E.S. Calipari3, D.D. Kiraly1,2
1
Departments of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai,
New York, NY 10029, USA, 2Department of Psychiatry, Friedman Brain Institute, Icahn School of
Medicine at Mount Sinai, New York, NY 10029, USA and 3Department of Pharmacology, Vanderbilt
Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
The resident bacteria of the gastrointestinal tract, collectively dubbed the gut microbiome, have been
shown to have profound effects on both brain and behavior. To date, the majority of research into the
gut microbiome in neuropsychiatric pathology has focused on affective and neurodegenerative disor-
ders. We recently demonstrated that altering the gut microbiome effects the development of addic-
tion-like behaviors and synaptic plasticity in important limbic reward circuits. Animals with depleted
gut flora exhibited increased locomotor sensitization and a lower threshold for conditioned place pref-
erence for cocaine. Additionally, these mice had altered regulation of genes encoding brain-derived
neurotrophic factor, the D1 dopamine receptor, and other important mediators of addiction-like
behaviors. To investigate the role of the microbiome in a more translationally-relevant manner, we
utilized a cocaine self-administration paradigm and behavioral economics modeling to assess how
shifts in the gut microbiome directly affect motivation to seek and take drug. As previously published,
rats with their gut microbiome depleted with non-absorbable antibiotics were then trained to self-
administer cocaine on a fixed-ratio 1 schedule until stably administering for 5 days. Self-administra-
tion acquisition rates for high dose cocaine did not differ between groups. Animals were then
assessed using a behavioral economics threshold task, a within-session method used to assess an
animal’s motivation to self-administer a reinforcer in the face of increasing cost. Microbiome-depleted
rats were insensitive to increases in cost (as measured by effort required) for each milligram of
cocaine. This insensitivity to increasing drug cost is analogous to insensitivity to cost seen in human
drug abusers. When cue and drug were removed, microbiome-depleted rats exhibited more rapid
extinction of lever pressing. However, after allowing for an incubation period after completion of
extinction, microbiome-depleted rats exhibited enhanced reinstatement for both cue and cocaine
stimuli. Taken together, these findings suggest that changes in the gut microbiome can alter motiva-
tion to seek drug, and affect how animals update reward contingencies in a complex manner. We
hypothesize that the gut microbiome may be an important component for the development and per-
sistence of addiction-like behaviors more generally, and may represent an important therapeutic tar-
get for treating substance use disorders.
2 correlation with an addictive phenotype. Cocaine-induced increases in G-CSF were through central
ACETYL-COA SYNTHETASE LINKS LIVER ALCOHOL METABOLISM TO DYNAMIC HISTONE
ACETYLATION IN THE BRAIN
P. Mews, S. Sidoli, G. Donahue, G. Egervari, R. Nativio, E.J. Nestler, B.A. Garcia, S.L. Berger
Perelman School of Medicine, Epigenetics Institute, University of Pennsylvania, Philadelphia, PA,
USA
A compelling body of evidence suggests an intimate relationship between metabolic state and chro-
matin regulation. We found that acetyl-CoA production by metabolic ACSS2 regulates histone acety-
lation and gene expression in neurons. Notably, alcohol metabolism in the liver generates acetate,
the key substrate used by neuronal ACSS2 to generate acetyl-CoA for histone acetylation. In fact,
acute alcohol consumption leads to highly elevated blood acetate levels and has been linked to
altered histone acetylation in the brain. However, it remains unknown whether liver metabolism can
manipulate neuronal histone acetylation directly. To elucidate whether hepatic acetate from alcohol
breakdown fuels dynamic histone acetylation in neurons, we applied in vivo SILAC mass spec to
track isotopically labeled ethanol in mice. We demonstrate that – within minutes of acute alcohol
administration – EtOH-derived acetyl-groups are incorporated into dynamic histone acetylation in
hippocampus and cortex. Notably, such incorporation is far lower in muscle tissue, where, corre-
spondingly, ACSS2 expression is reduced compared to neuronal tissue. To establish that neuronal
histone acetylation linked to alcohol ingestion is indeed dependent on ACSS2, we attenuated
ACSS2 expression in the dorsal hippocampus using shRNA knockdown (KD) and performed SILAC
mass spec to monitor incorporation of labeled EtOH carbons. Our data show that label incorporation
is not changed in the ventral hippocampus of KD animals. In contrast, dynamic labeling is attenuated
in the dorsal hippocampus, indicating that acetate generated by hepatic alcohol metabolism is acti-
vated by neuronal ACSS2, a process we show to readily manipulate gene-regulatory histone acety-
lation that is known to control neural function. Our data establish a link between hepatic alcohol
metabolism and neuronal histone acetylation, and provide first evidence for dynamic signaling from
liver metabolism directly to epigenetic regulation in neurons. These findings may pave the way to
novel therapeutic interventions in alcohol addiction and other neuropsychiatric disorders.
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3
GENE-MICROBIOME INTERACTIONS IN DRUG ABUSE-RELATED BEHAVIORS
A. Baud, O. Polesskaya, Center for rat GWAS, A.A. Palmer
Department of Psychiatry, University of California San Diego, San Diego, CA 92130, USA
The gut microbiome is emerging as an important modulator of behavior, including drug and alcohol
abuse-related behaviors. Experimental manipulations of the rodent microbiome (e.g., antibiotic treat-
ment, controlled inoculation of germ-free mice) have demonstrated causal effects of changes in gut
microbiota on drug abuse-related behaviors, suggesting that manipulations of the gut microbiota in
humans (e.g., using pre- and pro-biotics) may represent a potential target for treatment of substance
information on the variation in gut microbiota that exists in natural populations and the variation in
drug abuse behaviors that may result. One source of such variation is individual (host) genetics. Host
genetics has been shown to influence both gut microbiota composition and drug abuse-related
behaviors, but it is unclear whether the same variants underlie both influences. We looked at gene-
microbiome interactions on drug abuse-related behaviors in a population of 1200 genetically diverse
male and female rats, from the NIH Heterogeneous Stock (HS). The NIH HS is derived from eight
inbred strains through more than 80 generations of outbreeding so that more than 7 million genetic
variants segregate in the population. As a consequence, HS rats vary both in their behavior and gut
microbiota composition. The genetic makeup of all 1200 rats was fully characterized, numerous
addiction-related phenotypes were collected and the rats’ cecal microbiome was profiled using 16S
sequencing. As expected, we observed differences gut microbiome composition as a function of
housing colony. We also observed differences between males and females. We used leading edge
genetic analysis methods to investigate the extent to which the same genetic variants control micro-
biome composition and addiction phenotypes, providing novel insights into causal paths between
microbiome and addiction behaviors in natural populations. 16S data were generated through the
Center for Microbiome Innovation Seed Grant Program.
4
GRANULOCYTE-COLONY STIMULATING FACTOR CONTROLS NEURAL AND BEHAVIORAL
PLASTICITY IN RESPONSE TO COCAINE
E.S. Calipari1,2, A. Godino1,2, E.G. Peck1,2, M. Salery1,2, N.L. Mervosh1,2, J.A. Landry1,2,
S.J. Russo1,2, Y.L. Hurd1,2, E.J. Nestler1,2, D.D. Kiraly1,2
1
Department of Pharmacology, Vanderbilt Center for Addiction Research, Vanderbilt University
School of Medicine, Nashville, TN, USA and 2Fishberg Department of Neuroscience, Friedman
Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
There is a growing body of literature suggesting a role for immune dysregulation in the pathophysiol-
ogy of psychiatric disease, including addiction. Studies of patients with cocaine use disorders have
shown dysregulation of multiple peripheral cytokines – some of which correlate with extent of drug
use, and addicts show altered immune system reactivity in response to drug cues. Here we aimed to
define the complex interaction between cocaine use and cytokine signaling and how these factors
alter reward, motivation, and economic decision making to drive addiction. By performing a broad
multiplex screen of serum immune factors, we defined several that are altered with cocaine expo-
sure. However, while multiple immune factors were regulated by cocaine, only one – granulocyte-col-
ony stimulating factor (G-CSF) – showed upregulation in multiple treatment paradigms as well as
actions. Direct stimulation of the mPFCâNAc pathway in isolation increased G-CSF levels in the
NAc. G-CSF increased cocaine-induced activation of reward circuits, increased cocaine place pref-
erence, enhanced motivation to self-administer cocaine, and enhanced lever pressing for low proba-
bility cocaine, without affecting response to natural rewards. Infusion of G-CSF neutralizing antibody
into the nucleus accumbens abrogated these effects, providing a direct link between central G-CSF
actions and cocaine reward. Importantly, we show that systemic injections of G-CSF are sufficient to
alter the motivation for cocaine, providing an avenue to develop a pharmacotherapy to manipulate
reward circuits and addictive behaviors without abuse potential.
272A ABSTRACTS-SPEACKERS

SUNDAY, JUNE 17 10:00AM–11:30AM 7

SYMPOSIUM 5–8
Sex-Dependent Alcohol Associated Comorbidities SEX-DEPENDENT DIFFERENCES IN REGULATING SKELETAL MUSCLE PROTEIN BALANCE
AFTER LONG-TERM, BUT NOT ACUTE, ETHANOL CONSUMPTION
Organizer/Chair: Liz Simon C.H. Lang
Cellular & Molecular Physiology, Penn State College Medicine, Hershey, PA 17033, USA

5 Excessive ethanol consumption results in the erosion of lean body mass with the prevalence of
chronic alcohol skeletal muscle myopathy estimated to be greater than 40% making it one of the
OVARIAN HORMONES EXCACERBATE THE CARDIOTOXIC EFFECT OF ALCOHOL: ROLE most prominent muscle diseases. This myopathy is characterized by proximal muscle weakness that
OF ESTROGEN REGULATION OF ALCOHOL METABOLISM compromises quality of life indices and the atrophy is proportional to total lifetime alcohol ingestion.
A.A. Abdel-Rahman Early studies in humans suggested that women had a lower threshold for the development of skeletal
Department of Pharmacology and Toxicology, The Brody School of Medicine at East Carolina muscle myopathy than men; however, this sexual dimorphism has subsequently received little atten-
University, Greenville, NC 27834, USA tion. This presentation will review evidence on sex differences related to the effect of acute alcohol
intoxication and chronic alcohol consumption on the development of skeletal muscle wasting. Data
Background: The reasons why women and female rats are more vulnerable to alcohol-evoked car- will be presented demonstrating there is no difference between male and female rats pertaining to
diotoxicity remain poorly understood. In men and male rats, compensatory increases in sympathetic acute alcohol-induced decreases in muscle protein synthesis and mTOR (mammalian target of rapa-
tone and aldehyde dehydrogenase (ALDH2) activity mitigate alcohol-evoked myocardial dysfunc- mycin) signaling. In contradistinction, whereas chronic alcohol ingestion also decreases the mTOR-
tion. dependent changes in muscle protein synthesis and translation initiation in male rats, no such
Scientific premise: While the sex/estrogen (E2)-specific lower sympathetic tone and higher ALDH2 changes were detected in female rats consuming equivalent amounts of alcohol. However, female
and catalase activities confer cardioprotection, these traits might become detrimental in the presence rats did demonstrate a alcohol-induced increases in the skeletal muscle-specific ubiquitin-E3 ligases
of alcohol. atrogin-1 and MuRF1, suggesting an increase in muscle proteolysis, which was not seen in chronic
Hypothesis: Acetaldehyde (ACA) over-production, by hyperactive catalase, creates cellular envi- alcohol fed male rats. Hence, data from nutritionally well-controlled rodent studies suggest female
ronment conducive to a paradoxical transformation of E2 into a proinflammatory hormone, and the rats are less sensitive, not more sensitive as seen in humans, to chronic alcohol-induced muscle
exacerbation of ethanol-evoked cardiotoxicity in females. wasting.
Methods: Hemodynamic and telemetry studies were conducted in conscious sham-operated (SO),
ovariectomized (OVX in absence or presence of E2) and male rats treated with acute (1.5 g/kg) or
chronic (approx. 8 g/kg/day in liquid diet) along with ex vivo molecular studies. Pharmacological
interventions included inhibitors of alcohol metabolizing enzymes and selective agonists or antago-
nists of the three E2 receptor (ER) subtypes.
Results: (1) Similar alcohol doses caused more evident myocardial oxidative stress and dysfunc- 8
tion in proestrous SO rats than in OVX or male rats; (2) The protection against alcohol-evoked
SEXUAL DIMORPHISM IN ALCOHOL INDUCED ADIPOSE INFLAMMATION RELATES TO
myocardial oxidative stress/dysfunction is lost following E2 replacement in OVX or male rats; (3) E2-
LIVER INJURY
replete alcohol-treated rats lacked the rescue mechanisms (increases in ALDH2 and sympathetic
M.A. Fulham, P. Mandrekar
tone), and exhibited higher cardiac catalase activity. Next, we discerned the mechanisms of E2 acti-
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
vation of cardiac catalase (catalyzes ethanol oxidation to ACA). Pharmacologic loss or gain of func-
tion studies suggest a pivotal role for ERa translocation to the myocyte membrane in: (1) catalase Alcoholic liver disease occurs due to chronic, heavy drinking and is driven both by metabolic alter-
activation, and (2) PI3K-Akt-ERK1/2-NOS activation, which mediates ethanol/ACA-evoked myocar- ations and immune cell activation. Women are at a higher risk than men for developing alcohol
dial oxidative stress/dysfunction. induced liver injury and this dimorphism is reflected in animal models of alcoholic liver disease. The
Conclusions: The findings yielded new insights into the molecular mechanisms implicated in the importance of adipose tissue in alcoholic liver disease is emerging. Chronic alcohol consumption
E2-dependent higher vulnerability of women and female rats to alcohol-evoked cardiotoxicity. causes adipose tissue inflammation, which can influence liver injury. Sex differences in body fat com-
position are well known. However, it is still unclear if alcohol-induced adipose tissue inflammation
occurs in a sex-dependent manner. We hypothesize that alcohol induces greater adipose inflamma-
tion in females and relates to liver injury. To test the hypothesis, we used the clinically relevant
NIAAA model of chronic-binge alcohol consumption to investigate the sexual dimorphism. Ten-week
6 old male and female C57BL/6J mice were subjected to Lieber-DeCarli alcohol diet followed by single
alcohol gavage (5 g/kg body weight) nice hours before sacrifice. Perigonadal adipose tissue was
EPISODIC ALCOHOL EXPOSURE ACCELERATES OVARIECTOMY-INDUCED BONE LOSS excised and blood collected to determine immune parameters and serum markers of liver injury
AND IMPAIRS FRACTURE HEALING IN RODENTS respectively. We report that female mice have greater liver injury as assessed by high serum ALT
J.J. Callaci, P.M. Roper, A. Spotts, O. Vetter, P. Whiteside, F. Sharieh than male mice despite lower alcohol consumption. Chronic-binge alcohol induces adipose tissue
Department of Orthopaedic Surgery and Rehabilitation, Stritch School of Medicine: Alcohol inflammation in vivo in female mice, which is illustrated by increased expression of TNFa, IL-6, and
Research Program, Loyola University Chicago, Loyola University Health Sciences Campus, CCL2, compared to only IL-6 induction in male adipose tissue. Further, macrophage activation mark-
Maywood, IL, USA ers such as CD68 as well as the pro-inflammatory activation markers CD11b and CD11c were higher
in female adipose tissue. Interestingly, alcohol induced expression of TLR2, 3, 4, and 9 in female but
Excessive alcohol consumption is damaging to both the intact and injured skeleton. Alcohol con- not male adipose tissue, without affecting the TLR adaptor, MyD88. Higher trends of serum endo-
sumption is a risk factor for osteoporosis, orthopaedic injury and fracture nonunion. Women may be toxin in female mice may likely contribute to adipose tissue inflammation. In vitro chronic alcohol-
especially at risk for skeletal-related consequences of alcohol due to their increased risk for osteo- mediated sensitization of macrophages to endotoxin is independent of sex. In summary, we demon-
porosis. Using a model of episodic alcohol exposure, we previously demonstrated that alcohol treat- strate for the first time that there is a sexual dimorphism in alcohol-induced adipose tissue inflamma-
ment increased the rate of bone loss in ovariectomized female rats compared to saline treated tion and female mice exhibit a higher degree of inflammation than male mice.
animals. Fracture nonunion is a serious complication of fracture injury resulting in increased patient
morbidity and mortality. We have previously shown that episodic alcohol exposure prior to infliction
of a tibial fracture has dramatic effects on early bone fracture repair in rodents. We observe
decreases in fracture callus size, changes in callus tissue composition and decreases in biomechan-
ics strength. We believe that the mechanism(s) underlying these effects likely involve an alcohol-per-
turbation of signaling pathways which control MSC differentiation at the fracture site. To test this
hypothesis, we have examined signaling activity in fracture callus tissue from saline and alcohol-trea-
ted mice, and found an alcohol-related inhibition of Canonical Wnt signaling with a concurrent activa-
tion of FoxO-specific signaling activity. This suggests that alcohol may promote a cellular stress
response favoring FoxO-specific stress signaling at the expense of Canonical Wnt signaling, which
regulates early MSC differentiation at the fracture site required for callus formation and normal frac-
ture healing. To examine this hypothesis mechanistically, we cultured primary rodent MSC in chon-
drogenic and osteogenic differentiation media in the presence of 50 mM ethanol and then examined
early markers of both chondrogenic (Col2a1, Sox9) and osteogenic (Osterix, Col1a1) differentiation.
We found that ethanol significantly inhibits the expression of these chondrogenic and osteogenic dif-
ferentiation markers, and that the inhibition of FoxO signaling (through siRNA or pharmacologic inhi-
bitors) restores normal differentiation of MSC of alcohol exposed cells. This data suggests that
alcohol, through activation of FoxO signaling, may inhibit fracture callus formation by perturbing nor-
mal MSC differentiation towards a chondro-osteo lineage. This effect of alcohol on MSC differentia-
tion may be therapeutically targeted by agents which dampen alcohol-related FoxO activation in
MSC, restoring normal activity to stem cells and subsequent callus formation at the site of a fracture
injury.
ABSTRACTS-SPEACKERS
SUNDAY, JUNE 17 10:00AM–11:30AM
SYMPOSIUM 9–12
Translational Genetics of Alcohol Use Disorders: Multidisciplinary
Approaches to Identifying Novel Therapeutic Targets
Organizers/Chairs: Amanda Barkley-Levenson and Abraham Palmer
9 genetic studies in animals and large genome-wide association studies on alcohol use disorder
BIOINFORMATICS ANALYSIS OF AMYGDALA GENE EXPRESSION IDENTIFIES A TARGET
FOR REDUCING ETHANOL DRINKING AND ANXIETY-RELATED BEHAVIORS
P.J. Mulholland
Department of Neuroscience, Charleston Alcohol Research Center, Medical University of South
Carolina, Charleston, SC 29425, USA
Anxiety and mood disorders are comorbid psychiatric illnesses with alcohol use disorder (AUD) and
are critical components in the development, maintenance, and reinstatement of alcohol dependence
and harmful alcohol-seeking behaviors. Because of the high comorbidity between AUD and mood
disorders, it is necessary to determine the genetic underpinnings driving heavy ethanol drinking and
anxiety-related behaviors. To identify novel genetic targets that may lead to more efficacious treat-
ment options, partial least squares (PLS) analysis was used to extract covariance patterns between
amygdala K+ channel gene expression levels and anxiety- and stress-related phenotypes in BXD
recombinant inbred strains of mice. Next, heavy ethanol intake and anxiety-like behaviors were char-
acterized in C57BL/6J mice treated with chronic intermittent ethanol (CIE) vapor in inhalation cham-
bers and repeated forced swim stress. Finally, a pharmacology approach was used to validate the
bioinformatics results in ethanol-dependent, stressed C57BL/6J mice. PLS analysis revealed that
amygdala expression of two genes in the Kcnn family – Kcnn2 and Kcnn3 – were strong predictors
(i.e., high variable importance in projection scores) of anxiety- and stress-related phenotypes in BXD
strains. C57BL/6J mice treated with CIE and repeated swim stress consumed more ethanol in their
home cages and showed hyperneophagia on the novelty-suppressed feeding test (NSFT) during
prolonged abstinence. Pharmacologically targeting KCa2 channels encoded by Kcnn genes with the
positive modulator 1-EBIO significantly decreased ethanol drinking and reduced the latency to
approach food during the NSFT in ethanol-dependent, stressed mice. By showing that heavy drink-
ing and aberrant anxiety-like behaviors are influenced by KCa2 channels, these studies validate anal-
ysis of genetic expression-phenotype relationships in BXD strains as an analytical approach to
identify targets for treating alcohol dependence and comorbid psychiatric disorders.
10
EVALUATION OF GLYOXALASE 1 AS A NOVEL THERAPEUTIC TARGET FOR EXCESSIVE
ETHANOL CONSUMPTION AND COMORBID DISORDERS
A.M. Barkley-Levenson, A. Der-Avakian, A.A. Palmer
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
Alcohol use disorders (AUD) are complex heterogeneous disorders and the limited number of
approved medications is only effective in a subset of individuals. Identifying novel genetic risk factors
for AUD is a critical step in determining new treatment targets with the ultimate goal of developing
more pharmacotherapies. One approach is to harness the genetic control available in model organ-
isms to identify and validate possible candidate genes for therapeutic targeting in humans. Here we
describe work done with glyoxalase 1 (Glo1), a novel potential target for the treatment of AUD and
comorbid psychiatric disorders (anxiety, depression). Glo1 was identified as a gene of interest in anx-
iety-like behavior through gene expression profiling in inbred mouse strains. It has subsequently
been shown to act through a GABAergic mechanism and is implicated in both anxiety- and depres-
sion-like behavior in mouse models. Genetic and pharmacological manipulation of Glo1 can also
reduce ethanol binge-like drinking without affecting locomotor activity or water consumption. To fur-
ther explore the role of Glo1 in ethanol drinking we have used intracranial self-stimulation (ICSS) to
assess Glo1’s effects on ethanol enhancement of reward sensitivity. We show that ethanol dose-
dependently alters response thresholds in the ICSS procedure, with lower doses decreasing
response thresholds (i.e., enhancing reward sensitivity) and higher doses increasing response
thresholds (i.e., decreasing reward sensitivity/increasing aversion). Pretreatment with a Glo1 inhibitor
can block the effect of ethanol on response thresholds, indicating that Glo1 inhibition may reduce
sensitivity to the rewarding effects of ethanol. When tested alone, a Glo1 inhibitor had no effect on
ICSS response threshold, suggesting that there is a low potential for abuse liability. These findings
suggest that Glo1 inhibitors may have therapeutic potential for reducing ethanol intake by blocking
the reward enhancing effects of ethanol. We also show that ICSS can be a powerful tool in rodent
models for screening both the abuse liability of potential therapeutics as well as their ability to modu-
late sensitivity to ethanol reward and aversion.
273A
11
TRANSLATING MODEL ORGANISM GENE NETWORKS TO THERAPEUTIC TARGETS FOR
ALCOHOL USE DISORDER
M.F. Miles, K.M. Mignogna, A.D. van der Vaart
Department of Pharmacology & Toxicology, Neurology, The VCU Alcohol Research Center, Virginia
Commonwealth University, Richmond, VA 23298, USA
Recent advances in genomic studies on ethanol actions in humans and animal models, behavioral
(AUD) have identified a prodigious number potential therapeutic targets for development of future
therapeutic approaches. The current difficulty therefore lies in validating and prioritizing such candi-
dates, understanding their mechanisms of action and identifying optimal targets for therapeutic inter-
vention or diagnostic risk analysis. Our laboratory has employed a gene network analytic approach
using behavioral and gene expression studies on ethanol responses in rodent genetic panels to iden-
tify key networks regulated by acute or chronic ethanol and/or correlating with ethanol behaviors,
including progressive consumption. Furthermore, by co-analyzing such rodent expression networks
with human GWAS data, including recent very large published studies on ethanol consumption, we
have identified novel networks regulated by ethanol and over-represented for GWAS signals. This
presentation will focus on our findings regarding this cross-species analysis which has identified sev-
eral novel network-level targets for possible future therapeutic intervention. Rodent gene network
studies in the BXD panel of inbred mice have also identified target genes recently validated for etha-
nol behaviors using gene targeting or viral vector approaches. Such networks involve known promi-
nent ethanol targets such as Kcnma1 and recently replicated GWAS hits such as Klb. Furthermore,
we show that one member of such networks, Gsk3b, is a potential new therapeutic target for inter-
vention in AUD by virtue of having a role both as risk factor and mechanistic hub for ethanol action.
Gsk3b over-expression in medial prefrontal cortex increased ethanol consumption while localized
deletion of the gene in infra-limbic neurons or pharmacological inhibition of GSK3b activity decreased
ethanol consumption. These studies could provide immediate new targets for clinical investigation
and promise an approach for identification of future avenues of intervention in AUD. Supported by
NIAAA grants U01AA016667, P50AA022537 and R01AA020634 to MFM and F30AA024382 to
ADV.
12
IDENTIFYING GENES FOR EXTERNALIZATION, TOWARDS TARGETED INTERVENTION
D. Goldman, H. Akil, P. Blandino, S. Watson, C. Hodgkinson, Z. Zhou
Laboratory of Neurogenetics, Office of Clinical Director, National Institute on Alcohol Abuse and
Alcoholism, Rockville, MD 20852, USA
Alcohol use disorder is etiologically and clinically complex, suggesting that an endgame in their treat-
ment will involve targeting of pathophysiologic mechanisms specific to particular patients. External-
ization is an innate, addiction associated trait that can be genetically analyzed in both humans and in
animal models. In humans, we previously associated an HTR2B stop codon with severe externaliza-
tion, and AUD. The MAOA STR is another well-known, and far more common, locus influencing
externalization. High Response/Low response rats, created by Akil and colleagues via artificial selec-
tion, are a model for rapid development of sign tracking and punishment-resistant responding for
addictive drugs. Via exome sequencing we identified genomic regions, genes and specific exonic
variants segregating between HR and LR rats. Via F2 linkage analyses we mapped seven genome
wide significant QTLs for locomotory response to novelty. Together these account for >50% of the
total variance in rat novelty response, and some 35% of the genetic variance. Based on the QTL
mapping, the HR trait is oligogenic, and the loci we detected are additive in mode of action. Oli-
gogencity of this particular addiction associated trait is also supported by rapid response to selection
and phenotypic dispersion of F2 rats. These conclusions contrast with some recent findings, from
human GWA, implicating thousands of loci in alcoholism and other addictions. The prime candidate
gene at the strongest eQTL, on Chromosome 1, is Apba2, an amyloid-related protein, this one locus
accounting for more than 10% of the genetic variance. Genotyping the syntenic region in humans,
we observe significant association of APBA2 to externalization (Novelty Seeking) and drug addiction
in two datasets, and are seeking to identify the locus that may alter expression or function of APBA2.
274A
SUNDAY, JUNE 17 10:00AM–11:30AM
SYMPOSIUM 13–16
Predicting Outcomes of Fetal Alcohol Exposure in the CIFASD Cohort
Organizers/Chairs: Michael Charness and Edward Riley
13
PRENATAL ETHANOL EXPOSURE INDUCES A “TRANSIENT CILIOPATHY”: A NOVEL
MECHANISM FOR ETHANOL’S PATHOGENESIS
K.E. Boschen, E.W. Fish, S.E. Parnell
Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC 27599, USA
It has been well established that prenatal ethanol exposure (PAE) during gastrulation (3rd week of
human development) induces the abnormal brain and craniofacies typical of Fetal Alcohol Syndrome
(e.g., smooth philtrum, hypotelorism, holoprosencephaly, corpus callosum dysgenesis). However,
recent research in both mice and humans has demonstrated that PAE during slightly later periods of
development has its own unique brain and craniofacial signature manifesting as hypertelorism and
expanded ventral midline regions of the brain. These ethanol-induced dysmorphologies phenocopy
those observed in certain ciliopathy syndromes, such as Joubert’s syndrome. Primary cilia are critical
for the proper transduction and regulation of several morphogenic signaling gradients, such as sonic
hedgehog (Shh), and even brief disruptions in their normal function can result in significant abnormal-
ities. Some genetic ciliopathies occur following mutations in key primary cilia-related genes, resulting
in an abnormal activation of the Shh pathway. To test the involvement of primary cilia in mediating
ethanol’s pathogenesis, ethanol was administered acutely to C57BL/6J mice on their 9th day of preg-
nancy (mid-neurulation; equivalent to the 4th week of human development), and embryos were col-
lected 6, 12, and 24 h after the beginning of exposure. First, the number of cilia was assessed within
the rostroventral neural tube (RVNT). Ethanol exposure altered cilia number at the early time points,
an effect that returned to baseline by 24 h. Next, to determine the downstream effects of these cilia
abnormalities, key Shh pathway and Shh target genes were examined. Several aspects of the Shh
pathway were dysregulated, and several key Shh target genes were upregulated, suggesting a cau-
sative mechanism for the observed dysmorphologies. To explore the potential mechanism(s) by
which ethanol might be decreasing cilia number, RNA-Seq was performed in the RVNT from control
and ethanol-exposed embryos 6 h after the beginning of exposure. These data show that ethanol
altered the expression of many key ciliogenesis genes. Finally, to further demonstrate the interaction
of PAE and primary cilia function, we show that mice missing one copy of the key cilia gene Kif3a
were significantly more susceptible to ethanol than their wild-type littermates. Collectively, these
novel data demonstrate that ethanol can induce a transient ciliopathy that contributes to develop-
mental brain abnormalities.
14
USING 3D FACIAL ANALYSIS TO IDENTIFY MINOR FACIAL ANOMALIES AND ETHNIC
DIFFERENCES IN EFFECTS OF PRENATAL ALCOHOL EXPOSURE
M. Suttie, L. Wetherill, S.W. Jacobson, J.L. Jacobson, E.H. Hoyme, S. Mattson, E.R. Sowell,
C. Coles, J.R. Wozniak, E.P. Riley, K.L. Jones, R. Mukherjee, T. Foroud, P. Hammond
Nuffield Department of Obstetrics and Gynaecology, Big Data Institute, University of Oxford, Oxford,
UK
Prenatal alcohol exposure damages the developing central nervous system and causes a variety of
craniofacial effects depending on the timing of exposure. The individual morphological changes in
the face are well documented, but there remains a clinical challenge identifying those who do not fit
the typical diagnostic criteria. The primary aim of this study is to utilise a 3D image based approach
to detect the full spectrum of facial effects associated with prenatal alcohol exposure. Also, we
explore the potential for introducing 3D imaging into the clinical workflow by developing computer-
based tools for screening facial form. High-resolution 3D facial images of Caucasian, and South Afri-
can Cape Coloured subjects were obtained through the CIFASD (Collaborative Initiative on Fetal
Alcohol Spectrum Disorders) consortium and the University of Cape Town (UCT) respectively. The
Cape Coloured: Caucasian diagnostic subgroup sizes were as follows: controls (69:141); FAS
(22:35); heavily exposed but not meeting FAS/PFAS criteria (75:73). 3D images were used to build
models of facial form to support discrimination studies and to produce surface curvature-based delin-
eations. Taking what we have learnt from this, and previous studies, we apply techniques to test a
3D image based clinical screening tool. Consistency of agreement between clinical diagnosis and
control-FAS facial form classification is lower for midline facial regions and higher for non-midline
regions. We found specific control-FAS differences within and between the cohorts, and curvature
changes in facial profile induced by prenatal alcohol exposure differ between cohorts. Interestingly,
we identify a subset of Cape Coloured heavily exposed individuals, linked by their facial dysmor-
phism, who exhibit orbital hypertelorism. Facial curvature assists in the recognition of facial form
associated with prenatal alcohol, which can be utilised by a clinician. Identifying orbital hypertelorism
in a subset of exposed individuals supports the long standing notion that time dependent alcohol
exposure can cause increased separation of the brain hemispheres. Greater depth of understanding
of the facial profile contributes significantly to the tools which we can provide to clinicians.
ABSTRACTS-SPEACKERS
15
ALCOHOL INTAKE AND IMMUNE FUNCTION: ASSOCIATIONS BETWEEN MATERNAL
IMMUNE NETWORKS AND CHILD NEURODEVELOPMENTAL OUTCOME
T.S. Bodnar, C. Raineki, W. Wertelecki, L. Yevtushok, L. Plotka, N. Zymak-Zakutnya,
G. Honerkamp-Smith, A. Wells, M. Rolland, T.S. Woodward, C.D. Coles, J.A. Kable,
C.D. Chambers, J. Weinberg, The CIFASD
Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC
V6T1Z3, Canada
Background and Purpose: Chronic or binge alcohol consumption can increase circulating levels
of proinflammatory cytokines. Cytokines can cross the placenta to affect the fetus directly, and can
act on the placenta to stimulate downstream elaboration of the maternal cytokine signal in the fetal
compartment. As cytokines are CNS neuromodulators, disruption of the finely tuned fetal cytokine
balance could impact both fetal immune regulation and fetal brain development. Importantly, cytoki-
nes act in concert to orchestrate complex, coordinated responses. As such, we evaluated both indi-
vidual cytokine levels and interactive cytokine networks to provide a broad understanding of
alcohol’s effects on both maternal and fetal outcomes.
Methods: As part of an ongoing longitudinal study (CIFASD.org), we assessed: (1) Effects of alco-
hol during pregnancy on maternal cytokine networks; (2) Association of maternal cytokine networks
with infant neurodevelopmental outcome; and (3) Effects of in utero alcohol exposure on child cyto-
kine levels. Participants were women reporting moderate/heavy or low/no alcohol consumption in
the peri-conceptional period and the most recent month of pregnancy, selected from a larger cohort
enrolled at two prenatal care facilities, and alcohol-exposed/unexposed children (2–3.5 years) seen
at two ONMI-Net sites in Western Ukraine. Cytokines were assayed using Meso Scale Discovery
(MSD) human biomarker 40-plex kit.
Results: We identified specific maternal cytokine profiles, with distinct clusters of cytokines differen-
tially activated/inhibited in relation to both maternal alcohol consumption and infant neurodevelop-
mental outcome, allowing us to identify immune changes linked to alcohol-related versus alcohol-
independent neurodevelopmental delay. Preliminary results also suggest differential patterns of pro-
and anti-inflammatory cytokines in alcohol-exposed compared to unexposed children, including
higher C-reactive protein (CRP) levels with alcohol exposure, suggestive of chronic, low-grade
inflammation.
Conclusions: Altered cytokine levels during critical developmental periods may underlie some of
the long-term effects of prenatal alcohol exposure on cognitive, behavioral, immune, and health out-
comes. Evaluation of both individual cytokines and cytokine networks provides a richer, more com-
plex and more functionally relevant understanding of the immunological milieu than can occur with
evaluation of individual cytokines alone. Funding: NIH-NIAAA U01AA014834 and NIH Office of Diet-
ary Supplements to CDC; U24 AA014811-12 (Developmental Project), UO1 AA026101, R37
AA007789, and R01 AA022460 to JW.
16
A GROWTH MODELING APPROACH TO PREDICTING FUTURE NEURODEVELPMENTAL
PERFORMANCE IN INFANTS WITH PRENATAL ALCOHOL EXPOSURE
C.D. Chambers, A. Wells, R. Xu, W. Wertelecki, C.D. Coles, J. Kable, N. Zymak-Zakutnya,
L. Yevtushok
Pediatrics, University of California San Diego, La Jolla, CA 92093, USA
Purpose: Early intervention has been shown to improve neurodevelopmental outcomes in children
with Fetal Alcohol Spectrum Disorders. However, early identification of alcohol-affected infants is
challenging in routine clinical settings. As pre- and postnatal growth is often affected by prenatal alco-
hol exposure (PAE), and growth measurements are repeatedly captured in routine clinical practice,
we examined the utility of using individual growth trajectories to predict early neurodevelopmental
performance in infants with PAE.
Methods: As part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD), a
prospective cohort study has been ongoing at two sites in Western Ukraine from 2007 to 2018. Preg-
nant women with and without moderate to heavy PAE were enrolled in the study, and their offspring
were followed longitudinally for growth and development. From the cohort, 441 singleton infants were
selected (192 PAE and 249 low/unexposed) for whom multiple measures of height, weight and head
circumference had been obtained from routine prenatal ultrasound and postnatal pediatric visits.
Neurodevelopment was assessed using the Bayley Scales of Infant Development Version II at
approximately 12 months of age. A novel fast covariance estimation (FACE) method was used to
extract growth features for each child in predicting performance on the Bayley. Quantity and fre-
quency of alcohol use in pregnancy, as well as demographics, health history and substance use
were obtained from maternal interviews and were also considered in the prediction models.
Results: Among the 192 PAE infants, the areas under the curve (AUC) in models predicting lower
scores (<85 vs. 85 or higher) on the Bayley Mental Developmental Index (MDI) and Psychomotor
Developmental Index (PDI) were 0.81 and 0.85, respectively. The explained variation in continuous
Bayley scores for the same infants in the PAE group was 37% and 33%, respectively. These predic-
tion models performed less well in low/unexposed infants.
Conclusion: Routinely collected growth measurements combined with other readily available clini-
cal data may be useful in clinical practice in predicting neurodevelopmental impairment in infants with
PAE who should be targeted for early intervention.
ABSTRACTS-SPEACKERS 275A

SUNDAY, JUNE 17 10:00AM–11:30AM 19

SYMPOSIUM 17–20
The Development of Heavy Drinking in African Americans: Understudied Risk TRAUMA, SOCIOECONOMIC STATUS, AND FREQUENCY OF ALCOHOL USE IN AFRICAN
AMERICAN ADULTS: A POLYGENIC RISK SCORE X ENVIRONMENT STUDY
and Protective Factors J.L. Meyers, M. Cerda,S. Galea,K.M. Keyes,A.E. Aiello,M. Uddin,D.E. Wildman, K.C. Koenen
Organizer: Angela Haeny Department of Psychiatry, State University of New York Downstate Medical Center, Brooklyn, NY
Chair: Carolyn Sartor 11203, USA

Exposure to trauma has been shown to increase heavy drinking and risk for alcohol use disorder
(AUD). However, recent studies have shown that some trauma exposures are not as strongly associ-
17 ated with AUD among African Americans. The paradoxical elevated trauma exposure but lower alco-
hol involvement in African Americans versus European Americans raises questions regarding the
THE ASSOCIATION OF RACIAL AND SOCIOECONOMIC DISCRIMINATION WITH TWO mechanisms linking trauma and drinking behaviors in African Americans. Using data from African
STAGES OF ALCOHOL USE IN AFRICAN AMERICAN YOUTH American participants in the Detroit Neighborhood Health Study, a longitudinal cohort of men and
A.M. Haeny, C.E. Sartor, K.K. Bucholz women living in Detroit, Michigan (N = 1,547; 56.9% female; Mage = 49.0, SDage = 17.1), we exam-
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA ined the association between trauma exposure and frequency of alcohol use in a genetically informa-
tive framework. A checklist including 19 potentially traumatic events was used to create a sum score
Etiologic models of problematic alcohol use, developed largely on predominantly European Ameri-
of 7 assaultive (e.g., mugged or threatened with a weapon, sexually assaulted, etc.) and 12 non-
cans, do not fit as well for African Americans (AAs), and risk factors relevant for AAs, such as racial
assaultive (e.g., natural disaster, diagnosed with a life-threatening disease, etc.) traumatic expo-
discrimination, have been understudied. Racial discrimination has been linked to problem drinking
sures. Frequency of alcohol use was measured using the following item, “In the past 30 days, on
among AAs, but its contribution to progression through stages of alcohol use has yet to be examined.
those days when you drank alcohol, on average, how many alcoholic beverages did you consume
The present study investigated the association of racial discrimination with the timing of transitions
per day?” We constructed a polygenic risk score (PRS) based on genome-wide association findings
through two stages of use: initiation and first use to problem drinking. Maternal discrimination experi-
from the Psychiatric Genomics Consortium’s analysis of DSM-IV alcohol dependence (Walters
ences were included to capture intergenerational transmission of discrimination-related risk and,
et al., 2017, unpublished), and examined interactions with non-assaultive and assaultive traumatic
given that AAs are overrepresented in low socioeconomic status communities, socioeconomic dis-
event sum scores. Linear-Poisson regression analyses revealed a stronger association between the
crimination was also examined. Data were drawn from a high-risk alcoholism family study ascer-
PRS and alcohol use frequency among individuals with a higher number of assaultive traumatic
tained in the Midwest. Mothers and their offspring (N = 806; Mage = 17.87, SDage = 3.91; 50%
events (B: 0.16, p: 0.03. When indicators of socioeconomic status (SES), i.e., household and neigh-
female) were assessed via telephone interview for substance use, psychiatric disorders, and related
borhood income and education level, were added to the model, effects were no longer statistically
psychosocial factors. Cox proportional hazard regression analyses were used to assess for associa-
significant (B: 0.09, p: 0.21). Findings suggest that assaultive trauma increases liability to express
tions between discrimination and age at first drink and progression to problem drinking (one or more
genetic vulnerability to heavy alcohol use and that SES accounts in part for the link between assaul-
DSM-5 alcohol use disorder symptoms). Analyses were conducted in four stages, all adjusting for
tive trauma and frequency of alcohol use in African Americans.
demographic characteristics and study design and including discrimination: (1) discrimination only;
(2) maternal discrimination experiences; (3) interactions between discrimination and religious
involvement and social support; (4) psychiatric covariates (conduct disorder, marijuana use, cigarette
smoking, depression, and anxiety) and childhood maltreatment. Neither maternal discrimination nor
moderating effects of religious involvement or social support were observed. Racial (HR: 1.35, CI:
1.06–1.70) and socioeconomic (HR: 1.46, CI: 1.04–2.05) discrimination predicted timing of initiation,
even after adjusting for demographic and psychiatric covariates. However, socioeconomic discrimi-
20
nation predicted a more rapid transition from first use to problem drinking exclusively in the unad- EDUCATIONAL EXPERIENCES AND ATTAINMENT IN PATHWAYS TO HEAVY DRINKING
justed model (HR: 1.62, CI: 1.12–2.34). These findings suggest both racial and socioeconomic AMONG AFRICAN AMERICANS: A LONGITUDINAL STUDY FROM ADOLESCENCE TO
discrimination are robust risk factors for timing of alcohol use initiation, but may not play a significant MIDLIFE
role in the transition from first use to problem drinking among AAs. Prevention efforts targeting the N. Mulia, J. Witbrodt, K.J. Karriker-Jaffe, C. Lui, T.C.B. Zapolski
impact of discrimination in the years prior to peak risk for initiation are needed to reduce risk for alco- Alcohol Research Group, Public Health Institute, Emeryville, CA 94608, USA
hol use in AA youth.
Prior research has consistently demonstrated protective effects of higher education on adult heavy
drinking and alcohol-related problems, but few studies have prospectively investigated specific edu-
cation-related pathways influencing risk for adult alcohol outcomes. In view of African Americans’
lower levels of education and disproportionate burden of alcohol-related problems in adulthood, we
investigated education-related pathways to heavy drinking among African Americans, focusing on
18 two questions: (1) how does early socioeconomic disadvantage affect schooling experiences and
educational attainment? and (2) what mechanisms underlie protective effects of higher education on
DOES RACIAL IDENTITY BUFFER THE EFFECT OF DISCRIMINATION ON HEAVY ALCOHOL alcohol outcomes? Data are from the 1979 National Longitudinal Study of Youth (NLSY), which has
USE IN AFRICAN AMERICANS? VARIATIONS IN PROTECTION BY IDENTITY TYPE followed adolescents recruited in 1979 (ages 14–21 at baseline) to the present (N = 1226 African
D.E. Banks, T.C.B. Zapolski Americans, with data from 1979 to 2012; 51% female). Path modeling in Mplus was used to examine
Department of Psychology, Indiana University—Purdue University Indianapolis, Indianapolis, IN pathways from low parental education to heavy drinking frequency (6+ drinks/occasion) in young
46202, USA adulthood (ages 24–32) and at midlife (ages 42–52). Hypothesized mediators included adolescent
poverty duration, school characteristics (disadvantaged school, unsafe school), low academic perfor-
Among African Americans, perceived racial discrimination has been identified as an important risk
mance, suspension/expulsion, expected educational attainment, high school diploma (by age 19)
factor for heavy alcohol use. Although racial identity has been found to buffer the effect of discrimina-
and 4-year college degree (by age 25); adulthood mediators included Pearlin’s mastery scale, adult
tion on psychological distress among African American adults, research examining whether racial
poverty duration and repeated unemployment. Findings from the full sample indicate a significant
identity buffers the effect of discrimination on alcohol use is limited. The current study used a commu-
direct effect of low parental education on educational attainment, with indirect effects through path-
nity sample of African American young adults (N = 139; 81% women; age 18–30) to examine the
ways involving adolescent poverty and school experiences. Gender-stratified models show that for
interactive relationship of racial discrimination and three types of racial identity on monthly drinking
males, adolescent poverty duration is significantly associated with increased suspension and lower
frequency: centrality (how fundamental race is to one’s self-definition), belonging (affective attach-
academic performance, and both in turn are associated with lower educational attainment. For
ment and pride towards one’s race), and exploration (behavioral attempts to learn about one’s race).
females, attendance at disadvantaged and unsafe schools is directly associated with lower educa-
Negative binomial regression was used to estimate coefficients after adjusting for age, gender,
tional expectations, and indirectly with educational attainment. In females, suspension and poor aca-
employment, and education. Results revealed an inverse relationship between race belonging and
demic performance are also significant risk factors for lower educational attainment. Addressing our
alcohol use (IRR = 0.55, 95% CI: 0.31, 0.96); however, unexpectedly, race centrality was positively
second question, significant protective effects of higher education on midlife heavy drinking occur
related to alcohol use (IRR = 1.36, 95% CI: 1.12, 1.65). A null relationship was found for race explo-
indirectly through less frequent heavy drinking in young adulthood. These preliminary results suggest
ration and alcohol use. When examining the moderating effect of racial identity on the relationship
cascading effects of early socioeconomic disadvantage on educational attainment and midlife heavy
between discrimination and alcohol use, a significant effect was observed for both race belonging
drinking, and the intergenerational consequences of low educational attainment. Findings also sug-
(IRR = 0.622, 95% CI: 0.41, 0.94) and exploration (IRR = 1.60, 95% CI: 1.03, 2.48). Specifically,
gest that interventions to reduce childhood poverty and improve schooling experiences might be a
discrimination was positively related to alcohol use only among those low in belonging or high in
form of alcohol prevention.
exploration. Findings provide evidence that racial identity mitigates the effect of discrimination on fre-
quency of alcohol use among African Americans, but suggest that only race belonging is protective,
whereas race exploration may compound the effects of discrimination. Taken with previous research
that has found a null relationship of race centrality on heavy alcohol use, these results suggest that
race centrality does not impact the relationship between discrimination and alcohol use, but may
pose risk for heavy use among African American young adults. Results suggest that future research
should include multiple conceptualizations of identity to clarify its relationship with heavy alcohol use
among African Americans. Further examination of the mechanisms of racial identity on heavy alcohol
use is also needed to clarify their value as intervention targets.
276A ABSTRACTS-SPEACKERS

SUNDAY, JUNE 17 10:00AM–11:30AM 23

SYMPOSIUM 21–24
New Directions in the Diagnosis of Alcohol and Substance Use Disorders ADDICTIONS NEUROCLINICAL ASSESSMENT: INITIAL VALIDATION AND NEXT STEPS
L.E. Kwako, M.L. Schwandt, V.A. Ramchandani, N. Diazgranados, C. Blanco, D. Goldman
Organizer: Laura Kwako Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD
Organizer/Chair: Chris Martin 20892-1108, USA
Chair: Kenneth Sher
This presentation describes an overview and initial validation efforts of the proposed Addictions Neu-
roclinical Assessment (ANA), which organizes a set of measures around three neuroscience
domains relevant for addiction. These domains include incentive salience, negative emotionality,
21 and executive function. Instruments within the ANA comprise behavioral tasks, self-report measures,
and neuroimaging assessments, along with ancillary phenotypic data related to demographics,
STATISTICAL OPTIMIZATION OF ALCOHOL USE DISORDER DIAGNOSIS THROUGH broad health and functioning, and alcohol use history, as well as genetic data. These measures will
PERMUTATIONS be piloted within the National Institute on Alcohol Abuse and Alcoholism (NIAAAA) intramural
J.E. Stevens, D. Steinley,, K.J. Sher research program, using a screening and natural history protocol (SNHP) of individuals along the
Psychological Sciences, University of Missouri, Columbia, MO 65201, USA spectrum of alcohol use and misuse, up to and including those seeking treatment for alcohol addic-
tion. The present inquiry uses data obtained from an earlier version of the SNHP, which included
Valid diagnostic systems are critical for research and clinical practice for alcohol problems. However,
deep phenotypic and genetic assessment but did not focus on the three ANA neuroscience domains.
existing research has failed to adequately exploit empirical techniques and existing databases to
The goals here are threefold: (1) use exploratory and confirmatory factor analysis to identify whether
derive criteria considered optimal with respect to predicting external correlates. It is imperative to
existing SNHP measures may be divided into the ANA neuroscience domains; (2) contrast these fac-
derive more reliable, stable, and concise criterion sets to reduce clinical diagnostic burden and
tor analytic results between individuals with and without alcohol dependence (AD); and (3) provide a
increase validity of the diagnosis. The goal of the current project is to use permutations to optimize a
progress report on the implementation of the ANA. Using factor analysis in a sample of 454 individu-
diagnosis of Alcohol Use Disorder (AUD).In the DSM-V, a diagnosis of AUD is found if 2 of the 11 cri-
als, we identified three factors, which largely map onto the ANA neuroscience domains. Measures
terion are endorsed. The current optimization approach will consider all possible rules given that A of
included in the factor analysis assessed personality, impulsivity, aggression, mood, anxiety, and
B items are endorsed out of a larger pool of C items (where C is greater than or equal to B). In the
craving for alcohol. Further, we identified significant predictors of these factors, comprising family his-
case of diagnosing AUD, C would be equal to 11 and A would be a subset of the full criterion set use
tory of alcoholism, age at first drink, exposure to early life stress, and demographic variables. In the
to diagnosis with a threshold of B. The number of criterion sets by set size and threshold will result in
second analysis, we found that individuals with AD scored higher on all three factors than individuals
a total of 11,264 unique rules. The goal was to maximize the distance (based on Cohen’s d) between
without AD, with differences in model fit between the groups. Finally, this presentation will include an
mean levels of the optimization criteria (i.e., consumption and functional impairment) in those with an
update on the implementation of the ANA within the NIAAA intramural research program, describing
AUD diagnosis versus those without. In contrast with current convention, AUD is derived transpar-
accrued sample characteristics and challenges of implementation. We will conclude by discussing
ently using a data driven approach informed by the criterion used for a DSM-5 diagnosis. After identi-
future directions for the ANA in particular and addiction nosology broadly.
fying potential optimal diagnostic sets, external validation techniques were completed assessing the
performance of the new optimal solution against alternative diagnostic algorithms (i.e., DSM-IV,
DSM-V, ICD-10). Optimization was performed on two nationally representative samples, NESARC
(National Epidemiological Survey on Alcoholism and Related Conditions) and NSDUH (National Sur-
vey on Drug Use and Health) and one sample with an oversampling of treatment seeking individuals,
COGA (Collaborative Studies on Genetics of Alcoholism). Results from optimization procedures indi-
cate that the diagnostic set can be reduced without a loss of validity.
24
SUBSTANCE USE DISORDERS IN A HIERARCHICAL TAXONOMY OF PSYCHOPATHOLOGY
T.A. Widiger
Department of Psychology, University of Kentucky, Lexington, KY 40506, USA

It has become readily apparent that the categorical model of classification employed within the Amer-
22 ican Psychiatric Association’s (APA) Diagnostic and Statistical Manual of Mental Disorders is sorely
problematic. A proposed solution to the shortcomings of the traditional categorical taxonomies is
USING NETWORK MODELS TO STUDY ALCOHOL AND SUBSTANCE USE DISORDERS emerging in the form of a quantitative nosology, an empirically-based dimensional organization of
M. Hoffman psychopathology. Indeed, a team of investigators has proposed a Hierarchical Taxonomy Of Psy-
Department of Psychiatry and Behavioral Sciences, Charleston Alcohol Research Center (ARC) chopathology (HiTOP), as an alternative to the traditional categorical classification (Kotov et al.,
Addiction Sciences Division (ASD), Medical University of South Carolina Charleston, SC 29425, 2017). HiTOP includes, at the highest level, a general factor of psychopathology, beneath which are
USA the broad domains of internalizing, externalizing, and thought disorder. Further down are the five
domains of detachment, antagonistic externalizing, disinhibited externalizing, thought disorder, and
Networks are used to model entire systems of interacting parts, considering both the entities being
internalizing, along with provisional sixth somatoform dimension. The purpose of the current paper is
studied (nodes) and the connections or relationships between them (edges). Network science,
to discuss the place and understanding of substance use disorders within HiTOP, including advan-
including the methods to build and analyze networks, is utilized in a range of fields from computer
tages as well as potential limitations and concerns.
science to sociology. Recently, the tools of network analysis have found a new application in epi-
demiological research: symptom or criterion networks. Here, the symptoms or criteria used to diag-
nose a disorder are the nodes, and they are connected by edges that estimate some relation
between them (e.g., co-occurrence, belonging to the same disorder). This is posed as an alternative
to the more traditional methods of examining symptoms such as item response theory, where the
symptoms are indicators of a “latent,” underlying disorder. Modeling the disorder as a network of
symptoms allows the researcher to study the individual symptoms within the context of the other
symptoms. This provides the basis to ask different types of research questions, such as identifying
“central” symptoms or “bridge” symptoms, and to potentially examine causal pathways of criteria
both within and between disorders. While this methodology holds clear potential for further research
into the nuances of diagnosis and symptomology, the tools to create these networks are relatively
new and untested. With the focus on the individual symptoms of a disorder rather than the overall
diagnosis, there are different potential analytical problems that must be considered before interpret-
ing a symptom network. The goal of this talk is to demonstrate both the possible benefits of using
these new methods of analysis for substance abuse research, as well as the difficulties that arise in
the estimation and analysis of symptom networks.
ABSTRACTS-SPEACKERS 277A

SUNDAY, JUNE 17 10:00AM–11:30AM 27

SYMPOSIUM 25–28
Novel Ways to Target Adolescent Alcohol and Cannabis Use: Promising New THE EFFECT OF COGNITIVE BIAS MODIFICATION ON ADOLESCENT CANNABIS AND
ALCOHOL USE: A MULTISITE INVESTIGATION
Findings From Behavioral, Cognitive, and Pharmacological Intervention L.M. Squeglia1,2, C.T. Taylor1,2, K.M. Gray1,2, L.R. Meredith1,2, A.M. Porter1,2, I. Li1,2, N. Castro1,2,
Approach J. Jacobus1,2
1
Organizers/Chairs: Lindsay Squeglia and Margot Peeters Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina,
Charleston, SC 29425, USA and 2Department of Psychiatry, University of California San Diego, La
Jolla, CA 92093, USA

25 Background: Approach Avoidance Training (AAT) is a computerized cognitive bias modification

intervention that aims to retrain approach biases toward harmful cues and has been effective in treat-
TRAJECTORIES OF ALCOHOL AND CANNABIS USE FROM EARLY TO LATE ADOLESCENCE ing alcohol use disorder in adults. The effects of AAT have not been examined in adolescents or can-
AND IMPORTANT DETERMINANTS FOR INTERVENTION PURPOSES nabis users. The aim of this multi-site study was to understand the effect of marijuana AAT (MAAT)
M. Peeters, W.J. Boendermaker, R.C. Veltkamp, A.J. Oldehinkel, W.A.M. Vollebergh on adolescent cannabis and alcohol use outcomes.
Interdisciplinary Social Science, Utrecht University, Heidelberglaan 1, PO Box 80.140, Utrecht, The Methods: Eighty non-treatment-seeking regular cannabis users (50% female; average
Netherlands age = 19 years; using cannabis ~4 days per week and alcohol 1–2 days per week) were recruited
from two geographic locations (Charleston, South Carolina and San Diego, California) and were ran-
Alcohol and cannabis use are subject to change during the adolescent period. Social, contextual and
domized to complete either six sessions of MAAT or sham training. No other treatment was provided
developmental factors influence the patterns of use of these substances. Longitudinal trajectory
within the study. Substance use interviews and approach bias assessments were administered pre-
studies can shed light on the normative development of the use of these substances as well as on
and post-intervention.
problematic patterns of use. It is important that underlying determinants of problematic and relatively
Results: Participants randomized to MAAT reported, on average, 7% less cannabis use days ver-
normal use are identified so treatment efforts can be aligned towards these determinants. Results
sus 0% for sham, but 10% more alcohol use days versus 3% for sham post-intervention (ps < 0.05).
are therefore discussed with a focus on informing the development of effective intervention strate-
Approach bias for cannabis cues decreased in the MAAT condition compared to sham (p = 0.06).
gies. In this study, data of large longitudinal national representative study are presented including
Conclusion: Computer-based cognitive bias modification paradigms may be promising interven-
+/
2,230 adolescents who were followed from 11–22 years (study is ongoing). Trajectories of alco-
tions for reducing adolescent cannabis use and modifying approach biases; however, reduction of
hol and cannabis use covering the whole adolescent period (14–22 years) are evaluated in relation
one substance may have unintended effects on co-occurring use. Future work should consider
to important cognitive determinants such as behavioral control and reward sensitivity. Latent transi-
developing a paradigm that addresses both alcohol and cannabis use in motivated treatment seek-
tion analyses revealed that pubertal development as well as reward sensitivity are important predic-
ers or as an adjunctive treatment to existing substance use interventions.
tors of the increase in both substances. Relatively stronger increase in behavioral control skills
predicted decrease in the use of alcohol use, not in cannabis use, and only in a small group of ado-
lescents (<10%). Post hoc analyses revealed that socio-cultural and adult role factors such as edu-
cational level explained the predictive effect of behavioral control. First, these results underline the
difference and similarities between developmental patterns and important determinants of alcohol
and cannabis use in adolescents. Second, the results reveal the importance of considering the con-
text, including important (adult role) transitions, in which substance use takes place. Lastly, the
28
results suggest that treatment efforts focusing on behavioral control might be useful though not so EFFECTS OF TOPIRAMATE ON CANNABIS USE AMONG ADOLESCENTS AND YOUNG
much in targeting adolescents’ alcohol use directly but rather in supporting naturally occurring devel- ADULTS IN A RANDOMIZED CONTROLLED CLINICAL TRIAL TARGETING ALCOHOL MISUSE
opments in adolescence and emerging adulthood. Future directions using computer technology in H. Treloar Padovano, R. Miranda
targeting adolescents alcohol and cannabis use are discussed, particularly focusing on new emerg- Department of Psychiatry and Human Behavior, Center for Alcohol and Addiction Studies, Brown
ing computerized intervention methods such as the use of serious gaming approaches. University, Providence, RI 02903, USA

Despite clinical demand for effective substance-use interventions for youth, less than one-third expe-
rience sustained benefit from the best available psychosocial treatments. In addition, adolescents
and young adults often misuse multiple substances, namely alcohol and cannabis, which requires
treatment approaches that yield cross-drug beneficial effects. The major objective of this study was
26 to address the urgent need for empirical data on medications that may advance treatment options for
youth. Specifically, we randomized 82 youth, ages 14 to 24 to topiramate (up to 200 mg/day) or pla-
VIEWING ADOLESCENT ADDICTION TREATMENT RESPONSE VIA THE BRAIN cebo, combined with biweekly motivational enhancement and cognitive behavioral therapy, for
S.W. Feldstein Ewing, K.A. Hudson, J. Caouette, B. Hyun 8 weeks using a two-group, double-blind design. Topiramate is an anticonvulsant medication shown
Department of Child & Adolescent Psychiatry, Oregon Health & Science University, Portland, OR, to be efficacious for reducing alcohol use among adults, and recent preliminary data suggest it also
97239, USA may reduce cannabis use (Miranda, Treloar, Blanchard, et al., 2017). It is the only medication that
reduces drinking in adults that has approval from the Food and Drug Administration for use with ado-
Our goal is to develop more efficacious treatments for adolescents who struggle with addiction. Our
lescents, albeit for other indications. Although youth were recruited from the community specifically
perspective is that substantive treatment advances are most likely to stem from integrative
for alcohol misuse, 64.6% also reported cannabis use during the trial. Of this subset, half (52.8%)
approaches reflective of the developing brain, in order to guide articulated interventions to this very
were randomized to topiramate. These youth were primarily White (66.0%) or Black (20.8%); 17%
specific period of neural development. To elucidate how adolescents respond to clinician language
Hispanic or Latino ethnicity; 39.6% were female; average age was 20.3 years (SD = 2.2). Results
during psychosocial addiction treatment, we have enrolled N = 92 binge drinking adolescents ages
showed youth assigned to topiramate reported 12.0 fewer cannabis use days and smoked 7.3 fewer
14–19 (M age = 18.63; 66% female; M alcohol problems score = 7.63; M cannabis problems
grams of cannabis than youth assigned to placebo, during the 28-day period at target dose. In a
score = 4.70), and randomized them to receive 2.1-h individual sessions of motivational interviewing
regression including participant baseline demographics, topiramate treatment predicted reduced use
(MI) or 2.1-h individual sessions of brief adolescent mindfulness (BAM). All youth are then brought
days, b =
0.38, p = 0.004, and reduced total grams smoked, b =
0.38, p = 0.022. Indeed, topi-
into the functional magnetic resonance imaging (fMRI) environment to complete our Neural In-Ses-
ramate accounted for an additional 10% of the variance in cannabis-use outcomes over and above
sion Language (NILE) task. Here, youth are re-presented visually and auditorily with the voice of their
the influences of gender, age, race, and ethnicity, R2 = 0.28 and 0.22 for use days and grams
study therapist in three therapist language conditions: Complex Reflections for the MI condition (e.g.,
smoked, respectively; Δ R2 = 0.14 and 0.10, respectively. This study provides much needed data on
“Your drinking puts your safety at risk, and this really scary.”); Mindfulness statements for the BAM
the tolerability and efficacy of topiramate for treating substance misuse among adolescents and
condition (e.g., “You notice the link between drinking and your safety”); and, Confronts as a control
young adults while adding important new information about its potential for reducing cannabis use
condition representative of standard addiction treatment approaches in this age group (e.g., “Your
among youth who also misuse alcohol.
drinking puts your safety at risk”). Thus far, imaging data reflects significant main effects for all three
types of therapist language (e.g., Complex Reflections: activation within precuneus, parahippocam-
pal gyrus, insula; Mindfulness statements: activation in precentral gyrus, right posterior cingulate;
Confronts: activation within superior frontal gyrus). We have also observed differential activation by
therapist language type, with significantly greater activation for Complex Reflections versus Con-
fronts (within the precentral gyrus) and for Complex Reflections versus Mindfulness statements
(within the superior frontal gyrus and left inferior frontal gyrus). We believe that these data continue
to highlight the specific nature and developmental function of the adolescent brain in the addiction
context, as well as their specific neurodevelopmental response to addiction treatment elements.
These data are critical to elucidating a framework for future adolescent addiction treatment develop-
ment efforts.
278A ABSTRACTS-SPEACKERS

SUNDAY, JUNE 17 1:20PM–2:50PM 31

SYMPOSIUM 29–32
Comorbidities Promoting Excessive Alcohol Drinking NEUROBIOLOGICAL UNDERPINNINGS OF ESCALATED ALCOHOL DRINKING AFTER
TRAUMATIC BRAIN INJURY
Organizer/Chair: Elizabeth Fucich E.A. Fucich, Z.F. Stielper, P.J. Stoulig, S. Edwards, J.W. Middleton, N.W. Gilpin, P.E. Molina
Organizer: Patricia Molina Departments of Physiology and Cell Biology & Anatomy, Louisiana State University Health Sciences
Chair: Amanda Pahng Center at New Orleans, New Orleans, LA 70112, USA

29
EARLY LIFE ALCOHOL EXPOSURE PROGRAMS THE NEUROENDOCRINE-IMMUNE SYSTEM
TO PROMOTE STRESS HYPERRESPONSIVENESS AND ALCOHOL ABUSE IN ADULTHOOD
D.K. Sarkar, L.G. Chastain, N. Boyadjieva, S. Jabbar, E.A. Mead, O. Gangisetty, C. Zhang,
D. Govorko, M. Agapito
Rutgers Endocrine Research Program, Department of Animal Sciences, Rutgers University, New
Brunswick, NJ 08901, USA
Exposure to moderate to high levels of alcohol during prenatal period or during early life in humans is
known to increase the risk for alcohol abuse in adulthood. Studies using laboratory rodents corrobo-
rates the data obtained in humans. Laboratory rodent studies also show a causal relationship
between stress system abnormalities and alcohol abuse disorders. Additionally, proopiome-
lanocortin-producing neurons in the hypothalamus have been shown to reduce both stress response
and alcohol-drinking behaviors. We have recently obtained evidence that early life alcohol epigeneti-
cally modifies hypothalamic proopiomelanocortin gene to suppress its inhibitory control of the stress
hormones and anxiety-like behaviors. Additionally, we found that early life alcohol epigenetically pro-
grams hypothalamic microglia, CNS immune cells, to reduce proopiomelanocortin neuronal func-
tions and hyper-activate body stress responses. Treatment with minocycline, an inhibitor of
microglial activity, or epigenetic modifiers, 5-aza-20 -deoxycytidine, trichostatin A or choline, reduces
the stress hyper-response in prenatally alcohol exposed animals. These data suggest that the early
life exposure to ethanol may epigenetically modify neuroendocrine-immune system to increase body
stress response and the propensity for heavy alcohol drinking behaviors in adulthood.
Traumatic brain injury (TBI) is associated with psychiatric comorbidities like alcohol use disorder
(AUD) and anxiety, and we have previously shown that a rat model of TBI produces an escalation of
operant alcohol self-administration. This model also produces increased neuroinflammation and
neuronal hyperexcitability at the site of injury, which we have shown can be prevented by inhibiting
endocannabinoid degradation post-injury. We have recently found that our TBI model also impairs
cognitive function and increases anxiety-like behavior in addition to increasing motivation for alcohol,
and that these TBI-induced changes can also be attenuated with post-injury inhibition of endo-
cannabinoid degradation. Because of the role of the amygdala in anxiety and alcohol motivation, and
the characteristic amygdala hyper-responsivity seen in AUD and anxiety-related disorders, we
hypothesized that these TBI-induced behavioral changes may be more directly related to TBI-
induced amygdala hyperexcitability. Our results show that TBI increases spontaneous excitatory
post-synaptic currents in the basolateral amygdala 10 days post-injury as well as increases gluta-
mate receptor phosphorylation (a marker of excitability) in the central amygdala, which is prevented
by post-injury inhibition of endocannabinoid degradation. These findings suggest that TBI-induced
alcohol motivation and anxiety-like behavior could be attributed to hyperexcitability of the amygdala,
and that these TBI-induced behavioral and neural changes can be prevented by inhibiting endo-
cannabinoid degradation.
32
CENTRAL REINFORCEMENT CENTER CORRELATES OF PAIN AVOIDANCE BEHAVIOR IN
OPIOID VS. ALCOHOL DEPENDENCE
A.R. Pahng, R.I. Paulsen, M.A. McGinn, M.E. Schindler, K.N. Edwards, S. Edwards
LSU Health Department of Physiology, New Orleans, LA 70112, USA

In contrast to their analgesic properties, excessive use of either alcohol or opioids produces a para-
30 doxical emergence of heightened pain sensitivity to noxious stimuli, termed hyperalgesia, which may
promote further drinking or use of opioids to manage worsening pain symptoms. Hyperalgesia has
DYSREGULATED ENDOCANNABINOID SIGNALING IN THE CENTRAL AMYGDALA: traditionally been measured in rodents via reflex-based assays, including the von Frey method. To
INFLUENCE OF CHRONIC ALCOHOL EXPOSURE VERSUS PREMORBID VULNERABILITY better model the cognitive/motivational dimension of pain in a state of alcohol/opioid dependence
L.A. Natividad, R. Ciccocioppo, R. Martin-Fardon, M. Roberto, L.H. Parsons and withdrawal, we employed a recently developed non-reflex-based method for measuring pain
Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA avoidance-like behavior in animals (Mechanical Conflict Avoidance test). Adult male Wistar rats were
administered an escalating dose regimen of morphine (opioid-dependent group) or repeated saline
Chronic alcohol exposure dysregulates brain stress signaling and contributes to problem anxiety and
(control group). Morphine-dependent rats exhibited significantly greater avoidance of noxious stimuli
excessive alcohol consumption. Further, individuals with innate sensitivity to stress and emotional
during withdrawal. Such pain avoidance-like behavior exhibited a modest correlation with mechanical
dysfunction are increasingly susceptible to alcohol use disorder. In this regard, genetically-selected
paw withdrawal thresholds as measured via the von Frey method (r =
0.4413, p = 0.0452), indicat-
rodent lines such as Marchigian Sardinian alcohol-preferring (msP) rats replicate many characteris-
ing that the two behavioral assays measure overlapping but not entirely similar pain-like conditions.
tics of the post-dependent state including increased amygdalar corticotropin-releasing factor (CRF)
We next investigated individual relationships between pain avoidance-like behavior and alterations
signaling, heightened stress sensitivity, spontaneous alcohol consumption, and an anxiety-like phe-
in protein phosphorylation in central motivation-related brain areas. We discovered that pain avoid-
notype. Interestingly, dysregulated neural signaling in the central amygdala (CeA) is common to both
ance-like behavior was significantly correlated with alterations in phosphorylation status of protein
alcohol-dependent Wistar rats and alcohol-na€ıve msP rats. Brain endocannabinoid (eCB) signaling
kinases (ERK, CaMKII), transcription factors (CREB), presynaptic markers of neurotransmitter
via 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide; AEA) plays an
release (Synapsin), and the rate-limiting enzyme for dopamine synthesis (TH) across specific brain
important homeostatic role in the constraint of stress responses, and impaired eCB signaling confers
regions. Separate groups of male Wistar rats were made dependent on alcohol via exposure to
increased stress sensitivity and anxiogenic-like responses. Acute alcohol consumption alters brain
chronic, intermittent ethanol vapor and compared to air-exposed (non-dependent) controls. Here,
eCB levels, and from this we hypothesize that chronic alcohol exposure dysregulates CeA eCB sig-
alcohol-dependent animals exhibited enhanced pain avoidance-like behavior of shorter probe
naling in a manner that influences negative affective states and excessive alcohol consumption.
heights that were innocuous (i.e., not avoided) in non-dependent animals, indicative of a state of allo-
Moreover, we hypothesize that pre-existing disruptions in eCB function underlie innate sensitivity to
dynia. We are currently examining the neural correlates of pain avoidance in these groups to com-
co-morbid factors observed in msP rats. We find that binge-like alcohol consumption by Wistar rats
pare to our results in opioid-dependent animals. Our findings suggest that alterations in
progressively dysregulates CeA 2-AG processing, promoting reduced 2-AG tone and impaired
phosphorylation events in specific brain centers may support cognitive/motivational responses to
stress- and alcohol-induced changes that modulate inhibitory and excitatory transmission in this
avoid pain, and that qualitatively distinct dimensions of pain avoidance-like behavior (hyperalgesia
region. qPCR analyses suggest that this may result from alcohol-induced disruptions of hydrolytic 2-
vs. allodynia) may exist in opioid- versus alcohol-dependent animals.
AG clearance enzymes. In contrast, alcohol-na€ıve msP rats exhibit diminished CeA AEA levels with
no phenotypic disruption in 2-AG transmission. The deficits in msP AEA levels result from increased
AEA hydrolysis by the clearance enzyme fatty acid amide hydrolase (FAAH), a phenotype that is
reversed by sub-chronic CRF1 receptor antagonism. Acute FAAH inhibition bolsters CeA AEA
levels, attenuates CeA excitatory transmission, and alleviates the anxious phenotype in msP rats.
Our findings suggest that dysregulated eCB signaling in the CeA contributes to both dependence-
related behaviors in Wistar rats and innate dependence-like features in msP rats, though the nature
of eCB dysregulation differs in these animals. Supported by: K99-AA025393 (LAN), P60-AA006420
(RM-F and MR), R01-AA020404 (RM-F), R01-AA022249 (RM-F), R01-AA015566 (MR), and R37-
AA017447 (MR and RC).
ABSTRACTS-SPEACKERS
SUNDAY, JUNE 17 1:20PM–2:50PM
SYMPOSIUM 33–36
Neuro and Behavioral Economic Approaches to Understanding Alcohol Misuse
Organizer/Chair: Samuel Acuff
33
EXPERIMENTALLY MANIPULATING BEHAVIORAL ECONOMIC ALCOHOL DEMAND: A META-
ANALYSIS
S.F. Acuff, M. Amlung, A.A. Dennhardt, J. MacKillop, J.G. Murphy
Department of Psychology, The University of Memphis, Memphis, TN 38152, USA
Behavioral economic theory suggests that alcohol misuse is the result of malfunctioning reinforce-
ment processes that result in excessive valuation for alcohol relative to alternative reinforcers. This
excessive valuation for alcohol, known as behavioral economic alcohol demand, is often measured
with hypothetical purchase tasks in which alcohol consumption during a hypothetical scenario is
reported over a series of escalating prices. The prices generate a demand curve, creating theoreti-
cally relevant indices such as intensity (alcohol consumption at $0), Omax (maximum expenditure),
and elasticity (rate of change in consumption as a function of price). Greater alcohol demand demar-
cates greater severity of problematic engagement and is related to alcohol consumption, related
problems, and alcohol use disorder; yet, studies also show that demand is malleable under certain
conditions, such that changes in internal affective and drive states and the environmental context will
result in fluctuations in substance demand. Understanding the factors that either increase or
decrease alcohol demand would guide intervention efforts that attempt to either minimize risk factors
or maximize protective factors. Thus, the present study is a meta-analysis summarizing the current
literature exhibiting the conditions in which behavioral economic demand has been manipulated and
identifying conditions in which demand is malleable v. stable. Per PRISMA guidelines, the authors
identified within- and between-subject human studies (N = 45; 231 effect sizes, 101 alcohol-related
effect sizes) examining differences in demand indices (1) after a manipulation; and (2) measured
with purchase tasks and multiple-choice questionnaires. Of the alcohol studies, the experimentally
manipulated demand indices included stress (n = 9), craving (n = 17), next-day responsibilities
(e.g., class, tests, volunteering, working; n = 45), pharmacological treatment (n = 4), psychological
intervention (n = 10), and situational variables (e.g., time constraint, amounts of alcohol; n = 17).
We will examine the magnitude of effect size (Cohen’s d) for each manipulation category both overall
and separated by each demand index. Further, we will examine if the results are consistent between
populations and levels of alcohol consumption. These results will be compared to the results found
for other substances or commodities of abuse (e.g., cigarettes, marijuana cocaine, indoor tanning).
These findings provide novel information about factors that influence the valuation of alcohol and
have the potential to guide future intervention and prevention efforts.
34
BEHAVIORAL ECONOMIC ANALYSIS OF ALCOHOL AND CANNABIS CO-USE
M. Amlung, V. Morris, H. Patel, K. Naish, J. Metrik
Peter Boris Centre for Addictions Research, McMaster University, Hamilton, ON L8N 3K7, Canada
A significant proportion of alcohol users also concurrently use other drugs. These polysubstance
users often drink at higher amounts and experience worse outcomes in treatment compared to alco-
hol-only users. However, research examining the factors that contribute to co-use of alcohol and can-
nabis remains relatively limited. The discipline of behavioral economics provides a general
framework for examining reward-based decision making in the context of addictive disorders. The
two primary decision-making variables that have been imported from behavioral economics are sub-
stance demand (e.g., the reinforcing value of an addictive drug) and delay discounting (e.g., prefer-
ences for smaller-sooner rewards). Prior research has shown that alcohol and tobacco co-users
show elevated demand for alcohol compared to drinkers only. However, whether these decision-
making differences are also present in a different type of co-use, alcohol and cannabis, remains
unknown. The present study recruited a large sample of participants from Amazon MTurk (target
N = 3,500). Participants completed measures of alcohol demand (alcohol purchase task), monetary
and alcohol discounting ($10, $100, 10 drinks), and validated scales of alcohol and cannabis use
severity. Data collected to date (N = 2,654; M age = 35.4; 56% female) revealed 910 alcohol/canna-
bis co-users and 1,296 alcohol-only users, with the remaining participants reporting not using either
substance. Analyses conducted to date indicated that co-users reported significantly elevated alco-
hol demand (higher alcohol consumption across the majority of prices on the demand curve), even
after controlling for differences in drinking level between groups. No significant differences between
groups were evident for delay discounting of either monetary or alcohol rewards. This study provides
further evidence for increased reinforcing value of alcohol among users of multiple addictive sub-
stances, and is consistent with prior research on tobacco and alcohol co-users. Interestingly, these
differences do not seem to extend to preferences for smaller-immediate rewards over larger-later
rewards, which is inconsistent with prior research finding increased impulsive discounting among
poly-substance users.
279A
35
NEURAL CORRELATES OF INTERTEMPORAL CHOICE AMONG SOCIAL DRINKERS AND
ADULTS WITH ALCOHOL USE DISORDER
M.N. Koffarnus, H.U. Deshpande, J.M. Lisinski, S.E. Snider, W.K. Bickel, S.M. LaConte
Virginia Tech Carilion Research Institute, Roanoke, VA 24016, USA
Adults with alcohol use disorder are known to have higher delayed discounting rates compared to
social drinkers, but less is known about the neural correlates of these behavioral differences. The
present study sought to determine how these two populations differentially recruit decision-making
networks in the brain with an in-scanner delay discounting task designed to maximize the ability to
detect differences among trial types of differing difficulty, delay presentation, and participant choice.
Participants with alcohol use disorder (n = 62) and social drinkers (n = 22) completed this individual-
ized discounting task in an fMRI paradigm. Four social drinkers and six individuals in the alcohol use
disorder group were excluded from fMRI analyses due to excessive motion. Analyses were con-
ducted to compare the task as a whole across groups as well as between discrete sets of trial types
within the task, including hard versus easy choices, delayed versus immediate choices, and trials
with an immediate option presented versus two delayed options. Results show activation in areas
including the dorsolateral prefrontal cortex, premotor area, supplementary motor area, and ventrolat-
eral prefrontal cortex in both groups during the task as a whole. More medial and inferior frontal corti-
cal regions were associated with hard choices and trials in which only delayed options were present.
Overall, preliminary analyses reveal activation maps characteristic of intertemporal decision making
in both groups.
36
AUD SYMPTOMS ARE ASSOCIATED WITH CHRONIC DEFICITS IN ENVIRONMENTAL
REWARD AMONG EMERGING ADULT HEAVY DRINKERS
J.G. Murphy, A.A. Dennhardt
Department of Psychology, University of Memphis, Memphis, TN 38152, USA
Purpose: Reward deprivation has been implicated in severe substance abuse, and there is com-
pelling laboratory research demonstrating that drug and alcohol use are most likely in environments
with few alternative substance-free reinforcers. However, the association between reward depriva-
tion and alcohol use disorder (AUD) symptoms in non-treatment-seeking young adult drinkers is less
clear. The goal of this study was to explore the association between reward deprivation, defined as a
lack of access to natural rewards, and AUD symptoms.
Methods: This study evaluates the longitudinal association between reward availability (measured
using the environmental suppressor subscale of Reward Probability Index; Carvalho et al., 2011)
and AUD symptoms in a sample of 392 young adults (60.4% female, 85.1% Caucasian, M = 16.8
drinks per week at baseline) who reported recent heavy drinking (65% met criteria for AUD, including
77 participants with moderate AUD and 54 participants were severe AUD). Participants were non-
treatment seeking college students who were participating in a brief alcohol intervention trial.
Results: Low reward availability was significantly associated with both DSM-5 AUD symptoms after
controlling for age, gender, and depressive symptoms. Specifically, for each additional 1-unit
increase in environmental suppressor subscale score, the likelihood of experiencing no AUDS
increased by 0.12. Further, conditional that 1 or more AUDS were experienced, for each additional
1-unit increase in environmental suppressor subscale score, the count of AUDS endorsed
decreased by 0.03. Moreover, heavy drinkers with an AUD at baseline demonstrated significantly
lower reward availability than heavy drinkers without AUD across all 4 follow-up time points (1, 6, 12,
& 16 months, ps < .05).
Conclusion: These results suggest that AUD symptoms are associated with chronic diminished
access to environmental reward among young adults and provides support for behavioral economic
models that emphasize reward deprivation as a unique risk factor for AUD.
280A
SUNDAY, JUNE 17 1:20PM–2:50PM
SYMPOSIUM 37–40
Addressing Alcohol Use Disorder With Contemporary Technology:
Leveragingsocial Network Sites for Assessment, Prevention, and Treatment
Organizer/Chair: Brandon Bergman
37
AUTOMATIC AOD RELAPSE PREDICTION USING SOCIAL MEDIA POST
B.L. Curtis, R.D. Ashford, S. Giorgi, C. Hamilton, A. Buffone, L.H. Ungar, H.A. Schwartz, K. Lynch
Center on Continuum of Care in Addictions, Perelman School of Medicine, University of
Pennsylvania, Pennsylvania, PA 19104, USA
Addiction research has not yet taken advantage of emerging changes in communication media and
methods to analyze social media interactions to predict relapse. We conducted a 26-week observa-
tional study that adapted advanced data analytic techniques to examine social media use by individ-
uals in AOD treatment. We used differential language analysis (DLA), an open-vocabulary analysis
technique that extracts a data-driven collection of words, phrases, and topics as functions of known
treatment outcomes and relapse factors. We examined the associations between traditional assess-
ments (ASI6) and relapse, and between social media language features, personality, and relapse.
For the traditional assessment data, the “best” model included the ASI drug and alcohol variables,
with AIC = 190,
2LogLike = 172 (LR chi-square(5) = 22.6, p = 0.0004), and AUC = 0.76. For the
social media features, the best model included the drug/alcohol features, with AIC = 208,

2LogLike = 144 (LR chi-square(28) = 50.3, p = 0.006), and AUC = 0.85. Adding the social media
alcohol/drug features to the ASI alcohol/drug variables yielded a model with AIC = 192,

2LogLike = 119 (LR chi-square(28) = 52.2 relative to the model with ASI variables, p = 0.004),
and AUC = 0.90. Finally we analyzed social media language to find language features across mil-
lions of Facebook messages that distinguished participants who relapsed. The topics with negative
affect states such as loneliness (lonely, alone, abandoned; r = 0.26), frustration (life’s a bitch, karma,
upset; r = 0.28), and hopelessness (plans, ruined, future; r = 0.023) were significantly correlated
with relapse (p < 0.01). Functional social support (family, support caring for; r =
0.17, p < 0.01);
self-efficacy (control, serenity, overcome; r =
0.16, p < 0.01); and positive affect states (grateful,
happy, joy; r =
0.16, p < 0.01) were negatively correlated with relapse. Thus, these analyses on a
small sample suggest that we can extract useful features from social media language on drug and
alcohol use that supplement the information from a traditional assessment and that the information
gained from social media improves our prediction of relapse.
38
THE SOCIAL MINDFEED PROJECT: USING OBJECTIVE ASSESSMENT METHODS TO
BETTER UNDERSTAND THE NATURE OF SOCIAL-MEDIA BASED PEER ALCOHOL
INFLUENCE
S.C. Boyle
Department of Psychology, Loyola Marymount University, Los Angeles, CA 90045, USA
Despite growing interest in how social media (SM) might be leveraged in efforts to prevent, treat, and
promote recovery from alcohol abuse and alcoholism, methodological challenges have forced critical
questions about the role of SM in young adults’ alcohol-related cognitions and decisions to remain
unanswered. Meanwhile, a thorough and precise understanding of the negative impacts of SM as it
relates to alcohol use among young people would provide a useful foundation for researchers aiming
to effectively leverage SM in prevention/intervention efforts. As such, this innovative NIAAA funded
study utilizes technologically advanced, objective SM assessment methods to answer critical ques-
tions about SM alcohol influence and, importantly, elucidate the psychological mechanisms that
account for prospective links between SM use, SM alcohol exposure, and drinking. Three-hundred
and twenty incoming college students were recruited to participate in the Social Mindfeed Project in
August 2017. During two distinct periods (one pre-matriculation and one during the first month in col-
lege), an application installed on participants’ computers and smartphones recorded the time they
spent using Facebook and Instagram and a novel software program systematically sampled, anon-
ymized, and archived posts visible to participants in their Facebook and Instagram newsfeeds. Fol-
lowing both periods, web-based assessments measured participants’ explicit and implicit alcohol-
related cognitions, alcohol consumption, and negative alcohol-related consequences. Machine
learning software was trained to recognize and code all alcoholic beverages in the >900,000 posts
captured from students’ newsfeeds. Participants will report their alcohol consumption and experi-
ence of negative consequences in a final survey (T3) in April 2018. Results, to be presented for the
first time in this symposium, seek to replicate and expand on findings from our self-report pilot stud-
ies. Specifically, we anticipate finding a substantial link between first semester SM alcohol exposure
and second semester drinking, explained by increases in alcohol-specific peer norms, beliefs,
expectancies, and positive implicit associations. Analyses will also identify the types of SM posts
most influential and reveal the characteristics of participants most susceptible to SM influence. Find-
ings are anticipated to substantially bolster our understanding of the SMS-alcohol relationship and
implications for effectively leveraging SMS in alcohol prevention, treatment, recovery efforts for
young adults will be discussed.
ABSTRACTS-SPEACKERS
39
LEVERAGING SOCIAL MEDIA AND GAMIFICATION TO INCREASE THE EFFICACY OF WEB-
BASED, REMOTELY DELIVERED PERSONALIZED NORMATIVE FEEDBACK
J.W. LaBrie
Department of Psychology, Loyola Marymount University, Los Angeles, CA 90045, USA
Although web-based, remotely delivered, personalized normative feedback (PNF) alcohol interven-
tions are cost-effective and popular strategies to reduce alcohol-related risks on college campuses,
effect sizes in intervention studies have been modest. Further, recent findings suggest that exposure
to alcohol-related content on popular social media sites may inflate college students’ perceptions of
peer drinking norms, potentially undermining the effectiveness of these interventions. This presenta-
tion explores how specific social media site features and digital game mechanics beloved by college
students might be strategically leveraged to increase the effectiveness of web-based PNF interven-
tions. Two distinct studies (Study 1 N = 237, Study 2 N = 320) compare the effectiveness of tradi-
tional-online survey delivered alcohol PNF with a social media integrated, gamified condition that
delivered the same alcohol PNF within a game designed to test students’ perceptions of classmates
and college life. In both studies, participants assigned to the social media integrated, gamified PNF
condition reported significantly reduced peer drinking norms and alcohol use at follow-up relative to
students assigned to receive the same PNF delivered by online survey. Further, examination of mod-
erators in Study 2 revealed social-media integrated gamified PNF to be particularly effective among
heavy drinkers, and students who frequently use social media for social information-seeking pur-
poses. The promise of social media and gamification in the PNF context are discussed in terms of
Self-Determination Theory and the next steps for this program of research are discussed, including
the development of a more elaborate, self-sustaining Facebook-connected social game which deliv-
ers tailored doses of alcohol feedback over students’ first-year of college as well as Facebook-inte-
grated social app for sexual minority women which delivers gamified PNF on alcohol use, stress-
coping, and preventive health behaviors while simultaneously connecting community members with
local alcohol treatment, recovery, mental health, and health-related resources.
40
IN CONTEXT: A NATURALISTIC INVESTIGATION OF ONLINE TECHNOLOGY-ASSISTED
SUBSTANCE PROBLEM RESOLUTION IN A REPRESENTATIVE SAMPLE OF U.S. ADULTS
B.G. Bergman, J.F. Kelly
Recovery Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston,
MA 02114, USA
Purpose: Alcohol and other drug (AOD) researchers are increasingly developing and testing online
technologies – including social network sites (SNSs) and mobile smartphone applications – to help
individuals reduce or quit AOD use. Very little is known about how individuals with AOD problems
naturalistically use these platforms to aid problem resolution, and what demographic and clinical
characteristics (e.g., primary substance) predict use. This knowledge would boost the field’s epi-
demiological understanding of AOD-related, online technology engagement, and inform future
research on the use of online technologies to assess, prevent, and treat AOD disorder.
Method: From the National Recovery Study, the first geodemographically representative sample of
U.S. adults who resolved an AOD problem (N = 2,002), we used descriptive statistics to examine
the prevalence of different forms of online technology use to “cut down on substance use, abstain
from substances, or strengthen one’s recovery”, and logistic regression to examine unique demo-
graphic and clinical predictors of this online technology use from an initial pool of variables with signif-
icant univariate associations.
Results: Regarding overall prevalence, 11% used any online technology, including 5% general-
interest SNSs, 3% recovery-specific SNSs, 4% online mutual-help meetings, and 6% other (non-
SNS) types of online technology. There were no differences for alcohol-primary versus other drug-
primary individuals (p > 0.05). Results of the logistic regression showed that younger age (Odds
Ratio [OR] = 1.025, e.g., 2.5% greater odds of using online technology if 1 year younger), non-White
race/ethnicity (OR = 1.5), identifying as a person “in recovery” (OR = 2.4), not abstinent from all
substances (OR = 1.46), use of formal AOD services (e.g., treatment; OR = 2.33), and higher levels
of psychological distress (OR = 1.07) were significant, unique predictors of online technology use.
Conclusion: Approximately one of every 10 U.S. adults who resolved an AOD problem used an
online technology to aid these efforts. On average, it may be somewhat easier to engage younger,
non-White individuals, who have more severe AOD profiles (e.g., greater distress and seeking formal
services) with online technology resources to reduce or quit AOD use. The contradictory finding that
both being “in recovery” and non-abstinent predicted online technology use will receive special atten-
tion.
ABSTRACTS-SPEACKERS
SUNDAY, JUNE 17 1:20PM–2:50PM
SYMPOSIUM 41–44
A New Alcohol Epidemic in the United States? Current Population-Level
Trends in Alcohol Use and Binge Drinking, Implications for Public Health
Organizer/Chair: Katherine Keyes
41
VARYING TIME TRENDS IN U.S. BINGE DRINKING, ALCOHOL USE DISORDERS, AND
OTHER ADVERSE OUTCOMES OF DRINKING
D.S. Hasin
Psychiatry and Epidemiology, Columbia University, New York, NY 10032, USA
Purpose: To present time trends in adult binge drinking and DSM-IV alcohol use disorders (AUD)
from two surveys, the 2001–2002 National Epidemiologic Survey on Alcohol and Related Conse-
quences (NESARC), and the 2012–2013 NESARC-III, to place these trends in the context of other
contemporaneous trends in drinking and adverse alcohol outcomes from different sources of data,
and to examine gender differences in the trends.
Methods: Prevalence of past-year binge drinking measures and alcohol use disorders are com-
pared between NESARC and NESARC-III. These trends are then placed in the context of two sets
of national findings. One set consists of two outcomes that have been the focus of substantial public
health and law enforcement efforts, drinking during pregnancy (two distinct data sources, one based
on survey self-reports and the other based on treatment admissions) and driving under the influence
(DUI; from roadside survey data and fatality data). The other set includes alcohol outcomes that have
not been the focus of concerted public health/legal efforts, including per capita alcohol consumption,
ICD-9-CM diagnoses of alcohol use disorders in hospitalized inpatients, alcoholic liver disease in
young adults, and alcohol-related liver cirrhosis mortality.
Results: Comparing NESARC and NESARC-III surveys, adult binge drinking and DSM-IV AUD
increased significantly and substantially over time. Both indicators of drinking during pregnancy and
of DUI showed decreases over time. In contrast, the data on all the other alcohol outcomes showed
increased over time, with converging rates in men and women in most outcomes.
Conclusions: Greater public health attention is needed to the growing US population prevalence of
alcohol-related harms, especially in women.
42
DECLINES IN THE RELATIONSHIP BETWEEN ADOLESCENT DEPRESSIVE AFFECT AND
BINGE DRINKING: IMPLICATIONS FOR PUBLIC MENTAL HEALTH
K.M. Keyes
Department of Epidemiology, Columbia University, New York, NY 10032, USA
Purpose: Depression and suicidality are increasing among US adolescents. Historically, binge
drinking is a strong predictor of mental health risk, and a warning sign for parents and clinicians. Yet
binge drinking has been precipitously declining among adolescents for more than a decade. Given
evident changes in adolescent mental health, examining the extent to which the relationship between
binge drinking and depressive symptoms is changing provides novel information.
Methods: Data were drawn from 25 annually-conducted nationally-representative cross-sectional
surveys of 8th, 10th, and 12th grade high-school attending in the United States from 1991–2015.
Current depressive affect measured with a four item scale creating a continuous score. Binge drink-
ing measured as any episode of 5+ drinks in the past 2 weeks. Linear regression with depressive
affect as the outcome, binge drinking as the independent variable, and controls for grade, sex, race/
ethnicity, and parental education were estimated; standardized regression coefficients reported.
Results: Overall, depressive affect increased among adolescents during the study period whereas
binge drinking decreased. In 1991–1995, binge drinking in the past 2 weeks was associated with a
1.4-point increase in depressive score (p < 0.01). By 2014–2015, the magnitude of that association
diminished by over 40% (beta = 0.85, p < 0.01). There was subgroup variation in the magnitude of
the change in the relationship over time. Among males, the relationship declined by 50%, from a beta
of 1.15 in 1991–1995 to 0.57 2014–2015, while among girls, the relationship was more stable, from
1.76 in 1991–1995 to 1.10 in 2014–2015. Variation was evident by race as well.
Conclusion: The relationship between depressive affect and binge drinking is increasingly de-
coupled, suggesting that binge drinking is less of a salient risk factor for mental health problems now
than in previous generations. The reasons why depressive affect is increasing among US adoles-
cents remains urgently important to understand, as these results correspond to several other studies
showing historically unprecedented increases in adolescent depression and suicidality.
281A
43
TRENDS IN ALCOHOL VOLUME, BEVERAGE CHOICE AND HIGH INTENSITY DRINKING IN
THE US NATIONAL ALCOHOL SURVEYS
W.C. Kerr, C.K. Lui
Alcohol Research Group, Public Health Institute, Emeryville, CA 94608, USA
Purpose: To estimate and evaluate trends in alcohol use patterns from 1984 to 2015.
Methods: Weighted estimates of past year alcohol volume, 5+ days, 8+ days and 12+ days from
the graduated frequency measures and beverage-specific volume are compared over time for gen-
der, age, race/ethnicity and educational attainment subgroups.
Data: The National Alcohol Surveys are population-based samples of randomly selected U.S. adults
aged 18 years and over that were conducted approximately every 5 years in 1984 (n = 5,221;
response rate (RR) = 72%), 1990 (n = 2,058; RR=70%), 1995 (n = 4,925; RR = 77%), 2000
(n = 7,612; cooperation rate (CR) = 58%), 2005 (n = 6919; CR = 56%), 2010 (n = 7,969;
CR = 52%), and 2015 (n = 7,071; CR = 44%). Key changes have occurred in sampling design and
survey mode with a shift from multi-stage clustered design with in-person interviews to random-digit-
dialing (RDD) in 2000 and to duel-frame landline and mobile RDD in 2010, both with telephone inter-
views. African Americans and Hispanics were oversampled in all surveys except for 1990.
Results: Alcohol volume in the NAS increased by 18% from 198 mean drinks per year in 2000 to
220 drinks in 2010 but did not change between 2010 and 2015. However, between 2010 and 2015
men’s mean volume reduced by 10% to 298 drinks while women’s volume increased by 32% to 145
drinks, with women’s volume nearing half of men’s as compared to about 1/3 in the previous surveys.
This increase for women appears to be driven by changes in the heavy drinking day measures with
the highest mean number of 5+, 8+ and 12+ days in any of the surveys seen in 2015. These substan-
tial increases in alcohol volume and heavy drinking days among women occurred specifically in the
18–39 age group overall and for each of the Black, White and Latino subgroups. Increases were also
seen for Black men 18–49 and 60+ and for Latino men 40 to 59, in contrast to declines in other age
groups and for White men 18–59.
Conclusions: Analyses of the NAS series indicate increased alcohol volume and heavy drinking
from 2000, generally consistent with per capita consumption and other survey series, and gender
convergence occurring particularly in 2015 with high intensity occasions as a key factor.
44
TRAJECTORIES OF NEIGHBORHOOD CHANGE AND ASSOCIATIONS WITH ALCOHOL USE
AMONGST ADOLESCENT GIRLS
C. Mair, R.W.S. Coulter, S.M. Watson, T.L. O’Malley, T. Chung, A.E. Hipwell
Department of Behavioral and Community Health Sciences, University of Pittsburgh Graduate
School of Public Health, Pittsburgh, PA 15261, USA
Purpose: Adolescent girls begin to use substances at younger ages than their male counterparts.
Furthermore, national trends show that girls’ rates of substance use are increasing at a more rapid
rate than adolescent males’. Neighborhood environments are important domains for adolescent
development, and changes in these environments may contribute to shifting patterns of risk behav-
iors. The goals of this study were to describe changes in the physical and social environments in
Pittsburgh, Pennsylvania (a city that has undergone rapid shifts in economic and demographic condi-
tions in the two past decades) over a thirteen-year time period, and the relationships of these
changes to adolescent girls’ alcohol use patterns.
Data and Methods: We analyzed thirteen annual waves of data from the Pittsburgh Girls Study
(PGS), a multiple cohort, longitudinal study of a community sample of 2,450 Black and White girls.
Interviewers administered surveys to girls and their caretakers beginning early in development (ages
5–8 years) and extending into late adolescence-early adulthood (17–20 years), with high annual
cooperation rates (86–97%). Assessments measured neighborhood environments, adolescent sub-
stance use, and girls’ geocoded addresses. Neighborhood physical disorder was assessed around
each girl’s home annually using interviewer-rated measures, which we used to create aggregated
neighborhood-level physical disorder scores by Census block group. We used longitudinal latent
class analyses to estimate common trajectories of neighborhood-level changes in physical disorder
and sociodemographics. Using logistic regression, we then tested how living in neighborhoods with
certain trajectories were associated with past-year alcohol use frequency and quantity over time.
Results: Five distinct neighborhood trajectories were found, with physical disorder remaining mark-
edly higher (though slightly decreasing) in block groups with >80% Black residents and where the
unemployment rate doubled from 2001–2013. Girls living in the two neighborhood classes with the
highest levels of physical disorder drank more frequently than those in the other classes. Girls who
moved from “worse” to “better” neighborhoods increased their drinking frequency less than those
who stayed.
Conclusions: Neighborhoods changed in Pittsburgh, with wealthier Census block groups, with a
higher proportion of White residents, having consistently lower levels of physical disorder. Differential
exposure to neighborhood environments appears to contribute to disparities in alcohol use through-
out adolescence.
282A
SUNDAY, JUNE 17 1:20PM–2:50PM
SYMPOSIUM 45–48
Interdisciplinary Perspectives on Prenatal Alcohol and Tobacco Exposure,
Parenting and Outcomes Among Offspring
Organizers/Chairs: Kimberly Kamper-DeMarco and Jennifer Fillo
45
MATERNAL AND PATERNAL LINEAGE CONTRIBUTIONS TO TRANSGENERATIONAL
EFFECTS OF PRENATAL ALCOHOL EXPOSURE
D.O. Popoola, J.D. Madera, M. Nizhnikov, N.M. Cameron
Department of Psychology, Binghamton University, Binghamton, NY 13902, USA
Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Research Institute on
Addictions, Buffalo University, Buffalo, NY 14203, USA
Our previous research in rats demonstrated that behavioral consequences of prenatal alcohol expo-
sure (PAE) transmit from an in utero-exposed F1 generation to their F2 and F3 offspring. In the pre-
sent study, we investigated the lineage responsible for such transmission to the F2 generation.
Dams pregnant with the F1 generation received 1 g/kg ethanol (E), water (W) or were undisturbed
as controls (C) during gestational days 17–20. F1 animals were subsequently interbred to produce
nine F2 treatment groups (dam-sire: C-C, C-E, C-W, W-C, W-W, W-E, E-C, E-W, and E-E). Both F1
and F2 animals were tested for ethanol consumption during infancy on postnatal day (PND) 14, alco-
hol consumption and preference during adolescence between PND 28–52, and sensitivity to etha-
nol-induced hypnosis during adolescence on PND 42. Adolescent F2-generation male cortical
gamma-aminobutyric acid type-A (GABAA) alpha-4 and delta subunit expression were quantified.
F1 generation E-group animals demonstrated greater alcohol consumption during infancy and
decreased sensitivity to ethanol-induced hypnosis during adolescence compared to C-group. In the
F2 infants, both maternal and paternal lineages influenced PND14 male and female ethanol intake
as offspring from E-group fathers or mothers consumed more ethanol than the C-group offspring.
Interestingly, the F2 offspring of W fathers also consumed more 5% ethanol in a two-bottle choice
test than offspring of C-group fathers. Adolescent F2 offspring of E-group mothers consumed less
ethanol compared to offspring of C-group mothers with no effect of sex or paternal lineage. In addi-
tion, sensitivity to 3.5 g/kg ethanol-induced hypnosis in the F2 adolescents was less in females than
males, and was only influenced by maternal lineage, as offspring of E-group mothers were less sen-
sitive to ethanol-induced hypnosis than offspring of C-group mothers. Interestingly, this effect existed
regardless of paternal lineage in females but only in male offspring of E-group fathers. Lastly, F2 E-
group males express lower cortical GABAA receptor alpha-4 and delta subunits compared to C-
group.
In summary, we are the first to report that while both maternal and paternal lineages are responsible
for transmitting PAE’s impact on infant ethanol consumption across generations, the maternal lin-
eage is responsible for transmitting changes in adolescent consumption and sensitivity to ethanol-
induced hypnosis. This effect may be linked to PAE modulation of the GABAA system.
46
MATERNAL PRENATAL AND POSTNATAL ALCOHOL USE, DYRESGULATION, AND
DISCIPLINE PRACTICES
S.A. Godleski, R.D. Eiden
Research Institute on Addictions, University at Buffalo, SUNY, Buffalo, NY 14203, USA
Parent alcohol use is an important public health concern as at least 1 in 10 children live with a parent
with alcohol or substance use disorder. Maternal prenatal and postnatal alcohol use are risk factors
for the development of behavioral problems for children as well as the subsequent development of
substance and alcohol use problems. In addition to potential teratological effects on fetal develop-
ment, one of the major pathways by which maternal alcohol use impacts child development is
through mother-child interactions. The present study investigated the role of maternal use throughout
development and harsh discipline as well as parent and child dysregulation. The sample consisted of
147 mother-infant dyads recruited prenatally and assessed from pregnancy through Kindergarten.
The sample was primarily Black/African American and receiving public assistance. Maternal sub-
stance use during pregnancy (i.e., cocaine and cigarettes), maternal age, and parity were controlled
for in analyses. Average number of drinks per week during pregnancy (beta = 0.23) and average
number of drinks per week postnatally (from 1 month to 60 months of child age; beta = 0.23) were
both predictors of maternal emotion dysregulation at Kindergarten [F(2,134) = 15.05, p < .001;
Rsquared = 0.54]. Pregnancy use predicted maternal physical discipline at Kindergarten (be-
tas = 0.24); however, postnatal use (beta = 0.29) and parent negative responses to child emotion at
48 months (beta = 0.24) were significantly associated with physical discipline even when controlling
for prenatal use and maternal characteristics, such as dysregulation [F(1,117) = 4.09, p < .001;
R2 = 0.30]. Postnatal use was also associated with child emotion dysregulation in early childhood
(r = 0.15–0.18).
Results highlighted the importance of persistent maternal alcohol use in ineffective parent and child
regulation and parenting strategies. In particular, maternal alcohol use may interfere with being con-
sistently warm and supportive as well as increase the risk of dysregulation and using ineffective par-
enting strategies, which can create maladaptive transactional interactions between parent and child.
Understanding pathways to risk to using ineffective and maladaptive parenting strategies could be
critical to intervening effectively.
ABSTRACTS-SPEACKERS
47
MATERNAL CHARACTERISTICS ASSOCIATED WITH PRENATAL EXPOSURE TO TOBACCO
IN A TREATMENT-SEEKING POPULATION
J. Fillo, K.E. Kamper-DeMarco, W.C. Brown, P. Stasiewicz, C.M. Bradizza
The State University of New York, Research Institute on Addictions, University at Buffalo, Buffalo,
NY 14203, USA
Approximately 14% of US women smoke during pregnancy, despite the well-known negative fetal
health consequences of prenatal tobacco exposure. An important step towards providing effective
smoking cessation interventions during pregnancy is to identify individuals who are more likely to
encounter difficulty quitting. In particular, pregnant smokers frequently report smoking in response to
intrapersonal factors (e.g., negative emotions), and research has demonstrated that the success of
cessation attempts can be influenced by interpersonal factors (e.g., verbal and behavioral feedback
from close others). The present research examined the influence of emotion regulation difficulties,
and positive and negative feedback from close others, on smoking cessation-related variables (e.g.,
smoking quantity, withdrawal symptoms) among pregnant smokers. Data were drawn from the base-
line wave of a smoking cessation treatment study enrolling low-income pregnant women who self-
reported smoking in response to negative affect (N = 73). Prior to treatment, participants smoked an
average 7.47 cigarettes (SD = 9.41) per day. Additionally, 53.4% of participants tested positive for
drugs (e.g., marijuana, opiates), and 20.5% had received some form of prior treatment or counseling
to stop or cut down on alcohol or drug use. Controlling for self-reported negative affect smoking,
analyses examined the roles of intrapersonal (i.e., emotion regulation difficulties) and interpersonal
factors (i.e., positive and negative feedback from close others) in predicting smoking quantity, fre-
quency, urges, withdrawal, and cessation self-efficacy. Results revealed that greater emotion regula-
tion difficulties were related to participants’ experience of greater smoking urges (b = 0.30,
p = 0.042) and withdrawal symptoms (b = 0.09, p = 0.003). Additionally, more negative feedback
(e.g., criticism) from close others was related to fewer number of smoking days per year (b =
1.28,
p = 0.042) and higher smoking cessation self-efficacy (b = 0.02, p = 0.002). These results suggest
that emotion regulation difficulties contribute to smoking during pregnancy by exacerbating women’s
negative experiences related to smoking cessation attempts. Identifying women with greater emotion
regulation difficulties and providing interventions focused on improving emotion regulation has the
potential to improve smoking cessation efforts, particularly during pregnancy. Surprisingly, close
others’ negative feedback was related to lower smoking frequency and greater confidence in quitting
smoking suggesting that this feedback may assist this highly stressed population in managing smok-
ing-related negative affect.
48
FINDINGS FROM THE 6-MONTH POST-INTERVENTION FOLLOW-UP ASSESSMENT OF THE
FAMILIES ON TRACK INTERVENTION FOR CHILDREN WITH FASD AND THEIR FAMILIES
C.L.M. Petrenko
Mt. Hope Family Center, University of Rochester, Rochester, NY 14608, USA
The purpose of this study was to evaluate outcomes from a pilot trial of the Families on Track Pro-
gram approximately 6-months post-intervention. The Families on Track Program was designed to
prevent secondary conditions in children with FASD and incorporates two empirically validated inter-
ventions: the Families Moving Forward (FMF) parent consultation program and the Promoting Alter-
native THinking Strategies (PATHS) curriculum for child social and emotional skill development. 30
families with children with FASD (ages 4–8) enrolled in the study; 16 were randomized to the inter-
vention condition, which was delivered over a 9 month period. Results from the immediate post-inter-
vention follow-up (Petrenko, Pandolfino, & Robinson, 2017) revealed medium to large intervention
effects for child emotion regulation, self-esteem, and anxiety, and important caregiver outcomes
including knowledge of FASD and advocacy, attributions of behavior, use of antecedent strategies,
parenting efficacy, family needs met, social support, and self-care. Medium-sized improvements in
disruptive behavior were observed for both intervention and assessment/referral groups. At the 6-
month follow-up time point (~18 months after study entry), data were available for selected outcomes
for 14 families in the intervention group and 10 families in the assessment/community referral group.
Data analysis emphasized calculation of effect sizes to inform future larger-scale trials. Improve-
ments in disruptive behavior were maintained for both groups, with no sizeable group effects. The
very large effect in child emotion regulation observed at immediate post-intervention declined to the
small-medium range; gains for the intervention group diminished somewhat whereas the comparison
group showed some relative improvements. The overall group effect for self-esteem diminished
slightly from the large to medium range. For caregiver outcomes, the intervention group evidenced
continued improvements in parenting efficacy, whereas the comparison group had moderate decli-
nes, resulting in a very large effect between groups at follow-up. Although both groups reported
some declines in family needs met in the follow-up period, the intervention effect remained large
between groups. Increases in knowledge of FASD and advocacy were maintained for the interven-
tion group. Both groups reported average levels of parenting stress at all three time points. Results
support further investigation of the Families on Track Program in a larger-scale trial.
ABSTRACTS-SPEACKERS 283A

SUNDAY, JUNE 17 1:20PM–2:50PM 51

SYMPOSIUM 49–52
Integration of Genetics and Genomics to Identify Novel Mechanisms ALCOHOL DEPENDENCE ASSOCIATED ALLELE SPECIFIC EXPRESSION AND REGULATION
IN HUMAN BRAIN TISSUE
Underlying Alcohol Use Disorders Y. Liu
Organizers/Chairs: R. Dayne Mayfield and Howard Edenberg Center for Computational Biology and Bioinformatics, Indiana University School of Medicine,
Indianapolis, IN 46202, USA

Alcohol abuse and alcoholism are significant public health problem. As a central nervous system
49 depressant, high level of alcohol intake over a long period of time may alter brain function to promote
alcohol addiction and have extensive damaging effects on the brain. Understanding the molecular
GENOMIC IDENTIFICATION OF CELL-TYPES AND POTENTIAL THERAPIES FOR ALCOHOL
mechanism of how alcohol affects the brain will be very important to prevent alcohol dependence
USE DISORDER
and to reverse the impact of heaving drinking on the brain. Animal models have been widely used to
E.K. Erickson, R.A. Harris, R.D. Mayfield, S.P. Farris
identify candidate mechanisms, which greatly advanced our knowledge of molecular basis of alco-
Waggoner Center for Alcohol and Addiction Research, Center for Computational Biology and
holism. However, due to ethical considerations, there were very limited molecular evidence from
Bioinformatics, The University of Texas at Austin, Austin, TX 78712-1095, USA
human brain. Through collaboration between the Collaborative Studies on Genetics of Alcoholism
Dissecting the cellular and molecular signatures underlying alcohol use disorder (AUD) is important (COGA) and Integrative Neuroscience Initiative on Alcoholism (INIA) Consortia, we obtained four
for identifying potential treatments for disease. We utilized rodent models of alcohol dependence and regions of brain tissues of 60 human samples from NSW Brain Bank (Australia), of which 30 were
human genetic and transcriptome data through collaboration with COGA and INIA-Neuroimmune to heavy drinker and 30 were social/non-drinker. By integrating deep RNA-seq data with GWAS array
identify molecular perturbations associated with AUD. Microglia and astrocytes are the primary neu- results, we identified 38 genes with differential allele-specific expression (ASE) in heavy drinkers,
roimmune effector cell-types and are implicated in alcohol-induced perturbation of brain gene compared to social/non-drinker, in the four brain regions. Some of these genes have previously been
expression. Therefore, we identified the microglia- and astrocyte-specific transcriptome responses implicated in neurological diseases and alcohol metabolism. As ASE provides a good model to study
to chronic intermittent ethanol vapor exposure (CIE), a mouse model of alcohol dependence. Both cis-regulatory mechanism (both alleles under the same cellular environment), we further examined
cell-types exhibited up-regulation of innate immune-related gene expression, such as interferon sig- SNVs in regulatory regions from GWAS array results, including upstream enhancer/promoter region,
naling, and gene network analyses revealed that these cell types expressed primarily non-overlap- gene body, 30 UTR and downstream regions. Based on the location of SNVs in open chromatin
ping gene network responses to chronic alcohol exposure. Microglial networks were enriched with region, identified as eQTLs in GTEx, and prediction of altering transcription binding, we nailed down
genes associated with neuroinflammatory disease and were negatively correlated with CIE treat- hundreds of SNVs as highly potential cis-regulators. We will then use massively parallel reporter
ment. Astrocyte networks associated with CIE treatment were enriched with genes involved in meta- assays to validate the regulatory role of SNVs in enhancer, promoter and 30 UTR regions. Our find-
bolism, developmental pathways, and glia-neuronal communication. Novel cell-type specific hub ings will advance the understanding of alcohol abuse associated gene regulation in human brain and
genes were identified which may play important roles in regulating neuroimmune genomic responses serve as a research framework for further study with expanded human brain tissues.
to alcohol. Combined analysis of RNA-Seq data for multiple postmortem human brain regions and
rodent expression profiles demonstrated convergent increases in neuroimmune gene expression
associated with AUD. To identify potential regulatory elements for human alcohol-related gene
expression, we used Encyclopedia of DNA Elements data to reveal consistent over-representation
for the glucocorticoid receptor (NR3C1, q < 0.05). Comparing genetic variation (e.g., COGA data)
and alcohol-responsive gene expression across brain-regions and species with the library of inte-
52
grated network-based cellular signatures ~1.7 million perturbagen profiles defined a limited series of MULTI ‘OMICS INTEGRATION AND NEUROBIOLOGICAL SIGNATURES OF ALCOHOL USE
molecular effectors capable of opposing AUD-associated changes. Several compounds, including DISORDER
glucocorticoid receptor effectors, were also identified in a LINCS analysis of alcohol-induced cell-type L.J. Bierut1,2,3, A. Jaffe1,2,3, C. Markunas1,2,3, N. Saccone1,2,3, E. Johnson1,2,3, D.B. Hancock1,2,3
specific differential expression, suggesting a major driver of alcohol-induced molecular adaptations 1
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63130, USA,
entails the glucocorticoid receptor and affiliated processes. Future work will test neuroimmune speci- 2
Lieber Institute for Brain Development, Baltimore, MD 20215, USA and 3Research Triangle
fic compounds predicted to counteract alcohol-induced molecular changes. This work was supported Institute, Research Triangle Park, NC 27709, USA
by NIH/NIAAA grants F31AA025508, K99AA024836, U01AA020926.
Changes in DNA methylation (DNAm) and RNA expression (RNAexp) are regulatory features that
predispose to alcohol use disorder as well as features that are altered by chronic alcohol exposure.
Integrating multiple “omics” generated in human brain tissue and connecting these findings to alcohol
use disorder GWAS results holds great promise for improving our understanding of the neurobiology
of alcohol use and addiction. To test this approach, we targeted known alcohol metabolizing genes
50 (ADH gene cluster on chromosome 4) to map cis-meQTLs and cis-eQTLs using DNAm array and
RNA-seq data in prefrontal cortex from physiologically normal decedents (N = 139 European Ameri-
ANALYSIS OF WHOLE GENOME-TRANSCRIPTOMIC ORGANIZATION IN BRAIN TO IDENTIFY
cans (EA) and 101 African Americans (AA)). Using Benjamini–Hochberg false discovery rate
GENES ASSOCIATED WITH ALCOHOLISM
(FDR) < 5%, we nominated meQTLs (smallest p = 9.8 9 10
37) and eQTLs (smallest
M. Kapoor, S.P. Farris, J.C. Wang, S. Bertelsen, H.J. Edenberg, Y. Liu, D. Mayfield, COGA and INIA
p = 3.5 9 10
14). To test these variants for association with alcohol use disorder, we amassed an
Collaborators, A. Goate
alcohol GWAS meta-analysis (N = 9,213; 4,988 EA and 42,25 AA). We found a set of meQTLs
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
(tagged by rs58827689) that were not highly correlated with prior GWAS-identified SNPs (r2 < 0.2)
Alcohol dependence (AD) is a complex disorder with high heritability (50–60%). The excessive use and were associated with alcohol use disorder after correction for multiple testing. Discovery of
of alcohol may also result in the change of global gene expression across different tissues. We com- rs58827689, associated with ADH1C DNAm (p = 2.3 9 10
14) and with alcohol use disorder
pared the transcriptomic organization of the Dorso-Lateral Pre-Frontal Cortex (DLFPC) in 143 post- (p = 2.3 9 10
5), was not possible in standard GWAS with current sample sizes, illustrating the util-
mortem brain samples from 66 alcoholics and 77 controls. Differential gene expression (DGE) was ity of focusing on QTLs to nominate and detect novel associations. Each ‘omics type (DNAm,
performed using DESeq2 package after correcting for effect of batch, gender, age and RNA integrity RNAexp, and GWAS), used in isolation, has yielded important discoveries for addiction, and combin-
number (RIN). 481 genes were differentially expressed between alcoholics and controls at 10% ing all three will accelerate our understanding of alcohol use disorder.
FDR. Ingenuity pathway analysis (IPA) showed enrichment of genes for GADD45 signaling, inter-
feron signaling and inflammatory response for the differentially expressed genes. We also performed
Weighted Gene Co-expression Network Analysis (WGCNA), which clustered the genes into 52 mod-
ules; modules having correlation of more than 75% were merged. Module-trait correlation analysis
identified a “white” module with 731 genes that was positively correlated with alcoholism classifica-
tion (DSM4, DSM5) and alcohol consumption. White module was also significantly correlated to age
and number of years of drinking in alcoholics and controls. Age-corrected module-trait correlation
analysis improved the association signal for DSM4, DSM5 and case-control classification, which
showed that this module also had significant correlation with alcoholism independent of age as well.
SNPs overlapping with “white module” genes were highly enriched for association signals with age
at onset of alcohol dependence in COGA European American (EA) dataset; the COGA extended
AD families are enriched for common factors increasing risk for AD. Genome-wide Cox proportional
hazards regression model was used to test for association between age at onset of AD and SNPs in
the COGA data. “White module” was found to be highly enriched for genes related to immune sys-
tem. By leveraging power from transcriptome and GWAS we identified novel genes and networks
associated with alcoholism.
284A
SUNDAY, JUNE 17 3:10PM–4:40PM
SYMPOSIUM 53–56
Drinking Buddies: Neurobiology of Alcohol Use and Co-Occurring Disorders
Organizer/Chair: Jibran Khokhar
53
EXCESSIVE ALCOHOL DRINKING DISRUPTS STRESS COPING THROUGH ALTERATIONS IN
BNST DYNORPHIN
L.S. Hwa, T.L. Kash
Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC
27599, USA
Chronic, excessive alcohol intake can lead to dynamic changes in stress coping behavior and
stress-related neural mechanisms. We aim to explore how long-term intermittent alcohol (IA)
changes how mice react to a variety of stressors and if the dynorphin (DYN)/kappa opioid receptor
(KOR) system influences these aberrant behaviors. After eight weeks of IA, mice show reduced abil-
ity to cope with a repeated forced swim stress, deficits in active coping in response to a TMT predator
odor, and altered escape strategy when faced with an overhead looming disc threat compared to
H2O-drinking mice. Further, we found that KOR antagonist norBNI could restore stress coping in the
repeated forced swim and responses to predator odor, but not the looming disc assay. To identify
which DYN/KOR populations may drive these altered stress reactions after chronic alcohol, c-fos
mapping was conducted using preprodynorphin-IRES-Cre::Rosa26-flox-stop-L10a-eGFP reporter
mice. Among other corticolimbic areas, the dorsal bed nucleus of the stria terminalis (dBNST)
showed the highest c-fos interaction between alcohol history and stress. We next performed
excitability and synaptic transmission experiments using whole cell patch clamp recordings of
dBNST DYN neurons. Overall, IA robustly silenced synaptic drive while the combination of IA and
stress significantly increased excitability and glutamatergic activity in DYN-containing cells in the
dBSNT. We are also exploring how other local signaling molecules like corticotropin-releasing factor,
in addition to KOR agonists, may drive the DYN/KOR system since CRF can also increase synaptic
drive in dBNST DYN cells. Chemogenetic and shRNA silencing of DYN remain future directions to
further control the distinct cell populations in vitro and in vivo. Altogether, this research shows a
behavioral representation of an allostatic shift of stress coping after long-term alcohol. The imbalance
of stress neuropeptide signaling may ultimately underlie this complex relationship between alcohol
and stress.
54
PROBING THE NEURAL CIRCUITS OF VULNERABILITY AND RESILIENCE TO ALCOHOL USE
DISORDER AND COMORBID ANXIETY/STRESSOR-RELATED DISORDERS
S.E. Ewin, A.G. Almonte, E.S. Carter, J.W. Morgan, N. McMullen, S. Sizer, J.L. Weiner
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem,
NC 27157, USA
Individuals suffering from anxiety or stressor-related disorders are two to three times more likely to
develop alcohol use disorder than the general population. Moreover, this dual diagnosis is associ-
ated with greater symptom severity of both disorders and poor treatment outcomes. Despite the fre-
quent co-occurrence of these disorders, the neural substrates underlying this comorbidity are
unclear. To address this gap in our knowledge, we have established a rodent adolescent social isola-
tion (aSI) model and shown that, in male rats, this model elicits robust, long-lasting alterations in
many behavioral risk factors for anxiety/stressor disorders or alcoholism. Relative to rats that were
group-housed throughout adolescence (aGH), aSI rats exhibit enduring increases in anxiety-like
behaviors, deficits in fear extinction, and escalated ethanol intake. We also identified a number of
neural adaptations that contribute to the maladaptive behaviors promotes by this model, including
long-lasting alterations in dopamine release dynamics in the nucleus accumbens and increased
excitability in the basolateral amygdala, nucleus accumbens, and ventral hippocampus. In this talk,
we will present new data suggesting that aSI results in similar dopaminergic adaptations in male and
female rats but that the behavioral changes promoted by this form of chronic adolescent stress may
be sexually dimorphic. We will also present recent evidence that the anterior and posterior basolat-
eral amygdala (BLA) play opposing roles in regulating operant ethanol self-administration and that
chemogenetic silencing of excitatory projections from the anterior BLA to the nucleus accumbens or
ventral hippocampus significantly reduces ethanol drinking behaviors. Collectively, our findings sug-
gest that aSI leads to the expression of many behaviors that may be considered risk factors for alco-
holism and comorbid anxiety/stressor-related disorders and that there may be important sex
differences associated with these aSI-related behavioral phenotypes. Our data also reveal novel cir-
cuits that may contribute to the frequent comorbidity between these disorders. Supported by
AA21099, AA17531, AA10422
ABSTRACTS-SPEACKERS
55
MODULATING VOLUNTARY ALCOHOL AND NICOTINE CO-CONSUMPTION IN MICE
J.C. Touchette, K.Y. O’Rourke, J.J. Maertens, A.M. Lee
Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
Alcohol and nicotine are often used together, and alcohol and nicotine dependence is frequently co-
morbid. We have developed models of alcohol and nicotine co-consumption in male and female mice
that utilize voluntary, oral consumption of unsweetened alcohol, nicotine and water. These models
enable us to examine the impact of drug concentration, availability and intermittency on simultane-
ous alcohol and nicotine consumption. We found that male and female C57BL/6 mice readily co-con-
sumed unsweetened alcohol and nicotine. Whether the mice increased or decreased their nicotine
consumption during a period of alcohol abstinence depended on the concentration of nicotine
offered. Intermittent co-consumption produced higher alcohol, but not nicotine consumption levels,
compared with continuous co-consumption procedures. Finally, we found that chronic alcohol and
nicotine co-consumption resulted in physical dependence. Using these models, we have tested the
effect of a pre-clinical nicotinic acetylcholine receptor (nAChR) drug, sazetidine-A, on alcohol and
nicotine co-consumption, as nAChRs are implicated in both alcohol and nicotine addiction. We found
that sazetidine-A (1 mg/kg, i.p.) reduced overnight alcohol consumption, but did not affect nicotine
consumption when presented either alone or concurrently with alcohol. Sazetidine-A did not reduce
water or saccharin consumption at any dose tested. Sazetidine-A also significantly reduced alcohol
consumption in an acute, binge drinking-in-the-dark procedure. Collectively, these data suggest a
novel role for the nAChR targets of sazetidine-A in specifically mediating alcohol consumption, sepa-
rate from the involvement of nAChRs in nicotine consumption.
56
IMPAIRED BRAIN REWARD CIRCUITRY MAY UNDERLIE ALCOHOL DRINKING IN A RAT
MODEL OF SCHIZOPHRENIA AND CO-OCCURRING ALCOHOL USE DISORDER
J.Y. Khokhar, H. Lu, E.A. Stein, A.I. Green
Department of Psychiatry, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
Purpose: Alcohol use disorder commonly occurs in patients with schizophrenia and contributes
greatly to its morbidity. We have suggested that alcohol use may transiently ameliorate a brain
reward circuit (BRC) dysfunction that underlies alcohol drinking in these patients. Additionally, very
few options are available for the treatment of co-occurring alcohol use disorder and schizophrenia.
To understand the mechanisms underlying, and to develop medications for, co-occurring alcohol
use in schizophrenia, we have turned to a model of alcohol drinking in schizophrenia based upon the
neonatal ventral hippocampal lesion (NVHL) rat.
Methods: Male Sprague-Dawley rat pups (n = 240) on post-natal day 7 (PND7) were bilaterally
injected with excitotoxic ibotenic acid (or aCSF in sham [unlesioned] animals) into their ventral hip-
pocampi. Rats were weaned on PND21 and then given access to 10% alcohol (v/v) in a 2 two-bottle
choice design from PND28-42. Upon reaching adulthood (PND90) animals were allowed to drink
20% alcohol in a free-access two-bottle preference design until a stable drinking baseline was estab-
lished. Animals either received drug treatment (vehicle, 8 mg/kg clozapine and 0.8 mg/kg).
Results: The NVHL rat, like patients with schizophrenia, drinks more alcohol than sham rats (2.5-
fold), and reduces its alcohol drinking when treated with clozapine, and not haloperidol. Importantly,
prior to alcohol drinking in adulthood, NVHL rats displayed impaired MRI resting-state functional con-
nectivity within the BRC (hypoconnectivity between the nucleus accumbens and pre-frontocortical
regions [i.e., anterior cingulate, orbitofrontal, infralimbic/prelimbic); this is consistent with a hypocon-
nected BRC observed in patients with schizophrenia and cannabis use disorder. Moreover, like
patients with schizophrenia alone, and those with alcohol use disorder alone, significantly higher glu-
tamine levels (1.4-fold) were observed in the anterior cingulate cortex after 1-month of alcohol absti-
nence, and the higher glutamine levels correlated significantly with alcohol intake on the last day of
drinking (R = 0.84; p = 0.002). Lastly, NVHL rats displayed persistent latent inhibition of sign-track-
ing (p < 0.05), which correlated significantly with future alcohol drinking (r =
0.73, p = 0.003).
Conclusions: Connectivity and neurometabolic abnormalities in the BRC, as well as cognitive dys-
functions, may underlie alcohol drinking in this model, and potentially in patients with schizophrenia.
Future studies using this model can help identify novel treatment approaches while uncovering the
mechanisms underlying alcohol use in patients with schizophrenia.
ABSTRACTS-SPEACKERS
SUNDAY, JUNE 17 3:10PM–4:40PM
SYMPOSIUM 57–60
Mechanistic and Therapeutic Insights Into Alcohol-Induced Inflammation and
Multi-Organ Pathology: Nutritional Aspects
Organizers/Chairs: Irina Kirpich and Craig McClain
57
ENDOGENOUS INCREASE IN N3/N6 PUFA RATIO AND RESOLVIN D1 TREATMENT
ATTENUATED LIVER INJURY INDUCED BY CHRONIC ALCOHOL ADMINISTRATION IN MICE
D.R. Warner, S. GhoshDastidar, Y.L. Song, J.B. Warner, C.J. McClain, I.A. Kirpich
Department of Medicine, Alcohol Research Center, University of Louisville, Louisville, KY 40202,
USA
Background/Aims: Alcohol-induced liver disease (ALD) is a significant health problem with limited
prevention and therapeutic options. Studies from our group and others have demonstrated that diet-
ary fat plays an important role in ALD development and progression. The Western diet, rich in x-6
polyunsaturated fatty acids (PUFAs) and low in x-3 PUFAs, is known to exacerbate ALD. Numerous
metabolites of x-6 PUFAs promote inflammation, whereas metabolites of x-3 PUFAs (resolvins,
maresins, and protectins) promote the resolution phase of the inflammatory response. In the current
project, we tested the hypothesis that: (1) endogenous increase in x-3/x-6 PUFA ratio, and (2) treat-
ment with resolvin D1 (RvD1) will attenuate ALD in mice.
Methods: Male and female fat-1+/
mice (provided by Dr. J.XKang), which are able to endoge-
nously convert x-6 to x-3 PUFAs, and their wild-type (WT) littermates were fed a Lieber-DeCarli
control or ethanol diets for 6 weeks. To simulate the severity of alcohol-induced liver pathology in
humans, the gut bacteria product, LPS (5 mg/kg), was given to mice 24 h prior to euthanasia. For
the treatment paradigm, WT mice received RvD1 (500 ng, i.p.) on the last four days. Liver injury and
inflammation were evaluated. Liver RNAseq analysis was performed to identify molecular pathways
affected by experimental treatments.
Results: A 6 week EtOH feeding resulted in elevated ALT levels in both WT and fat1+/
mice. LPS
administration further increased ALT activity; however, the magnitude of this effect was less in fat1+/

factor in the development of alcohol-induced gut dysbiosis, endotoxemia and hepatitis, whereas cel-
mice. Compared to WT littermates, fat1+/
mice exhibited lower EtOH+LPS-induced hepatic apop-
tosis and inflammation. RvD1 treatment resulted in similar effects as those seen in fat1+/
mice,
specifically, decreased ALT and modulation of hepatic gene expression toward an anti-inflammatory
response. Mechanistically, we identified alterations in Wnt signaling pathway (that promotes apopto-
sis through a pathway involving FOXO1) in WT mice compared to fat1+/
mice, as demonstrated by
decreased Axin2, an endogenous marker for Wnt signaling, and increased expression of Dkk3, the
Wnt inhibitor.
Conclusions: Results from this study demonstrated that increase in x-3/x-6 PUFA ratio and RvD1
treatment attenuated EtOH-induced liver damage, suggesting that increasing the level of endoge-
nous x-3 PUFAs or administering RvD1 may be a promising novel therapy for ALD.
58
ETHANOL TREATMENT RESULTS IN SHORT TERM INFLAMMATION BUT LONG TERM
TOLERANCE IN LIVER BUT CHRONIC INFLAMMATION IN BONE: EFFECTS OF DIETARY
ANTIOXIDANT
M.J. Ronis, K. Pedersen, C. Pulliam, K. Mercer, C.K. Lumpkin, A. Alund, C. Shearn, D. Petersen
LSU Health Sciences Center, New Orleans, LA 70112, USA
Alcoholic liver disease (ALD) progresses in a proportion of alcoholics from simple steatosis to steato-
hepatitis, fibrosis and cirrhosis. Development of oxidative stress and downstream inflammation
appear to be key factors in this process. However, the molecular mechanisms underlying alcoholic
inflammation are incompletely understood. In studies in male Sprague-Dawley rats we have
observed that short term feeding (14 d) results in significant elevation of TNFa, IFNg and IL-12
mRNAs. However, after chronic feeding of identical EtOH diets (150 d) inflammation was no longer
evident. Similar lack of a hepatic inflammatory response was observed in male SV/J mice fed EtOH
chronically for 120 d. It is possible that this phenomenon is associated with development of tolerance
to endotoxin. However, chronic EtOH exposure in SV/J mice did increase the sensitivity to inflamma-
tion, and matrix remodeling (MMP and collagen mRNAs) after an acute EtOH binge. Interestingly,
inflammatory responses to chronic EtOH treatment were maintained in SV/J GSTA4-4
/
mice
which have impaired ability to detoxify lipid peroxidation products. In addition, we have reported
increased necroinflammatory injury in PPARa/GSTA4-4 double knockout mice compared to single
knockouts in models of both ALD and nonalcoholic steatohepatitis. Collectively, these data suggest
that protein carbonylation by HNE and MDA contribute significantly to the inflammatory responses.
Treatment with the dietary antioxidant N-acetylcysteine was able to block oxidative stress and
necroinflammatory injury in the liver but unable to block other EtOH effects including steatosis and
impaired insulin/IGF signaling. In the skeleton, chronic EtOH treatment results in osteopenia as a
result of suppressed bone formation and increased bone resorption. At least in part, EtOH inhibition
of bone formation is associated with oxidative stress and chronic increases in bone marrow inflam-
mation particularly increases in TNFa and IL-1b. Soluble antibodies to these cytokines prevented
EtOH inhibition of fracture healing, reversed the effects of EtOH on anabolic skeletal rebuilding in
female rats post-weaning and reversed EtOH inhibition of distraction osteogenesis in both rats and
mice. In contrast, dietary antioxidants NAC and vitamin E blocked oxidative stress but only partly
reversed EtOH-induced osteopenia. These data suggest that antioxidant therapy alone is insufficient
to prevent alcohol-associated multi-organ pathology. Supported in part by R37 AA009300 (D.R.) and
R37
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59
SUPPRESSION OF PANETH CELL ALPHA-DEFENSINS MEDIATES ALCOHOL-INDUCED
PATHOGENESIS AT THE GUT-LIVER AXIS IN MICE: ROLE OF ZINC DEFICIENCY
W. Zhong, L. Hao, W. Zhang, X. Sun, Z. Zhou
Center for Translational Biomedical Research, University of North Carolina at Greensboro,
Kannapolis, NC 28081, USA
Background: Gut-derived bacterial pathogens contribute to the pathogenesis of alcoholic liver dis-
ease (ALD) with the mechanisms still not fully defined. Intestinal antimicrobial peptides (AMPs) play
a critical role in regulating microbiota homeostasis and limiting bacterial translocation. Paneth cells
are professional AMP-producing innate immune cells and, of note, the sole source of an important
type of AMPs-a-defensins. Given the facts that ALD is associated with zinc deficiency and Paneth
cells are enriched in zinc, the role of alcohol-induced zinc deficiency in Paneth cell function and its
pathophysiological consequences necessitate investigation.
Methods: The present study aimed at determining if alcohol exposure suppresses Paneth cell AMP
expression via zinc deficiency, and if a-defensin dysfunction mediates alcohol-induced dysbiosis and
hepatitis. Mouse models of chronic alcohol feeding, dietary, experimental and genetic zinc deple-
tions, and ex vivo intestinal crypt culture were conducted.
Results: Alcohol feeding for 8 weeks caused dysbiosis at the gut along with the development of
endotoxemia and hepatitis in mice. Expression of AMPs and the bactericidal activity of Paneth cells
were significantly reduced in the ileum of the alcohol-fed mice along with reduction of cellular zinc
levels. The MMP7
/
mice (deficient of active a-defensins) showed more severe gut dysbiosis, endo-
toxemia and hepatitis along with reduced intestinal bactericidal activity, compared to the wild type
mice. Dietary zinc deficiency exaggerated chronic alcohol-impaired Paneth cell bactericidal activity
through post-translational modification of a-defensins. Similar trend was observed in Paneth cell-con-
taining intestinal crypts after the treatment of zinc chelator; the mRNA levels of a-defensins were
decreased after zinc chelation in association with reduced p-STAT1 and p-STAT3, which implicate a
possible transcriptional regulation of a-defensins by zinc. Moreover, a Paneth cell-predominant zinc
transporter, ZIP8, was significantly decreased by chronic alcohol feeding; the reduction was through
acetaldehyde rather than zinc deficiency per se. Paneth cell specific-knockout of ZIP8 led to
decreased cellular zinc levels in Paneth cells and reduced production of a-defensins.
Conclusion: The present study suggest that Paneth cell AMP deficiency is a pathophysiological
lular zinc deficiency may mediate the deleterious effects of alcohol on Paneth cells via abrogating
STAT signaling.
60
PROBIOTICS AND THEIR SOLUBLE FACTORS PREVENT AND MITIGATE ALCOHOLIC
DISRUPTION OF GUT-LIVER-BRAIN AXIS BY AN EGF RECEPTOR-DEPENDENT MECHANISM
P.K. Shukla, A. Meena, R.K. Rao
Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA
One of the primary mechanisms involved in alcoholic tissue injury is disruption of gut barrier function
and endotoxin or the bacterial lipopolysaccharide (LPS) flux into portal circulation, liver and eventu-
ally into systemic circulation. In the liver, LPS triggers inflammatory responses leading to develop-
ment of alcoholic liver disease (ALD). The LPS in the systemic circulation is likely to target tissues in
all organ systems. A significant body of evidence indicates that LPS plays an important role in alco-
hol-induced neuro-inflammation. Therefore, the inflammatory interplay in the Gut-Liver-Brain axis
might play an important role in alcoholic tissue injury in these organs. Preventive and/or mitigating
factors that target these organs have high therapeutic value. Evidences support that probiotics may
have therapeutic value in treatment of alcoholic tissue damage. We investigated the potential role of
Lactobacillus species in prevention of alcoholic tissue injury in gut, liver and brain. Our studies show
that L. plantarum and L. casei not only block ethanol (EtOH) and acetaldehyde-induced disruption of
tight junctions (TJ) and barrier dysfunction in the intestinal epithelium in vitro, but also prevent chronic
EtOH feeding-induced disruption of colonic epithelial TJ, gut permeability and endotoxemia in mice
in vivo. Probiotics blocked EtOH feeding-induced fatty liver and plasma markers of liver damage.
EtOH feeding suppressed antioxidant gene expression, induced oxidative stress and elevated
expression of pro-inflammatory cytokine and chemokine genes in colon, liver and brain. Probiotics
blocked oxidative stress and changes in expression of antioxidant, cytokine and chemokine genes in
gut, liver and brain. Similar protection from EtOH was demonstrated by a fraction isolated from the
probiotic conditioned medium. Our data also demonstrate that probiotics mitigate gut, liver and brain
damage when administered after the injury occurred. In vitro studies indicated that EGF receptor
(EGFR) tyrosine kinase activity is involved in the protective effect of probiotics. Studies in mice by
conditional expression of EGFR* (a dominant negative mutant EGFR) demonstrated the role of
EGFR in EtOH-feeding induced injury in colon, liver and brain in vivo. Our studies demonstrate that
alcoholic injury in Gut-Liver-Brain axis can be controlled by probiotic feeding. (Supported by
AA12307 grant from NIAAA).
286A
SUNDAY, JUNE 17 3:10PM–4:40PM
SYMPOSIUM 61–64
Behavior Under Cue Control: Neural Processes And Implications for
Alcoholuse Disorders and Addiction
Organizers/Chairs: Joyce Besheer and Nadia Chaudhri
61
DRUGS AND CUES: WHAT GETS CONDITIONED?
H. de Wit
Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637,
USA
It is widely accepted that drug-related cues can elicit craving in humans, and they may also increase
drug-seeking. Drug cues are thought to acquire their motivational properties through Pavlovian con-
ditioning, by which a stimulus paired with a drug acquires properties of the drug itself. However, it is
not always known which drug responses become conditioned, or how these responses affect future
behavior. Drugs produce numerous effects, any of which might become conditioned, and any of
which might influence future drug-taking behavior. Although experimenters create the conditions for
conditioning, they have little control what drug effects become conditioned or how they influence
future drug-taking. We have conducted a series of studies using Pavlovian conditioning procedures
in healthy human volunteers, using drugs such as alcohol and amphetamine as the drug (uncondi-
tioned stimulus), and measuring different types of conditioned responses. We have used both a
human conditioned place preference procedure, and a simple drug-stimulus pairing procedure using
visual and auditory stimuli. The conditioned responses include self-report measures such as positive
or negative mood states and ratings of “liking” of the conditioned stimulus, as well as objective mea-
sures such as cognitive or physiological reactions, including measures of brain activation. We will
review the findings from these studies and consider their implications for understanding how condi-
tioned responses might affect subsequent drug-seeking behavior.
62
INTERNAL DRUG STATES: A NICOTINE+ALCOHOL COMPOUND INTEROCEPTIVE DRUG
CUE DRIVES REWARD SEEKING BEHAVIOR
P.A. Randall
Bowles Center for Alcohol Studies, UNC Chapel Hill School of Medicine, Chapel Hill, NC 27599,
USA
Internal drug states and an organisms’ ability to recognize them, are an important aspect of drug use
and ultimately, drug dependence. One method by which to probe sensitivity to these interoceptive
drug cues in an animal model is Pavlovian drug discrimination in which the internal drug state deter-
mines whether or not an environmental cue (i.e., stimulus light) is followed by reward (i.e., sucrose).
Using this procedure, we assess the interoceptive effects of both nicotine and alcohol in combination
as these are two of the most commonly co-used drugs and pose a significant public health risk. We
show that rats readily learn to discriminate the interoceptive effects of the N+A cue and that the cue
represents a unique internal drug state from either component alone. To examine the neural circuitry
underlying sensitivity to the N+A compound cue, we focused on the medial prefrontal cortex (mPFC;
prelimbic) and its projections to nucleus accumbens core (AcbC), as these two brain regions are
important for aspects of associative learning and reward-related behavior. As such, inhibitory (Gi)
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were injected bilaterally
into mPFC-PL and microinjection cannulae were bilaterally implanted targeting AcbC. Silencing the
mPFC-PL enhanced sensitivity to the N+A cue. However, when projections from mPFC-PL to AcbC
were silenced, the opposite effect was observed, as sensitivity to the N+A cue was blocked. In sepa-
rate experiments, we assessed if extinction of the N+A cue and its components would have differen-
tial effects on reinstatement of behavior. Reinstatement was observed following extinction of the
alcohol component, whereas reinstatement was blocked following extinction of the N+A cue or the
nicotine component. Taken together, these experiments demonstrate that N+A acts as a potent inte-
roceptive cue, driving reward-related behavior. Moreover, the mPFC-PL and its projections to AcbC
play an important role in modulating sensitivity to interoceptive drug cues. In addition, our extinction
findings suggest that nicotine is an important aspect of this reward association. These findings illus-
trate the importance of interoceptive drug cues in driving reward-related behavior.
ABSTRACTS-SPEACKERS
63
CONTEXT AS A CRITICAL CUE FOR ALCOHOL: STRIATAL AND AMYGDALA MECHANISMS
M.D. Valyear, S.S.-Y. Khoo, N. Chaudhri
Psychology, Center for Studies in Behavioral Neurobiology/FRQS Groupe de recherche en
al, QC H4B 1R6, Canada
neurobiologie comportementale, Concordia University, Montre
The past decade has seen a rise in empirical support for the hypothesis that alcohol-associated con-
texts can facilitate alcohol-seeking and pose a serious threat to abstinence.
We have investigated this hypothesis using preclinical models in male Long-Evans rats. All rats are
first exposed to alcohol in the home cage using an intermittent-access two-bottle choice schedule,
and then given Pavlovian conditioning sessions in which a discrete, auditory conditioned stimulus
(CS) is paired with alcohol. Entries into a fluid port where alcohol is delivered for oral consumption
are measured to assess the acquisition and expression of Pavlovian alcohol-seeking behaviour.
When conditioning is conducted in one context and extinction in a second, different context then sub-
sequently returning subjects to the conditioning context elicits a robust renewal of CS-elicited alco-
hol-seeking. In a different task, conditioning sessions in one context are alternated with periods of
equivalent exposure to a different, neutral context where neither the CS nor alcohol are presented.
At test, responding to the non-extinguished CS in the absence of alcohol is measured in both con-
texts. We observe a robust increase in CS-elicited alcohol-seeking at test in the alcohol context, rela-
tive to the neutral context or a novel context. These behavioural findings underscore the capacity of
context to function as a critical cue for alcohol. Using neuropharmacological and chemogenetic
approaches, we have investigated the mechanistic underpinnings of CS-elicited alcohol-seeking in
different contexts. This body of research revealed three primary findings. First, we uncovered evi-
dence of a functional dissociation in the contributions of the nucleus accumbens core and shell sub-
regions to alcohol-seeking elicited by discrete and context cues, respectively. Second, the
basolateral amygdala appears to be a critical locus for renewal effects, as unilateral inactivation of
this structure abolishes context-induced renewal. Lastly, glutamatergic transmission at AMPA, but
not mGluR5 receptors in the basolateral amygdala is necessary for conditioned responding elicited
by a discrete CS, regardless of the context in which the CS is experienced. The broad implications of
this research are that context can have a marked influence on alcohol-seeking elicited by extin-
guished or non-extinguished discrete cues. Controlling for this influence of context can allow for
greater refinement in our understanding of underlying neural mechanisms.
64
CONTEXT EFFECTS ON VOLUNTARY BEHAVIOR AND ITS INHIBITION
M.E. Bouton
Department of Psychological Science, University of Vermont, Burlington, VT 05405, USA
This presentation will review basic laboratory research that has examined the effects of context on
voluntary behavior as it is represented in instrumental (operant) behavior in rats. Cues in the back-
ground, or context, can have a powerful influence on such behavior after it has been inhibited. For
example, after an instrumental behavior has been extinguished or punished, a change of context
can result in the renewal (relapse) of the suppressed response. Research indicates that many differ-
ent kinds of stimuli can play the role of context, including (1) background room or apparatus cues, (2)
the passage of time, interoceptive (3) deprivation or (4) stress cues, (5) recent reinforcers, and (6)
other behaviors that have preceded the target behavior in a regular sequence or behavior chain. Vol-
untary behavior is inherently context-dependent. But the context-specificity of behavioral inhibition is
even stronger, leaving inhibited behavior susceptible to lapse and relapse after treatment. Implica-
tions for treatment strategies will be discussed. One of the most important principles is that treat-
ments that encourage generalization of treatment across contexts will be most effective in the long
run.
ABSTRACTS-SPEACKERS
SUNDAY, JUNE 17 3:10PM–4:40PM
SYMPOSIUM 65–68
Cross-Species Data Integration for Characterization, Prediction and
Treatment of Alcohol Use Disorders
Organizer/Chair: Elissa Chesler
65
FINDING CONVERGENT BEHAVIORAL FEATURES OF ALCOHOL USE DISORDER THROUGH
FUNCTIONAL GENOMIC COMPARISON ACROSS SPECIES
E.J. Chesler, T. Reynolds, J.A. Bubier, C.A. Phillips, M.A. Langston, E.J. Baker
The Jackson Laboratory, Bar Harbor, ME 04609, USA
Extensive functional genomic analysis of model organism phenotypes has enabled efficient discov-
ery of genes, networks and pathways associated with various facets of alcohol drinking, alcohol pref-
erence, alcohol response and alcohol withdrawal. These molecular correlates of behavior are
increasingly precise, and are matched with equally granular behavioral and neurobiological assess-
ment. However, translation of findings to clinical features of AUD has relied extensively on face valid-
ity. The aspect of AUD modeled by each assay and therefore, the translational utility of findings, is
often uncertain. The underlying construct validity of many assays remains controversial because it is
unclear whether convergence of behaviors is mediated through shared biological pathways and
therefore which of these behaviors will be most informative in the search for novel therapeutic ave-
nues. Through the aggregation of extensive functional genomic data resources from model organism
genetic and genomic analysis and comparison of human genetic studies to model organism pheno-
types, it is now possible to identify those model organism phenotypes that are biologically relevant to
AUDs. Whole genome comparison of genetic and genomic data resources provides simultaneous
identification of convergent phenotypes and the biological basis for the similarity. Generalized Jac-
card similarity of experimentally derived rodent genomic data and human genetic analysis results
reveals statistical similarity of precise animal behaviors, symptom scores, quantitative assessments
and diagnoses. These precise comparisons across species reveal the biological nature of cross spe-
cies similarity. Such understanding is critical for the identification of valid assays for drug discovery
and development, variant modeling and other translational applications.
66
INTEGRATIVE PRIORITIZATION OF GENOMIC LOCI FOR ALCOHOL USE DISORDERS
R.H. CPalmer, J. Yang, J. Bubier, C. Bachman, J. Srijeyanthan, L. Brick, J. McGeary, E. Chesler
Behavioral Genetics of Addiction Laboratory, Department of Psychology, Emory University, Atlanta,
GA 30322, USA
Purpose: Recent computational advances have fostered the development of new methods/tools
that facilitate the integration of gene expression and functional experimentation evidence (across
species) into human-based association analyses (Baker et al., 2012; Yang et al., 2017). A recent
integrative functional genomics analysis for “altered response to Alcohol” in mice provided the first
evidence that resources, such as GeneWeaver, can be used to identify and confirm novel alcohol-
related loci. Unfortunately, applications of experimental results from humans and model-organisms
in human genetic association analyses have been limited to post-genomewide association study
screens of only the most-highly associated variants, which fail to replicate. The present study investi-
gates how highly connected genes that are linked by their association to alcohol-related behaviors
and processes in humans, Drosophila, mice and rats, contribute to individual differences in alcohol
dependence severity (AD). The primary aim of this study is to use genomic data on alcohol depen-
dence from several human studies available from dbGAP (e.g., COGA, SAGE, and Australian
GWAS) to identify SNPs in genes that are highly connected to AD.
Methods: We will compare several gene sets for alcohol-related behaviors and processes using
the GeneWeaver database. Gene sets will be limited to those from curated studies/experiments
focused on differential expression and gene mapping in model organisms; human candidate gene
and GWAS studies are excluded. Intersection among the gene sets will be determined using the
maximal biclique enumeration algorithm that is implemented in GeneWeaver’s Hierarchical Similarity
Graph function. Relevance to alcohol dependence severity in humans will be determined using
mixed linear model association analyses implemented in Genomewide Complex Trait Analysis. In
addition, we apply a novel Bayesian Hierarchical Model with annotation-specific effect-size priors to
our combined set of AD GWAS datasets.
Data: Gene expression data are drawn from curated genesets in GeneWeaver and a plethora of
dbGAP samples with AD phenotypes (SAGE, COGA, the Australian Study of Twins and Families, to
name a few).
Results and Conclusions: Our models will describe how well highly represented genes among
our gene sets predict individual differences in AD. Moreover, results from our Bayesian GWAS will
identify loci with the strongest enrichment for causality amongst the set of alcohol-related variants
identified using GeneWeaver.
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67
BRAIN TRANSCRIPTIONAL CHANGES IN THE MOUSE AND MACAQUE ASSOCIATED WITH
EXCESSIVE ETHANOL CONSUMPTION
R. Hitzemann, O. Iancu, P. Darakjian, D. Oberbeck, A. Colville, N. Walter, C. Zheng, J. Daunais,
S. McWeeney, R. Searles, J. Crabbe, P. Metten, K. Grant
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239,
USA
Extensive data are now available for the transcriptional features associated with the risk of develop-
ing and/or the consequences of excessive ethanol consumption and withdrawal. Data have been col-
lected in flies, mouse, rat, macaque and human samples. One assumes that there will be some
conservation of these transcriptional features and that it is the conserved features that will present
the best opportunities for developing new therapeutic targets. Here we examine a subset of these
data focusing on mice selectively bred from heterogeneous stock (HS) for ethanol preference (2-bot-
tle choice) or for high drinking in the dark (HDID) and on both rhesus and cynomolgus macaques
chronically exposed to ethanol (choice consumption). Transcriptional data were collected using both
microarrays and RNA-Seq and in multiple brain regions. The mouse data focus on detecting risk fac-
tors associated with two different excessive consumption phenotypes that are not strongly geneti-
cally related. From a network perspective the gene modules most closely associated with risk in both
models share ontologies for enrichment in genes associated with synaptic function including GABA
and glutamate receptors, synaptic tethering proteins (e.g., Snap25), cell-cell adhesion molecules
(cadherins & protocadherins), genes associated with the extracellular matrix (collagens & matrix
metalloproteases) and intracellular signaling genes, particularly those associated with MAP kinase
pathways. Hub nodes, strongly affected by selection include Grin2a, Grik1 and Gabrg1. The maca-
que data identify network coexpression modules strongly associated with consumption and enriched
in synaptic genes e.g., Chrm3, Chrna4, Chrna7,Glra2, Grm1and Grm2. The latter has been found to
be associated with the selection of the P and NP rats (Zhou et al. 2013). The discussion will focus on
strategies for prioritizing targets for therapeutic manipulation. Supported in part by AA 13484, AA
10760, AA 13510 and AA 19431.
68
CONNECTING GENE NETWORKS TO DRUG DISCOVERY ACROSS SPECIES
R.A. Harris, L.B. Ferguson, S.P. Farris, R.O. Messing, R.D. Mayfield
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX
78712, USA
Novel computational strategies and drug databases now allow researchers to integrate gene expres-
sion signatures associated with disease with those induced by drug treatments. These integrated
analyses have uncovered new drugs for cancer and other complex diseases and have recently been
applied to psychiatric illnesses. Pharmacotherapies for alcohol use disorder (AUD), a complex psy-
chiatric disease with strong genetic and environmental risk factors, are limited in number and effi-
cacy. However, there are many brain transcriptomes now available for mice and rats selected for
genetic differences in alcohol consumption as well as transcriptomes for human alcoholics and other
species treated with alcohol. We asked if gene expression differences in the High Drinking In the
Dark (HDID-1) mouse line could be used to nominate novel drugs that would decrease alcohol con-
sumption. Using multiple computational methods, we queried LINCS-L1000 (Library of Integrated
Network-based Cellular Signatures), a database populated with the gene expression signatures of
thousands of compounds, to predict and prioritize drugs with the greatest potential to target the HDID
molecular signature and decrease excessive alcohol consumption and/or reduce blood alcohol
levels. Our analysis successfully uncovered novel compounds for testing, and we validated two of
the top candidates in vivo (Ferguson, Ozburn et al., Neuropsychopharmacology, in press). We are
now applying this approach to gene expression networks from human alcoholics and rodents treated
with alcohol. Common druggable networks include those related to neuroimmune signaling. We sug-
gest that brain gene expression data can be integrated with informatics tools, such as LINCS-L1000,
to successfully predict drugs that decrease drinking in animal models of AUD. Effective drug treat-
ments for many psychiatric diseases are lacking, and the emerging tools and approaches outlined
here give researchers studying complex diseases renewed opportunities to discover or repurpose
existing compounds and expedite treatment options. Support: NIH/NIAAA Integrative Neuroscience
Initiative on Alcoholism-Neuroimmune and F31 AA024332 to LBF.
288A
SUNDAY, JUNE 17 3:10PM–4:40PM
SYMPOSIUM 69–72
Neural Correlates of Executive Functioning in Heavy-Drinking Adolescents
and Young Adults: Findings Across Neuroimaging and Recording Studies
Organizers/Chairs: Anita Cservenka and Ty Brumback
69
NEURAL CORRELATES OF EMOTIONAL DISTRACTION DURING INHIBITORY CONTROL IN
COLLEGE BINGE DRINKERS
J.E. Cohen-Gilbert, L.D. Nickerson, J.T. Sneider, E. Oot, A. Seraikas, M.M. Silveri
McLean Hospital, Belmont, MA 02478, USA
Purpose: The transition to college is associated with an increase in heavy episodic alcohol use, or
binge drinking, during a time when the prefrontal cortex and prefrontal-limbic circuitry continue to
mature. Traits associated with this immaturity, including impulsivity in emotional contexts, may con-
tribute to risky and heavy episodic alcohol consumption.
Methods: Functional magnetic resonance imaging (fMRI) was used to assess brain activation dur-
ing a task that required participants to ignore background images with positive, negative, or neutral
emotional valence while performing an inhibitory control task (Go-NoGo).
Data: Subjects were college freshmen (18–20 years old) who engaged in a range of drinking behav-
ior (past 3 months’ binge episodes range = 0–19, mean = 4.6, total drinks consumed range = 0–
104, mean = 32.0). Brain activation on inhibitory trials (NoGo) was contrasted between negative and
neutral conditions and between positive and neutral conditions.
Results: Results showed that a higher recent incidence of binge drinking was significantly associ-
ated with decreased activation of brain regions strongly implicated in executive functioning (dorsolat-
eral and dorsomedial prefrontal cortex (DLPFC/DMPFC), and anterior cingulate cortex (ACC))
during negative relative to neutral inhibitory trials. No significant associations between binge drinking
and brain activation were observed for positive relative to neutral images. Thus, while task perfor-
mance was not significantly associated with binge drinking in this sample, subjects with heavier
recent binge drinking showed decreased recruitment of executive control regions under negative ver-
sus neutral distractor conditions.
Conclusions: These findings suggest that in young adults with heavier recent binge drinking, pro-
cessing of negative emotional images interferes more with inhibitory control neurocircuitry than in
young adults who do not binge drink often. This pattern of altered frontal lobe activation associated
with binge drinking may serve as an early marker of risk for future self-regulation deficits that could
lead to problematic alcohol use. These findings underscore the importance of understanding the
impact of emotion on cognitive control and associated brain functioning in binge drinking behaviors
among young adults.
70
ELECTROPHYSIOLOGICAL CORRELATES OF PERFORMANCE MONITORING IN BINGE
DRINKING: IMPAIRED ERROR-RELATED BUT PRESERVED FEEDBACK PROCESSING
S. Lannoy, F. D’Hondt, V. Dormal, J. Billieux, P. Maurage
Laboratory for Experimental Psychopathology, Universite  catholique de Louvain, Louvain-la-Neuve,
1348, Belgium
Purpose: Performance monitoring allows efficient behavioral regulation by using either internal (er-
ror processing) or external (feedback processing) cues. However, while cognitive functioning has
been widely investigated in binge drinking, performance monitoring has little been explored until
now, despite its adaptive importance in everyday life, and particularly in the regulation of alcohol con-
sumption. This study aims to determine the behavioral and brain correlates of performance monitor-
ing in binge drinking.
Methods: Event-related potentials were recorded during two experimental tasks: (1) a speeded Go/
No-Go Task investigating inhibition and internal error processing by two electrophysiological compo-
nents [Error-Related Negativity (ERN) and error positivity (Pe)], (2) a Balloon Analogue Risk Task
investigating risk-taking and external feedback processing by two electrophysiological components
[Feedback-Related Negativity (FRN) and P3].
Data: Behavioral and electrophysiological (peak amplitude and latency) data were collected from
two groups of drinkers, differing in their pattern of alcohol consumption: 20 binge drinkers and 20
matched non-binge drinkers.
Results: No group difference was observed at the behavioral level but electrophysiological results
indicated that binge drinkers presented modified error-monitoring components (i.e., larger ERN
amplitude and delayed Pe latency). Internal performance monitoring is thus impaired in binge drin-
kers, showing an abnormal processing for errors detection (ERN) and a slower processing of errors’
motivational significance (Pe). However, binge drinkers did not differ from non-binge drinkers regard-
ing feedback-related components.
Conclusion: These results suggest that the electrophysiological correlates of inhibitory control
allow identifying the specific binge drinking pattern.
ABSTRACTS-SPEACKERS
71
CENTRAL EXECUTIVE NETWORK FUNCTIONAL CONNECTIVITY IS ASSOCIATED WITH
ALCOHOL USE BEHAVIORS IN EMERGING ADULTHOOD
L.M. Lesnewich, S. Ray, S.G. Helton, S. Gohel, J.F. Buckman, M.E. Bates
Center for Alcohol Studies, Rutgers University, Piscataway, NJ 08854, USA
Purpose: The central executive network (CEN) is a large-scale neural network implicated in higher-
order executive functioning. Individuals with alcohol use disorder (AUD) typically demonstrate lower
resting-state functional connectivity (rsFC) across some CEN regions compared to non-problem
drinkers, a difference hypothesized to contribute to impaired control of alcohol use. The present
study aimed to identify differences in CEN rsFC between low-risk drinkers and individuals with AUD
in a resting-state task following exposure to alcohol cues.
Methods: Participants were 43 (46.5% female, 18–25 years) emerging adults: 21 NIAAA low-risk
drinkers and 22 drinkers meeting criteria for DSM-IV-TR alcohol dependence (i.e., AUD). The neu-
roimaging paradigm included a 5-min exposure to visual alcohol cues followed by a 6-min resting-
state scan. Resting-state fMRI data were preprocessed and analyzed using FSL and AFNI.
Data: We employed independent components analysis to identify the CEN and restricted analyses
to 5 core anatomical regions to reduce multiple comparisons: bilateral dorsolateral prefrontal cortex
(dlPFC), bilateral posterior parietal cortex (PPC), and the paracingulate gyrus (PCG). To determine
rsFC between regions, we extracted mean time series and calculated Pearson correlations. Two-
sample t-tests identified group differences in rsFC strength between the low-risk and AUD groups,
and Pearson correlations determined relationships between rsFC and alcohol use behaviors.
Results: The AUD group exhibited significantly greater rsFC (D = 0.672, moderate effect size)
between the right dlPFC and right PPC (t(41) =
2.21, p < 0.05). The AUD group exhibited less
rsFC (D = 0.510, moderate effect size) between the left PPC and the PCG compared to low risk drin-
kers, although this difference did not reach statistical significance. Connectivity between the left PPC
and PCG had significant (p < 0.05) negative correlations with past year quantity and frequency of
alcohol use and past month frequency of alcohol use and number of binge drinking episodes.
Conclusions: Our results support previous findings that decreased frontoparietal rsFC of the left,
but not right CEN is associated with AUD and drinking behaviors. Our result of increased frontopari-
etal rsFC within the right CEN in the AUD group is novel and may indicate priming for greater cogni-
tive allocation towards alcohol cues following cue exposure. Together, these findings suggest
alcohol may have neurotoxic effects on the CEN by early adulthood.
72
EXECUTIVE CONTROL NETWORK IN COLLEGE BINGE DRINKERS
pez-Caneda, A. Sampaio
A. Crego, S.S. Sousa, P. Marques, O.F. Goncßalves, E. Lo
School of Psychology, University of Minho, Braga 710-057, Portugal
Purpose: Neuronal communication tuning and tissue organization are major neuromaturational pro-
cesses that occur between adolescence and early adulthood having an impact on higher order cog-
nitive processes. In fact, the structural and functional immaturity observed in this developmental
stage has been associated to imbalanced circuit level interactions, leading to a diminished profi-
ciency of the inhibitory system and adolescents more prone to take risky choices such as binge
drinking (BD). Although recent studies have highlighted the role of the executive control network
(ECN) in self-regulatory processes, the characterization of the ECN functional connectivity in young
binge drinkers (BDs) is still scarce. Therefore, considering that BD is associated with diminished self-
control, we hypothesized altered functional connectivity within the ECN in a pre-clinical sample of
young binge drinkers (BDs).
Methods: Herein we assessed the architecture of the resting state networks (RSNs) brain func-
tional connectivity using functional magnetic resonance imaging (fMRI) in a group of 34 college stu-
dents, 20 BDs and 14 alcohol abstinent controls (AACs) by analyzing a task-positive network – the
executive control network (ECN).The resting state fMRI acquisition was performed using a blood
oxygen level dependent (BOLD) sensitive echo-planar imaging (EPI) with the following parameters:
39 interleaved axial slices, repetition time (TR) = 2,000 ms, echo time (TE) = 29 ms, flip angle
(FA) = 90°, slice thickness = 3, slice gap = 3.75 mm, in-plane resolution = 3 9 3 mm2, field of
view (FoV) = 222 mm and 210 volumes.
Data: Resting state fMRI data preprocessing procedures were applied using FMRIB Software
Library (FSL v5.07; http://fsl.fmrib.ox.ac.uk/fsl/) tools. Independent Component Analysis (PICA) was
performed with MELODIC (Multivariate Exploratory Linear Optimized Decomposition into Indepen-
dent Components). For statistical analysis, two-way analysis of variance was performed. Gender
and group were included as between subject factors and age as covariate.
Results: Increased activation of the left middle frontal region of the ECN at rest was observed in the
BDs group, when compared with the AACs group.
Conclusions: These results suggest alterations of functional connectivity in the BDs within the
ECN, which may be related to abnormal self-regulatory processes in BDs.
ABSTRACTS-SPEACKERS
SUNDAY, JUNE 17 3:10PM–4:40PM
SYMPOSIUM 73–76
Alcohol-Involved Sexual Assault: Novel Perspectives From Laboratory Studies
Organizers/Chairs: Anna Jaffe and Christine Hahn
73
THE ROLES OF ALCOHOL, EMOTIONAL AROUSAL, AND EMOTION REGUATION ON MEN’S
SELF-REPORTED SEXUAL ASSAULT PERPETRATION INTENTIONS
E.C. Neilson, K.C. Davis, J. Norris, W.H. George
Department of Psychology, University of Washington, Seattle, WA 98195, USA
This study used an alcohol administration paradigm and examined the effects of emotional arousal
and emotion regulation on the association between alcohol and self-reported likelihood to perpetrate
sexual assault against a casual sexual partner. It was hypothesized that emotional arousal would
mediate the association between alcohol and sexual assault. It was further hypothesized that emo-
tion regulation would moderate the alcohol – emotional arousal – sexual assault perpetration associ-
ations. Single, moderate- to heavy-drinking men (N = 100) were randomly assigned to a drink
condition [control or alcohol (BAC .10 gm%)] and then projected themselves into a sexual assault
scenario. Men’s emotional arousal and emotion regulation during the sexual assault scenario were
assessed via self-report and two biomarkers: respiratory sinus arrhythmia and galvanic skin
response reactivity. Men then reported their intentions to perpetrate various sexual assault behaviors
against the hypothetical female partner. Moderated mediation using ordered probit analyses with
maximum likelihood estimation was conducted to test the hypotheses. Results and conclusions will
emphasize the translational applications of these findings to prevent and intervene in sexual assault
perpetration. This study adds to the current literature by examining the mediating and moderating
effects of emotional arousal and emotion regulation, assessed through both self-report and biomark-
ers, in the context of acute alcohol intoxication.
74
ALCOHOL-RELATED SEXUAL ASSAULT: A CONTROLLED LABORATORY-BASED
INVESTIGATION OF INTOXICATED BYSTANDERS
L.S. Ham, A.J. Melkonian, J.D. Wiersma-Mosley, K.N. Jozkowski, A.J. Bridges, The Alcohol and
Bystander Intervention Research Group
Department of Psychological Science, University of Arkansas, Fayetteville, AR 72701, USA
Alcohol-related sexual violence continues to be a significant public health problem. Despite the popu-
larity of bystander intervention programs to prevent sexual assault, these programs may be limited in
addressing bystander intoxication because the effects of bystander intoxication on intervening in a
sexual assault are unknown. This NIAAA-funded experiment addressed this gap by examining the
effects of alcohol intoxication on the five steps of bystander intervention in a sexual assault. Young
adults (N = 28; 50% women) were randomly assigned to consume alcohol (target BAC = 0.08%;
n = 64) or a non-alcoholic control beverage (n = 64) in a simulated bar-lab. Next, participants were
presented with a sexual assault vignette involving a convivial drinking context in which the perpetra-
tor was sober and the victim was intoxicated. The different steps of Latane and Darley’s (1970)
bystander intervention model were then assessed in an interview. Results suggest alcohol impair-
ment in the early steps related to risk detection, but not the later steps (i.e., taking responsibility for
intervening; being willing and able to intervene effectively) of bystander intervention. Step 1 (noticing
the event): compared to sober participants, intoxicated participants overestimated perpetrator intoxi-
cation and underestimated the victim’s intoxication. Step 2 (interpreting the situation as risky and
requiring intervention): participants in the alcohol group reported the situation as less uncomfortable,
less likely to be a sexual assault, and perceived less need for intervention than those in the control
group. Gender did not moderate the effects of intoxication on the bystander intervention steps.
Together, findings suggest that alcohol-related violence prevention programs should consider alco-
hol’s effects on detecting a sexual assault and identifying the need to intervene. If intoxicated bystan-
ders do not detect a sexual assault, then the bystander will not reach the critical steps required to
effectively intervene.
289A
75
PERITRAUMATIC ALCOHOL INTOXICATION AND INTRUSIVE MEMORIES OF A TRAUMA
FILM: IMPLICATIONS FOR ALCOHOL-INVOLVED SEXUAL ASSAULT
A.E. Jaffe, D. DiLillo
Department of Psychology, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
Although sexual assault often occurs when victims are under the influence of alcohol—and acute
intoxication has the potential to impact risk factors for intrusive memories (e.g., via cognitive process-
ing, stress response)—the influence of peritraumatic (i.e., at the time of assault) alcohol intoxication
on post-assault trauma symptoms is not well understood. To address this issue, the current study uti-
lized an experimental design involving lab-based alcohol administration (high dose of 0.72 g/kg, low
dose of 0.36 g/kg, and a placebo beverage). Participants were 98 community women (ages 21–30
without a personal history of victimization) who consumed their randomly assigned beverages,
viewed a trauma film depicting a sexual assault, then reported film-related intrusive memories via a
smartphone app during the subsequent week. Controlling for days of diary completion, participants
in the high dose group reported the highest number of intrusive memories (Madjusted = 7.42,
SE = 0.89) compared to placebo (Madjusted = 5.28, SE = 0.56), p = 0.044, with the low dose condi-
tion (Madjusted = 5.60, SE = 0.89) falling in between. Mechanisms underlying the effect of alcohol on
intrusions were examined, including alcohol myopia (via a novel free recall task) and stress response
(via heart rate reactivity). Structural equation models revealed marginally significant indirect effects
for proposed mechanisms. Implications for the influence of alcohol on intrusive memories via alcohol
myopia and stress response will be discussed.
76
REMEMBERING RAPE: THE EFFECTS OF ACUTE ALCOHOL INTOXICATION AND ALCOHOL
EXPECTANCIES ON WOMEN’S MEMORY FOR FORENSIC INFORMATION IN RAPE
SCENARIOS
H.D. Flowe, L.L. Smith
School of Psychology, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
This study tested the effects of alcohol-intoxication on how accurately women remember forensically
relevant information from a hypothetical rape scenario. A balanced placebo design was employed,
with participants (N = 78) randomly assigned to alcohol dose (0.00% vs. 0.075% BAC) and alcohol
expectancy (told tonic vs. told alcohol) conditions. Memory was tested seven days later. Mean mem-
ory accuracy was higher for information about pre-assault consensual sexual activities compared to
the perpetrator’s actions during the offense (M = 86% [CI0.95: 81–89%] vs. M = 51% [CI0.95: 46–
56%]). Mean memory accuracy was higher if women expected to consume alcohol rather than tonic
water (M = 72% [CI0.95: 67–77%] vs. M = 65% [CI0.95: 60–70%], respectively), suggesting alcohol
expectancy led to hypervigilance during encoding. Consuming alcohol compared to tonic water did
not affect memory accuracy for consensual sexual activities (M = 86% [CI0.95: 80–91%] vs.
M = 86% [CI0.95: 81–89%], respectively) or for the perpetrator’s actions (M = 47% [CI0.95: 39–54%]
versus M = 55% [CI0.95: 48–63%], respectively). Calibration analyses indicated that accuracy
increased with confidence level, regardless of intoxication level or alcohol expectancy condition, but
that women tended to be overconfident in general. Implications and limitations of the research will be
discussed.
290A
MONDAY, JUNE 18 9:15AM–10:45AM
SYMPOSIUM 77–80
HIV and Alcohol Co-Morbidities: Multi-Organ Injury
Organizers/Chairs: Natalia Osna and Kusum Kharbanda
77
BLOOD BRAIN BARRIER (BBB) INJURY IN ALCOHOL ABUSE, NEUROINFLAMMATION AND
HIV-1 CNS INFECTION: MECHANISMS AND PROTECTIVE STRATEGIES
Y. Persidsky
Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University,
Philadelphia, PA 19140, USA
Purpose of the study: To investigate the role of neuroinflammation and BBB impairment in the set-
ting of HIV infection and alcohol abuse.
Methods: We studied injury mechanisms after alcohol exposure using in vitro BBB models (primary
human brain endothelial cells, BMVEC) and in vivo [NOD severe combined immunodeficient (SCID)
mice reconstituted with human peripheral blood lymphocytes (PBL), hu-PBL-NOD-SCID], and
encephalitis induced by intracranial injection of autologous HIV-1 infected monocyte-derived macro-
phages. Elimination of HIV-1+ macrophages by virus-specific cytotoxic T lymphocytes and viremia
were previously demonstrated by our group in this model.
Results: Using pathophysiologically relevant ethanol concentrations, we showed rapid decrease in
BBB integrity in vitro and enhanced migration of monocytes across barrier models. We demonstrated
that molecular mechanisms of BBB disruption by alcohol included alcohol metabolism in BMVEC
causing oxidative stress, Ca2+ release, activation of myosin light chain kinase, phosphorylation of
tight junction proteins, and activation of metalloproteases (MMP-1 and MMP-9). Similar mechanisms
of BBB injury were documented by us using stimuli relevant to HIV infection. Next, we used hu-PBL-
NOD-SCID mice fed with an ethanol-containing diet. We showed that alcohol feeding resulted in
increased viremia, diminished anti-viral immune responses associated with signs of oxidative stress
resulting in increased levels of HIV-1 infected macrophages in the brain. We found increased micro-
glial activation in an animal model for HIV encephalitis (HIVE) that was further enhanced by alcohol
exposure. Despite widely acknowledged inhibitory effects of ethanol in vivo on leukocyte migration in
alcohol-treated animals, alcohol did not affect the amount of T cell brain infiltration in the HIVE model.
Rather, the immunosuppressive effects of alcohol were mediated by impaired immune responses
secondary to oxidative stress and dysfunction of immunoproteasomes playing an important role in
antigen presentation. We also found diffuse microglial activation affecting gray and white matter in
the brain tissues of patients with a history of alcohol abuse as compared to control brain tissues
(without alcohol exposure) as well as in HIV-infected tissue with or without anti-retroviral therapy.
Such changes in human brains were accompanied by signs of BBB injury.
Conclusion: Diminution of neuroinflammation constitutes a logical approach for prevention of HIV-
1 and alcohol mediated neurodegeneration.
78
HIV AND ALCOHOL INDUCE EXTRACELLULAR VESICLES RELEASE: CONTRIBUTION TO
LIVER INFLAMMATION
M. Ganesan1,2, R.S. Dahur1,2, E. Makarov1,2, S. Kidambi1,2, L. Poluektova1,2,N. Osna1,2
1
Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE,
USA and 2Department of Internal Medicine University of Nebraska Medical Center, Omaha, NE
68105, USA
There is a high rate of alcohol consumption in HIV-infected people. Heavy drinking influences HIV
progression, adherence to therapy and outcomes. In a new era of improved patient survival, new
players, such as hepatobiliary disorders and liver injury has become a major cause of mortality in
HIV-infected persons, even regardless the side-effects from antiretroviral therapy (ART). This study
is focused on the mechanisms by which alcohol exacerbates HIV-induced liver damage. Here, we
hypothesize that ethanol promotes apoptosis in HIV-pre-sensitized hepatocytes and induces extra-
cellular vesicles release; the engulfment of these extracellular vesicles (apoptotic bodies, AB and
exosomes, Exo) by non-parenchymal cells, macrophages and hepatic stellate cells (HSC), promotes
inflammation and fibrosis development. For these studies, primary human hepatocytes (HH) plated
on 2D synthetic soft gel that preserves their ethanol-metabolizing capacity, monocyte-derived human
macrophages (MDM) and LX-2 HSC were used. Ethanol treatment suppressed total HIV DNA in
HH, but increased HIV DNA integration into human genome. We observed increased caspase 3
cleavage in HIV-infected HH exposed to ethanol. The combination of HIV and ethanol also induced
the highest Exo release. Engulfment of AB by MDM enhanced activation of inflammasome, based
on mRNA induction of receptor NLRP3, caspase 1, IL-1b, IL-18 and other pro-inflammatory cytoki-
nes (IL-6, TNFa, IL-8). Treatment of HH with ART reversed inflammatory effects of AB on MDMs,
indicating the involvement of pathogen-associated molecular pattern (PAMP) signaling. We con-
clude that ethanol stresses HIV-infected HH causing exosome release and promoting apoptosis,
thereby initiating macrophage-dependent inflammation in the liver.
ABSTRACTS-SPEACKERS
79
ALCOHOL- AND HIV-INDUCED INTESTINAL PERMEABILITY: RELEVANCE TO IMMUNE
DYSFUNCTION
S. Ghare, S. Joshi-Barve, P. Peyrani, C. McClain, S. Barve
Department of Medicine, Alcohol Research Center, University of Louisville, Louisville, KY 40202,
USA
Background: Excessive alcohol consumption and human immunodeficiency virus type 1 (HIV-1)
infection frequently occur together and are associated with dysregulated immune responses. Both
chronic alcohol abuse and HIV-1 infection induce alterations in gut microbiome (dysbiosis) and
cause an increase in intestinal permeability and microbial translocation (MT). Importantly, gut-
derived microbial antigens are major pathogenic drivers of local and systemic inflammation and
immune dysfunction. Further, the depletion and loss of function of CD4+ T lymphocytes are key com-
ponents of alcohol and HIV-1 associated immune suppression. The present study investigates the
alcohol- and HIV- induced gut barrier dysfunction and its negative impact on immune responses, par-
ticularly on CD4+ T lymphocytes.
Method: Plasma samples from alcoholic and HIV-1-infected patients were evaluated for intestinal
permeability and microbial translocation markers. The concentrations of different cytokines and
chemokines were measured using multiplex kits. Additionally, freshly isolated CD4+ T lymphocytes
from alcoholic and HIV-1 infected subjects were used to investigate the epigenetic mechanisms
underlying alcohol- and HIV- induced CD4+ T cells dysfunction by examining histone modifications
at the promoters of two critical genes IL-2 and FasL.
Results: Our data showed that the plasma concentrations of markers of gut barrier damage
(iFABP) and monocyte activation (sCD14 and sCD163) were significantly higher in HIV infected indi-
viduals when compared to the healthy controls. Among HIV-1 infected individuals, iFABP showed a
strong positive correlation with markers of systemic inflammation- sCD14 and TNF-a (an inflamma-
tory cytokine) whereas showed a negative correlation with CD4+ T lymphocytes indicating immune
dysfunction. Importantly, data showed that compared to non-alcoholic individuals, alcoholic individu-
als had higher plasma iFABP and sCD14 levels suggesting that alcohol abuse increases microbial
translocation in HIV-1 infected individuals. Notably, the data showed that alcohol and HIV-1 infection
induced immune dysfunction involves differential promoter histone modifications at FasL and IL-2
promoters leading to aberrant gene expression in primary CD4+ T lymphocytes.
Conclusion: The present work suggests that alcohol- and HIV- induced gut barrier dysfunction con-
tributes to aberrant immune activation and dysregulated CD4 + T lymphocyte function, which can
potentially exacerbate the pathogenesis of HIV-1 infection.
80
ALCOHOL-SIV/HIV-ART INTERACTIONS & RESULTING COMORBIDITIES
P.E. Molina, A.A. Duplanty, R.W. Siggins, L. Simon
Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences
Center, New Orleans, LA 70112, USA
Alcohol use disorders (AUD) are common in people living with HIV/AIDS (PLWH). Increased survival
resulting from antiretroviral therapy (ART) has elevated the risk for comorbid conditions, arising from
both chronic alcohol consumption and HIV infection, including myopathy, insulin resistance, predia-
betes, and lipodystrophy. Mitochondrial dysfunction can significantly contribute to chronic alcohol,
human immunodeficiency virus (HIV) and antiretroviral therapy (ART)-mediated decreases in skele-
tal muscle (SKM) functional mass. We have previously demonstrated that chronic binge alcohol
(CBA) induces mitochondrial gene dysregulation in non-ART-treated SIV-infected macaques at end-
stage disease. The aim of this study was to determine the interaction of CBA and ART on SKM fiber
oxidative capacity and mitochondrial respiration during the asymptomatic stage of SIV-infection.
Myoblasts were isolated from muscle at 11 months post SIV infection from CBA/SIV/ART+ and from
time matched sucrose-treated SIV-infected (SUC/SIV/ART+) macaques and age-matched controls.
Mitochondrial respiration was determined using Seahorse XF analysis. To determine if an exercise
mimetic can improve mitochondrial function, myoblasts were also treated with formoterol, a b2
adrenergic agonist. Our results indicate that CBA and ART decreased succinate dehydrogenase
(SDH) activity in type 1 and type 2b fibers. Additionally, myoblasts isolated from CBA/SIV/ART+
macaques had decreased maximal oxygen consumption rate (OCR) compared to myoblasts iso-
lated control and SUC/SIV/ART+ myoblasts. Formoterol increased PGC-1a expression, mtDNA
quantity, and maximal OCR in control myoblasts. Additionally, formoterol treatment of myoblasts iso-
lated from CBA/SIV/ART+ macaques was able to rescue the decreased maximal OCR. In summary,
chronic binge alcohol administration impairs skeletal muscle mitochondrial function in SIV infection.
The study also provides evidence that exercise or an exercise mimetic can potentially ameliorate
mitochondrial dysfunction due to alcohol and ART in SIV/HIV.
ABSTRACTS-SPEACKERS 291A

MONDAY, JUNE 18 9:15AM–10:45AM 83

SYMPOSIUM 81–84
Medications to Treat Alcohol Use Disorder (AUD): From Computer to Bench
to Bedside
Organizer/Chair: Robert Messing
Chair: Lorenzo Leggio
81
USING TRANSCRIPTOMICS TO IDENTIFY CANDIDATE DRUGS FOR REPURPOSING TO
TREAT AUD
L.B. Ferguson, R.A. Harris, R.O. Messing, I. Ponomarev, R.D. Mayfield
Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX
78712, USA
Alcohol Use Disorder (AUD) is a chronic, relapsing disease that is a major public health problem.
Though recovery is possible, there are few pharmaceutical treatments available to aid in the recovery
process. Drug repurposing (finding novel clinical use for an approved drug) and drug rescue (finding
clinical use for a stalled drug; Phase 2 or beyond) are appealing since they reduce overall costs of drug
development and expedite treatment to patients. Drug repurposing has been serendipitous and
dependent on side effect observation. While this approach has been somewhat successful for brain
diseases, there is need for improved strategies. Systems-based computational strategies that inte-
grate gene expression signatures of pharmaceuticals and disease states have shown promise for
identifying compounds that treat disease symptoms (called in silico gene mapping or connectivity map-
ping) (Lamb et al., 2006). In silico gene mapping compares the gene expression signatures of disease
and pharmaceuticals to find compounds (or combination of compounds) that oppose the disease-
state’s molecular disruption. The basis of the compound selection algorithm is that the compounds with
signatures that oppose that of the disease state will “correct” the biological functions of the system and
ameliorate disease phenotype. After describing the steps for in silico gene mapping for drug repurpos-
ing, I will review successful, state-of-the-art applications of these approaches to brain diseases, includ-
ing the identification of novel compounds, terreic acid and pergolide, that reduced ethanol drinking in a
genetic mouse model of binge-like drinking (Ferguson, Ozburn et al., Neuropsychopharmacology, in
press). We constructed gene network signatures using brain gene expression data from two genetic
rat models of AUD and their controls (alcohol-preferring (P)/non-preferring (NP) rats; High Alcohol
Drinking (HAD-1)/Low Alcohol Drinking (LAD-1) rats). Using these signatures, our drug selection algo-
rithm identified several novel compounds that could decrease ethanol intake or preference in these lines,
including an anti-inflammatory compound, actarit, for P rats and several HDAC inhibitors for HAD rats. I
conclude by highlighting critical challenges that must be overcome for transcriptome-based drug discov-
ery to reach its full potential for AUD and other psychiatric illnesses. We suggest that, although still in its
infancy, in silico gene mapping can successfully guide drug discovery and repurposing efforts for AUD.
PRECLINICAL AND CLINICAL EVIDENCE OF GLUCOCORTICOID RECEPTOR ANTAGONISTS
AS POTENTIAL NEW MEDICATIONS FOR ALCOHOL USE DISORDERS
L.F. Vendruscolo, B. Mason, G.F. Koob
Neurobiology of Addiction Section, NIH/NIDA – IRP/INRB, Baltimore, MD 21224, USA
Alcoholism is a major public health concern for which more effective treatments are urgently needed.
Chronic alcohol consumption and withdrawal disrupt glucocorticoid receptor (GR) signaling at multi-
ple physiological levels. Our hypothesis is that overactivation of the hypothalamic-pituitary-adrenal
(HPA) axis by alcohol intoxication and withdrawal leads to a GR-mediated cascade of stress activa-
tion and ultimately a hypofunctional reward system and hyperfunctional brain stress systems. These
changes contribute to negative emotional states that drive compulsive alcohol drinking. In a rat
model of alcohol dependence, rats were made dependent on alcohol via chronic, intermittent alcohol
vapor exposure. Glucocorticoid receptor expression and function were altered in cortical and subcor-
tical brain regions in dependent rats compared with nondependent rats. Systemic, intra-central
nucleus of the amygdala, intra-ventral tegmental area, and intra-nucleus accumbens GR antagonism
with mifepristone blocked the development of alcohol dependence and/or reversed dependence-
induced increases in alcohol drinking during acute withdrawal and protracted abstinence. Using
selective compounds, we found that the reduction of alcohol drinking was mediated by GR antago-
nism and not by progesterone receptor antagonism. The effect of GR antagonism was specific to
alcohol, given that the intake of sweetened water was unaffected by GR blockade. We tested various
GR antagonists and found a range of efficacy on alcohol drinking, indicating the complexity of GR-
mediated effects. These preclinical discoveries encouraged us to conduct a human laboratory study
with non-treatment-seeking individuals with alcohol use disorders. Seven days of mifepristone treat-
ment significantly reduced craving for alcohol and alcohol consumption compared with individuals
who received placebo. In conclusion, these preclinical and clinical findings support a key role for GR
signaling in driving increased alcohol drinking in alcohol dependence. Glucocorticoid receptor antag-
onists may constitute a potential novel pharmacotherapy for alcohol use disorders.
84
MEDICATION DEVELOPMENT EFFORTS FOR ALCOHOL USE DISORDER VIA NOVEL GUT-
BRAIN NEUROENDOCRINE PATHWAYS
L. Leggio1,2
1
Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, NIAAA DICBR
and NIDA IRP, National Institutes of Health, Bethesda, MD 20892, USA and 2Brown University,
Center for Alcohol and Addiction Studies, Providence, RI 02912, USA
The reward properties of natural and chemical reinforcers are mediated via multiple and complex
pathways in the brain. There is an underlying disruption in reward processing in animal models of
addictions and individuals with alcohol and drug use disorders. This raises the possibility that endo-
crine signals from the gut traditionally known to regulate appetite and food intake may play an impor-

82 tant role in reward regulation as well as in development of alcohol use disorder (AUD), therefore
representing promising novel targets towards medication development. Dr. Leggio will present
recent human data on the stomach-derived hormone ghrelin in AUD. Preliminary clinical studies indi-
TWO BIRDS WITH ONE STONE: ALLOSTERIC MODULATORS OF NICOTINIC
cate that there is a relationship between endogenous blood ghrelin levels and drinking status and
ACETYLCHOLINE RECEPTORS FOR THE TREATMENT OF AUD
craving for alcohol in patients with AUD. A double-blind placebo-controlled human laboratory study
J. Wang, H.L. Chapman, J. Lindstrom, T.M. Kamenecka, P.J. Kenny, R.O. Messing
demonstrated, for the first time, that intravenous administration of exogenous ghrelin resulted in
Division of Pharmacology and Toxicology, Department of Neuroscience, University of Texas at
acute increase of cue-induced alcohol craving in a bar-lab setting. More recently, another double-
Austin, Austin, TX 78712, USA
blind placebo-controlled human laboratory study indicated that intravenous administration of exoge-
Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, nous ghrelin results in increased alcohol self-administration and differentially modulates brain activity
Philadelphia, PA 19104, USA during alcohol versus food cues while patients are performing a fMRI-based reward task (data in
Purpose: There is the potential to develop medications that target nicotinic acetylcholine receptors press). Additionally, unpublished data will be presented on how pharmacological manipulations of
(nAChRs) to treat alcohol use disorder (AUD) because the agonist, varenicline (Chantixâ), the most ghrelin signaling may result in changes in other gut-brain neuroendocrine pathways and the signifi-
effective drug for smoking cessation, reduces alcohol consumption and craving. However, its effective- cance of these results will be discussed. Altogether, these findings suggest that blocking the ghrelin
ness is limited by side effects, such as nausea, insomnia and increased signs of ethanol intoxication. receptor may be a novel pharmacological approach to treat AUD. Specific to this discussion, two sets
The goal of this study is to develop positive allosteric modulators (PAMs) of nAChRs that are as effec- of unpublished data will be presented: (1) recent ongoing efforts toward the development of a novel
tive as varenicline but avoid its side effects. PAMs have greater therapeutic potential than agonists and ghrelin receptor knock-out rat model; and (2) recent human preliminary data testing a novel ghrelin
antagonists because they do not constantly activate or inhibit nAChRs, and because they are more receptor inverse agonist in individuals with AUD. Together, this line of research supports additional
selective. Varenicline is a potent partial agonist for a4b2 nAChRs. This most prevalent neuronal sub- efforts aimed to investigate whether the ghrelin system may represent a novel potential target for
type includes two stoichiometric forms, (a4)2(b2)3 and (a4)3(b2)2. Little is known about their roles in medication development for AUD.
alcohol responses. Our development of PAMs mainly focuses on these two stoichiometric forms.
Method: To test whether targeting one stoichiometric form is sufficient, we used a known PAM
selective for (a4)3(b2)2 nAChRs. Using C57BL/6J mice, we studied its effect on ethanol consumption
(an intermittent access 2-bottle choice procedure), ethanol intoxication (loss of the righting reflex—
LORR, accelerating rotarod performance) and clearance. To develop new PAMs with different phar-
macological profiles, we used an in vitro high throughput assay, ligand-based structure activity rela-
tionship study, and protein-based molecular modeling and docking.
Results: We found that administration of 10 mg/kg NS9283 significantly reduced ethanol intake in
male mice by 29% in the initial three hours, which was similar to 2 mg/kg varenicline. Additionally,
subthreshold doses of NS9283 (2.5 mg/kg) and varenicline (0.1 mg/kg) synergized to reduce etha-
nol drinking. Unlike varenicline (2 mg/kg), neither NS9283 (10 mg/kg) nor NS9283 (2.5 mg/kg) with
varenicline (0.1 mg/kg) altered ethanol-induced LORR, rotarod performance, or ethanol metabolism.
In vitro, NS9283 increased sensitivity of (a4)3(b2)2nAChRs to activation and desensitization by
varenicline. Besides NS9283, we identified three a4b2 selective PAMs that differently potentiate the
activation and desensitization of (a4)2(b2)3 and (a4)3(b2)2 nAChRs. Their effects on ethanol related
behaviors are to be determined.
Conclusion: In addition to treating nicotine addiction, a4b2 nAChR PAMs could be new therapeu-
tics, with fewer side effects than varenicline, for the treatment of excessive drinking.
292A
MONDAY, JUNE 18 9:15AM–10:45AM
SYMPOSIUM 85–88
Efficacy of Social Network-Based Intervention Approaches for Hazardous
Alcohol Use and Problem Behavior: Innovative Applications in Varied
Populations
Organizer: Graham DiGuiseppi
Chairs: Nancy Barnett and Matthew Meisel
85
ENLISTING PEER COOPERATION IN THE SERVICE OF ALCOHOL USE PREVENTION IN
MIDDLE SCHOOL
M.J. Van Ryzin, C.J. Roseth
Oregon Research Institute, 1776 Millrace Eugene, OR 97403, USA
We propose a new approach to prevention of adolescent alcohol use that leverages theory and
research on the role of peer influence. Escalation in alcohol use has been linked to the process of
deviant peer clustering, whereby socially marginalized youth self-aggregate and reinforce antisocial
behavior, including alcohol use. If the process of deviant peer clustering could be interrupted and at-
risk youth could be provided with the opportunity to develop relationships with lower-risk youth, then
these relationships could confer a degree of protection by providing a context in which prosocial
(rather than antisocial) behavioral norms are transmitted. We attempted to counteract the process of
deviant peer clustering through the implementation of collaborative learning activities in school,
which we hypothesized would give at-risk students the opportunity to develop new friendships,
reduce social alienation and rejection, and interrupt the process of deviant peer clustering. We pro-
vided periodic training for middle school staff in cooperative learning, a set of techniques that teach-
ers can use to create their own collaborative learning activities using existing curricula. Cooperative
learning has been found to have strong effects on academic engagement and achievement, but has
not yet been tested as a prevention strategy targeting social and behavioral problems among adoles-
cents.
In a cluster randomized trial using 15 middle schools in Oregon, we found significant reductions in
alcohol and tobacco use and self-reported deviant peer affiliation. We also found significant differ-
ences in peer networks, such that students in intervention schools reported lower levels of alcohol
and tobacco use in their friendship networks compared to students in control schools; this difference
in friendship networks, in turn, mediated intervention effects on participant alcohol and tobacco use,
respectively. These findings suggest that the process of deviant peer clustering was occurring at a
lower rate in intervention schools as compared to control schools. Given that cooperative learning
does not require the purchase of expensive curricula or materials, and does not require the sacrifice
of instructional time (unlike existing curriculum-based social-emotional learning or substance use/
bullying prevention programs), it can be a win-win prevention strategy for schools that can promote
academic engagement and achievement while simultaneously addressing the peer processes that
can lead to alcohol use.
86
EXAMINING SPILLOVER EFFECTS OF A BRIEF MOTIVATIONAL INTERVENTION TO REDUCE
ALCOHOL CONSUMPTION AND HARMS IN A SOCIOCENTRIC FIRST-YEAR COLLEGE
STUDENT
N.P. Barnett, G. DiGuiseppi, M. Meisel, S. Balestrieri, M. Ott, J. Light, M. Clark
Center for Alcohol and Addiction Studies, Brown University, Providence, RI 02905, USA
Heavy alcohol use is a serious public health issue among young adults, with college students resid-
ing on campus showing the highest rates of hazardous use. Peer relationships are a primary source
of influence on alcohol use, but interventions utilizing peer social networks to induce change in heavy
drinking have not been developed for college student populations. The primary purpose of this inves-
tigation was to examine the efficacy of a Brief Motivational Intervention (BMI) to produce a “spillover”
or indirect effect on the alcohol use of BMI recipients’ social ties. We also investigated hypothesized
social influence mechanisms whereby BMI recipients might influence their friends, and change in
network ties themselves as a function of the intervention.
Method: First-year students (N = 1,313; 81% enrollment of the class) from one college completed
a survey on alcohol use and nominated up to 10 other first-year students as friends. BMI and control
groups were established according to the geography of first-year residences. Influential network
members were selected (n = 71 BMI, n = 74 control), BMI recipients received BMI shortly after
baseline, and follow-up surveys were completed five months later.
Results: BMI recipients showed steeper reductions in alcohol consumption over time, compared to
control. There was also evidence of an indirect effect of the BMI (compared to control) on drinks per
week among heavy drinkers who did not receive the intervention. Evidence of social influence mech-
anisms were found in that BMI recipients’ close friends perceived a change in BMI recipients’ drink-
ing (relative to controls), and the more close friends perceived heavy drinking and approval of heavy
drinking among the intervention recipients, the more the friends drank. Furthermore, social network
ties changed significantly as a function of the intervention: BMI recipients’ heavy drinking friends
were more likely to drop ties with other heavy drinkers in the network, suggesting the BMI reduced
homophily on heavy drinking in the network.
Conclusions: Results provide modest support for an indirect effect of a BMI on heavy drinkers who
received no intervention. Implications for possible mechanisms of social influence within networks
and the potential for networks themselves to change as a result of intervention are particularly com-
pelling.
ABSTRACTS-SPEACKERS
87
A MOTIVATIONAL INTERVIEWING SOCIAL NETWORK INTERVENTION TO REDUCE
SUBSTANCE USE AMONG HOUSING FIRST RESIDENTS
D.P. Kennedy, K.C. Osilla, S.B. Hunter, D. Golinelli, E. Maksabedian, J.S. Tucker
RAND Corporation
This presentation will demonstrate findings of a pilot test of a Motivational Interviewing social network
intervention (MI-SNI) to enhance motivation to reduce high risk alcohol and other drug (AOD) use
among formerly homeless individuals transitioning to living in a Housing First program. New Housing
First residents must negotiate complicated shifts in their social environments, including breaking
some ties with network connections who remain living on the street while maintaining ties with others,
making new connections with some residents but not others, and re-connecting with network ties that
were not maintained during homelessness. These residents must negotiate these complicated social
shifts while also striving to reduce their own AOD use in an environment where AOD abstinence is
not a requirement to maintain housing. Delivered in-person by a facilitator trained in MI, this four-ses-
sion computer-assisted intervention provides personalized social network visualization feedback to
help participants understand the people in their network who trigger their alcohol and other drug
(AOD) use and those who support abstinence. If ready, participants are encouraged to make
changes to their social network to help reduce their own high-risk behavior. Participants were 41 indi-
viduals (33 male, 23 African-American) who were transitioning from homelessness to permanent
supportive housing. They were randomly assigned to either the MI-SNI condition plus usual perma-
nent supportive housing services or usual care only. Results demonstrate that intervention partici-
pants rated the intervention as highly acceptable and had significantly higher readiness to change,
abstinence self-efficacy, and decreased alcohol use compared to controls receiving usual care after
3 months, controlling for baseline measures. This presentation extends these findings by investigat-
ing the role that changes in social networks played in facilitating changes in substance use and
enhancement of motivation to change. Intervention recipients reported fewer and less central risky
network contacts, including fewer drinking partners and fewer risky network members who were also
supportive compared to controls. Analysis of qualitative data highlight strategies that intervention
recipients develop to distance themselves from social contacts that trigger substance use. These
results suggest that providing visual network feedback with a guided motivational interviewing dis-
cussion is a promising approach for supporting behavioral change by triggering changes in social
networks.
88
MOBILIZING DRUG-FREE SUPPORT AND MODIFYING SOCIAL NETWORK TIES USING
CLOSE NETWORK SUPPORTS
M.S. Kidorf
Johns Hopkins University School of Medicine, Baltimore, MD, USA
Aims: People with opioid dependence (PWOD) are often embedded within social networks that
reinforce continued alcohol and other drug (AOD) use and risk behaviors. It is important to recognize
that these individuals have drug-free family or friends in their personal social networks, assets that
are greatly underutilized in recovery efforts. We are conducting two 12-week studies to evaluate the
preliminary feasibility and efficacy of a novel intervention that activates a drug-free network member
and enlists their participation (with the PWOD) in a community support group.
Methods: In Study 1 (single group design), PWODs are recruited from a community syringe
exchange. In Study 2 (randomized trial), PWODs are recruited from a methadone maintenance pro-
gram. In both studies, the PWOD attends a weekly community support group with a drug-free family
or friend (verified via urinalysis). The dyads are scheduled to participate together in weekly commu-
nity activities (e.g., self-help groups, church) to further expand drug-free social support and facilitate
network change for the PWOD. These efforts are reviewed at each group session, using role plays
to enhance participation and engagement. Primary outcomes for each study are rates of AOD use
and changes in social support and social network variables.
Results: Data collection is ongoing for both studies. For Study 1, 18 PWODs (and their network
supports) have attended at least one group. Support persons are most often friends (44%) or parents
(28%). PWODs and their supports have attended 64% of scheduled sessions, and have participated
in 66% of scheduled community activities. Group leaders demonstrate good fidelity to the group pro-
tocol (43 ratings: overall fidelity = 0.97). Interim repeated measures analyses show reductions in
heroin use (27 vs. 17 days/month; p < 0.05) and any IV drug use (27 days vs. 20 days/month;
p < 0.05), and number of injections (123 vs. 48 injections/month; p < 0.05). Data from Study 1 pro-
vide early support for the clinical benefits of mobilizing and harnessing the powerful influences of
drug-free community support for PWODs. This presentation will include new data from both studies
that will further evaluate the efficacy of this intervention approach on AOD use, social support, and
social network ties.
ABSTRACTS-SPEACKERS
MONDAY, JUNE 18 9:15AM–10:45AM
SYMPOSIUM 89–92
How Can Diverse Populations Help us Elucidate the Genetic Contributions to
Alcohol and Drug Related Phenotypes?
Organizers/Chairs: Tatiana Foroud and Dongbing Lai
89
EXAMINING GENETIC EFFECTS ON ALCOHOL AND DRUG RELATED PHENOTYPES IN THE
COLLABORATIVE STUDY OF THE GENETICS OF ALCOHOLISM
T. Foroud, The Collaborative Study of the Genetics of Alcoholism (COGA) Investigators
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis,
IN 46202, USA
Purpose: Although lifetime prevalence of alcohol use disorders (AUD) is markedly lower in African
Americans (AAs) as compared with European Americans (EAs), heavy drinking has increased in
AAs in recent years. AAs have the highest rates of admission in treatment centers for alcohol and a
comorbid substance, and rates of substance dependence are higher in AAs compared to other racial
groups except Native Americans. There have been a limited number of studies examining whether
unique genetic risk factors underlie these racial differences.
Methods: The Collaborative Study of the Genetics of Alcoholism (COGA) recruited ethnically
diverse families affected with alcohol dependence who completed an extensive assessment, allow-
ing the analysis of unique alcohol- and drug-related phenotypes. Genomewide SNP arrays have
been genotyped in the entire COGA sample (N > 12,000), including 3,500 AA participants. Associa-
tion analyses of alcohol and drug phenotypes were performed in the AAs and EAs separately to iden-
tify unique association in each subset. Meta analyses were then performed to identify associations in
both racial groups.
Results: Unique genomewide significant associations were identified in the AA and EA subsets for
the phenotypes. Eight regions in AAs only: DSM4 alcohol dependence (AD) symptom count on chro-
mosomes 3 and 5; Internalizing Factor Score on chromosomes 2 and 9; DSM4 AD on chromosome
6; any drug dependence on chromosome 3, and DSM5 AUD on chromosomes 4 and 6. Five regions
were identified in both AAs and EAs: two demonstrated stronger association in AAs than EAs -
DSM4 AD on chromosome 1 and Externalizing Factor Score on chromosome 20, and three regions
were stronger in EAs than AAs - subjective response to ethanol (SRE) on chromosome 11 and
Externalizing Factor Score on chromosomes 6 and 16. Other than ADH1B on chromosome 4, one
region demonstrated association in EAs only: SRE on chromosome 6. Admixture analyses are being
used in the AA subsample to dissect the chromosomal origin of the associations.
Conclusion: These results reinforce that alcohol and drug phenotypes as well as internalizing and
externalizing factors, have multiple unique genetic contributions depending on racial background,
and the study of diverse cohorts is essential to understand the complex interplay between genetics
and environmental factors (Supported by U10AA008401).
90
POPULATION DIFFERENCES IN FINDINGS FROM GWASS OF ALCOHOL, OPIOID, COCAINE,
CANNABIS, AND NICOTINE DEPENDENCE
H.R. Kranzler, J. Gelernter, L. Farrer, R. Sherva
Department of Psychiatry, Center for Studies of Addiction, University of Pennsylvania Perelman
School of Medicine, Philadelphia, PA 19104, USA
The Yale-Penn sample comprises 13,000 individuals [N = ~5,600 African Americans (AAs) and
N = ~5,900 European Americans (EAs)] ascertained for alcohol, opioid, or cocaine dependence,
and screened controls. All participants were deeply phenotyped using the Semi-Structured Assess-
ment for Drug Dependence and Alcoholism and more than 9,000 have undergone genome-wide
genotyping. Despite roughly equal numbers of AAs and EAs, more than 2/3 (i.e., 13 of 19) of the gen-
ome-wide significant (GWS) findings for dependence on alcohol (AD), opioid (OD), cannabis (CaD),
cocaine (CD), and nicotine (ND) have been limited to (or mostly characteristic of) the AA part of the
sample. Of the remaining 6 GWS findings, 2 were present in both populations and 4 were present in
EAs only. In addition, all 4 GWS findings in GWASs of addiction-related traits, including methadone
dosing in OD and AD+major depression, were seen in AAs only. In many cases, these findings
reflect associations with population-specific variants, but in some cases, the variants associated in
AAs, although also present in EAs, are not associated with phenotype in that population. These find-
ings underscore the importance of including multiple populations in GWASs, and in particular in
GWASs of AD and other substance dependence traits. In this presentation, we will explore potential
explanations for the substantially higher rate of variant discovery in GWASs of substance depen-
dence in the AA part compared with the EA part of our sample.
293A
91
LOW COVERAGE WHOLE GENOME SEQUENCING FOR ALCOHOL AND OTHER
SUBSTANCE USE-RELATED PHENOTYPES IN AN AMERICAN INDIAN SAMPLE
C.L. Ehlers, Q. Peng, I. Gizer, C. Bizon, N. Schork, K. Wilhelmsen
Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA
Purpose: Low coverage whole genome sequence data was used to search for variants associated
substance use-related phenotypes in an American Indian community sample.
Methods: Participants were recruited from Indian Reservations and assessed using the Semi
Structured Assessment for the Genetics of Alcoholism (SSAGA). DNA was acquired from blood
samples and genotypes were called using a linkage disequilibrium-aware variant calling approach,
and were tested for associations to phenotypes using EMMAX. Gene-dropping simulations and per-
mutation were conducted to calculate empirical p-values.
Results: Associations between alcohol-related phenotypes in the genomic regions around the
ADH1-7 and ALDH2 and ALDH1A1 genes were found. Seventy-two (72) ADH variants showed sig-
nificant evidence of association with a severity level of alcohol drinking-related dependence symp-
toms phenotype. Seventeen (17) variants showed a significant positive association with the largest
number of alcohol drinks ingested during any 24-h period. Variants in or near ADH7 were signifi-
cantly negatively associated with alcohol-related phenotypes. Another genome wide significant find-
ing was observed for high voltage EEG alpha activity, a phenotype previously found to be associated
with risk for alcoholism in EuroAmericans and less intense response to alcohol in this populations.
Variants upstream of ACCN1/ASIC2 were identified to be significantly associated with this pheno-
type. Genomewide significant findings were also observed for a variant 50 kb from CTNNA2 on chro-
mosome 2 for a behavioral impulsivity phenotype. A locus on chromosome 1 near the KCNK2 gene
was found to be associated with the severity of alcohol dependence symptoms.
Conclusion: These studies suggest that whole genome sequencing of a Native American popula-
tion can yield genome-wide significant results that identify unique variants associated with alcohol
and substance related phenotypes (supported by AA10201, DA030976).
92
GENETICS OF COMORBID ADDICTION, ANXIETY, AND DEPRESSION IN THE SAN ANTONIO
MEXICAN AMERICAN FAMILY STUDY
L. Almasy1,2, K. Hodgson1,2, E.E. Knowles1,2, J.W. Kent1,2, J.E. Curran1,2, T.D. Dyer1,2,
H.H. Go€ring1,2, R.L. Olvera1,2, P.T. Fox1,2, G.D. Pearlson1,2, R. Duggirala1,2, J. Blangero1,2,
D.C. Glahn1,2
1
Department of Genetics, Children’s Hospital of Philadelphia, University of Pennsylvania,
Philadelphia, PA, USA and 2Department of Biomedical and Health Informatics, Philadelphia, PA
19104, USA
Background: Comorbidity between substance dependence and psychiatric illness is strikingly high,
particularly between commonly abused substances and depressive and anxiety disorders, the most
prevalent mental illnesses. As the severity of substance misuse increases, the rate of depressive or
anxiety disorders likewise increases. Twin and family studies suggest that substance use and mood/
anxiety disorders share overlapping genetic effects. We conducted bivariate genetic analyses to
identify genetic factors jointly influencing risk of addiction and depression or anxiety.
Methods: Addictive and mental health diagnoses were assessed with the Mini-International Neu-
ropsychiatric Interview – Plus in 1284 participants of the San Antonio Mexican American Family
Study (SAMAFS). Individuals who met criteria for panic disorder, agoraphobia, social phobia, speci-
fic phobia, OCD, PTSD, or generalized anxiety disorder were considered to have anxiety disorder.
Substance dependence included any drugs other than alcohol or tobacco. Participants ranged in
age from 18–97 years (mean = 46.08) and were 62.7% female. Bivariate variance component anal-
yses were conducted using the SOLAR software.
Results: Prevalence of addictive disorders and anxiety/major depression in the SAMAFS are con-
sistent with rates published in the initial National Comorbidity survey (NCS19) for lifetime alcohol
dependence (20% vs. 23% in SAFS), substance dependence (9% vs. 11%) and anxiety disorders
(19% vs 23%). We observed a dramatic increase in the likelihood that an individual with major
depression will have comorbid alcohol dependence (Odds Ratio 3.14, p = 1.3 9 10
12) or sub-
stance dependence (3.4, p = 2.8 9 10
9). Similar results were observed for anxiety disorders: alco-
hol dependence (2.4, p = 1.1 9 10
6), substance dependence (3.6, p = 9.1 9 10
9). Consistent
with previous reports, both major depression and anxiety disorders show strong genetic correlations
with alcohol and substance dependence (rhoG 0.63–0.79, p < 8 9 10
3). In genome-wide linkage
analyses, a locus jointly influencing alcohol dependence and anxiety was mapped to chromosome
9q (LOD = 3.054), substance dependence and anxiety to chromosome 18p (LOD = 3.425), and
cannabis use and depression to chromosome 11q (LOD = 3.229).
Conclusions: We have identified a number of significant quantitative trait loci that partially account
for the genetic overlap of addiction, anxiety, and depression. The regions identified show some con-
vergence with previous literature, but also highlight a number of novel genomic loci involved in the
comorbidity of these psychiatric traits.
294A
MONDAY, JUNE 18 9:15AM–10:45AM
SYMPOSIUM 93–96
Using Translational Science to Develop Treatments for Women With
Alcoholuse Disorders
Organizer/Chair: Cathryn Glanton Holzhauer
93
HORMONAL AND NEURAL FACTORS UNDERLYING RISK FOR ALCOHOL ABUSE IN WOMEN
J. Weafer, H. de Wit
Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637,
USA
Rates of alcohol use disorders are increasing rapidly among women, likely due in part to changing
social and cultural norms. Additionally, animal studies show that females are more vulnerable to sub-
stance use than males, suggesting that biological factors also contribute to increased risk in females.
As such, it is important to identify biologically-based risk factors for problematic alcohol consumption
in women in order to develop sex-specific prevention and treatment efforts. Here we examined neu-
robiological factors underlying poor inhibitory control, a risk factor that we and others have shown is
more strongly linked to heavy drinking in women than in men. Specifically, we assessed the degree
to which sex hormones influence neural correlates of inhibition. We recruited heavy-drinking women
with regular menstrual cycles and a control group of men, matched on demographic and alcohol con-
sumption measures. Participants performed the stop signal task to assess inhibitory control while
undergoing fMRI. Women were tested once in the early follicular phase of their menstrual cycle and
once in the late follicular phase, and men were tested twice at similar intervals. Blood samples were
taken to assess serum levels of the sex hormone estradiol at both sessions. Preliminary analyses
confirmed that estradiol levels were low in the early follicular phase (mean = 50 pg/mL), and high in
the late follicular phase (mean = 185.2 pg/mL). Further, women showed less brain engagement dur-
ing response inhibition in the early compared to the late follicular phase in right frontal regions, includ-
ing the right inferior frontal gyrus, middle frontal gyrus, and supplementary motor area. As data
collection continues, we will test associations between individual differences in estradiol levels and
brain engagement during response inhibition, as well as sex differences in brain engagement across
the menstrual cycle. These data suggest that the inhibitory impairments observed in heavy-drinking
women are influenced by fluctuating levels of estradiol. Further, they suggest that inhibitory deficits
may be exacerbated in the early follicular phase of the menstrual cycle, possibly contributing to
increased difficulty controlling alcohol consumption during this time. Identification of such vulnerable
periods for problematic alcohol consumption could have important implications for prevention and
treatment of alcohol use disorders in women.
94
THE EFFECT OF PROXIMAL EMOTION REGULATION STRATEGY USAGE AND MOOD ON
THE ASSOCIATION BETWEEN WOMEN’S SEXUAL ASSAULT HISTORIES AND HEAVY
DRINKING
C.A. Stappenbeck, K.F. Kajumulo, W.H. George, K.C. Davis
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98105,
USA
A history of sexual assault (SA) has been associated with heavy drinking, and emotion regulation
(ER) difficulties may explain this association. However, ER difficulties are typically assessed as a glo-
bal construct despite an understanding that proximal factors impact one’s use of ER strategies such
as suppression or reappraisal. The present study examined mood as a proximal factor thought to
moderate the association between SA histories and use of ER strategies on drinking behavior using
multiple
methods: (1) a 30-day assessment of the daily use of ER strategies, mood, and alcohol consump-
tion; and (2) an experiment manipulating mood (positive versus negative) using a hypothetical sce-
nario, and beverage condition (alcohol versus control) using an alcohol administration paradigm to
examine the impact of SA histories, mood and beverage conditions, and anticipated ER usage on
drinking intentions. Our sample consisted of 500 heavy drinking women aged 21–30 recruited from
the community. Findings from the daily monitoring assessment revealed that on days of greater than
average positive mood, women consumed more alcohol. Negative mood was not related to daily
drinking. Furthermore, engaging in the ER technique suppression buffered the effects of one’s SA
history on daily drinking for women with less severe SA histories. For women with more severe SA
histories, the extent to which they engaged in suppression that day did not impact their drinking
behavior. Findings from the experimental portion of the study revealed that women who consumed
alcohol in the lab were more likely to report that they would drink in response to the hypothetical sce-
nario and indicated that they would consume a greater number of drinks compared to women who
did not consume alcohol. Additionally, women with a greater history of SA indicated they would con-
sume more alcohol in response to the hypothetical scenario than those with a less severe SA history.
Intentions to use ER strategies and in-the-moment mood were not associated with drinking inten-
tions in the lab. Findings confirmed associations between SA and heavy drinking, and suggest that
improved ER skills may reduce drinking for women with less severe SA histories. More research is
needed to identify intervention targets to reduce drinking among women with more severe SA histo-
ries.
ABSTRACTS-SPEACKERS
95
EMOTION DYSREGULATION AS A THERAPEUTIC TARGET AMONG WOMEN VETERANS
WITH ALCOHOL MISUSE
C.G. Holzhauer
Division of Research, Central Western Massachusetts, VA Healthcare System, Leeds, MA 01053,
USA
Research suggests that, among women with alcohol misuse, the association between negative emo-
tion and drinking may be mediated by poor inhibitory control (IC). Negative emotion depletes IC and
increases craving, which are two factors that increase the likelihood of alcohol misuse. Furthermore,
women with co-occurring depression/post-traumatic stress disorder (PTSD) have particular difficulty
regulating emotion, and therefore may be at greater risk of impulsively using alcohol to regulate neg-
ative emotion. This study examines whether an emotion regulation strategy (cognitive reappraisal,
CR) ameliorates the effect of negative emotion on IC and craving among women veterans with alco-
hol misuse, and whether this effect is moderated by co-occurring symptoms of PTSD and depres-
sion. In the first of two sessions, women complete baseline measures (stop-signal task to measure
IC) and are engaged in the development of a personalized negative emotion induction script. CR is
examined via a microintervention design (the discrete application of a therapeutic technique to study
how that technique leads to change). Women are randomized to the experimental condition in which
they receive the CR microintervention, or to a control psychoeducational group. The second session
consists of the negative emotion induction, followed by women in the experimental group implement-
ing CR to examine its effects. Alcohol craving, emotional state, and IC are assessed throughout the
second session. Generalized Linear Modeling will be used to test main effects of condition and mod-
erating effects of co-occurring symptoms on alcohol craving and IC across three time points. Prelimi-
nary data show an increase in craving and negative emotion after the emotion induction; after
implementing CR, women in the experimental condition demonstrated a sharp decrease in craving
and negative emotion. Further, initial results show that women with clinical levels of PTSD/depres-
sion have poorer IC, higher alcohol craving, and higher negative emotion at baseline, compared to
women with alcohol misuse alone. Additionally, they showed greater increases in craving and nega-
tive emotion in response to the emotion induction, with steep decreases after the microintervention.
Ongoing data collection will allow for significance testing (final n = 40). The findings from this study
will have implications for treatment of alcohol misuse among women veterans, a population with high
rates of AUD, depression, and PTSD.
96
INDIVIDUAL VERSUS GROUP FEMALE-SPECIFIC COGNITIVE BEHAVIOR THERAPY FOR
ALCOHOL USE DISORDER
E.E. Epstein, B.S. McCrady, K.A. Hallgren
Center of Alcohol Studies, Rutgers, The State University of New Jersey, 607 Allison Road,
Piscataway, NJ 08854, USA
Purpose: Research supports the efficacy of single-gender AUD treatment for women when female-
specific programming is provided. There are few evidence-based, single gender Cognitive-beha-
vioral (CBT) female-specific group therapy protocols for AUD, despite the preponderance of group
therapy in community treatment settings for AUD, and the growing popularity of CBT. This study
aimed to modify and test our efficacious individual modality Female Specific Motivational Enhance-
ment/Cognitive Behavioral Therapy (I-FS-MET/CBT, Epstein et al., in press) for delivery in group for-
mat using a “pure comparison” randomized controlled trial (Sobell et al., 2009), comparing a female-
only, female-specific group therapy (G-FS-MET/CBT) to I-FS-MET/CBT.
Method: Women with AUD (n = 155) were randomly assigned to 12 manual-guided sessions of
G-FS-MET/CBT or I-FS-MET/CBT; 138 women attended at least one treatment session.
Results: G-FS-MET/CBT was delivered with high adherence, therapeutic alliance and patient satis-
faction. Quality of intervention delivery was good in both treatment conditions, but higher in G-FS-
CBT. The groups achieved an intended climate as cohesive, task-oriented, semi-structured, and
coping skills-based. Women in G-FS-MET/CBT attended fewer sessions (M = 7.6) than women in
I-FS-MET/CBT (M = 9.7; p < 0.001). Women in both treatments significantly reduced their percent
drinking days (PDD) and percent heavy days drinking (PHD) during treatment and maintained gains
in the 12 month follow up with no condition effects. Significant improvements with no condition differ-
ences were made during treatment in depression, anxiety, autonomy, and interpersonal problems
and were maintained during the follow-up period, while significant gains made during treatment in
use of coping skills, self-efficacy for abstinence, self-care, and sociotropy deteriorated over follow up
but remained improved compared to baseline.
Conclusions: Findings support the feasibility, acceptability, and efficacy of G-FS-MET/CBT for
AUD – a new 12-session, single gender, community friendly, group therapy with programming specif-
ically for women. G-FS-/METCBT successfully addresses both drinking problems and other issues
found to be prevalent in populations of women who seek treatment for AUD. Furthermore, it has col-
lateral benefits in improving some health outcomes (Bold et al., 2017), and is useful for a wide range
of female patients, including those who have co-morbid drug use problems (Epstein et al., 2015).
ABSTRACTS-SPEACKERS
MONDAY, JUNE 18 9:15AM–10:45AM
SYMPOSIUM 97–100
Simultaneous Alcohol and Marijuana Use Among Adolescents and Emerging
Adults: From Brain to Behavior
Organizers/Chairs: Helene White and Megan Patrick
97
NEURAL HEALTH AND NEUROCOGNITION IN ADOLESCENT AND EMERGING ADULT
ALCOHOL AND MARIJUANA USERS
J. Jacobus, M.A. Infante
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
Purpose: Marijuana use has become increasingly prevalent over the past decade and changing
legal policies have aroused public concern about the potential for use and co-use with alcohol to
increase further among youth. Therefore, there is a growing need to understand how co-occurring
alcohol and marijuana use affect the developing adolescent brain, particularly structural brain health
and neurocognition.
Methods: Repeated measures analysis of covariance examined structural brain health and neu-
rocognition in a prospective sample of adolescents and emerging adults (N = 69; ages 12–22), pre-
and post-initiation of combined marijuana and alcohol use, alcohol use only, and non-use. Partici-
pants underwent magnetic resonance imaging, neuropsychological, and substance use assess-
ments at both time points.
Results: Evidence for alterations in cortical thickness and surface area trajectories and poorer neu-
rocognition (ps < 0.05) were identified for those engaging in co-occurring alcohol and marijuana use
compared to those reporting alcohol use only and minimal substance use. More specifically, evi-
dence for thicker cortices, increased and decreased surface area estimates, and poorer perfor-
mance on tests of learning and complex attention were identified for those reporting co-use.
Conclusions: Combined use of alcohol and marijuana use may be uniquely linked to altered neu-
rodevelopmental trajectories and compromised neural health. Future prospective work should aim to
better understand the unique effects of alcohol and marijuana when used alone and in combination.
This study was supported by NIDA and NIAAA grants R01 AA013419, U01 DA041089, T32
AA013525 and NCATS KL2 TR001444
98
PATTERNS, MOTIVATIONS, AND CONSEQUENCES OF ALCOHOL AND MARIJUANA USE:
ARE THERE DIFFERENCES BETWEEN CONCURRENT AND SIMULTANEOUS USERS?
K.M. Jackson, K. Hayes, A. Sokolovsky, H.R. White
Center for Alcohol and Addiction Studies, Brown University, Providence, RI 02912, USA
Purpose: Little is known about how patterns, modes, motivations, and consequences differ for
simultaneous alcohol-marijuana (SAM) users compared to alcohol and marijuana users who use
both but not together (concurrent [CAM] users). This study explores these issues among full-time
college students enrolled across three sites varying in legal status of marijuana use.
Methods: Past-year alcohol and marijuana users age 18–24 (N = 1,390) completed a 30–45-min
web survey assessing alcohol and marijuana use, motivations for use, and consequences.
Results: Among past-year users, 12% reported alcohol use only, <1% reported using only mari-
juana; 28% reported CAM use, and 59% reported SAM use in the past 3 months. Mean number of
past 30-day SAM use occasions among SAM users was 3.4 (SD = 3.9), although 60% reported only
1–2 instances of SAM use. Leaf marijuana was the primary form used by all users, but CAM, com-
pared to SAM, users were more likely to report edibles as their primary marijuana form. Participants
reported typically using alcohol first on a SAM occasion. The most highly reported motivations for
SAM use were to be social and to enhance the positive effects of each substance; few participants
indicated using marijuana in order to drink more alcohol or using alcohol to offset negative effects of
marijuana. A comparison of alcohol-only, CAM, and SAM users indicated that for both alcohol and
marijuana use, social, coping, and enhancement motives were significantly greater for SAM than the
other two groups. Additionally, even controlling for past 3-month alcohol and marijuana frequency,
sex, race/ethnicity, age, SES, GPA, and Greek status, SAM users endorsed significantly (p < 0.005)
more consequences associated with cognitive dysfunction (blackout, not as mentally sharp, hang-
over), increased tolerance, and less energy and motivation to function as compared to CAM users.
Conclusions: Using alcohol and marijuana simultaneously appears to adversely affect both cogni-
tive and motivational performance relative to only drinking or using both substances but not at the
same time. Given that differences in frequency of consumption were controlled, intervening on inten-
sity of use is not sufficient to mitigate adverse outcomes of alcohol and marijuana use. Further inves-
tigation into the unique risk and adverse outcomes of simultaneous use is warranted. Funded by
NIDA grant R01DA040440.
295A
99
SIMULTANEOUS ALCOHOL AND MARIJUANA USE WHILE PREGAMING: EXAMINING THE
CO-OCCURRENCE IN ENTERING COLLEGE STUDENTS
A. Haas, T. Hyke, B. Borsari
Palo Alto University, Palo Alto, CA 94304, USA
Purpose: Pregaming is a ubiquitous behavior among college students, which to date has been
exclusively studied vis-a  -vis alcohol use. However, many students engage in simultaneous alcohol
and marijuana (SAM) use and may do so while pregaming. This study examines SAM use while
pregaming and whether it represents an additive risk for increased consumption and/or alcohol-
related problems compared to non-SAM use and engagement in SAM use but not while pregaming.
Methods: Paper-and-pencil assessments were administered to entering freshmen across three
years (2008, 2009, and 2010) during university-sanctioned precollege welcome activities. Items
assessed demographics, marijuana use (lifetime prevalence and frequency/past 3 months), past 3-
month alcohol consumption (overall and pregaming-specific) and consequences. Dichotomous
items assessed SAM use overall and while pregaming. Students with prior alcohol use (N = 1,033;
48.7% female, 69% White, Mage = 18.11) were stratified into three groups: (1) non-SAM (n = 724),
(2) SAM, not while pregaming (SAM: n = 127), and (3) SAM while pregaming (SAM-p: n = 182).
Results: SAM-p was reported by 16% of drinkers and was associated with being male and earlier
ages of initiation for both alcohol and marijuana (ps < 0.01). SAM users (including SAM and SAM-p)
consumed more drinks per typical occasion compared to non-SAM users (p < 0.01). Similarly, SAM-
p users pregamed on more drinking events than SAM and non-SAM users (40.13% vs. 30.83% and
18.42%, respectively; p < 0.01). As such, group differences in marijuana use, pregaming (quantity,
time/event), and alcohol-related problems were modeled using Poisson regression or ANCOVA, with
overall alcohol involvement (QFI) and pregaming frequency entered as covariates to control for gen-
eral alcohol consumption. The non-SAM group served as reference. Logistic regression examined
differences in alcohol-related blackouts. Results indicated that marijuana use was significantly
greater for SAM-p and SAM compared to non-SAM users (IRRs = 8.68 and 6.85, respectively).
SAM and SAM-p groups consumed slightly more alcohol per pregaming event (IRRs > 1.20), and
reported more alcohol-related problems (IRRs > 1.33). Higher rates of blackouts were also observed
for both SAM groups (SAM: OR = 2.53; SAM-p: OR = 1.82).
Conclusions: SAM use is linked to greater consumption and consequences, even when controlling
for overall drinking. However, co-occurrence of pregaming and SAM was not associated with omni-
bus elevations in risk or pregaming consumption.
100
CROSS-FADING IN A DAILY STUDY OF ALCOHOL AND MARIJUANA USE IN EMERGING
ADULTS: LINKS WITH LEVEL OF USE, INTOXICATION, AND CONTEXT
C.M. Lee, C. Fleming, A.M. Fairlie, D.A. Abdallah, K. Spychalla, M.E. Patrick
Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98105, USA
Purpose: Alcohol and marijuana are psychoactive substances commonly used by emerging adults
and are independently associated with numerous acute and long-term consequences. Many emerg-
ing adults engage in simultaneous alcohol and marijuana (SAM) use to cross-fade (i.e., to enhance
the effects of intoxication and of getting high). The current study examined pilot data on alcohol, mar-
ijuana, and SAM use among a sample of high-risk SAM users.
Methods: 39 young adults (age 18–25; M age = 22.33, SD = 2.04; 54.6% women) who reported
SAM use at least one time in past month were recruited to complete twice daily web-based assess-
ments for 14 consecutive days. Retention rates were high; 87.6% of all surveys were completed.
Results: Among 508 reported days, 15.7% were alcohol-only days, 30.3% marijuana only, 6.9%
both alcohol and marijuana but no SAM, 16.9% SAM, and 30.1% neither alcohol nor marijuana.
Examining all drinking days, multilevel models indicated young adults drank more alcohol (number of
drinks; B = 0.96, SE = 0.51) and got more intoxicated (B = 0.42, SE = 0.15) on SAM days com-
pared to other drinking days. Examining all days of marijuana use, days with SAM use were associ-
ated with greater intensity of the high (B = 0.25, SE = 0.12), more hours high (B = 1.06,
SE = 0.38), and consuming more grams of marijuana (B = 0.68, SE = 0.16) compared to other
marijuana days. Emerging adults were more likely to endorse being with friends on days with SAM
use compared to other marijuana use days (OR = 3.83) and compared to other alcohol use days
(OR = 3.46). Similarly, days with SAM use were related to higher fun/enhancement motives com-
pared to other marijuana use days (B = 0.36, SE = 0.14) and compared to other alcohol use days
(B = 0.51, SE = 0.13).
Conclusions: In this sample of SAM-using emerging adults, simultaneous use was associated with
consuming more alcohol and more marijuana compared to when the substances were not used
simultaneously. Consistent with other research, being with friends and fun/enhancement motives
were associated with SAM use. Analyses will further explore the impact of SAM use on negative con-
sequences and the discussion will focus on potential targets of intervention, especially in the context
of real-time personalized interventions.
296A
MONDAY, JUNE 18 9:15AM–10:45AM
SYMPOSIUM 101–104
Identifying Prenatal Alcohol-Affected Individuals Early in Life: The Use of
Novel Screening Tools and Methodologies in Human Populations
Organizers/Chairs: Christina Chambers and Bill Dunty
101
HEMODYNAMIC CHANGES IN THE PREFRONTAL CORTEX AS MEASURED BY FUNCTIONAL
NEAR-INFRARED SPECTROSCOPY AND THEIR RELATIONSHIPS TO NEUROBEHAVIORAL
OUTCOMES IN CHILDREN WITH FASD
J.A. Kable, C.D. Coles
Departments of Psychiatry and Behavioral Science1 and Pediatrics, Emory University School of
Medicine, Atlanta, GA 30306, USA
Objective: Children with a history of prenatal alcohol exposure (PAE) have been found to have
altered hemodynamic changes in the prefrontal cortical (PFC) as measured by functional near-infra-
red spectroscopy (fNIRS) relative to both typically developing children and those who have other
neurobehavioral problems. The purpose of this study was to evaluate the relationships between
indices of PFC functioning and the neurobehavioral outcomes in children with FASD and to deter-
mine if these relationships differed from other groups of children.
Methods: Levels of oxygenated (HBO) and deoxygenated (HBR) hemoglobin were assessed dur-
ing a computer task designed to elicit arousal in children with a history of PAE (n = 33) and children
without PAE who were typically developing (Controls, n = 25) or had other neurobehavioral prob-
lems (Clinical Contrast group, n = 22). The task elicits emotional arousal by alternating positive
(Win) and negative (Loss) arousal while playing a game. The linear relationships between neurobe-
havioral outcomes (behavioral problems and word generation skills) and the mean levels of HBO
and HBR for each of the conditions were assessed for group differences using the Potthoff regres-
sion procedure, which allows for simultaneous and separate tests of regression intercepts and
slopes across groups.
Results: Within the entire sample, indices of PFC activation were related to externalizing problem
behaviors and word generation skills, a measure of executive functioning, but PFC activation in the
lateral areas of the PFC differentiated children in the PAE group from both other groups. Specifically,
slopes of the relationship between Left Lateral HBO levels and rule-breaking behavior were higher in
children with PAE and slopes of the relationship between Lateral Left HBR levels and withdrawn/de-
pression symptoms were more negative. Performance on a word generation task was differentially
predicted by indices of Right Lateral PFC activation with children in the PAE group having more neg-
ative slopes in the linear relationships with HBR levels than both other groups.
Conclusion: Children with a history of PAE had unique characteristics in the relationships between
the indices of PFC functioning and neurobehavioral problems that may be useful in differentiating
alcohol-exposed children from typically developing children and those who have neurobehavioral
problems not associated with PAE.
102
EARLY IDENTIFICATION OF EFFECTS OF PRENATAL ALCOHOL EXPOSURE: INFANT
CARDIAC ORIENTING RESPONSE AS A BIOMARKER
C.D. Coles,J.A. Kable, D.A. Mesa, T.P. Coleman, K.L. Jones,L. Yevtushok, Y. Kulikovsky,
W. Wertelecki,C.D. Chambers
Departments of Psychiatry and Behavioral Science and Pediatrics, Emory University School of
Medicine, Atlanta, GA, USA
Problem: Early identification of neurodevelopmental deficits associated with prenatal alcohol expo-
sure (PAE) would allow more effective intervention and treatment and could prevent some negative
outcomes. Due to the nature of development in infancy, such identification has been challenging.
Measures typically used in infant assessment require professional administration and may not target
those aspects of cognition impacted by alcohol exposure (information processing and memory). Car-
diac orienting response (COR) permits assessment as young as 6 months of age and has been
found to be sensitive to the effects of PAE. Deceleration in heart rate at the presentation of novel
stimuli is an indicator of efficiency of information processing and encoding and dishabituation with
the presentation of a novel stimulus requires effective retrieval. COR has been found to predict exec-
utive function and intellectual development later in childhood more effectively than typical infant
motor-based measures.
Methods: In the current study, the predictive value of individual COR performance was evaluated in
a longitudinal sample of 235 Ukrainian preschool children whose mothers were recruited prenatally.
Women were recruited as heavy drinkers or no/low level drinkers and children were evaluated at 6
and 12 months and as preschoolers. COR was measured at 6 and 12 months and infants were
tested using the Bayley Scales of Infant Development, 2nd Edition. At 3 1/2 to 41/2 years of age,
children completed a nonverbal battery including the Differential Ability Scales, 2nd Edition.
Results: Supervised logistic regression classifier models were used to predict preschool outcomes
from infant data. Outcomes were based on prediction within individuals rather than on group out-
comes making results more relevant for clinical use. We found that the most efficient prediction
resulted from a combination of 6 and 12 month COR scores, yielded a Negative Predictive Value
(NPV) of 83.33% and a Positive Predictive Value (PPV) of 51.52%.
Conclusion: These results suggest that the COR could be used as a relatively quick and inexpen-
sive assessment for later developmental risk with this high risk population.
ABSTRACTS-SPEACKERS
103
miRNAs AS BIOMARKERS OF PRENATAL ALCOHOL EXPOSURE AND INFANT OUTCOME
A.H. Mahnke, R.C. Miranda, G.D. Sideridis, R.C. Carter, N.A. Salem, N.C. Dodge, A.M. Tseng,
A.B. Rathod, J.L. Jacobson, S.W. Jacobson
Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science
Center, Bryan, TX 77807, USA
Prenatal alcohol exposure (PAE) can result in developmental deficits collectively termed Fetal Alco-
hol Spectrum Disorders (FASD). Not all children who are exposed to alcohol prenatally present with
overt physical indications of FASD. We, and others, have shown that circulating miRNA profiles are
changed following PAE in pregnant sheep and humans and can predict infant outcome, i.e., which
PAE infants develop behavioral or growth deficits. Here, in this pilot study from a larger longitudinal
study of the South African Cape Coloured population, we assessed plasma miRNAs from infants, at
2 week and 6.5 months, to determine if circulating miRNAs were sensitive to PAE and also predicted
developmental outcomes. PAE significantly altered plasma miRNA expression and at 2 weeks of
age, but not at 6.5 months, the altered miRNAs showed inter-chromosome correlated expression,
indicating coordinated expression of miRNAs. We also found evidence that PAE had a sex specific
effect on some circulating miRNAs. Confirmatory factor analysis, followed by pathway analysis, iden-
tified miRNAs associated with growth and hematopoiesis as well as skeletal patterning and inflam-
mation at 2 weeks of age. At 6.5 months of age, identified miRNAs were associated with
inflammation and immune cell/neural crest development, stress/neuroendocrine, and extracellular
matrix and morphogenesis/angiogenesis. Mediation analysis showed that circulating miRNA profiles
predicted growth deficits at 2 weeks of age, including decreased height, weight, and head circumfer-
ence. Moreover, for head circumference, the identified 2 week miRNAs directly mediate ethanol’s
effects, i.e., when the variability due to these factors is removed from analysis, there is no longer a
significant correlation between ethanol and head circumference. These data show that PAE infants
have altered plasma miRNAs composition, which can be assessed up to 6.5 months into postnatal
development. Such PAE-altered miRNAs may also mediate developmental deficits commonly seen
in FASD. Further research is warranted to understand the direct relationship between altered miR-
NAs and the symptoms of FASD as well as the potential contribution of child sex to FASD.
104
DEVELOPMENT OF AN EPIGENETIC BIOMARKER FOR PREDICTION OF FETAL ALCOHOL
SPECTRUM DISORDERS
A. Baldwin, J. Jones, A. Negrusz, M. Jones, D. Lewis
United States Drug Testing Laboratories, Inc., Department of Research and Development, Des
Plaines, IL 60018, USA
Strong evidence supports that adverse environmental exposures, in utero or in early postnatal life
can cause epigenetic changes that can impact the developmental health and wellbeing outcomes for
an individual from infancy to adulthood. This includes multiple recent studies that have demonstrated
that in utero alcohol exposure alters DNA methylation patterns and that this epigenetic dysregulation
can transmit the teratogenic effects caused by fetal alcohol exposure. The objective of our research
is to identify sensitive and specific epigenetic biomarkers of prenatal alcohol exposure that could
potentially be used to stratify risk for developmental disabilities associated with FASD at birth. To
identify potential epigenetic biomarkers of prenatal alcohol exposure, we examined the DNA methy-
lation patterns of 12 newborns with known prenatal alcohol exposure, based on biomarker analysis.
Alcohol-exposed newborns were positive for DBS Phosphatidylethanol (PEth), positive for meco-
nium FAEE, and had confirmation of maternal alcohol consumption during pregnancy. Non-exposed
newborns had negative biomarker tests and maternal self-report of abstinence during pregnancy.
We examined genome-wide cytosine-guanine dinucleotide (CpG) methylation using the
HumanMethylation450K BeadChip to identify 188 differentially methylated sites, which were mapped
to 326 genes located within ten kilobases of the probes. These sites were able to separate alcohol-
exposed and non-exposed newborns based on their different methylation patterns. We selected 14
sites with the largest mean methylation difference between the exposed and non-exposed groups
for further analysis as potential epigenetic biomarkers of prenatal alcohol exposure. To examine the
quantitative differences in these methylation patterns, we are developing bisulfite pyrosequencing
assays to screen newborn blood spot cards that have also been screened for PEth. A number of
sites that we have selected to examine further in our current studies encode proteins with biological
functions that are important during multiple stages of fetal development. The fact that the epigenetic
alterations in these genes play important roles in embryogenesis, morphogenesis and particularly,
neural development, suggest that the differential methylation observed may lead to the aberrations
observed in FASD. The development of an epigenetic biomarker of prenatal alcohol exposure that
could also predict risk for FASD could significantly impact the clinical diagnosis of FASD early in life
when interventions and treatments are most beneficial.
ABSTRACTS-SPEACKERS
MONDAY, JUNE 18 1:20PM–2:50PM
SYMPOSIUM 105–108
Non-Coding RNA in Alcoholism: Mechanisms, Biomarkers and Therapeutic
Targets
Organizers/Chairs: Subhash Pandey and Antonio Noronha
105
MICRORNAS AND ADOLESCENT ALCOHOL EXPOSURE: CHROMATIN REMODELING IN THE
AMYGDALA AND INCREASED ANXIETY SUSCEPTIBILITY IN ADULTHOOD
S.C. Pandey1,2, E.J. Kyzar1,2, H. Zhang1,2
1 ders (AUD) and alcoholic liver disease (ALD).
Department of Psychiatry, Center for Alcohol Research in Epigenetics, University of Illinois at
Chicago, Chicago, IL, USA and 2Jesse Brown VA Medical Center, Chicago, IL 60612, USA
Adolescent binge drinking is a risk factor for the development of alcohol use disorder (AUD) and
comorbid anxiety in adulthood. MicroRNAs (miRNAs) are involved in the neuronal response to etha-
nol and also in neurodevelopment. We investigated the role of miRNAs in the amygdala in adoles-
cent intermittent ethanol (AIE) exposure-induced adult psychopathology. Male rats were exposed to
2 g/kg ethanol (2 days on/off; AIE) or intermittent n-saline (AIS) during postnatal days (PND) 28–41
for a total of 8 injections and allowed to grow to adulthood for analysis of behavior, miRNA expres-
sion by microarray and qPCR, mRNA expression by qPCR, and chromatin occupancy by chromatin
immunoprecipitation (ChIP). A separate subset of rats was cannulated in the central nucleus of
amygdala (CeA) and infused with a locked nucleic acid (LNA) antagonist of miR-137 (antagomiR-
137) prior to anxiety measures using elevated plus maze (EPM). AIE adult rats show increased anxi-
ety-like behavior and altered miRNA expression profiling by microarray. miR-137, a crucial neurode-
velopmental miRNA involved in the regulation of epigenetic enzymes, was significantly increased in
AIE rats after validation by qPCR. mRNA levels of miR-137 target genes lysine-specific demethy-
lase1 (Lsd1) and Lsd1 + 8a were decreased in the AIE adult amygdala. AIE adult rats show
decreased expression of methyl CpG binding protein 2 (Mecp2) and decreased occupancy of
MeCP2 at specific sites of the miR137 promoter and gene body, possibly explaining the increase in
expression. Infusion of antagomiR-137 directly into the CeA rescues the increased anxiety-like
behavior in AIE rats, as well as the increased H3K9me2 occupancy at the Bdnf IV promoter, possibly
by rescuing the decreased Lsd1/Lsd1 + 8a expression and LSD1 occupancy at Bdnf IV seen in AIE
adult rats compared to AIS rats. These novel results show that adolescent alcohol exposure leads to
a long-lasting increase in miR-137 that is regulated by epigenetic effectors and additionally causes
downstream effects on chromatin remodeling and behavior. Our results highlight miR-137 in the
amygdala as a potential therapeutic target for anxiety susceptibility and alcohol use disorders
(Funded by NIAAA-NADIA UO1-AA019971, U24-AA024605 and P50-AA 022538 grants as well as
VA senior research career scientist award to SCP and F30 AA024948 grant to EJK).
106
ENDOCRINE MIRNAS IN PREGNANT WOMEN, PREDICTIVE OF FASD INFANT OUTCOMES,
CONTROL PLACENTAL TROPHOBLAST GROWTH, SURVIVAL, AND MATURATION
A.M. Tseng, S. Balaraman, A.M. Allan, C. Chambers, R.C. Miranda, CIFASD
Texas A&M Health Science Center, Neuroscience and Experimental Therapeutics, Bryan, TX
77807, USA
Fetal alcohol exposure is a leading non-genetic cause of developmental disability. There is an urgent
need to develop strategies to detect and mitigate the harmful effects of fetal alcohol exposure. We
used a qPCR array to analyze the 2nd and 3rd trimester plasma microRNA (miRNA) profiles of 68
pregnant Ukrainian women who consumed alcohol or abstained. We identified 11 miRNAs which
were significantly elevated (ANOVA miRNAs) in the plasma of mothers whose infants were affected
by maternal alcohol consumption (HEa) compared to those infants who were unaffected (HEua) or
unexposed (UE). IPATM pathway overrepresentation analysis indicated these ANOVA miRNAs influ-
ence pathways related to fetal and placental growth and maturation, including the epithelial-
mesenchymal transition (EMT) pathway. Our prenatal alcohol exposure (PAE) mouse model also
showed impairment of the EMT pathway in placenta, with significant elevation in transcript and pro-
tein levels of the epithelial E-Cadherin marker. To investigate whether ANOVA miRNAs mediate the
effects of ethanol on the placenta, we assessed their effects on BeWO and HTR8 human trophoblast
cell lines. Overexpression and knockdown of ANOVA microRNAs significantly reduced growth,
retarded cell cycle progression, and reduced the migratory/invasive capacity of both cell lines, point-
ing to their role in modulating the placental growth and invasion deficits seen in PAE. Subsequent
analysis of EMT pathway members, following ANOVA miRNA overexpression, showed impairment
of EMT pathway in both HTR8 and BeWO cells with increased expression of E-Cadherin in BeWO
cells and reduced Vimentin expression in HTR8 cells. Overexpression of ANOVA miRNAs prevented
the reduction in E-Cadherin expression following forskolin-induced BeWO syncytialization (matura-
tion) without interfering with syncytialization-dependent increases in placental hormone expression.
Taken together, these data suggest that maternal circulating miRNAs may affect placental growth
and invasion, and, following PAE, selectively interfere with the EMT pathway, thereby contributing to
the pathology of FASD.
297A
107
LNCRNA AND MIRNA IN ETHANOL INDUCED NEUROIMMUNE GENE INDUCTION IN ALD AND
AUD
F.T. Crews, V. Massey,M. Calabresse, L. Qin, J. Zou, R. Bataller, L. Coleman
Department of Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina at
Chapel Hill, Chapel Hill, NC 27517, USA
Purpose: Innate immune genes are induced by ethanol through complex mechanisms. Although
ethanol activates NFkB transcription, differential NFkB genes are induced as pathology progresses.
Recent studies indicate that ncRNA are involved in innate immune signaling and induction of specific
genes. This is accomplished through specific gene repression of transcription regulation and non-tra-
ditional, e.g., direct RNA TLR receptor activation, mechanisms in the context of Alcohol use disor-
Methods: Innate immune gene mRNA and ncRNA were assessed by PCR or RNAseq. Protein
was assessed with ELISA, immunohistochemistry, or Western blot. Human post-mortem brain, as
well as mouse brain, rat brain slice culture or neuronal-microglial cultures were used to investigate
mechanisms.
Results: Both lncRNA and miRNA expressions are modified by ethanol exposure. The lncRNA
NEAT1 and MALAT1 are expressed in the brain and contribute to the regulation of mRNA and
nuclear paraspeckle formation. Humans with acute alcoholic hepatitis as well as post-mortem alco-
holic brain have altered expression of NEAT1 ncRNA and increased expression of IL8, a unique
human cytokine. Studies suggest that NEAT1 removes a specific IL8 gene repressor, resulting in
progressive IL8 induction as the pathology of ALD, and perhaps AUD, progresses. In addition, we
recently discovered that the miRNA let-7 is an agonist at TLR7 receptors in neurons that can induce
IFN genes associated with depression. TLR7 is known to respond to ssRNA and ethanol induces the
release of let-7 miRNA bound to HMGB1 in microvesicles. Ethanol exposure induces TLR7 in brain
and liver as alcoholic pathology progresses. Further, ethanol induction of TLR7 leads to enhanced
induction of innate immune genes by TLR7 agonists. The role of TLR7 in ethanol responses is sup-
ported by studies using TLR7 antagonists. Hepatic expression of TLR7 and let-7b significantly corre-
late with hepatic IL8 mRNA and NEAT1 expression in acute alcoholic hepatitis. Studies find multiple
let-7 miRNA are induced by ethanol and are released from cells that are able to activate neuronal,
and perhaps hepatocyte, TLR7 receptors inducing specific innate immune responses and cell death.
Conclusions: ncRNA contribute to ethanol induction of a unique group of innate immune genes
that are associated with the progressive pathology of alcoholism.
108
LONG NON-CODING RNAS AS A FUNCTIONAL SUBSTRATES FOR ALCOHOL USE
DISORDER
S.P. Farris, C.M. Borghese, E.A. Osterndorff-Kahanek,Y.A. Blednov, G.E. Homanics, R.D. Mayfield,
R.A. Harris
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX
78712-1095, USA
Purpose: Non-coding RNA transcripts represent a large ill-defined class of molecules that remain
to be biologically characterized to the same extent as protein coding transcripts. Long non-coding
RNAs (lncRNAs) are one broad class of non-coding RNAs (>200 bps) with over 100,000 human
lncRNAs currently reported. The functional significance of lncRNAs in the central nervous system
(CNS) and in disease remains uncertain. Prioritizing and functionally testing cellular perturbation of
lncRNAs in diverse systems is necessary for understanding the pathophysiology of human diseases,
including alcohol use disorder (AUD).
Methods: To determine the involvement lncRNAs in AUD, and their potential biological functions,
we conducted RNA-Seq profiling of multiple human postmortem brain regions (e.g., superior pre-
frontal cortex, nucleus accumbens, basolateral amygdala, and central nucleus of amygdala). Bioin-
formatics analysis of RNA-Seq led to the prioritization of LINC01559 and the NMDAR1/NMDAR2B
receptor complex for functional testing. To determine the predicted effects of test these human tran-
scripts we used two-electrode voltage clamp within Xenopus laevis oocytes.
Results: Consistent with previously reported restricted expression patterns of lncRNAs, distinct
brain-region specific changes occurred in postmortem AUD tissue. Using a graph-theory based com-
putational approach we discerned coordinate expression of molecular networks associated with vari-
ation in the expression of multiple human lncRNAs. Although many lncRNAs are suggested to be
evolutionary divergent, we identified over 100 lncRNAs with potential genomic conservation in mice.
Among these conserved lncRNAs was LINC01559; which resides on chromosome 12 adjacent to
the alcohol-responsive glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B). To test the
hypothesis that LINC01559 may affect regulation of glutamatergic function, Xenopus oocytes were
co-injected with LINC01559 and NMDAR1/NMDAR2B receptor complex. LINC01559 caused a sig-
nificant reduction (~80%) in maximal glutamate elicited currents. To test for potential non-specific
effects of LINC01559 on ion-channel expression and function we examined major non-glutamatergic
inhibitory receptors GABAA (a1b2c2) or Glycine (a1 GlyR). In contrast to NMDAR1/NMDAR2B,
LINC01559 did not alter maximal currents for non-glutamatergic inhibitory receptors GABAA
(a1b2c2) or Glycine (a1 GlyR).
Conclusions: Overall, our work demonstrates a functional relationship for human alcohol-respon-
sive lncRNAs with evidence for preservation in model organisms. Specifically, we show that a
lncRNA which is increased in alcoholic brain can also regulate NMDA receptors providing a novel link
between a lncRNA and a key brain signaling system. Bioinformatics can assist in the prioritization of
novel non-coding RNAs for further validation and establish the cellular circuits and behavioral sys-
tems impacted in the pathophysiology of AUD.
Acknowledgements: This work was generously supported by the National Institute of Alcohol
Abuse and Alcoholism (NIAAA) grants K99AA024836 and U01AA020926.
298A
MONDAY, JUNE 18 1:20PM–2:50PM
SYMPOSIUM 109–112
Alcohol Use Disorder and PTSD: From Animal Models to Human Studies
Organizer/Chair: Judson Chandler
109
MODULATION OF GLUTAMATERGIC MECHANISMS RECOVERS BEHAVIORAL DEFICITS IN
MULTIPLE MODELS OF AUD/PTSD COMORBIDITY
C.E. Petyak, T. Valvano, J.T. McGonigal, R.J. Newsom,, J.T. Gass
Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA
There is a considerable gap in our knowledge concerning how alcohol use disorder (AUD) and PTSD
interact to cause significant deficits in behavior. Critical needs include the development of novel phar-
macological treatments and further examination into the sex differences associated with AUD/PTSD
comorbidity. The current studies utilized different rodent models of PTSD that mimic features of the
disorder. The first set of studies examined the impact of chronic alcohol exposure on fear condition-
ing, extinction learning and recall, and cue induced ethanol consumption in both male and female
rats. In the first experiment, adult rats were exposed to a fear conditioning procedure and then
exposed to either chronic intermittent ethanol (CIE) or air for 2 weeks. This was followed by extinc-
tion training (daily sessions of 10 tone presentations). Rats were then exposed to an extinction recall
test. Both CIE male and female rats showed fear extinction deficits and this deficit was greater in
male CIE rats. These deficits were recovered when rats from both sexes were treated with the
mGlu5 modulator, CDPPB, during extinction. Sex differences were observed in extinction recall and
alcohol consumption. CIE exposure resulted in an extinction memory recall deficit in male rats only.
Additionally, exposure to fear-related cues significantly increased alcohol consumption only in male
CIE-exposed rats. The second experiment exposed adolescent rats to chronic ethanol exposure
(AIE) and examined fear conditioning in adulthood. These results indicated that AIE also produced
deficits in fear extinction and extinction memory recall in adulthood and these deficits were prevented
with CDPPB treatment during extinction training. In a separate set of studies, rats were first exposed
to acute restraint stress (2 h) paired with sandalwood odor. Rats were treated with N-Acetyl Cysteine
(NAC) for 5 days prior to and following restraint stress. The results showed that restraint stress pro-
duced in a significant and lasting increase in operant alcohol self-administration and this effect was
blocked with NAC treatment. Following extinction training, presentation of the stress-related odor sig-
nificantly reinstated alcohol-seeking behavior compared to a neutral odor and this effect was also
prevented with NAC treatment. Together, these findings highlight the potential efficacy of glutamater-
gic modulation as a novel treatment for AUD/PTSD comorbidity.
110
MECHANISMS AND BEHAVIORAL CONSEQUENCES OF STRESS-ENHANCED FEAR
LEARNING IN A RAT MODEL OF POST-TRAUMATIC STRESS DISORDER
J.N. Perusini1,2, S. Gonzalez1,2, E.M. Meyer1,2, V.A. Long1,2, V. Rau1,2, J. Maksymetz1,2,
V.N. Marty1,2, I. Spigelman1,2, M.S. Fanselow1,2
1
Department of Psychology, UCLA, Los Angeles, CA 90095, USA and 2Division of Oral Biology &
Medicine, UCLA Sch Dent, Los Angeles, CA 90095, USA
Purpose: Post-traumatic stress disorder (PTSD) patients exhibit high rates of alcohol abuse.
Stress-enhanced fear learning (SEFL) in rats mimics several PTSD features, including resistance to
exposure therapy and chronic anxiety. We previously showed that SEFL produces long-term
increases in voluntary alcohol intake, without affecting sucrose/quinine consumption. Here we
assessed the involvement of basolateral amygdala (BLA) in SEFL, examined the role of corticos-
terone (CORT) in SEFL-induced functional changes within the BLA, and assessed the effect of vary-
ing the number of foot-shocks on SEFL expression.
Methods and Results: Prior stress with 15-shocks enhanced conditioning to 1-shock in a novel
context, indicating SEFL. Selective bilateral inactivation of the BLA with muscimol before but not after
stress eliminated SEFL. The CORT synthesis inhibitor metyrapone was administered before or after
15-shocks in context A. Plasma CORT levels and fear responses were measured then and in a novel
context 6 days later. Metyrapone pre- but not post-treatment decreased the CORT response to the
stressor and blocked SEFL, but CORT levels were not significantly changed during the context test.
Pre-stress CORT injections rescued the freezing response from metyrapone. CORT without stress
did not produce SEFL. Western blots of BLA tissue revealed increases in the glutamate a-amino-3-
hydroxy-5-methylisoxazole-4-propionic acid receptor 1 (GluA1) subunit in SEFL versus control rats;
the increases were prevented by metyrapone pre-treatment. Similarly, the g-aminobutyric acid A
receptor (GABAAR) a3 subunit was increased in SEFL rats and prevented by metyrapone pre-treat-
ment. These data indicate CORT, as well as the BLA, are necessary for SEFL initiation, which leads
to increased expression of BLA GluA1 and GABAAR a3 subunits. We also showed that by parametri-
cally varying the number of unsignaled, unavoidable shocks, we can mimic the rate of PTSD found
in traumatized humans.
Conclusion: Thus, the SEFL model may be used to explore the mechanisms that underlie suscep-
tibility and resilience to PTSD, as well as a platform to test putative therapeutics for the co-morbid
PTSD and AUD disorders.
ABSTRACTS-SPEACKERS
111
POMC NEURON ACTIVATION BY ALCOHOL AND POSSIBLE INTERACTION WITH STRESS
E.K. Nagy1, J.M. Newbern2, M.F. Olive1
1
Department of Psychology, Arizona State University, Tempe, AZ, USA and 2School of Life
Sciences, Arizona State University, Tempe, AZ, USA
Purpose: POMC-derived neuropeptides such as beta-endorphin are implicated in alcohol depen-
dence and PTSD. We examined the effects of acute alcohol intake and trauma-like stress exposure
on activation of POMC-expressing neurons in the arcuate nucleus of the hypothalamus.
Methods: Adult male and female POMC-EGFP transgenic mice (Jackson Labs #009593) were uti-
lized. Animals were housed individually starting one week prior to drinking-in-the-dark (DID) proce-
dures. Bottles containing 20% ethanol were placed on home cages for 2 h starting 3 h into the dark
cycle for 3 consecutive days. On the next day, mice were provided with the ethanol solution for either
20 min or 4 h to allow for low or high ethanol intake, respectively. Separate control animals received
access to only water under the same conditions. For acute stressor exposure, several drops of the
predator odor 2,3,5-trimethyl-3-thiazoline (TMT) were placed on filter paper atop the cage at the
same time points and for the same duration as ethanol/water bottles during a single session. Follow-
ing alcohol/water intake or stress exposure, mice were left undisturbed in the home cage for 60 min,
followed by blood collection and harvesting of brain tissue for c-fos immunohistochemistry. The num-
ber of c-fos positive neurons that co-expressed EGFP in the arcuate nucleus as well as in the den-
tate gyrus, where EGFP is ectopically expressed in POMC-lacking immature neurons in this strain,
were quantified.
Results: Averages of 1.17  0.45 and 2.96  0.76 g/kg ethanol were consumed during short
(20 min) and long (4 h) access, respectively. c-fos immunoreactivity was observed in 20–45% of
arcuate EGFP-positive neurons in ethanol consuming animals, which was correlated with blood
ethanol levels. In water-consuming animals, c-fos immunoreactivity was observed in <2% of EGFP-
positive neurons. EGFP expressing cells in the dentate gyrus showed no c-fos immunoreactivity in
either group. Effects of TMT exposure are currently being analyzed.
Conclusions: Ethanol intake increases the activity of POMC-containing arcuate neurons in a dose-
related manner, but has no effect on the activity of POMC-lacking immature neurons in the dentate
gyrus. Given prior evidence for a role of POMC-related neuropeptides in stress responses, activation
of these neurons may be a common neural substrate of both ethanol and stressor exposure.
112
ATTENUATION OF ANXIETY AND CRAVING USING NEUROSTEROIDS AMONG INDIVIDUALS
WITH ALCOHOL USE DISORDER AND COMORBID PTSD
E. Ralevski, J.S. Jane, J. Newcomb, I. Petrakis
Yale University School of Medicine VACT Healthcare System 950 Campbell Avenue, #116A West
Haven, CT 06516, USA
Purpose: The role of stress in the vulnerability, initiation and maintenance of AUD and PTSD is well
established. Stress is linked to relapse to drug and alcohol use in and human laboratory models have
been used to explore this relationship. Neurosteroids are central in the regulation of the hypothalamic
pituitary adrenal (HPA) axis and the stress response. They act on a number of different receptors;
most notably gamma-aminobutyric acid (GABA) and glutamate. Of all neurosteroids, progesterone
through its metabolite allopregnanolone has the most direct effect on GABAa receptors. The primary
goal of this study is to determine whether pretreatment with progesterone will attenuate trauma-
induced alcohol craving and trauma-induced anxiety in patients with AUD and PTSD.
Methods: This is an ongoing, double-blind, randomized, between subject, placebo-controlled study
designed to compare pretreatment with progesterone (3 days of 200 mg. bid) to placebo. On a sin-
gle test day trauma (based on each patient traumatic experiences) and neutral cues consisting of
personalized 5 min scripts are presented in random order. The main outcomes, administered before
(pre), shortly after (post) and 10 min (recovery) after script presentation, include trauma-induced
alcohol craving and trauma-induced anxiety; other outcomes include subjective mood effects, cogni-
tive performance, and motor coordination.
Results: Progesterone when compared to placebo significantly reduced trauma-induced craving
(p < 0.05) measured using the Visual Analogue Scale (VAS). The same was true for anxiety mea-
sured using both the VAS anxiety scale (p < 0.05) and the Differential Emotions Scale -Revised
(DES-R) anxiety subscale (p < 0.05). Other negative emotions like fear and anger (measured using
the DES-R) were also significantly reduced after pretreatment with progesterone when compared to
placebo. Conclusions
The preliminary findings from our data show that progesterone is superior to placebo in reducing
trauma-induced craving and negative emotions. Our data also suggests that neurosteroids, specifi-
cally progesterone may have a role in treatment of AUD and PTSD.
ABSTRACTS-SPEACKERS
MONDAY, JUNE 18 1:20PM–2:50PM
SYMPOSIUM 113–116
The Endocannabinoid System and Compulsive Drinking: From Neural Circuits
to Human Behavior
Organizers/Chairs: Matthew Sloan and David Lovinger
113
ENDOCANNABINOID METABOLISM IN THE BRAIN OF HEAVY DRINKING YOUTH: A PET
STUDY WITH THE FATTY ACID AMIDE HYDROLASE RADIOLIGAND [11C]CURB
L.M. Best, C.S. Hendershot, S. Jagasar, J. Tong,B. Le Foll, S. Houle, R.F. Tyndale, R. Bazinet,
S.J. Kish, I. Boileau
Centre for Addiction and Mental Health, Toronto, ON M5T1R8, Canada
Purpose: Fatty acid amide hydrolase (FAAH) is the catabolic enzyme for anandamide, a major
endocannabinoid neurotransmitter. It has been suggested that lower FAAH levels might be associ-
ated with risk for alcohol use disorder (AUD). Preclinical studies found reduced FAAH levels in rats
bred to prefer alcohol prior to alcohol exposure, and we recently confirmed, using positron emission
tomography (PET), that humans with AUD have reduced FAAH brain levels. The goal of this study
was to determine whether FAAH brain levels are reduced in heavy-drinking youth at putative genetic
risk for AUD (based on a family history of AUD), and associated with behavioural phenotypes related
to risk for AUD.
Methods: FAAH levels were measured with PET imaging using the FAAH radioligand [11C]CURB
in 31 healthy males (n = 15) and females (n = 16) aged 19 to 25 (mean 21 years old), with either a
family history of AUD (n = 14) or no family history of AUD (n = 17) and who reported heavy drinking
in the past month. Subjects also completed an intravenous alcohol infusion session to assess alcohol
sensitivity. Blood samples were taken to determine FAAH C385A genotype (rs324420) and peripher-
ally-circulating endocannabinoid levels.
Results: There was no significant difference in FAAH levels between family history positive and
family history negative subjects; drinking outcomes were also not different across groups. Lower
FAAH levels were correlated with more alcohol use per week (drinks / week), greater scores on the
Alcohol Use Disorders Identification Test (AUDIT), and lower self-reported sedative / intoxicated
effects of alcohol during alcohol challenge (max score, Biphasic Effects of Alcohol Scale).
Conclusion: Preliminary findings show no association between family history of AUD and reduced
FAAH levels in the brain. Our findings that lower FAAH levels in the brain (associated with greater
anandamide levels) is associated with lower subjective responses during alcohol challenge and
greater AUDIT scores suggest that FAAH may be a potential predictor of vulnerability to alcohol use
problems in humans.
114
ENDOCANNABINOID MODULATION OF ALCOHOL WITHDRAWAL ANXIETY
G. Bedse, T. Patrick, S. Patel
Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville,
TN 37232, USA
Negative affective symptoms trigger relapse in abstinent subjects with alcohol use disorder (AUD),
however, treatment options for anxiety and depressive disorders in patients with AUD is limited and
these co-morbidities are often refractory to conventional treatments. Augmentation of endogenous
cannabinoid signaling has been suggest to represent a novel treatment for anxiety and depressive
disorders but a potential role for this mechanism in the treatment of negative affective states associ-
ated with alcohol withdrawal has only begun to be investigated. We will describe a model of voluntary
alcohol consumption and forced abstinence resulting in a long-lasting anxiety like phenotype in C57
mice. We describe studies aimed at understanding synaptic and biochemical adaptations in endo-
cannabinoid signaling the extended amygdala, and the potential therapeutic utility of endocannabi-
noid augmentation strategies in this model. Elucidating novel approaches to target negative affective
symptoms associated with alcohol withdrawal could have significant impact on co-morbid mood and
anxiety disorders and in relapse prevention in patients with AUD.
299A
115
CHRONIC INTERMITTENT EXPOSURE TO ETHANOL CAUSES PERSISTENT CHANGES IN
THE CB1 AND CRF REGULATION OF GABA RELEASE ONTO VTA DOPAMINE NEURONS
B.J. Harlan, J.J. Woodward, H.C. Becker, A.C. Riegel
Department of Neuroscience, Medical University of South Carolina (MUSC), Charleston, SC 29425,
USA
The acute rewarding actions of ethanol are associated with changes in dopamine and GABA trans-
mission in the Ventral Tegmental Area (VTA). Under control conditions, neuromodulators such as
the stress neuropeptide Corticotrophin Releasing Factor (CRF) and endocannabinoids help coordi-
nate neurotransmitter release. How chronic ethanol exposure and the prolonged period of absti-
nence that follows alter the actions of CRF and endocannabinoids in the VTA remain unclear. We
hypothesize that chronic ethanol exposure causes a persistent reduction in the CRF-regulation of
GABA transmission in the VTA, through increased activation of cannabinoid type 1 (CB1) receptors.
To test this hypothesis, we recorded VTA dopamine cells in the current and voltage clamp configura-
tions in brain slices from mice with a history of exposure to chronic intermittent ethanol (CIE) or air
controls. Under control conditions, the activation of presynaptic CRF receptors with either bath
applied CRF (200 nM) or urocortin (200 nM) facilitated GABA release. The CRF facilitation was
blocked by co-application of the CRF-R1 antagonist CP154156, but not the CRF-R2 antagonist
K41498. Acute bath application of ethanol produced similar increases in GABA release. Pharmaco-
logical studies indicated that the potentiation by CRF or ethanol required a PKC-mediated release of
calcium via intracellular IP3/ryanodine receptors. Acute stimulation of CB1 receptors reversed the
facilitation of GABA release produced by ethanol or CRF. To determine if in vivo exposure to ethanol
also altered the acute actions of CRF or ethanol on GABA transmission, we measured GABA
responses during a 40 day abstinence period following exposure to CIE (28 days). Under these con-
ditions, the acute CRF/ethanol actions were occluded by a persistent activation of CB1 receptors.
This adaptation could be reversed by blockade of presynaptic CB1 receptors with AM251 or chela-
tion of intracellular calcium with BAPTA. Thus, the abstinence period following exposure to CIE is
associated with reduced GABA release and reduced sensitivity to the stress peptide CRF, while acti-
vation of CB1 appeared increased. These findings demonstrate that both acute and repeated expo-
sure to ethanol dysregulates CRF/CB1 plasticity in VTA GABA synapses in a manner that would be
expected to facilitate mesolimbic dopamine output. Such findings may hold relevance for alcohol
seeking in humans.
116
ACUTE ALCOHOL EXPOSURE ALTERS CIRCULATING CANNABINOID LEVELS IN HUMANS
M.E. Sloan, T.D. Klepp, B.L. Stangl, H.W. Brewton, R. Cinar, L.E. Kwako, R. Sinha, G. Kunos,
V.A. Ramchandani
Section on Human Psychopharmacology, National Institute on Alcohol Abuse and Alcoholism,
Bethesda, MD 20892, USA
Purpose: Recent evidence suggests that severity of alcohol dependence is associated with the fatty
acid amide hydrolase (FAAH) C385A polymorphism, a functional polymorphism that leads to
decreased anandamide metabolism in humans. Although higher anandamide levels may affect alco-
hol consumption, it remains unclear whether alcohol consumption alters anandamide levels. The
objective of the current analysis is to determine the effects of acute ethanol administration on circulat-
ing anandamide levels in humans.
Methods: Twenty-five healthy social drinkers were genotyped for FAAH C385A and participated in
an intravenous alcohol self-administration study in which they underwent three personalized imagery
sessions. During each session, the participants were presented with one of three 5-min auditory
scripts: an alcohol-craving script, a stressful script, and a neutral script. Following script presentation,
the participants were given the opportunity to self-administer alcohol intravenously for a 120-min per-
iod. To avoid the potentially confounding effects of stress-induction and alcohol craving, data were
analyzed for the neutral script session only. Circulating anandamide levels were obtained prior to
script presentation and at minute 45 of the intravenous alcohol self-administration session for 23 of
the 25 participants.
Results: In the neutral script session, the mean anandamide level was 2.26 pmol/mL (SD = 0.64)
at baseline and 1.41 pmol/mL (SD = 0.50) at minute 45 of the alcohol self-administration session. A
paired t-test revealed a significant reduction in mean anandamide level by minute 45 of the infusion
(t(22) = 7.61, p < 0.001). Analysis split by FAAH genotype revealed similar reductions in both C/C
homozygotes (mean difference = 0.81 pmol/mL, t(9) = 4.689, p = 0.001) and A allele carriers
(mean difference = 0.89 pmol/mL, t(8) = 5.34, p = 0.001). A trend was observed such that the peak
blood alcohol level attained during the first 30 min of the session was moderately correlated with the
change in anandamide levels at minute 45 of the session (r =
0.43, p = 0.065).
Conclusions: These results indicate that alcohol decreases circulating anandamide levels in
humans irrespective of FAAH genotype. Our findings also suggest an exposure-response relation-
ship between alcohol intake and anandamide reduction, such that individuals who consume larger
amounts of alcohol have greater reductions in anandamide levels.
300A ABSTRACTS-SPEACKERS

MONDAY, JUNE 18 1:20PM–2:50PM 119

SYMPOSIUM 117–120
Brain Dynamics in Human Alcoholism: From ERPS to Functional DEFAULT MODE NETWORK ALTERATIONS IN ALCOHOLISM: FUNCTIONAL CONNECTIVITY
OF RESTING EEG AND FMRI
Connectivity C. Kamarajan1,2, B.A. Ardekani1,2, A.K. Pandey1,2, B. Porjesz1,2
Organizer: Chella Kamarajan Henri Begleiter Neurodynamics Lab, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.
Chairs: Bernice Porjesz and Ashwini Pandey
Center for Advanced Brain Imaging, Nathan Kline Institute for Psychiatric Research, Orangeburg,
NY 10962, USA.
Neurocognitive impairments have been reported in individuals with alcohol use disorder (AUD) and
117 those at high risk (HR) to develop AUD, particularly those from families densely affected with alco-
holism. These impairments may reflect altered functional connectivity (FC), which has been
BINGE DRINKING: ELECTROPHYSIOLOGICAL INDICES OF ALLOSTASIS, COGNITIVE, AND observed in several psychiatric disorders, including AUD. EEG based default mode network (DMN)
EMOTIONAL DEFICITS connectivity in combination with fMRI-FC have not been studied in alcoholism. The goal of the pre-
K. Marinkovic sent study is to examine both EEG and fMRI based FC of the DMN in individuals with AUD and those
Psychology, San Diego State University, San Diego, CA 92182, USA at risk. The AUD sample comprised 30 detoxified adult male alcoholics and 30 male controls, and
the HR sample comprised 60 adolescents and young adults with a range of family history density
Binge or heavy episodic drinking is prevalent among young adults and is a public issue of increasing
(FHD) of alcoholism. The resting state fMRI-FC was computed as a linear correlation between the
importance. It is associated with a range of harmful consequences including increased risk of devel-
BOLD time series of the DMN seed regions, while the eyes-closed resting state EEG-FC (from 61
oping alcohol use disorder (AUD). However, the extent of neural changes and deficits may not be
scalp electrodes) represented linear lagged connectivity computed using the eLORETA software.
fully appreciated since they are often apparent only when measured directly with sensitive methods
The results showed that alcoholics, relative to the controls, manifested decreased fMRI-FC across
while group differences on behavioral measures are subtle or nonexistent. Initiation and mainte-
hippocampal formation (HCF) and anterior and posterior cingulate cortices (ACC and PCC), while
nance of binge drinking are accompanied by deficits in executive and affective domains but the neu-
showing increased EEG-FC in fast beta frequencies across prefrontal cortex (PFC), inferior parietal
ral dynamics of underlying changes is poorly understood. In a series of EEG studies we have
lobule (iPL), lateral temporal cortex (lTC), and HCF regions. By contrast, individuals with high FHD
compared groups of young binge drinkers (BD) and low-drinking (LD) participants matched on demo-
showed increased fMRI-FC across the DMN regions (PFC, ACC, PCC, iPL, and l-TC) in the left
graphic variables, family history of alcoholism, and cognitive capacity. In the absence of group differ-
hemisphere but decreased EEG-FC in theta (lTC, ACC, and iPL) as well as fast beta frequencies
ences on performance measures, binge drinkers showed selective attenuation of event-related theta
(ACC, HCF, and PFC), compared to those with low FHD. These findings of altered connectivity in
oscillations during Go-NoGo response inhibition and greater early beta decrease after controlling for
alcoholics as well as those at risk from high density families may indicate underlying neurocognitive
anxiety, depression, and impulsivity. These changes are indicative of deficits in circuitry subserving
deficits as well as hyperexcitability in distinct brain networks.
response inhibition. On a Stroop task, binge drinkers showed increased interference and lower differ-
ential sensitivity to response conflict as reflected in event-related theta power. When presented with
emotionally evocative images, the BD and LD groups did not differ in their subjective ratings. How-
ever, affective modulation of event-related theta power was attenuated in BD suggesting the blunted
long-range corticolimbic integration which is consistent with compromised affective functions in
AUD. The analysis of spontaneous EEG oscillations during wakeful rest showed slower alpha peak
frequency, which is suggestive of dysregulated thalamocortical network. Overall, these effects corre-
120
lated with a range of alcohol-related variables and were particularly evident in individuals engaging in PARALLEL ICA ANALYSIS RELATING EEG COHERENCE TO FMRI RESTING STATE
hazardous drinking. In another set of studies, activity in early visual cortex was attenuated by acute SYNCHRONY IN LONG-TERM ABSTINENT ALCOHOLICS
alcohol intoxication in social drinkers. In contrast, it was increased in sober BDs and it correlated with V.A. Cardenas
AUDIT scores. These findings indicate hyperexcitability confirming the allostasis-based opponent- Neurobehavioral Research, Inc., Kahului, Maui, HI 96732, USA
process theory. In sum, electrophysiological indices are sensitive to the effects of neurotoxicity asso-
ciated with excessive consumption. They can potentially serve as biomarkers of transition to depen- Purpose: Recent work suggests that faulty co-activation or synchrony of multiple brain regions
dence and may guide development of intervention strategies aimed at preventing transition to comprising “networks,” or an imbalance between opposing brain networks, is important in alco-
alcoholism. holism. Our prior work demonstrated higher fMRI resting state synchrony (RSS) within the executive
control (inhibitory control and emotion regulation) networks and lower RSS within the appetitive drive
network in long-term (multi-year) abstinent alcoholics (LTAA) versus non-substance abusing controls
(NSAC).
Method: We used parallel ICA for multimodal data fusion in order to determine if there were EEG
networks reflecting appetitive drive and executive function network fMRI synchrony.
118 Data: Resting-state fMRI and 64-channel eyes-open spontaneous EEG for 20 LTAA and 21 NSAC.
Results: Parallel ICA identified a pair of components that significantly separated NSAC from LTAA
REGIONAL DIFFERENCES IN CORTICAL THICKNESS ARE ASSOCIATED WITH EVENT- and were correlated with each other. Examination of the resting-state fMRI seed-correlation map
RELATED POTENTIAL COMPONENTS: ANALYSES BY FAMILIAL RISK FOR ALCOHOL component showed higher bilateral nucleus accumbens seed-correlation in the dorsolateral pre-
DEPENDENCE frontal cortex bilaterally and lower seed-correlation in the thalamus. This single component thus
S.Y. Hill, S.R. Steinhauer encompassed both the executive control and appetitive drive networks, consistent with our previous
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA work. The correlated EEG coherence component showed mostly higher theta and alpha coherence
in LTAA compared to NSAC, and lower gamma coherence in LTAA compared to NSAC.
Background: Familial risk differences in amplitude of specific ERP components have been demon-
Conclusions: The EEG theta and alpha coherence results suggest enhanced top-down control in
strated in multiple replications across labs. Some of these differences appear to change with devel-
LTAA and the gamma coherence results suggest impaired appetitive drive in LTAA. Our results sup-
opment most likely in association with maturation of brain structures. Cortical thickness is one
port the notion that fMRI RSS is reflected in spontaneous EEG.
measure of brain morphology that changes with development. It is also reported to be positively
related to general intelligence (Menary et al 2013) though negatively related to specific neuropsycho-
logical measures (Sequelia et al 2013). With the capability of assessing multiple brain regions using
FreeSurfer, we tested whether regional differences in cortical thickness map to specific ERP mea-
sures.
Methods: Participants (N = 217) from high (N = 113) and low risk (N = 104) for alcohol depen-
dence families were scanned using magnetic resonance imaging (MRI) at 3T. The subjects were
ages 13–38 at the time of MRI scan (mean = 25.2 + 4.9; median = 25.5). Cortical thickness was
analyzed using FreeSurfer. The subjects were part of longitudinal study in which multiple event-
related potential recordings were obtained during childhood, adolescence and young adulthood.
Using the visual ERP recording nearest in time to the MRI scan, preliminary analyses were com-
pleted to determine the patterns of associations between brain regions and ERP components. Those
regions showing significant association were tested for familial risk group differences.
Results: First level analysis revealed a greater number of significant associations between regional
cortical thickness and P300 amplitude than with earlier components (N1 and N2). Those correlations
showing significance at p < 0.01 were tested for their relationship to familial risk status. Among the
significant correlations were cortical thickness of the right hemisphere (rh) pars opercularis and later-
alorbital region in the left hemisphere (lh). These regions were significantly related to risk group sta-
tus: (lh lateralorbital F = 7.31, df 1, 215, p = 0.007 and rh pars opercularis F = 6.98, df = 215,
p = 0.009). Conclusions
Neural activity reflected in P300 amplitude is positively related to cortical thickness in regions found
to differ by familial risk status and involved in impulsivity and decision-making.
ABSTRACTS-SPEACKERS
(MONDAY, JUNE 18 1:20PM–2:50PM
SYMPOSIUM 121–124
Long-Term Consequences of Heavy Drinking in Different Populations:
International Perspectives
Organizers/Chairs: Michie Hesselbrock and Susumu Higuchi
121
LIVER STIFFNESS PRIOR AND AFTER ALCOHOL DETOXIFICATION AS A NOVEL
PROGNOSTIC MARKER IN HEAVY DRINKERS: FIRST DATA FROM A PROSPECTIVE
COHORT
J. Mueller, H. Raisi, V. Rausch, I. Silva, T. Peccerella, F. Piecha, C. Dietrich, H.K. Seitz, S. Mueller
Department of Internal Medicine, Salem Medical Center and Center for Alcohol Research, University
of Heidelberg, 69121 Heidelberg, Germany
Background and Aims: Alcoholic liver disease (ALD) is the most common liver disease in the
western world. Although measurement of liver stiffness (LS) by transient elastography has been well
established for early diagnosis of fibrosis, no prospective long-term data on survival exist so far in
patients with ALD. We here present first data on the prognostic impact of LS on long-term survival of
Caucasian drinkers primarily presenting for alcohol detoxification. Method
Information of survival status was obtained in 225 (96.9%) of 232 screened patients that had pre-
sented for alcohol detoxification over a 10 year period from 2007–2017 with a mean daily consump-
tion of alcohol of 190.3 g. Mean observation time was 3.1 years and mean duration of heavy
drinking was 15.9 years. All patients had LS measurements by transient elastography and routine
lab tests.
Results: Initial distribution of fibrosis stage F0, 1–2, 3 and 4 was 51%, 14%, 12% and 22%. During
the observation time, 28 patients (13.5%) passed away. In 19 patients, a cause of death could be
identified which was liver-related in 11 cases (58%). Two patients with liver- related death had pri-
mary liver cancer (HCC). LS (r = 0.25), bilirubin (r = 0.29) and INR (r = 0.29) were all highly associ-
ated (p < 0.001) with liver-related death but not with overall mortality. LS was also a significant and
independent predictor of liver-related death (p < 0.005) in multivariate analysis. Mortality risk
increased by 4.1% per unit kPa of LS elevation. In 131 patients, we were able to assess laboratory
markers and LS prior and after alcohol detoxification during a mean detoxification period of 5.3 days.
To our surprise, LS after detoxification was significantly better in predicting death as compared to the
initial LS (0.0004 vs. 0.0015). Moreover, LS increased by 6.2 kPa in the cohort with liver-related
death during detoxification while it decreased by 1.9 kPa in the surviving cohort.
Conclusion: We here show that LS predicts long-term mortality in heavy drinkers primarily present-
ing for alcohol detoxification. Notably, LS values after alcohol detoxification are a better predictor of
survival as compared to the LS values prior to alcohol withdrawal.
122
PREDICTING TREATMENT OUTCOMES AMONG JAPANESE ALCOHOL DEPENDENT
PERSONS WHO RECEIVED INPATIENT COGNITIVE BEHAVIORAL THERAPY
M. Kimura, A. Yoshimura, J. Yoneda, H. Maesato, T. Takimura, H. Nakayama, H. Sakuma,
T. Toyama, A. Yokoyama, S. Matsushita, S. Higuchi
Department of Psychiatry Yokosuka, Kurihama Medical and Addiction Center, National Hospital
Organization, Kanagawa 2390841, Japan
Purpose: This study examined treatment outcomes and prognostic factors among alcohol depen-
dent patients who received inpatient Cognitive Behavioral Therapy (CBT).
Subjects and methods: Subjects included 637 patients (543 male, 94 female) diagnosed as alco-
hol dependent who were admitted to Kurihama Medical and Addiction Center during 2014–2015.
Most patients participated in an 8 week CBT-based treatment program. After discharge, each patient
was sent a questionnaire by mail for 12 months, once a month for the first 6 months and every
2 months for the following 6 months. Subjects who did not respond for three months in a row were
withdrawn from the study. The relapse rate was estimated using Kaplan–Meier method and analyzed
by log rank test.
Results: 439 patients responded in the first month and 241 patients were tracked for 12 months
after discharge. 125 patients were re-hospitalized due to alcohol problems, and 15 patients died.
The rate of the patients who never drunk any alcohol beverage during follow-up was estimated at
32% in men and 28% in women. However, 54% of the male patients and 48% of female patients had
not relapsed for 12 months when the relapse was defined as drinking more than 60 g of alcohol once
a week or more frequently. Better outcomes were found in the 60+ year old patients, particularly
among male patients. Patients with major depression and patients with antisocial personality disor-
der (ASPD) reported worse outcomes on their questionnaires. Moreover, patients who attended fol-
low-up sessions at the psychiatric clinic for the first month after discharge reported better outcomes.
Patients who consumed non-alcoholic beverages (e.g., alcohol-free beer) or smoked tobacco during
the first month post-discharge were more likely to relapse into binge drinking.
Conclusion: Approximately half of the patients who received inpatient CBT remained relapse-free
for 1 year post-discharge, although only about 30% of the patients were totally abstinent. Being
younger (<60 years old), female, having a comorbid psychiatric disorder (e.g., depression, ASPD),
smoking and use of alcohol-free beverages was associated with higher relapse rates.
301A
123
PERSISTENT ALCOHOL USE & PROBLEMS AMONG ALCOHOL DEPENDENT ADULTS OVER
A 20 YEAR PERIOD
V. Hesselbrock, M. Hesselbrock, G. Chan, COGA Colleagues
Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT 06030-
2103, USA
Purpose: Alcohol dependence occurs across the lifespan, with varying alcohol related conse-
quences occurring at different life stages. Alcohol use typically begins in adolescence often progress-
ing to alcohol use disorder in young adulthood. While the rates of heavy drinking tend to decline as
people age, some continue heavy drinking. Chronic heavy drinking is associated with both physical
and psychological deleterious consequences, including a high mortality rate. However, the longitudi-
nal course of chronic heavy alcohol consumption among adults has not been well documented. This
presentation will examine the drinking status, health status and use of treatment among a large sam-
ple of adults re-assessed 20 years after their initial assessment.
Methodology: Subjects are participants in the Collaborative Study of the Genetics of Alcoholism
(COGA) beginning in 1991. Detailed information was gathered across a variety of domains from both
treated and untreated alcohol dependent adult subjects. Recently, a 20+ year follow-up telephone
interview was conducted with 657 subjects [55% male; avg. age = 60.4 years] to obtain information
regarding their current demographic, alcohol use, physical and mental health status, and the use of
treatment services. Possible predictors of persistent heavy drinking and mortality were examined.
Results: 56% of subjects reported having a drink within 12 months of the interview, while 204 sub-
jects (31.1%) had not had a drink for over 10 years. More than half of subjects reported having high
blood pressure; other reported physical problems included diabetes, emphysema, cancer and heart
disease. While fewer current drinkers rated their overall physical and mental health as excellent, no
difference in specific health problems was found among those who are current drinkers, those who
have had a drink either in the past 5 years or in the past 10 years. However, nearly one-third of those
drank during the past 5 years had also received more recent treatment for alcohol problems.
Conclusions: Our data suggest that former heavy drinkers with alcohol dependence who quit drink-
ing may do so because of their poor health.
124
LONG-TERM MORTALITY ASSOCIATED WITH HEAVY DRINKING AND STABLY DIAGNOSED
AUD IN A COMMUNITY SAMPLE
K.K. Bucholz
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA
Purpose: To determine 14-year mortality rates among 3 groups of a general population sample with
different histories of AUD and to identify specific AUD symptoms associated with mortality.
Methodology: Data from 711 community-dwelling individuals (20% female, 25% Black) who partici-
pated in two assessment waves conducted about one year apart from 1981 to 1983 as part of the St.
Louis Epidemiologic Catchment Area (ECA) study were followed up 14 years later. Three groups
were selected: those who met lifetime DSM-III criteria for AUD at both ECA waves (Stably-diagnosed
AUD- “SA”), heavy drinkers without AUD (“HD”) and nonheavy drinkers, non AUD (low risk- “LR”).
HD and LR groups were matched by demographic characteristics to SA. Death certificates were
obtained. Baseline characteristics including demographics and AUD symptoms were analyzed
across the 3 groups to determine associations with mortality.
Results: Crude mortality rates over the 14 year follow up was 21.5% overall, and higher in SA
(26%) than in HD (19%) or LR (20%). In logistic regressions, controlling for age, gender, and race/
ethnicity, compared to their HD counterparts, SA were 1.7 times more likely to have died over the
interval (OR = 1.7, 95% CI 1.01–2.86), and twice as likely to have died compared to their LR coun-
terparts (OR = 2.01, 95% CI 1.13–3.58). In contrast, there were no differences in odds of death
between HD and LR. (OR = 1.04 95% CI 0.60–1.81). Examination of associations of mortality with
specific AUD symptoms at baseline, controlling for all other AUD symptoms, along with age, gender
and race/ethnicity, revealed that for both SA and HD, those who reported that others (not solely clini-
cians) had told them they were drinking too much were over 3 times as likely to die in the 14 year
period. Having shakes after heavy drinking was also associated with a 2-fold increase in odds of
death among SA.
Conclusions: Findings are suggestive that having peers recognize and communicate concerns
about excessive drinking may be linked to a greater likelihood of death in both those with AUD and
heavy drinkers without AUD. Utility of this information for clinical practice is considered.
302A
MONDAY, JUNE 18 1:20PM–2:50PM
SYMPOSIUM 125–128
Ecological Momentary Assessment of Impulsivity in Alcohol Studies
Organizer/Chair: Kevin King
Organizer: Sarah Pedersen
125
MEASURING IMPULSIVITY IN THE MOMENT: MULTILEVEL CONFIRMATORY FACTOR
ANALYSIS OF BETWEEN- AND WITHIN-PERSON VARIABILITY IN IMPULSIVITY
M.A. Halvorson, K.M. King
University of Washington, Seattle, WA 98195, USA
Ecological momentary assessment (EMA) methods allow researchers to explore psychological pro-
cesses in the moment. However, items used in EMA designs are largely adapted from question-
naires developed to discern between-person differences (i.e., Whiteside & Lynam, 2001; Sharma
et al., 2014), and have not been psychometrically validated in EMA data. As impulsivity is a critical
predictor of alcohol use (Grekin, Sher & Williams, 2005), we examined the factor structure of EMA-
assessed impulsivity and relations with alcohol use. Using data from two EMA studies with teens
(n = 61) and young adults (n = 161), we conducted multilevel confirmatory factor analyses in MPlus
8.0 to test the between- and within-person factor structure of three scales of the UPPS (Whiteside &
Lynam, 2001). We examined six urgency items (with affective content removed; hereafter referred to
as acting on impulse, AOI), three planning items, and four persistence items. Participants completed
a baseline assessment of the UPPS and problem alcohol use (the RAPI, White & LaBouie, 2000),
and reported on impulsivity three times a day over a period of ten consecutive days via SMS-initiated
web surveys (completion rate > 86%). All items exhibited considerable between- and within-person
variability (ICCs 0.28–0.41). We first examined the multilevel single-factor models for the three impul-
sivity facets. In the single-factor models, all items loaded at 0.65 or above except for one AOI item
(0.47) and one persistence item (0.46); these items were dropped from multi-factor models. Next, we
fit a multilevel CFA model with correlated factors for AOI, planning, and persistence. This model gen-
erally fit the data well (CFI = 0.916, RMSEA = 0.040, SRMR between = 0.038, SRMR within =
0.049), with all items loading at 0.65 or above at both levels. Consistent with prior work, planning and
persistence were highly correlated both within (0.80) and between (.78) individuals, and AOI was
weakly negatively correlated with planning and persistence (
0.08 to
0.22). EMA-assessed impul-
sivity correlated modestly with retrospective trait reports of impulsivity (0.32–0.52) and with problem
alcohol use at comparable magnitudes to trait reports. Results generally support distinctions
between UPPS facets at the momentary level, and suggest EMA-assessed traits may differ in impor-
tant ways from retrospectively reported traits, offering novel insights into their relations to problem
alcohol use.
126
NEGATIVE URGENCY IN THE WILD: DO TRAIT REPORTS REFLECT DAY-TO-DAY
PROCESSES?
M.C. Feil, K.M. King
Department of Psychology, University of Washington, Seattle, WA 98195, USA
Negative urgency, the tendency to act impulsively under negative affect, is a personality trait that is
strongly associated with alcohol problems. However, retrospective recall of behavior is biased
because autobiographical recall involves an active reconstruction process (Shiffman, Stone, & Huf-
ford, 2008), and may be particularly biased among those high on urgency due to its strong associa-
tions with neuroticism (Ruiz-Caballero & Bermu dez, 1995). Thus, Ecological Momentary
Assessment (EMA) of behavior and emotions are critical to understanding the momentary process
that characterizes negative urgency, and to explaining its links to alcohol use. We used EMA to test
whether negative urgency strengthened the association between negative emotions, impulsive
behaviors and alcohol use. We sampled college students who reported at least weekly heavy drink-
ing (n = 152). Participants completed a baseline survey, and then 10 days of EMA assessments (3
times per day) sent via SMS to their web-enabled smartphones. We measured trait negative urgency
with the UPPS (Whiteside & Lynam, 2001), EMA impulsivity with six trait items modified to remove
affective content, and affect with the PANAS (Watson, Clark & Tellegen, 1988). Number of drinks
and intoxication the prior day were measured at the first assessment of each day. Generalized mixed
linear models in R 3.4.2 indicated that on average, negative affect at each assessment was associ-
ated with more impulsive behaviors at the next (b = 0.11, p < 0.001). Trait urgency strongly associ-
ated with higher levels of impulsive behaviors on average (b = 0.81, p < 0.001), but did not
moderate the effects of negative emotions on impulsive behaviors. We found similar mixed effects
on alcohol use: although within-person variation in impulsive behaviors (prior to the start of alcohol
use) was related to alcohol use (RR = 2.64, p < 0.01) and intoxication (RR = 3.23, p < 0.01), the
effects of impulsive behaviors were not moderated by negative affect. Daily variation in impulsive
behaviors reflects the real-time unfolding of trait urgency, and is strongly predictive of daily alcohol
behaviors. To understand the role of negative emotion in negative urgency, it may be critical to disag-
gregate negative affect to identify emotion-specific motivators of impulsive behavior.
ABSTRACTS-SPEACKERS
127
REAL-WORLD INCREASES IN IMPULSIVITY FOLLOWING ALCOHOL CONSUMPTION:
DIFFERENCES ACROSS RACE AND ADHD HISTORY
S.L. Pedersen, K.A. Fleming, B.S.G. Molina
University of Pittsburgh, Pittsburgh, PA, 15213, USA
Laboratory-based studies on adults with ADHD have shown increased behavioral impulsivity follow-
ing alcohol consumption relative to adults without ADHD (Fillmore, 2009). Trait negative and positive
urgency are two domains of impulsivity that may partially account for the association between ADHD
and alcohol problems (Pedersen et al., 2016). The current study extends this prior research by
examining multiple domains of state impulsivity in the natural environment before and after alcohol
consumption for adults with and without a history of ADHD. Differences between Black and White
drinkers, a notably understudied topic, were also examined. Adult drinkers (N = 239; n = 123 ADHD,
n = 79 Black; Mage = 28; 75% male) completed a 10-day ecological momentary assessment proto-
col. At each assessment, participants completed seven modified items of the UPPS-P impulsivity
scale to assess three domains of state impulsivity (negative urgency, positive urgency, sensation
seeking). The current study utilized data from the first three assessments of each day and the self-
initiated report following the first alcoholic drink of that day. Multilevel models were conducted with
sex, ADHD history, and race predicting change in impulsivity from the first three time points of the
day to later that day after one drink. Significant interactions between ADHD, race, and assessment
type (drink vs. non-drink) were found in models predicting sensation seeking (F(3005) = 12.39,
p < 0.001), negative urgency (F(3005) = 14.71, p < 0.001) and positive urgency (F(3005) = 15.59,
p < 0.001). Sensation seeking increased after one drink for all participants except Black drinkers with
a history of ADHD. ADHD was related to increased negative urgency after drinking across race.
Black drinkers without ADHD had a larger increase in positive urgency after one drink relative to
White drinkers without ADHD. The current findings are the first to show that multiple impulsivity
domains increase after only one alcoholic drink in the real-world. Intervention strategies that aim to
buffer these effects while drinking, particularly related to negative and positive urgency, may be ben-
eficial for drinkers with ADHD or Black drinkers – populations that are vulnerable to experiencing
alcohol-related problems. Additional research examining contextual factors affecting impulsivity
post-drinking could further identify periods of increased risk.
128
MEASURING IMPULSIVITY IN THE MOMENT: ASSOCIATIONS WITH ALCOHOL USE
R. Tomko, A. Wycoff, S. Lane, T. Trull
Department of Psychological Sciences, University of Missouri, Columbia, MO 65211, USA
Heightened disinhibition or impulsivity is associated with a number of psychiatric and substance use
disorders. In particular, impulsivity is thought to be both a risk factor for and consequence of chronic
alcohol use. Though numerous retrospective, self-report measures assessing trait impulsivity exist
and state-based deficits in inhibitory control can be measured with controlled laboratory-tasks, little is
known about how impulsivity results in increased risk for alcohol use “in-the-moment.” A number of
situational factors may increase or decrease an individual’s propensity for impulsive responding at
any given moment. Using a psychiatric sample of 105 adults with borderline personality disorder or a
depressive disorder, a brief 4-item scale for measuring impulsivity in near real-time was developed.
Participants completed surveys on a mobile device for 28 days, up to six times per day. They were
asked about substance use and impulsivity since the last session. The impulsivity measure, when
averaged across all time points, showed modest associations with traditional, retrospective assess-
ments. In a sub-sample of individuals who reported alcohol or marijuana use (n = 77), heightened
momentary impulsivity was associated concurrently with increased alcohol use. However, because
alcohol use at the previous assessment did not predict current impulsivity, it is still difficult to disen-
tangle the temporal order of alcohol use and impulsivity. Additional analyses linking an independent
momentary impulsivity measure to electrodermal activity in real-time will be discussed, as impulsivity
may interact with physiological arousal to heighten risk for alcohol use. Future research should
examine temporal associations between impulsivity, alcohol use, and other characteristics of the
drinking episode using event-based reports. Additionally, other conceptualizations of impulsivity and
“impulsive alcohol use” should be considered to better understand how high trait impulsivity mani-
fests “in-the-moment” to increase risk for problematic alcohol use.
ABSTRACTS-SPEACKERS
MONDAY, JUNE 18 3:10PM–4:40PM
SYMPOSIUM 129–132
Alcohol-Induced Neuroinflammation; Cell Injury and Ethanol Volition
Organizers/Chairs: Fulton Crews and Adron Harris
129
PERIPHERAL ORIGINS OF NEUROINFLAMMATION IN ALCOHOL-USE-DISORDER
€rkel, N.M. Delzenne, G. Petit, S. Leclercq
P. de Timary, P. Sta
 catholique de Louvain, 1200
Department of Adult Psychiatry, Institute of Neuroscience, Universite
Brussels, Belgium
Numerous studies arising mainly from animal models have supported that alcohol-consumption
induces the development of an important neuro-immune signaling and this neuro-inflammation was
shown to contribute to alcohol-drinking behaviors, notably through LPS and TLR4 related mecha-
nisms. Large questions remain regarding the origins of this neuroinflammation, which may arise from
a direct interaction of ethanol with the neuronal and immune brain cells, but also from the generation
of an inflammation outside of the brain, in peripheral organs. Ethanol in particular interacts with the
largest source of immune compounds of the body, the intestine, to develop a an increase in gut per-
meability, that is also related to modifications of the composition of the gut microbiota. This leaky gut
leads to the liberation of bacterial fragments in the systemic circulation and to the induction a pro-
inflammatory responses in the systemic circulation and peripheral organs, and in particular in the
liver. Peripheral cytokines or activated peripheral cells may cross the blood-brain barrier and activate
neuro-inflammation. In humans, peripheral inflammation and intestinal dysbiosis are related to symp-
toms of alcohol use disorders (AUD), such as depression, anxiety and alcohol-craving. In this pre-
sentation, we will expose evidences in support of the role of the periphery to the generation of a brain
inflammation and modification of behavior in AUD, including recent observations made by our labora-
tory. This peripheral pathway may lead to new treatment targets for AUD.
130
ETHANOL ACTIVATES ‘DEATH RECEPTOR’ SIGNALING VIA TLR7 TO CAUSE
NEURODEGENERATION
L.G. Coleman1,2, J. Zou1,2, M. Calabrese1,2, W. Liu1,2, L. Qin1,2, F.T. Crews1,2
1
Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill NC,
USA and 2Department of Pharmacology, University of North Carolina School of Medicine, Chapel
Hill, NC, USA
Alcohol addiction is associated with neurodegeneration in the hippocampus and cortex. We discov-
ered that ethanol contributes to hippocampal neurodegeneration via a novel immune activating
micro-RNA signaling pathway. Ethanol releases the miRNA let-7b in microvesicles. Let-7b activates
the interferon-inducing single-stranded RNA virus sensing Toll-like Receptor 7 (TLR7) causing neu-
rodegeneration. We now investigate the mechanism of TLR7-mediated neurotoxicity. RNASeq
found ethanol causes interferon stimulated gene induction in SH-SY5Y neurons. TLR7 inhibition with
a novel inhibitor (MSC2581131) blocked ethanol-induced neuroimmune activation in hippocampal-
entorrhinal slice culture (HEC). Ethanol activated the death receptor pathway, specifically the TNF-
related apoptosis-inducing ligand (TRAIL). Both TRAIL receptors, DR4 and DR5, were upregulated.
Acute binge ethanol (6g/kg) increased TRAIL in mouse brain by nearly two-fold (**p < 0.01, 24 h)
as well as in plasma (4-fold, 12h) after ethanol. Ethanol increased TRAIL in BV2 microglia, by (2.3-
fold, **p < 0.01) and SH-SY5Y neurons (1.5-fold, *p < 0.05) at 24 hours. Ethanol caused a 140%
increase in DR5 expression in BV2 microglia at 12 hours after ethanol. Immunofluorescent co-label-
ing found the majority of TRAIL was present in neurons in vivo. In SH-SY5Y neuronal cultures, DR4
and DR5 were increased by 125% and 155% respectively 12 hours after ethanol treatment. Interest-
ingly, neurons released TRAIL into the media in response to ethanol (*p < 0.05, 6 h). To assess the
effect of ethanol on TRAIL-mediated neurodegeneration, HEC was used. Ethanol (100mM)
increased TRAIL (1.5-fold, *p < 0.05), DR4 and DR5 in HEC at 48 h of ethanol exposure. Pre-treat-
ment of slices with ethanol (48h) followed by addition of TRAIL resulted in a robust enhancement of
neurodegeneration, evidenced by a near 3-fold increase in propidium iodine uptake greater than
either TRAIL or ethanol alone (*p < 0.05). Thus, ethanol-induction of TRAIL involves TLR7. TRAIL
may represent a novel therapeutic target for neurodegeneration associated with alcohol abuse.
303A
131
FUNCTIONAL ROLE FOR GLIA IN VOLUNTARY ALCOHOL CONSUMPTION
A.S. Warden, E.K. Erickson, G.R. McCarthy, S.P. Farris, Y.A. Blednov, R.D. Mayfield,
R.O. Messing, R.A. Harris
Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX
78712, USA
Voluntary ethanol consumption in rodents alters glial gene expression. The contributions of different
glial cell types to the overall changes in gene expression in animal models of voluntary drinking are
largely unknown. Moreover, the causal role of voluntary drinking on glial gene expression remains
elusive. We performed RNA-sequencing on isolated astrocytes and microglia from prefrontal cortex
of C57BL/6J mice to identify cell type-specific expression changes in response to every-other-day
drinking (EOD). In astrocytes, EOD produced differential regulation of genes involved in calmodulin
and extracellular matrix binding. In microglia, EOD produced coordinated changes in innate immune
genes associated with toll-like receptor (TLR) and transforming growth factor beta signaling. Little
overlap was observed in differential expression between astrocytes, microglia and total homoge-
nates, emphasizing the importance of studying cell-type specific expression changes to define the
molecular consequences of chronic ethanol exposure in brain. We hypothesized that alterations in
glial function and immune signaling result in an enhanced proinflammatory environment and altered
CNS plasticity, which drives alcohol consumption. To test this hypothesis, we examined the effects
of TLR3 activation on EOD. TLR3 is predominantly expressed in astrocytes and direct activation by
the TLR3 agonist, polyinosinic:polycytidylic acid (poly I:C), causes astrogliosis and microglial prolifer-
ation. We treated mice with poly I:C (2, 5 or 10 mg/kg, i.p.) every four days and measured ethanol
consumption in the EOD test. Poly I:C produced persistent increases in ethanol consumption in
C57BL/6J mice without changing total fluid intake or saccharin consumption, suggesting an ethanol-
specific effect. Finally, poly I:C significantly increased expression of TLR signaling genes, type-1
interferons, and reactive astrocytes, as measured by quantitative RT-PCR. These findings suggest a
functional role for reactive astrocyte expression in regulation of voluntary alcohol consumption.
132
ANTI-INFLAMMATORY MESENCHYMAL STEM CELLS AND N-ACETYL CYSTEINE INHIBIT
CHRONIC ETHANOL INTAKE AND ABOLISH RELAPSE BINGE DRINKING: PRECLINICAL
STUDIES
F. Ezquer1,2, M.E. Quintanilla1,2,P. Morales1,2, C. Lespay-Rebolledo1,2, D. Santapau1,2,
M. Ezquer1,2,M. Herrera-Marschitz1,2, Y. Israel1,2
1
Molecular & Clinical Pharmacology Program*, Center for Regenerative Medicine, Faculty of
Medicine-Clınica Alemana, Universidad del Desarrollo, ICBM, Regio n del Bıo Bıo, Chile and
2
Department of Neuroscience, Faculty of Medicine, University of Chile, Santiago, Chile
Studies in humans and rodents have shown that chronic ethanol intake leads to increases in sys-
temic and brain pro-inflammatory cytokines, generating neuroinflammation. In alcoholics, circulating
pro-inflammatory cytokines are positively correlated with craving. Further, in rodents, the systemic
administration of pro-inflammatory lipopolysaccharide (LPS) leads to increases in voluntary ethanol
intake. Noteworthy, neuroinflammation and high levels of reactive oxygen species (ROS) perpetuate
each other. We present evidence, that (1) the intravenous administration of anti-inflammatory mes-
enchymal stem cell spheroids (referred to as “guardians” of inflammation) isolated from fat depots
and (2) the oral administration of the antioxidant N-acetyl cysteine, a glutathione (GSH) precursor,
abolish alcohol-induced neuroinflammation, markedly reduce chronic ethanol intake and prevent
relapse binge-like drinking. Alcohol preferring rats (UChB) allowed access to ethanol solutions and
water for 14–17 weeks, consuming 10–12 g ethanol/day, were intravenously administered a single
dose of mesenchymal stem cell-spheroids (MSC-spheroids) or vehicle. The MSC-spheroids inhib-
ited chronic ethanol intake by 80–90% within 24-h, with a significant inhibition shown after 3-weeks,
while daily oral N-acetylcysteine (100 mg/kg) administration inhibited chronic ethanol intake by 50%.
After chronic intake and a subsequent alcohol deprivation period of 14-days, animals were allowed
re-access to the ethanol solutions for only 60 min, which led to a relapse-like binge drinking of 1.7–
2.0 g ethanol/kg/60 min (BAC 0.09–0.11 g/dL) while MSC-spheroids or oral N-acetylcysteine trea-
ted groups consumed 0.53 and 0.40 g ethanol/kg/60 min, respectively (BACs 0.017 and 0.019 g/
dL). The strong inhibitory effect of MSC-spheroids on relapse–like drinking was observed 5-weeks
after their administration. Animals consuming alcohol chronically showed 150% increases in hip-
pocampal oxidized/reduced glutathione (GSSG/GSH) ratio and 60–80% increases in astrocyte
inflammation. Both effects were fully normalized by the single administration of the MSCS-spheroids.
The intravenous MSC-spheroid administration also increased by 120–180 the astrocyte GLT-1 gluta-
mate transporter levels. Oral N-acetyl cysteine normalized the ethanol-induced decrease in total
plasmatic thiol groups and brain glutathione. Overall, studies support the hypotheses that neuroin-
flammation- and now oxidative stress- are causally associated with an elevated chronic ethanol
intake and relapse-like binge drinking and suggest novel approaches for the treatment of alcohol-use
disorders. Support: FONDECYT #1170712, #1150589, CONICYT No-21130739.
304A
MONDAY, JUNE 18 3:10PM–4:40PM
SYMPOSIUM 133–136
Neural Substrates of Binge Drinking: What We’ve Learned From “Drinking in
the Dark”
Organizers/Chairs: Angela Ozburn and Todd Thiele
133
LASTING EFFECTS OF INCREASING NUCLEUS ACCUMBENS ACTIVITY ON BINGE-LIKE
ALCOHOL DRINKING AND THE TRANSCRIPTOME
S.P. Farris1,2, E. Firsick1,2, A. Tran1,2, K. Townsley1,2, A.R. Ozburn1,2
1 would discuss recent unpublished data from our laboratory revealing a critical role for a “top-down”
Department of Behavioral Neuroscience, Oregon Health Science University, Portland, OR, USA
and 2VA Portland Health Care System, Portland, OR, USA
Binge drinking is a pattern of behavior that is problematic and often leads to alcohol use disorders.
While the adverse consequences of binge drinking are clear, the neurobiological mechanisms that
underlie this dangerous pattern of behavior are not well understood. We used “Drinking in the Dark”
(DID; a limited access drinking paradigm resulting in drinking to intoxication in mice) in combination
with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs; delivered via viral-
mediated gene transfer) to study the neural substrates of high intensity, binge-like drinking in mice.
We carried out two studies using mice selectively bred to reach high blood alcohol levels (High Drink-
ing In the Dark mice). In the first study, we assessed the effects of chronically increasing or decreas-
ing neuronal activity in the nucleus accumbens (NAc) on DID. We found that chronically increasing
NAc activity (28d) significantly decreased binge-like drinking, an effect which persisted during a 7d
vehicle wash-out period. We did not observe any CNO-induced changes in ethanol intake in mice
expressing the inhibitory DREADD (or in mice expressing mCherry, a negative control group). To fur-
ther study the behavioral plasticity observed in mice that received chronic stimulation of the NAc, we
carried out a second study (in which mice either had water or ethanol, and received either vehicle
and CNO or vehicle only). We again observed that chronically increasing NAc activity reduced
binge-like drinking, an effect which again persisted for at least 7d. We isolated NAc RNA from these
mice and performed RNA Seq to assess the effects of chronically increasing NAc activity on the
whole transcriptome. We found significant changes in a number of plasticity-related genes that were
altered in ethanol drinking mice and ameliorated in ethanol drinking mice that received chronic CNO
treatment (i.e., Hdac4 and Adamts4). These results show that chronically increasing activity in the
NAc was able to produce lasting effects on behavior and ameliorate the effects of chronic, high-inten-
sity, binge-like drinking on a molecular level. This work aims to develop potentially therapeutic strate-
gies for reducing harmful drinking. We are currently analyzing the effects of this treatment on
neuronal morphology and testing its efficacy in a model of relapse-like drinking. Supported by VA-
IK2-BX002488.
134
AGE OF BINGE-DRINKING ONSET AND FORCED ABSTINENCE INTERACT TO INFLUENCE
AUD-RELATED SYMPTOMS AND GLUTAMATE-BASED TREATMENT
K.K. Szumlinski, K.M. Lee
Department of Psychological and Brain Sciences, UCSB, Santa Barbara, CA 93106-9660, USA
Binge-drinking is the most prevalent form of alcohol abuse/alcoholism, particularly in adolescents
and young adults. Alcohol Use Disorder (AUD) is highly co-morbid with disordered affect, with epi-
demiological evidence suggesting that an early life history of excessive drinking is a major risk factor
for the manifestation of an affective disorder in later life. Using the Drinking-in-the-Dark (DID) murine
model of binge-drinking, we have sought to understand how the subject factors of binge-drinking,
age of drinking onset and abstinence (withdrawal from alcohol) interact to influence the manifestation
of behavioral signs of negative affect in male mice. In both adult- and adolescent-onset binge-drink-
ing mice, a 2-week history of alcohol consumption is sufficient to induce signs of hyper-anxiety, with
adolescent mice also exhibiting signs of depressive-like behavior. However, the time-course of these
negative affective signs vary as a function of drinking-onset, with adult mice exhibiting hyper-anxiety
in early withdrawal that dissipates with the passage of time. In contrast, the manifestation of hyper-
emotionality manifests in later withdrawal in mice with a history of adolescent-onset binge-drinking.
In both age groups, alcohol withdrawal-induced negative affect is associated with increased expres-
sion of Group1 mGlu receptors within the accumbens and central nucleus of the amygdala (CeA)
and reduced CeA expression of the scaffolding protein Homer2. However, systemic or intra-accum-
bens administration of mGlu5 inhibitors were considerably more efficacious at reducing withdrawal-
induced negative affect in adult-onset drinkers. In alcohol-na€ıve mice, CeA Homer2 over-expression
was anxiogenic and promoted alcohol-drinking, while knock-down in alcohol-experienced animals
produced the opposite effect. Combined, these data argue a complex interplay between the subject
factors of binge-drinking, age of onset of drinking and duration of abstinence in the manifestation of
glutamate-related changes within the extended amygdala that contribute to the manifestation of a
negative affective state, as well as the timing and efficacy of glutamate-related treatment strategies.
ABSTRACTS-SPEACKERS
135
TOP-DOWN AND BOTTOM-UP CONTROL OF BINGE-LIKE ALCOHOL DRINKING
T.E. Thiele, S.L. Robinson,N.W. Burnham
Department of Psychology & Neuroscience and Bowles Center for Alcohol Studies, University of
North Carolina at Chapel Hill, Chapel Hill, NC 27599-3270, USA
Our laboratory has been using “drinking in the dark” (DID) procedures to study the neurobiological
mechanisms underlying pre-dependent binge-like ethanol drinking for the last 10 years. Historically,
the primary focus of our research has been on the role of neuropeptide signaling in regions of the
extended amygdala (EA), and results from our research reveal dysregulation of neuropeptide signal-
ing in the EA that closely resemble findings obtained with models of dependence-induced ethanol
drinking. More recently, we have become interested in circuits beyond the EA. In this presentation I
neuropeptide Y (NPY)-responsive circuit originating from the medial prefrontal cortex (mPFC) and
terminating in the basolateral amygdala (BLA) in modulating binge-like ethanol drinking. We have
found that a history of binge-like ethanol drinking is associated with a significant reduction of mPFC
NPY. Consistently, site-directed infusion of an NPY Y1 receptor (Y1R) agonist blunts binge-like etha-
nol drinking, primarily by acting within the prelimbic (PL) region. Further, chemogenetic silencing of a
Y1R+ mPFC to BLA circuit in Y1R-cre mice significantly blunts binge-like ethanol drinking. This latter
observation is consistent with the idea that the mPFC modulates binge-like ethanol drinking via top-
down regulation of the EA. I will also discuss recent work from our laboratory revealing that a “bot-
tom-up” noradrenergic (NE) circuit from the locus coeruleus (LC) to the lateral hypothalamus (LH)
modulates binge-like ethanol drinking. Binge-like ethanol drinking increases the activity of LH and LC
neurons, and chemogenetic activation of the NE LC to LH circuit in TH-cre mice blunts binge-like
ethanol intake. Consistently, site-directed infusion of a-1R or bR agonists into the LH blunts binge
drinking. Thus, this NE circuit appears to play a protective role against excessive ethanol consump-
tion. Together, these studies provide insight into novel neurocircuitry, beyond the EA, that modulate
binge-like ethanol drinking stemming from DID procedures. Supported by NIH grants AA025811,
AA022048 & AA013573.
136
DYNORPHIN AND KAPPA OPIOID RECEPTOR SYSTEM ACTIVITY WITHIN EXTENDED
AMYGDALA CIRCUITRY MODULATES BINGE-LIKE ALCOHOL DRINKING
H.C. Becker, R.I. Anderson, H.L. Haun, M.F. Lopez, W.C. Griffin, T.L. Kash
Charleston Alcohol Research Center, Departments of Psychiatry and Neuroscience, Medical
University of South Carolina & VAMC, Charleston, SC 29464, USA
Using pharmacological and chemogenetic approaches, studies were conducted examining the role
of the dynorphin (DYN) and kappa opioid receptor (KOR) system in mediating binge-like drinking.
The central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST) were tar-
geted as two interconnected brain regions within extended amygdala circuitry that are rich in DYN
and KORs. A standard mouse model of binge-like drinking (“drinking in the dark”; DID) involving 2-hr
access to 20% ethanol for 3 days and then a 4-h test session on Day 4 was employed in all studies.
Pharmacological studies in C57BL/6J mice showed that systemic administration of the KOR agonist
U50, 488 (5 mg/kg) prior to Day 4 significantly increased alcohol intake whereas systemic adminis-
tration of the KOR antagonist LY2444296 (5 mg/kg) significantly decreased alcohol consumption.
Neither the KOR agonist nor KOR antagonist altered sucrose (0.5%) intake in separate groups of
mice. Further, direct bilateral infusion of the KOR antagonist nor-BNI (2.5 lg/side) into the CeA or
into the BNST (5 lg nor-BNI) 24 h prior to the test session significantly reduced binge-like alcohol
consumption in the DID model. Pdyn-IRES-Cre mice were used in chemogenetic studies to selec-
tively target DYN-containing neurons. Cre-dependent viral constructs containing an inhibitory
DREADD (AAV5-hSyn-DIO-hM4Di-mCherry) or control (AAV8-hSyn-DIO-mCherry) were bilaterally
infused (0.25 lL delivered over 5 min for each side) into the CeA of Pdyn-IRES-cre mice. Systemic
CNO (3 mg/kg) injection prior to the Day 4 test session significantly reduced drinking in mice harbor-
ing the inhibitory DREADD but not in those injected with control virus. Ongoing studies involve inject-
ing a retrovirus with an inhibitory DREADD (AAVretro-hSyn-DIO-hM4Di-mCherry) into the BNST
and implanting guide cannulae over the CeA in Pdyn-IRES-Cre mice. Microinjection of CNO (1 lM/
side) into CeA will test whether selective inactivation of DYN neural projections from CeA to BNST
also reduces binge-like drinking. Taken together, these pharmacological and chemogenetic results
suggest that the DYN/KOR system within CeA-BNST circuitry plays a role in binge-like alcohol drink-
ing. Funded by NIAAA grants U01 014095, U01 020929, P50 07061, and F32 023700, and VAMC
(BX000813).
ABSTRACTS-SPEACKERS
MONDAY, JUNE 18 3:10 PM–4:40 PM
SYMPOSIUM 137–140
Alcohol Promotion of Aggressive Tumors
Organizer/Chair: Dipak Sarkar
Chair: Jan Hoek
137
ALCOHOL AND BREAST CANCER STEM CELLS
J. Luo
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY
40536, USA
Alcohol exposure promotes the progression/aggressiveness of breast cancer. However, the underly-
ing cellular/molecular mechanisms are unclear. Cancer stem cells (CSCs), a subpopulation of can-
cer cells with self-renewal and differentiation capacity, play an important role in tumor initiation,
progression, metastasis, recurrence, and therapy resistance. We tested the hypothesis that alcohol
can stimulate CSCs using both in vivo and in vitro models. Chronic alcohol exposure increased
breast CSC population and enhanced the lung and colon metastasis in MMTV-neu transgenic mice.
Alcohol increased CSC population and mammosphere formation in breast cancer cells overexpress-
ing ErbB2/HER2. Alcohol also stimulated the phosphorylation of p38c MAPK (p-p38c) which was
down-stream of ErbB2. More importantly, p38c siRNA inhibited alcohol-induced increase in CSC
population, mammosphere formation and migration/invasion of breast cancer cells overexpressing
ErbB2. We further investigated the effect of alcohol on MMTV-Wnt1 transgenic mice which develop
spontaneous mammary tumors. MMTV-Wnt1 mice were exposed to alcohol during either adolescent
or adult period, and then tumorigenesis, metastasis and CSC population were evaluated. Although
alcohol exposure accelerated tumorigenesis in both adolescent and adult mice, the effects were
much more prominent in adolescent mice. Using ALDH and Thy1/CD24 as markers for CSCs, we
showed that alcohol exposure increased CSCs in both adolescent and adult mice; but alcohol-
induced increase in adolescent group was much more drastic than adult mice. Taken together, alco-
hol may enhance the aggressiveness of breast cancer by stimulating CSCs. Supported by NIH
grants (AA017226 and AA015407).
138
ALCOHOL MODULATES HORMONAL AND ONCOGENIC SIGNALING IN BREAST CANCER
N.R. Candelaria, R.C. Miranda, C.-Y. Lin
Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling,
University of Houston, Houston, TX, 77204, USA
Alcohol consumption is linked to increased breast cancer risks, especially for hormone-dependent
breast cancers. Mechanisms by which alcohol promotes breast tumorigenesis or disease progres-
sion, however, are not well understood. Our studies in cell line models of hormone-dependent breast
cancers have shown that alcohol treatment enhances estrogen and growth factor signaling pathways
and identified the proto-oncogene BRAF as a novel alcohol-responsive gene in breast cancer cells.
Recent study results also implicate non-coding RNAs in these alcohol-associated mechanisms.
Together, these findings suggest that alcohol enhances estrogen signaling through differential regu-
lation of BRAF and downstream kinases, ER target genes, and non-coding RNA networks, and their
actions may affect early events in hormonal carcinogenesis and disease progression. These mecha-
nistic insights additionally highlight potential markers and targets for the prevention and treatment of
alcohol-associated breast cancers.
305A
139
ALCOHOL PROGRAMS THE PITUITARY TO PRODUCE AGGRESSIVE PROLACTIN-
PRODUCING TUMORS
O. Gangisetty, S. Jabbar, G. Maglakelidze, O. Wyne, D.K. Sarkar
Rutgers Endocrine Research Program, Department of Animal Sciences, Rutgers University, New
Brunswick, NJ 08901, USA
Chronic alcohol consumption is known to increase prolactin levels in blood and cell proliferation in
pituitary prolactin-producing cells known as lactotropes, resulting in hyperprolactinemia in human
and animals. Using animal model of prenatal alcohol exposures, which maintains stable alcohol epi-
genetic marks on the genome, we determined whether prenatal alcohol exposure (PAE) increases
the susceptibility to estrogen-induced pituitary prolactin-secreting tumors. We obtained evidence that
PAE enhances development of aggressive pituitary tumors, as most tumors in the alcohol group
were hemorrhagic, some spread in the non-pituitary sites and tumor tissues contained densely
packed cells and showed strong nuclear p53, Ki67 and PTTG immunoreactivities. When pituitaries
of PAE rats were grown in cultures, cells rapidly grew and formed colonies, and in ultra-low attach-
ment plate developed spheres. These spheres expressed genes and proteins related to multipo-
tency and successfully induce tumor in athymic scid rats. In addition, pituitary tumor from PAE
animals showed strong immunoreactivity for N-cadherin, Snail and several epithelial-mesenchymal
transitions (EMT) factors. Furthermore, RNA-seq of genes in tumor pituitaries of PAE and control
rats revealed 8782 genes are significantly changed by alcohol. Many of these genes are involved in
the cell migration, actin cytoskeletal regulation and cell-cell junction formations which are the most
important phenotypes occur during EMT. These data provide evidence for the possible development
of aggressive prolactinoma in the pituitary after estrogen treatment in PAE rats. (This work is sup-
ported by a National Institute of Health grant R01 AA11591).
140
ALCOHOL INTERACTS WITH CIRCADIAN DISRUPTION TO PROMOTE COLON
CARCINOGENESIS
F. Bishehsari, N. Preite, S. Wilber, P.A. Engen, R.M. Voigt, K. Khazaie, C. Forsyth, M. Shaikh,
A. Keshavarzian
Section of Gastroenterology, Department of Internal Medicine, Rush University Medical Center,
Chicago, Illinois, USA
Background: Chronic alcohol consumption increases risk of colorectal (CRC). However the driving
mechanisms underlying the alcohol effect have not been established; thus our ability to identify at-
risk individuals remains limited. Our prior study showed inflammation as a mechanism underlying
alcohol-induced polyposis. Here we report effects of circadian disruption (CD), in different forms, on
alcohol induced CRC, and elucidate the potential mechanisms.
Method: Alcohol versus water were given to TS4Cre APClox468 mice under chow ad lib during the
dark (right-time fed, normal) versus the light (wrong-time fed/abnormal) on a standard light: dark
cycle for 3 months starting at 4 weeks of age. Polyposis was assessed macroscopically and histo-
logically. Fecal microbiota was measured using 16s rRNA analysis. Tissue staining for CRC related
immune markers were performed. RNA seq was used to estimate expression of colonic genes in
each group. Central and intestinal circadian rhythm was measured in B6 PER2::LUC mice.
Results: We recently found, CD by Light:dark shifting, exacerbates alcohol-induced polyposis. Here
we find wrong time eating, is a true inducer of CD as it shifted the phase of the colon circadian rhythm
and altered the Circadian rhythm pathway the most. Wrong time, alcohol-fed mice had worsening
polyposis with a pro-inflammatory profile characterized by an increase in pro-tumorigenic Th17/Treg
ratio. Consistent with crucial role of microbiota on Treg to Th17 plasticity, we found lower SCFA-pro-
ducing in the experimental group.
Conclusion: Our data show CD as a factor that aggregates alcohol induced CRC, and highlights
dysbiosis and pro-tumorigenic immune profile as potential mechanisms.
306A ABSTRACTS-SPEACKERS

MONDAY, JUNE 18 3:10 PM–4:40 PM 143

WORKSHOP 141–143
Workshop: Participant Recruitment and Retention in Alcohol Intervention TOOLS FOR PLANNING AND BUDGETING RELATED TO PARTICIPANT RECRUITMENT AND
RETENTION
Studies A.L. Begun1,2, L.K. Berger1,2, L.L. Otto-Salaj1,2
Organizer/Chair: Audrey Begun 1
College of Social Work, Ohio State University, Columbus, OH, 43210, USA and 2Helen Bader
Chair: Lisa Berger School of Social Welfare, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, USA

Introduction: This presentation is one of three proposed for the Participant Recruitment and Reten-
tion in Alcohol Intervention Studies workshop.
141 Purpose: The purpose of this third presentation, based on the presenting authors’ forthcoming
book, is to provide workshop participants with a set of practical tools and guides for planning and
PARTICIPANT RECRUITMENT IN ALCOHOL INTERVENTION STUDIES budgeting to engage in the participant recruitment and retention strategies discussed in the first two
L. Berger presentations. Alcohol intervention studies are most powerful when adequate resources have been
Department of Social Work, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, USA dedicated to ensuring that a representative sample of study participants are successfully recruited
and retained throughout the duration of longitudinal study course. Investigators will be provided with
Introduction: This talk is one of three submitted for the Participant Recruitment and Retention in
a set of planning and budgeting tools to guide them in developing proposals and in implementing the
Alcohol Intervention Studies workshop, based on our forthcoming book.
study.
Purpose: Many intervention studies do not meet targeted recruitment goals, and thus, statistical
Methods: The practical tools discussed in this presentation include: (1) strategies for setting realistic
analysis of study data is underpowered. Furthermore, if recruitment of participants is not diversely
recruitment and retention goals given appropriate sample size/power analysis calculations and par-
representative, study results may have limited generalizability. NIH, for example, has policies on the
ticipant availability to fulfill study design requirements, (2) identification of critical steps in the partici-
inclusion of women and minorities in clinical research to help promote diversity. In addition, one of
pant recruitment and retention planning process (i.e., identifying the target population and potential
the biggest challenges to recruitment is the overestimation of investigators to recruit participants.
recruitment options; developing recruitment and retention materials, and planning for their dissemi-
This presentation will draw upon experience and data in conducting multiple alcohol intervention
nation; how technology can help in developing and implementing effective tracking systems; devel-
studies over a number of years and will present challenges and practical solutions plus tools to
oping protocols for responding to participant inquiries, pre-screening, and screening potential
reaching participant recruitment goals. Newer online tools such as ResearchMatch and social media
participants; establishing protocol for consenting and enrolling/random assignment of participants
also will be discussed. Finally, a breakdown of the cost and effectiveness of various recruitment
that promote retention), (3) budgeting factors to consider in estimating staff, space, time, and dollar
methods based on recruitment yield will be presented.
resources for implementing strong participant recruitment and retention plans, and (4) assessing
Methods: Planning for recruitment begins with estimating the potential recruitment pool and willing-
cost-effectiveness for recruitment strategies.
ness of diverse groups to participate. A four-stage process for engaging in recruitment can be uti-
Data: Examples from the research experiences of the workshop authors and presented in the
lized: generating initial contacts, screening, consenting, and enrollment.
widely dispersed literature of many disciplines are presented.
Data: Recruitment numbers, recruitment yields at each of the four stages, plus the cost and effec-
Results: Participant recruitment and retention plan budget examples with formulas (Excel spread-
tiveness of various specific recruitment methods (e.g., television ads, provider referrals, etc.) based
sheets) will be made available to workshop participants. Also presented through examples are for-
on participant yield will be presented, including methods broken down by gender and minority/non-
mulas for calculating participant enrollment cost (PEC) as a ratio of recruitment and retention dollars
minority categories.
to number of participants fully enrolled, for conducting a recruitment yield effectiveness analysis
Results: In the recruitment planning process, data should be used to help estimate the potential
(RYE), and for computing recruitment yield cost-effectiveness (RYC) in terms of research dollars.
recruitment pool and pilot studies can help to inform the acceptability of the protocol to participants.
Conclusions: Investigators need to plan and budget for participant recruitment and retention in
Furthermore, recruitment methods that reach potential participants directly versus indirectly tend to
alcohol intervention studies, and these tools, resources can help.
have better participant yield.
Conclusions: Realistic planning is necessary in recruitment so as to not overestimate the ability to
recruit participants or assume incorrectly willingness to participate. Direct recruitment methods tend
to work better, and multiple recruitment methods may be needed to reach diverse groups.

142
PARTICIPANT RETENTION IN ALCOHOL INTERVENTION STUDIES
L.L. Otto-Salaj
Department of Social Work, University of Wisconsin-Milwaukee, Milwaukee, WI, 53201, USA

Introduction: This talk is one of three proposed for the Participant Recruitment and Retention in
Alcohol Intervention Studies workshop, based on the presenters’ forthcoming book.
Purpose: The purpose of this presentation is to explore the consequences of attrition in alcohol
intervention studies, as well as strategies to enhance participant retention. Participant retention is
central to alcohol intervention studies that employ longitudinal, repeated measurement designs.
Specific efforts are needed to ensure that sufficient numbers and diversity of participants not only are
recruited, but also are retained over time. Attrition can pose both internal and external threats to the
validity of study results. Especially significant are the internal validity threats imposed when study
attrition is unequal and non-random between intervention groups being compared in the study
design; non-random attrition may also threaten the external validity of study results. And, attrition is
most often non-random in nature.
Methods: Contemporary strategies for retention enhancement are discussed (developing and
maintaining rapport with participants, tracking and maintaining contact with participants, the use of
participant-generated letters to self and key informants, multi-method approaches to contact partici-
pants, use of locator services, approaches to reduce participant burden, use of incentives, and the
need to maintain enough methodological flexibility to respond to changes/dynamic situations in par-
ticipant availability/eligibility).
Data: Examples taken from the research experience of the workshop authors are presented, and
data concerning the degree of effort and persistence involved in successful retention are explored.
Results: The costs associated with implementing strong retention efforts may be less than the high
cost of participant attrition; specific examples are presented. Different ways of assessing retention
(various retention metrics) along with reasonable retention rates and attrition patterns over time are
presented. Conclusions
Retention rates to be achieved should be identified prior to the start of a study; strategies to enhance
participant retention and attain proposed retention rates should be evaluated for appropriateness
and feasibility for each study.
ABSTRACTS-SPEACKERS 307A

MONDAY, JUNE 18 3:10 PM–4:40 PM 146

SYMPOSIUM 144–147
Innovative Scientific Approaches for Identifying Novel Targets of Prevention INJUNCTIVE AND DESCRIPTIVE NORMS FOR ALCOHOL AND SEXUAL VIOLENCE AS
POTENTIAL INTERVENTION TARGETS
of Alcohol-Related Sexual Aggression A. Papova, J. Hartman, K. Richner, W.R. Corbin
Organizer/Chair: William Corbin Department of Psychology, Arizona State University, Tempe, AZ, 85287, USA
Chair: Kailey Richner
Comorbidity of alcohol use and sexual violence is high (Abbey, 2002). One potential avenue of inter-
vention includes normative feedback, which has been shown to be effective at reducing heavy drink-
ing through correcting misperceptions of peer use (descriptive norms) and attitudes. Injunctive
144 norms related to rape myth acceptance have also been linked to sexual aggression (Locke & Maha-
lik, 2005), but there is a lack of research into alcohol-specific rape supportive attitudes. Injunctive
ALCOHOL-RELATED SEXUAL AGGRESSION: A TEST OF TWO INTERVENTIONS norms regarding sociosexuality could also be a useful target of intervention as our prior work demon-
K.C. Davis, C.A. Stappenbeck, W.H. George, K.F. Kajumulo strates that sociosexual attitudes prospectively predict sexual violence, and men may feel more com-
Arizona State University, College of Nursing and Health Innovation, Phoenix, AZ 85004, USA fortable endorsing unrestricted sexual attitudes than rape supportive attitudes. There is surprisingly
little prior work on misperceptions related to descriptive norms given the strong evidence base for
Sexual aggression (SA) remains a significant public health problem in the US. More than half of sex-
descriptive norms based interventions in the alcohol literature. Moreover, work in our own lab has
ual assaults involve alcohol consumption by the victim, the perpetrator, or most commonly both.
found that descriptive norms prospectively predict sexual violence and moderate the relationship
Despite the proliferation of SA prevention programs over the past two decades, there remains a criti-
between alcohol use and sexual aggression. To broaden the literature on norms as a potential inter-
cal need for intervention efforts that target mechanisms underlying young men’s SA behavior. One
vention target, the current study examines misperceptions of peer alcohol-related rape myth accep-
such mechanism ripe for greater empirical attention is emotion regulation (ER), given that extant
tance (injunctive), sociosexuality (injunctive), and acts of sexual aggression (descriptive). Analyses
research suggests that ER difficulties are associated with both alcohol consumption and aggressive
were based on a sample of 345 male college students who completed an anonymous online survey.
behavior. Using a sample of heavy episodic drinking men aged 21–30 who have a history of SA per-
Due to low rates of endorsement of sexual aggression, we dichotomized engagement and percep-
petration, we evaluated the effects of two brief online ER interventions – cognitive restructuring and
tions of peer engagement. Results of paired sample t-tests demonstrated misperceptions of both
mindfulness – on men’s ER during an SA-related analogue. Additionally, effects were evaluated dur-
peer attitudes and behaviors. Men significantly overestimated the extent to which peers endorse
ing both sober and intoxicated states through a laboratory-based alcohol administration proximal
alcohol-related rape supportive attitudes (sample mean = 24.11; perceived peer mean = 41.53;
change experiment. After completing a screening procedure, participants (N = 102) completed an
t =
18.06, p < 0.001), sociosexuality (sample mean = 43.83; perceive peer mean = 56.24;
assessment of relevant background factors and were then randomly assigned to the cognitive
t =
18.93, p < 0.001), and sexual aggression (sample percentage = 17.68%; perceived peer per-
restructuring ER intervention, the mindfulness ER intervention, or an attention control group. After
centage = 85.80%; t =
25.77, p < 0.001). Cohen’s d effect sizes across all three outcomes were
receiving the intervention and practicing the targeted ER skill, participants were block randomized by
large, ranging from 0.97 to 1.39. These findings could have implications for intervention and preven-
intervention condition to receive either no alcohol or a high alcohol dose (target peak BAC = 0.08%).
tion efforts regarding alcohol use and sexual aggression. The large misperceptions of men’s atti-
They then completed a proximal change protocol that included (1) implementing the ER skill that they
tudes and behaviors suggest that normative feedback on both alcohol and non-alcohol related
learned in the intervention and (2) completing a SA analogue that assessed their SA-related emo-
sexual aggression could be important targets in prevention and intervention programs.
tions and intentions through the use of a hypothetical sexual scenario. Preliminary regression analy-
ses revealed a two-way interaction between intervention condition and beverage condition such that
intoxicated men in the attention control group reported greater sexual arousal during the SA ana-
logue than sober men and intoxicated men who received either the cognitive restructuring or mindful-
ness interventions. In turn, greater sexual arousal was associated with significantly stronger SA
intentions during the SA analogue. Findings suggest that, relative to the attention control, both the
cognitive restructuring and mindfulness interventions were effective at reducing alcohol-facilitated
147
sexual arousal which was associated with reduced SA intentions. Interventions targeting ER pro- RISK PROCESSING, BINGE DRINKING, AND COLLEGE WOMEN’S RISK FOR SEXUAL
cesses may thus be a particularly effective way of addressing alcohol-related SA behavior. VICTIMIZATION
E.A. Yeater1, T.A. Treat2, R.J. Viken3, A.D. Bryan4
1
University of New Mexico, 2University of Iowa, 3Indiana University and 4University of Colorado
Boulder

Background/Purpose: Most research examining etiological variables linked to sexual revictimiza-

145 tion has been cross-sectional and retrospective, making it difficult to establish whether identified cor-
relates are causes or consequential (Pittenger et al., 2016). In this study, we used a social
EFFECTS OF COGNITIVE TRAINING AND ALCOHOL CONSUMPTION ON MEN’S information-processing model (McFall, 1982) to conceptualize women’s risk for sexual victimization
PERCEPTIONS OF WOMEN’S SEXUAL INTEREST and tested prospectively whether processing patterns predicted sexual victimization and revictimiza-
T.A. Treat, R.J. Viken, W.R. Corbin, J.R. Smith tion. We also examined whether binge drinking moderated the hypothesized paths in our model.
Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA, 52242, USA Methods: Four hundred and eighty one college freshman women were assessed at baseline and
six months later (6 month follow-up = 453). At baseline, participants completed tasks assessing risk
Background/Purpose: Impoverished processing of women’s nonverbal affective cues is implicated
judgments and decision making for hypothetical social situations, as well as questionnaires measur-
in male-initiated sexual aggression toward female acquaintances. Alcohol consumption is associated
ing sexual victimization and binge drinking. They then reported on sexual-victimization experiences
with increased risk of perpetration and reduced sensitivity to women’s affect. The current study eval-
during the study at follow up.
uates the impact of a cognitive-training procedure and a moderate dose of alcohol on college men’s
Results: Path-analytic methods demonstrated that decoding and decision making prospectively
sexual perceptions and decision making in the lab.
predicted sexual victimization at follow up and accounted in part for the relationship between sexual
Methods: 180 college men first completed an experimental or control version of a sexual-interest
victimization at baseline and follow up. Three indirect effects were observed. First, judging more
judgment task, in which they viewed 224 full-body photographs of college women and judged the
social situations to be high risk at baseline was associated with more effective decision making,
women’s momentary sexual interest. Participants in the experimental condition also received instruc-
which prospectively predicted less severe victimization. Second, relying more on risk when making
tion about the greater validity of affective than non-affective cues when judging women’s current sex-
risk judgments at baseline correlated with more effective decision making, which prospectively pre-
ual interest; trial-by-trial feedback on the accuracy of their judgments; and block-by-block feedback
dicted less severe victimization. Third, more severe victimization at baseline prospectively predicted
on their reliance on affective versus non-affective information (i.e., provocativeness of dress, physi-
more severe victimization, which was partially accounted for by less effective decision making. A
cal attractiveness, sexual relevance of context). Next, participants either did or did not consume a
multiple-groups approach was used to evaluate whether binge-drinking status moderated the paths
moderate dose of alcohol (target BrAC = 0.06). Participants then completed five new tasks assess-
in the model. Participants who reported usually consuming four or more drinks when drinking were
ing sexual perception and decision making. Finally, participants completed one of the decision-mak-
placed in a “Usual Binge” (UB) group (28.9%); remaining participants were in a “Not Usual Binge”
ing tasks again, approximately 1 week later.
(NUB) group (71.1%). Binge-group status reliably moderated one path, such that prospective predic-
Results: The training procedure (1) enhanced attention to women’s affective cues; (2) increased
tion of victimization from decision making was reliably stronger among UB than NUB participants.
reliance on affect when judging a woman’s likely responsiveness to a sexual advance; (3) improved
Conclusions: Processing of sexual-risk information prospectively predicted future sexual victimiza-
sensitivity to a woman’s increasingly negative affect during a sexual encounter described in a written
tion among freshmen women, particularly those women who reported more frequent binge drinking.
vignette; (4) augmented participants’ ability to distinguish nonverbal dating-relevant cues; but (5) did
Sexual-risk processing also accounted in part for the relationship between prior and future victimiza-
not influence judgments of when a man should cease making sexual advances in a recording of a
tion. These findings suggest the potential utility of developing cognitive-training approaches to
simulated date rape. Alcohol (1) reduced attention to affective cues; (2) lessened sensitivity to a
enhance women’s processing of sexual-risk information.
woman’s increasingly negative affect during a sexual encounter; (3) decreased the distinguishability
of affective cues; but (4) did not affect decision-making processes. Training effects on affective reli-
ance during decision making were maintained at follow-up.
Conclusions: A 30-min cognitive-training procedure produced small-to-moderate improvements in
several aspects of college men’s sexual perception and decision-making in the lab, and these
improvements held up under a moderate dose of alcohol. Future research will focus on enhancing
the magnitude of the training effects and integrating motivational strategies into an augmented pro-
gram.
308A
MONDAY, JUNE 18 3:10 PM–4:40 PM
SYMPOSIUM 148–151
Alcohol Impaired Drivers Characteristics and Interventions
Organizer/Chair: Charles Mathias
Chair: Donald Dougherty
148
POTENTIAL EFFECTIVENESS OF LOWERING THE BAC LIMIT TO 0.05 IN THE US
J.C. Fell, M. Scherer
National Opinion Research Center (NORC) at the University of Chicago Bethesda, Maryland 20814,
USA
Background: In 2013, the National Transportation Safety Board (NTSB) issued a report recom-
mending that states lower the illegal blood alcohol concentration (BAC) limit for driving from 0.08 to
0.05 g/dL. The NTSB concluded that there is a strong evidence-based foundation for a BAC limit of
0.05 or lower. Most industrialized nations have already enacted a 0.05 illegal BAC limit. This study
was undertaken to contribute to the scientific evidence as to whether lowering the BAC limit to 0.05
will be an effective alcohol policy in the United States.
Methods: We accomplished our objective by (1) conducting a meta-analysis of qualifying interna-
tional studies to estimate the range and distribution of the most likely effect size from a reduction to
0.05 BAC or lower; (2) translating this synthesis toward estimating the effects of reducing the current
0.08 BAC limit to 0.05 in the U.S.; and (3) estimating the life-saving benefits of the proposed 0.03
reduction in the driving limit from 0.08 to 0.05 BAC.
Results: In our meta-analysis of studies on lowering the BAC limit in general, we found a 5.0%
decline in non-fatal alcohol-related crashes, a 9.2% decline in fatal alcohol-related crashes from low-
ering the BAC to 0.08, and an 11.1% decline in fatal alcohol-related crashes from lowering the BAC
to 0.05 or lower. We estimate that 1,790 lives would be saved each year if all states adopted a 0.05
BAC limit.
Conclusions: This study provides strong evidence of the relationship between lowering the BAC
limit for driving and the general deterrent effect on alcohol-related crashes.
149
CHARACTERISTICS AND LIFE CONTEXT OF WOMEN WITH SINGLE AND MULTIPLE DUI
CONVICTIONS
V.V. McCutcheon, A.K. Bender, A.C. Heath, K.K. Bucholz
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA
Purpose: Women are increasingly involved in drunk driving and fatal crashes, yet except for the
screening done in criminal justice settings, little is known about their life context, psychiatric histories,
and family backgrounds. The current study describes a sample of women with histories of arrest for
driving under the influence of alcohol (DUI) who were interviewed outside a criminal justice setting
and contrasts women with single versus multiple DUI convictions.
Methods: Women with recent documented histories of DUI were invited to participate in a study of
women’s health behaviors. Thirty-six women with one DUI and 64 with two or more DUIs participated
in a diagnostic telephone interview which assessed demographics, alcohol use and problems, psy-
chiatric problems, treatment, and partner violence.
Results: The sample overall had high rates of co-occurring psychiatric problems, parental alcohol
problems, early sexual and physical abuse, and head injuries. Alcohol use severity and the preva-
lence of head injuries and partner alcohol problems were significantly higher among women with
multiple DUIs than women with a single DUI. Measures reflecting life context, such as marital status,
number of children, and childhood trauma, were not associated with number of DUIs.
Conclusions: Findings suggest that DUI recidivism in women is accounted for primarily by AUD
severity and is not influenced by previous life events such as partner violence, psychiatric problems,
and family context such as divorce/separation or number of children. Multiple DUIs in women may
mark an alcohol severity threshold beyond which few factors account for additional risk.
ABSTRACTS-SPEACKERS
150
CONTRASTING THREE MODELS OF SOCIAL SUPPORT IN MOTIVATING REDUCTIONS
DRINKING AMONG DWI OFFENDERS
T.-.J. Moon, D. Dougherty, J. Mullen, T. Karns-Wright, N. Hill-Kapturczak, J. Roache, C. Mathias
Division of Neurobehavioral Research, Department of Psychiatry, University of Texas Health
Science Center at San Antonio
The purpose of this article is to understand the role of social support in motivating DWI offenders to
reduce their alcohol use. In particular, this study tested three models of the relationship between
social support and motivation to change their alcohol use. Main-effect model posits that the associa-
tion between social support and attitudinal change is mainly attributable to the beneficial effect of
social support itself. Buffering model argues that the primary role of social support is to protect per-
sons from potentially harmful effects of stressful events, suggesting an interaction effect between
social support and stressful conditions. Optimal matching model further claims that social support
can be beneficial when it matches to the needs of patients. To examine the role of social support in
motivating DWI offenders to change their drinking behavior, a total of 119 DWI offenders were
recruited from correctional treatment facility (n = 59) and community (n = 60) and finished interviews
to assess demographic, physical/psychiatric conditions, and other psychosocial factors. The first
analysis compared main-effect model with buffering model. After controlling for demographics, psy-
chiatric diagnoses, and legal history, significant positive associations between social support and
motivation to change (e.g., importance to change drinking behaviors and confidence in changes)
were found, supporting main-effect model. However, there were no significant interaction effects
between social support and alcohol-related problems predicting motivation to change, rejecting
buffering models. The second analysis further investigated the differences in types of social support
(i.e., recovery-specific social support and general social support) in predicting motivation to change.
The results indicated that only recovery-specific social support was positively associated with motiva-
tion to change, whereas general social support alone did not contribute to motivation to change.
Alternatively, general social support had a buffering effect only on readiness to change. These
results suggest that social support has an overall beneficial impact on motivating DWI offenders to
change their drinking behavior (i.e., main effect) and that social support can be beneficial for DWI
offenders particularly when it matches to their specific needs (i.e. optimal matching). Implications for
inclusion of recovery-specific social support within the context of treatment are discussed, highlight-
ing the impact on those who are sequestered to residential treatment or incarceration.
151
ALCOHOL IMPAIRED DRIVERS CHARACTERISTICS AND INTERVENTIONS
T.E. Karns-Wright, C.W. Mathias, N. Hill-Kapturczak, J.C. Fell, J.D. Roache, J. Mullen,
D.M. Dougherty
Department of Psychiatry, UT Health San Antonio, San Antonio, TX, 78230, USA
This presentation describes the process of developing a contingency management (CM) procedure
to reduce excessive alcohol consumption using transdermal alcohol monitoring for people arrested
for driving while intoxicated (DWI). First, a research study was conducted with 80 heavy-drinking,
non-treatment seeking, study volunteers to design a procedure for using CM to reduce heavy drink-
ing to moderate, safer levels of consumption. Participants engaged in 3 phases: (1) a 4-week obser-
vation period where they drank as usual while wearing a transdermal alcohol monitor; (2) a 12-week
CM period where they received $50 each week for transdermal alcohol concentrations lower than
0.03 g/dL; and (3) a 3-month period of follow up where self-reported alcohol consumption was evalu-
ated. Participants drank heavily significantly less often during the 12-week CM period than the obser-
vation period (p < 0.001) and that these trends continued during the follow-up period. After
establishing this CM procedure, the Motivational Alcohol Treatment to Enhance Roadway Safety
(MATTERS) Clinic was established to evaluate and intervene with people who have been arrested
for DWI and awaiting trial. Using a quality improvement methodology known as Plan-Do-Study-Act
(PDSA), the research-derived CM procedures were applied to volunteers who had been arrested for
DWI and who scored as high risk during a screening, brief intervention, and referral to treatment
intervention. To better serve the DWI population, 4 PDSA quality improvement cycles were con-
ducted resulting in changes to the transdermal alcohol concentration cutoffs for determining alcohol
use, the quantity of the reinforcers, and how the tamper alerts on the transdermal monitor were han-
dled. These quality improvement changes resulted in less dropout and a higher level of completion
when the 4 PDSA cycles were compared (all p’s < 0.05). Furthermore, the peak transdermal alcohol
concentrations during drinking weeks were lower by the final PDSA cycle. Currently, the MATTERS
Clinic is implementing a further research study to examine the CM procedures among those who
have been arrested for DWI and have been mandated to wear a transdermal alcohol monitor by the
court system. CM is an effective way to reduce heavy drinking among DWI offenders, and when
implemented swiftly, may be an appropriate procedure to be used within the criminal justice system.
ABSTRACTS-SPEACKERS 309A

MONDAY, JUNE 18 3:10 PM–4:40 PM 154

SYMPOSIUM 152–155
Level of Response to Alcohol and Alcohol Related Blackouts: Potential ALCOHOL-RELATED BLACKOUTS: CLINICAL PHENOMENA AND POTENTIAL GENETIC
INFLUENCES
Clinical and Genetic Relationships R.R. Wetherill
Organizer/Chair: Marc Schuckit Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia,
Chair: David Goldman PA 19104, USA

Alcohol use is a pervasive problem with well-known effects on memory. Alcohol’s effects on memory
vary in severity and range from mild to alcohol-related blackouts (ARBs). ARBs are defined as amne-
152 sia, or memory loss, for all (en bloc) or part (fragmentary) of a drinking episode and typically occur at
blood alcohol concentrations (BACs) above 0.14 mg/dL. During an ARB, a person is able to actively
GENETIC VARIANTS POTENTIALLY RELATED TO THE LEVEL OF RESPONSE TO ALCOHOL engage and respond to their environment; however, the brain is not creating memories for the
M.A. Schuckit events. ARBs are prevalent, with approximately 50% of college students who drink alcohol reporting
San Diego Medical School, Psychiatry, University of California, La Jolla, California, 92161, USA experiencing an ARB during their college years. ARBs are quite concerning, as ARBs are related to
other alcohol-related adverse consequences, such as unwanted sex, injury, and death. Interestingly,
Purpose: The goal of this study was to synthesize information about recent findings of genetic vari-
research suggests that even at comparable BACs, some individuals experience ARBs, yet other do
ants that might contribute to the level of response (LR) to alcohol as a risk factor for heavy drinking
not, suggesting that individual differences or biological vulnerabilities likely contribute to ARB occur-
and alcohol use disorders (AUDs). Special attention was paid to differences across studies regarding
rence. Indeed, research suggest genetic influences, including family history of alcohol problems and
the populations being evaluated and the methods for measuring LR, in an effort to help guide future
men with a maternal history of alcohol problems increase the risk for experiencing an ARB. Further,
research.
a longitudinal study of 398 college students found that higher rates of ARBs over time were associ-
Methods: The author carried out a review of English language papers reporting genetic variants
ated with European American ethnicity, female sex, and a low level of response to alcohol. Although
related to LR from the perspective of highlighting biological themes among these findings and rela-
additional genetic analyses are currently underway, these findings suggest that biological factors,
tionships between study methodology and specific results. This is the first critical synthesis of genetic
including familial and genetic influences, likely contribute to the occurrence of these alcohol-related
findings related to LR to be presented or published.
memory impairments.
Results: The synthesis identified: (1) two critically different non-AUD drinking populations being
studied (subjects in their early 20’s who are light to moderate drinkers divided into those with and
those without an elevated AUD risk based on family histories or ethnicity versus those in later 20’s
and early thirties divided into those with and without frequent alcohol binges at baseline); (2) four
major ways to test LR (oral alcohol consumed in 1 dose; oral alcohol in several doses; IV alcohol;
and retrospective questionnaires); (3) six different types of LR effects being measured (subjective
feelings, body sway, changes in stress hormones, EEG, ERP, and fMRI); and (4) two different evalu-
155
ations of LR’s relationship with outcomes (short and long term). The most impressive results to date THE GENETIC ARCHITECTURE OF ALCOHOL RESPONSES, FROM ANIMAL STUDIES
regarding genes related to LR appear to relate to genetic variants in GABA, glutamate, dopamine, D. Goldman, P. Metten, L. Kwako, N. Diazgranados, H. Sun, C. Hodgkinson, J. Crabbe, Z. Zhou
and opioid systems. Laboratory of Neurogenetics, Office of the Clinical Director, NIAAA, NIH Rockville, MD, 20852, USA
Conclusions: The analyses indicated the need for caution before combining results across different
paradigms into genome-wide association studies and drawing conclusions regarding specific gene Alcohol use disorder is etiologically complex but mediated in part by agent-specific pharmacokinetic
variants. Considering the heterogeneity in gene variants likely to relate to LR, analyses should con- and pharmacodynamic genetic variation. Towards measurement of alcohol response, instruments
sider focusing on more widely defined biological systems rather than specific receptors, and might measuring level of response (sometimes referred to as acute tolerance) and flushing have been
be most successful if they include analyses of gene-by-gene and gene-by-environment additive and devised, and we (Kwako, Diazgranados, Goldman) have developed a 50-item Mini Alcohol Screen-
interactive effects. In addition, analyses need to probe whether similar genes relate to additional ing Exam (MASE) to measure responses in five domains, namely Withdrawal, Acute Tolerance,
effects of alcohol, including vulnerabilities toward alcohol related blackouts. Blackouts, Flushing and Aggression. For at least four of these responses, parallel animal models
facilitate identification of genes and mechanisms, and as we are attempting to do using the intramu-
ral NIAAA clinical sample. For alcohol withdrawal severity, Crabbe and colleagues selected, from a
heterogeneous stock, replicate lines high and low for handling induced convulsions (HIC), creating
WSR1 (Withdrawal Seizure Resistant1), WSR2, WSP1, WSP2, C1 and C2 lines. We exome
sequenced these lines revealing putatively functional variants fixed in opposite configuration in one
153 or up to all four WSR/WSP line combinations. Having been maintained >120 generations, the WSP/
WSR lines are highly inbred, as shown by our exome sequencing, and as will create random associ-
CHARACTERIZATION OF ALCOHOL RESPONSE PHENOTYPES DURING ALCOHOL SELF- ations. As a next step towards locus validation, and partially mitigating the problem of random fixa-
ADMINISTRATION IN INDIVIDUALS ACROSS THE SPECTRUM OF ALCOHOL USE DISORDER tion, we performed QTL analysis in a large panel of F2 mice made from WSR and WSP F0 mice,
RISK and using a custom SNP panel providing genome wide coverage for meiotic linkage. HIC scores in
V.A. Ramchandani, B.L. Stangl, V. Vatsalya, J.L. Gowin, M.E. Sloan these F2’s were highly dispersed and multimodal, indicative of oligogenicity or even a major gene
NIH/NIAAA, Section on Human Psychopharmacology, Bethesda MD 20892, USA effect, and as is also consistent with the original rapid response to selection observed in the deriva-
tion of the WSR/WSP lines. A locus of major effect, with lod score >5 (depending on how the pheno-
Self-administration is the hallmark of all addictive drugs, including alcohol. Novel human laboratory
type was parsed), was mapped to chromosome 6, to a region where neither other alcohol responses
studies employing intravenous (IV) alcohol self-administration (IV-ASA) have enabled the assess-
nor seizure susceptibility have not previously been mapped. Study of alcohol responses is likely to
ment of pharmacologically-driven alcohol consumption and response phenotypes. The objective of
uncover genes with distinct effects, and for example metabolic enzyme variants leading to flushing,
this study was to characterize the variability in these phenotypes in individuals across the spectrum
as well as genes that act, in pleiotropic fashion, on more than one type of response.
of alcohol use and risk for alcohol use disorder. Data for this study was obtained from 211 individuals,
between 21 and 60 years of age, that underwent a 125-min free-access IV-ASA session. Partici-
pants also underwent a deep-phenotyping protocol to obtain measures of drinking history, psychi-
atric diagnostic history, family history of alcohol use disorder (FHA), alcohol-related expectancies
and self-rating of effects of alcohol (SRE), personality, and other traits. Participants were classified
into light, moderate and heavy drinkers based on weekly consumption patterns, Primary measures
included the rate and quantity of alcohol self-administered during the first 30-min, and subjective
responses of feeling, liking, and wanting alcohol, high and intoxication. Results indicated that IV-ASA
measures were strongly associated with drinking history measures, with heavier drinkers showing
greater and faster self-administration. IV-ASA exposure measures were also associated with subjec-
tive responses across drinking groups. Both FHA and SRE were associated with IV-ASA measures
and subjective response as well. Multiple regression analysis indicated drinking group to show the
strongest association with IV-ASA measures, possibly due to the significant correlation between
SRE and drinking history measures. In conclusion, drinking history was a major predictor of alcohol
response phenotypes associated with IV alcohol self-administration. The strong correlations
between alcohol consumption measures and subjective response measures suggests that these
phenotypes primarily reflect the rewarding hedonic effects of alcohol that may drive risk for excessive
alcohol use and associated consequences.
310A
TUESDAY, JUNE 19 9:15 AM–10:45 AM
SYMPOSIUM 156–159
Stress, Alcohol, and the Kappa Opioid System: What’s Age Got to Do with It?
Organizers/Chairs: Anushree Karkhanis and Marvin Diaz
156
BRIEF PRENATAL ETHANOL EXPOSURE ALTERS THE EXPRESSION OF DYNORPHIN- AND
NOCICEPTIN-RELATED GENES IN THE INFANT AND ADOLESCENT BRAIN
R.M. Pautassi
Department of Psychophysiology, Instituto de Investigaciones Medicas M. y M. Ferreyra (INIMEC-
CONICET-UNC), Co  rdoba, Co
 rdoba, CP 5000, Repu blica Argentina
We have found that prenatal ethanol exposure (PEE, 2.0 g/kg; gestational days 17–20) increases
the rewarding effects of ethanol, and heightens ethanol-induced activation of the mesocorticolimbic
pathway and ethanol intake in adolescence. These effects may be the result of a PEE-induced dys-
regulation of the kappa opioid receptor (KOR) system. We investigated, in infant and adolescent rats
exposed to PEE, brain expression of dynorphin (DYN) and nociceptin (NOC) related genes and
assessed anxiety-like behavior. PEE rats exhibited greater avoidance of the brightly lit areas in the
light-dark box (LDB) and in the concentric square field (CSF) test, greater preference for the shel-
tered area in the CSF test and hypoactivity in the open field (OF). These effects were associated with
upregulated PDYN and KOR mRNA levels in the ventral tegmental area (VTA) and KOR mRNA
levels in the prefrontal cortex. The changes in the VTA were accompanied by a reduction of DNA
methylation at the PDYN gene promoter, and by lower NOC receptor gene expression. PEE rats
also had lower PDYN – yet greater NOC– gene expression in the nucleus accumbens. These results
suggest that PEE upregulates the dynorphin system, resulting in an anxiety-prone phenotype, and
triggering compensatory responses in the nociceptin system.
157
ADOLESCENT STRESS-INDUCED SOCIAL ANXIETY AND ETHANOL CONSTUMPTION:
ALTERATIONS IN BASOLATERAL AMYGDALA KAPPA OPIOID RECEPTOR FUNCTION
E.I. Varlinskaya, T. Deak, J.M. Johnson, Y.A. Valentine, M.R. Diaz
Department of Psychology, Developmental Exposure Alcohol Research Center and Center for
Development and Behavioral Neuroscience, Binghamton University – SUNY, Binghamton, NY,
13902, USA
Stress and anxiety are significant factors that contribute to risk for developing an alcohol use disorder
and stress-induced upregulation of the DYN/KOR system is thought to underlie the negative affect
associated with stress and elevated ethanol consumption. The basolateral amygdala (BLA) is a key
structure associated with anxiety and ethanol consumption, and the DYN/KOR system can regulate
BLA neural activity in an age-dependent manner in stress-na€ıve animals. However, the role of the
DYN/KOR system in modulating short- and long-term anxiety and ethanol consumption following
adolescent stress is unknown. Using behavioral, molecular and electrophysiological techniques, we
examined the short- and long-term impact of a 2-day forced swim stress (FSS – 10 min each day) in
adolescents and adults. Adolescent males, but not adult males or females of either age, demon-
strated social anxiety-like behavioral alterations at 24 h following FSS. Alterations in social prefer-
ence 24 h-post FSS were significantly correlated with BLA KOR mRNA expression. Additionally,
FSS led to a robust switch in BLA KOR-modulation of GABA transmission. Interestingly, the effects
of adolescent stress on social behavior persisted into adulthood, during which adult males also
demonstrated increased ethanol consumption. These findings provide evidence for KOR-dependent
mechanisms that may contribute to age-dependent pathophysiological interactions with alcohol and
other subsequent stress challenges.
ABSTRACTS-SPEACKERS
158
SOCIAL ISOLATION STRESS INCREASES KAPPA OPIOID RECEPTOR SENSITIVITY IN THE
NUCLEUS ACCUMBENS OF RATS
A.N. Karkhanis, D. Leussen, J.L. Weiner, R. Chen, M. Bruchas, S.R. Jones
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem,
NC 27157, USA
Adverse social experiences, especially during adolescence, increase the risk of developing alcohol
use disorders during adulthood in humans. Similarly, rats reared in social isolation during adoles-
cence show greater ethanol intake in adulthood compared to group housed controls. Acute stress
elevates dynorphin levels, a kappa opioid receptor (KOR) ligand, which regulates dopamine. Activa-
tion of KORs inhibits DA release in the NAc. The NAc plays an integral role in the neurobiology of
stress, anxiety, and reward-seeking behavior. We recently showed that KOR function is increased in
the NAc following social isolation. However, this study did not examine whether the changes in KORs
were on a specific population of neurons or the mechanism of the increased function of KORs. In
order to investigate early-life stress-induced changes in KORs, we housed the rats individually (so-
cial isolation, 1 rat/cage) or in groups (group housed; 4 rats/cage) for six weeks (PD 28–74). After the
housing paradigm, we examined KOR function specifically on dopamine terminals in slices contain-
ing the NAc in TH:Cre rats using fast scan cyclic voltammetry. Optical stimulation of dopamine neu-
rons revealed that KORs specifically on dopamine terminals were hyper-responsive to the agonist,
U50488. Furthermore, the augmentation of KOR function was observed to be due, in part, to aug-
mented g-protein coupling and binding efficacy. These dopamine inhibiting effects were mimicked by
overexpression of KORs in dopamine neurons of group housed animals. Moreover, ethanol intake of
group housed animals with KORs overexpressed in dopamine neurons matched the heightened
ethanol intake of socially animals and was significantly greater than group housed animals infused
with a sham virus. Because KOR activation reduces dopamine release, it is possible that individuals
exposed to chronic stress experience a hypodopaminergic state chronically and therefore continue
to drink more alcohol as a means of self-medication.
159
DYNORPHIN/KOR ACTIVITY WITHIN THE CENTRAL AMYGDALA AND BNST MODULATES
STRESS-ENHANCED ETHANOL CONSUMPTION IN MICE WITH A HISTORY OF
DEPENDENCE
H.L. Haun, R.I. Anderson, M.F. Lopez, W.C. Griffin, H.C. Becker
Departments of Psychiatry and Neuroscience, Charleston Alcohol Research Center, Medical
University of South Carolina &VAMC, Charleston, SC 29464, USA
Repeated forced swim stress (FSS) has been shown to selectively increase voluntary ethanol
(EtOH) intake in male C57BL/6J mice with a history of dependence achieved through chronic inter-
mittent EtOH (CIE) exposure. Previous studies in our lab found that systemic administration of the
kappa opioid receptor (KOR) antagonist LY4244296 prior to drinking in this model was effective in
blocking escalated EtOH intake after CIE and FSS exposure, but the exact site action remains
unknown. The bed nucleus of the stria terminalis (BNST) is an attractive target in that it contains a
high density of KORs and is responsive to both CIE exposure and FSS. In the current study, bilateral
guide cannula were positioned over the BNST in male C57BL/6J mice and baseline ethanol (15% v/
v) intake was established. Subjects then received CIE exposure (16 h/day 9 4 days/week) to etha-
nol vapor (CIE group) or air (CTL group). Weekly cycles of inhalation exposure were alternated with
5-day, 1-h limited access drinking tests. FSS (10 min) occurred 4 h prior to each daily drinking ses-
sion. As expected, FSS enhanced CIE-induced escalated drinking without altering intake in CTL
mice (p < 0.05) Targeted microinjection (2.5-ug/side) of the long lasting KOR antagonist norbinaltor-
phimine (nor-BNI) into the BNST 18 h prior to ethanol drinking significantly decreased intake in mice
with a history of CIE and CIE + FSS (ps < 0.05). Projection neurons originating in the central amyg-
dala (CeA) produce dynorphin and have dense terminal fields within the BNST. In a separate study
of the same design, male transgenic prodynorphin-IRES-CRE (pDYN-CRE) mice were used for tar-
geted inhibition of dynorphin containing neurons within the CeA. Briefly, 0.25-uL of a CRE-dependent
inhibitory DREADD (AAV8-hSyn-DIO-hM4Di-mCherry) was bilaterally infused into the CeA over a
5 min period with a 5 min diffusion period. Preliminary data suggest that chemogenetic inhibition of
dynorphin-expressing CeA neurons is effective in reducing stress-enhanced ethanol consumption,
similar to microinjection of nor-BNI into the BNST. Together, these data implicate KORs within the
BNST in stress-enhanced ethanol consumption and suggest an important role for DYN/KOR activity
within CeA-BNST circuitry in mediating the enhancing effect of stress on ethanol intake in dependent
mice. Supported by NIAAA and VA Medical Research.
ABSTRACTS-SPEACKERS
TUESDAY, JUNE 19 9:15 AM–10:45 AM
SYMPOSIUM 160–163
Novel Insights into Alcohol-Induced Multi-Organ Carcinogenesis
Organizers/Chairs: Armen Petrosyan and Carol Casey
160
THE ROLE OF ALCOHOL-INDUCED GOLGI FRAGMENTATION IN PROGRESSION OF
PROSTATE CANCER
S. Manca1,2, C.A. LaGrange1,2, A.M. Pong1,2, A. Petrosyan1,2
1
University of Nebraska Medical Center, Omaha, NE, USA and 2The Nebraska Center for Integrated
Biomolecular Communication, Lincoln, NE, USA
Various population-based case-control studies have revealed a strong association of prostate cancer
(PCa) incidence and progression with alcohol consumption; however, neither the precise mecha-
nism of carcinogenesis nor the link of alcohol to the aggressiveness of PCa has been analyzed.
Recently we reported novel and exciting information that ethanol (EtOH)-induced Golgi fragmenta-
tion impairs N-glycosylation and trafficking of plasma membrane (PM)-bound proteins in the setting
of alcoholic liver injury. Here, we detected fragmented Golgi in the ventral prostate lobes of EtOH-fed
rats; also, these prostates demonstrated severe focal hyperplasia and varying degrees of dysplasia.
In vitro study of LNCaP cells revealed that Golgi disorganization is mediated by the alcohol dehydro-
genase (ADH)-catalyzed oxidation of EtOH. Further, we found that EtOH accelerates LNCaP and
DU145 tumor xenograft in athymic male mice. We emphasize three functional consequences of
EtOH-induced Golgi fragmentation. First, Golgi disorganization is accompanied by the impaired traf-
ficking and glycosylation of the membrane androgen receptor (mAR). This, in turn, diminishes bind-
ing of androgens to the mAR and attenuates pro-apoptotic signaling cascades. Second, the
signaling pathways induced by the action of intracellular androgen receptor (iAR) are commonly con-
sidered the main oncogenic drivers of prostate carcinogenesis. Also, it is known that the histone
deacetylase 6 (HDAC6) regulates the activity of heat shock protein 90 (HSP90) via its deacetylation,
and deacetylated HSP90 is essential for activation of iAR-dependent carcinogenesis in PCa. Herein,
we observed that Golgi fragmentation results in activation of HDAC6 via its phosphorylation. It, in
turn, deacetylates HSP90, thereby activating iAR maturation by HSP90 followed by intranuclear tran-
sition of iAR. Third, among the alterations described in PCa are abnormal expression and functions
of integrins and of their extracellular matrix ligands and overexpression of serine proteases, including
Matriptase. These proteins are retained at the cell surface and responsible for the cell proliferation,
migration, and differentiation, thus contributing to cancer progression. We observed that EtOH-
induced Golgi fragmentation alters Golgi docking site for the N-acetylglucosaminyltransferase-III
(MGAT3), but results in domination of N-acetylglucosaminyltransferase-V (MGAT5) in N-glycosyla-
tion. This, in turn, remodifies the glycan profile for both integrins and Matriptase, thereby facilitating
their retention at the PM of PCa cells via specific ligand-lectin interaction with Galectin-3.
161
CELL FATE REPROGRAMMING OF LIVER TUMOR-INITIATING STEM-LIKE CELLS INDUCED
BY ALCOHOL WESTERN DIET VIA PHOSPHORYLATED NUMB AND TBC1D15
H.R. Siddique, M. Zheng, P. Winer, D.B. Uthaya Kumar, A. Rokan, L. Sher, S.M. Tahara, M. Elowitz,
C. Liang, H. Tsukamoto,K. Machida
Departments of Molecular Microbiology and Immunology, Keck School of Medicine, University of
Southern California Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA
90033, USA
Tumor-initiating stem-like cells (TICs) are defective in their control of asymmetric division. The p53
interacting protein NUMB (cell fate determinant molecule) preserves this intrinsic cellular asymmetry
and functions as a vital barrier against unchecked expansion as seen in TICs. How TICs overcome
this control of asymmetric division to cause cancer is unknown.
Hypothesis: Accentuated TLR4-NANOG-mediated NUMB phosphorylation and the novel oncopro-
tein TBC1D15 upregulation promote self-renewal of TICs in liver oncogenesis caused by HCV and
alcohol.
Aim: To determined the causal roles of NUMB phosphorylation and TBC1D15 oncoprotein in alco-
hol-induced liver tumorigenesis.
Methods: Tumor incidence and pathophysiological changes were examined in liver-specific
TBC1D15 deficiency (Alb::CreERT2; Tbc1d15Flox/Flox; NS5A) or non-phosphorylatable mutations of
NUMB (Alb::CreERT2; Numb-3ALSL; NS5A) in HCV-Tg mice fed alcohol western diet (high-choles-
terol, high-fat diet) for 12 months.
Results: Liver-specific TBC1D15 deficiency or non-phosphorylatable mutations of NUMB (NUMB-
3A), reduce liver tumor incidence and tumor-associated NANOG + TICs in HCV NS5A Tg mice fed
alcohol Western diet. TICs lost asymmetric division capacity and overexpressed TBC1D15, which
associated with NUMB to promote aPKCf activity and NUMB phosphorylation. Thus, TIC self-
renewal is dependent on TBC1D15 and NUMB phosphorylation. Similarly, aPKCf-mediated NUMB
phosphorylation and induced TBC1D15 are mutually required for self-renewal. Furthermore,
TBC1D15 activated NOTCH via binding to NOTCH intracellular domain to trigger its proteolysis.
TBC1D15 interacts with all NOTCH isoforms, activates NOTCH pathway, and induces Nanog and
TIC self-renewal in a NOTCH-dependent manner.
Conclusions: TBC1D15 cooperates with the NOTCH pathway to support TIC tumorigenic activity
and an inhibitor of this interaction is potentially therapeutic. TBC1D15 has unique oncogenic activi-
ties involving p53 degradation and cooperation with the NOTCH pathway in TICs.
311A
162
BETA-ENDORPHIN NEURONAL REGULATION OF CANCER GROWTH, PROGRESSION AND
METASTASIS IN ALCOHOL-EXPOSED AND CONTROL ANIMALS
S. Murugan, C. Zhang, N. Boyadjieva, S. Jabbar, D. Sarkar
Rutgers University, Department of Animal Science, New Brunswick, New Jersey, 08901, USA
It is becoming increasingly clear that chronic alcohol drinking reduces body’s ability to cope stressful
life events which are known to impact cancer growth and metastasis by modulating nervous, endo-
crine and immune system of the body. Under the physiological condition, a neuroendocrine hormone
that plays a critical role in bringing the stress axis homeostasis is the opioid peptide beta-endorphin
(BEP). We have recently shown that promotion of endogenous levels of BEP in the hypothalamus
via BEP neuron transplantation reduces stress response, promotes immune function. Hence, we
have tested the effects of BEP cell transplantation in rat models of prostate, breast, liver and colon
cancers. We found that BEP neuron transplantation inhibits the growth and progression of all can-
cers tested. We have also found that BEP neuron transplantation inhibits the growth and progression
of fetal alcohol-induced mammary cancer. The cancer preventive role of BEP appears to be caused
by the suppression of sympathetic neuronal function and resulting in an increased peripheral NK cell
and macrophage activities, elevated levels of anti-inflammatory cytokines and reduced levels of
inflammatory cytokines. BEP inhibition of tumor progression also involves alteration in tumor
microenvironment possibly due to suppression of catecholamines and inflammatory cytokines pro-
duction that is known to alter cell-matrix attachments, angiogenic mechanisms, DNA repair and
epithelial-mesenchymal transition. Thus, possible therapeutic approaches exist that take advantage
of BEP cell therapy to prevent cancer growth and progression in alcoholic and non-alcoholic
patients.
163
CHRONIC ALCOHOL CONSUMPTION ENHANCES CANCER-ASSOCIATED CACHEXIA: THE
ROLE OF MYOSTATIN-TNF-Α AXIS
Y. Li1,2, F. Zhang1, H. Zhang1
1
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University,
Spokane, WA 99210-14952, USA and 2Department of oncology, The First Hospital of Shanxi
Medical University, Taiyuan 030001, China
Chronic alcohol consumption not only increases the incidence of multiple types of cancer, but also
decreases the survival of cancer patients. Cancer-associated cachexia (CAC) is a multifactorial
symptoms characterized by progressive body weight loss, specifically the loss of adipose tissues
and skeletal muscle. Around 85% of patients with advanced cancer experience CAC. As many as
30% of all cancer-related deaths are attributable to CAC. Epidemiological data and experimental ani-
mal studies indicate that alcohol consumption enhances CAC. However, the underlying mechanism
has not been explored. Using a mouse Lewis lung carcinoma model we studied how alcohol affects
CAC, specifically the loss of skeletal muscle. We found that alcohol consumption significantly
decreased the survival of tumor-bearing mice, accelerated the body weight loss, especially the loss
of skeletal muscle. The expression of myostatin and TNF-a, two key mediators forming positive feed-
back loop to induce muscle atrophy, was significantly increased in the skeletal muscle of alcohol-
consuming mice. Consistent with the upregulation of myostatin and TNF-a, alcohol consumption acti-
vated p38/Caspase-3 signaling pathway, enhanced SMAD/NF-jB/MAFbx/MuRF1-mediated protein
degradation pathway, and inhibited Akt/mTOR-mediated protein synthesis pathway in the skeletal
muscle. Using TNF-a knockout mice, we found that the depletion of TNF-a abrogated alcohol con-
sumption-induced body weight loss and significantly increased the survival of the alcohol-consuming
and tumor-bearing mice. Taken together, these results indicate that alcohol consumption by activat-
ing myostatin-TNF-a axis induces cell apoptosis, enhances protein degradation, and inhibits protein
synthesis in skeletal muscle. Depletion of TNF-a can abrogate alcohol consumption-enhanced CAC
and increase the survival of tumor-bearing mice. (This work was supported by NIH grant
R15AA024284)
312A ABSTRACTS-SPEACKERS

TUESDAY, JUNE 19 9:15 AM–10:45 AM 166

SYMPOSIUM 164–167
Extracellular Vesicles and Non-Coding RNA in Alcohol-Induced Organ THE MIRNA-21 ACTS AS A DOUBLE-EDGED SWORD ON LIPID METABOLISM AND
INFLAMMATION IN ALCOHOLIC FATTY LIVER
Damage: Mechanisms and Therapeutic Targeting L. Wang
Organizers/Chairs: Li Wang and Ekihiro Seki University of Connecticut, Storrs, CT 06269, USA
Chair: Peter Gao
Accumulation of lipid droplets and inflammatory cell infiltration in the liver is the pathophysiological
hallmark of alcoholic liver disease (ALD). The cell-type specific role of miR-21 in ALD remains
unknown due to the lack of cell-type specific knockout mice. We generated hepatocyte specific miR-
164 21 knockout mice to understand its pathophysiological role in ALD. Liver miR-21 RNA levels were
highly induced in WT mice fed the ethanol diet compared with mice fed the control diet. Moreover,
EXTRACELLULAR VESICLES FROM MICE WITH ALCOHOLIC LIVER DIESEASE CARRY A miR-21 levels were markedly upregulated in human patients with alcoholic cirrhosis versus normal
DISTINCT PROTEIN CARGO AND INDUCE MACROPHAGE ACTIVATION VIA HSP90 controls, demonstrating their roles in the pathogenesis of ALD. Hep-KO mice fed the ethanol diet
G. Szabo, B. Saha, I. Furi had increased hepatic triglyceride (TG) but decreased plasma TG levels, which was associated with
University of Massachusetts Medical School, Department of Medicine, Worcester MA 01605, USA increased lipogenesis (FASN, SCD1 and SREBP protein expression) but decreased VLDL secretion
(MTTP). Lipidomics analysis revealed increased TG but decreased PC and PE lipid species in Hep-
A salient feature of alcoholic liver disease (ALD) is Kupffer cell (KC) activation and recruitment of
KO versus WT mice. Interestingly, inflammation was attenuated in Hep-KO, as evident by the
inflammatory monocytes/macrophages (Mo/MØ). These key cellular events in the pathogenesis of
decreased serum AST and ALT levels, and reduced expression of key hepatic pro-inflammatory (Il-
ALD may be mediated by extracellular vesicles (EVs). EVs are heterogeneous, membranous, cell-
6, Ccr2, MIP1a, LyG6) genes. At the cellular level, MAPKs, AMPK and PPARs signaling pathways
derived vesicles that are classified as exosomes (40–150 nm) or microvesicles (MVs) (150–
were assessed to determine the key regulatory role of miR-21 in steatosis and inflammation, which
1,000 nm) based on their mode of biogenesis and size EVs transfer biomaterials, including proteins
showed that the activation of P38 and JNK were suppressed in Hep-KO. Using TargetScan, micro-
and miRNAs, and have recently emerged as important effectors of intercellular communication. We
rna and miRanda, we predicted a conserved miR-21 seed match region in mouse and human
hypothesized that circulating EVs from mice with ALD have a protein cargo characteristic of the dis-
DUSP16 30 UTRs; a gene known as a phosphatase of P38 and JNK. Transfection of miR-21 mimics
ease and mediate biological effects by activating immune cells. The total number of circulating EVs
reduced the DUSP16 protein in HepG2 and Hepa1 cells. In addition, the mouse DUSP16 30 UTR
was increased in mice with ALD (ALD-EV) compared to pair-fed controls (control-EV). Mass spec-
containing the miR-21 seed region was cloned into a luciferase reporter and miR-21 mimic inhibited
trometry analysis of circulating EVs revealed a distinct signature for proteins involved in inflammatory
DUSP16 30 UTR activity in a dose-dependent fashion, which was relieved when the miR-21 seed
responses, cellular development and cellular movement between ALD-EVs and control-EVs. We
region was mutated. Furthermore, DUSP16 protein expression was down-regulated in patients with
also identified uniquely important proteins in ALD-EVs that were not present in control-EVs. When
alcoholic liver cirrhosis, where miR21, P-P38 and P-JNK levels were elevated.
ALD-EVs were injected intravenously into alcohol-na€ıve mice, we found evidence of uptake of ALD-
Conclusion: Hepatocyte miR-21-deficiency promotes alcoholic steatosis, but ameliorates liver
EVs in recipient livers in hepatocytes and MØs. Hepatocytes isolated from mice after transfer of
injury and inflammation through the miR-21/DUSP16/P38 pathway. Our work provides novel insights
ALD-EVs, but not control-EVs, showed increased MCP-1 mRNA and protein expression suggesting
into the understanding of the molecular mechanism of non-coding RNAs as key regulators in alco-
a biological effect of ALD-EVs. Compared to control-EV recipient mice, ALD-EV recipient mice had
holic liver disease.
increased numbers of F4/80hiCD11blo KCs and increased percentages of TNFa+IL-12/23+ (inflam-
matory/M1) KCs and infiltrating monocytes (F4/80intCD11bhi) while the percentage of
CD206+CD163+ (anti-inflammatory/M2) KCs was decreased. In vitro, ALD-EVs increased TNFa and
IL-1b production in MØ and reduced CD163 and CD206 expression. We identified Heat shock pro-
tein 90 (Hsp90) in ALD-EVs as the mediator of ALD-EV-induced MØ activation.
Conclusion: Our study indicates a specific protein signature of ALD-EVs and demonstrates a func-
tional role of circulating EVs containing Hsp90 in mediating KC/MØ activation in the liver.
167
ACUTE-ON-CHRONIC ALCOHOL CONSUMPTION INDUCES NEUTROPHILIA AND
HEPATOTOXICITY VIA THE PRODUCTION OF MITOCHONDRIAL DNA-ENRICHED
EXTRACELLULAR VESICLES
B. Gao
National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA
165
Binge alcohol consumption induced neutrophilia and hepatic neutrophil infiltration in chronically etha-
ALCOHOL LIVER DISEASE ENHANCES METASTATIC TUMOR GROWTH THROUGH nol-fed mice and individuals with chronic alcohol use; however, the underlying mechanisms remain
EXTRACELLULAR MATRIX AND MIRNA-MEDIATED STELLATE CELL ACTIVATION obscure. Here, we demonstrated that chronic alcoholic patients with a history of recent excessive
E. Seki, Y.M. Yang drinking had higher serum levels of mitochondrial DNA (mtDNA)-enriched microparticles (MPs) than
Cedars-Sinai Medical Center, Los Angeles, 90048, USA alcoholics without recent drinking and healthy controls, which correlated positively with circulating
neutrophils. Similarly, mice with chronic-plus-binge ethanol feeding also had markedly elevated
Chronic alcohol consumption is known to promote primary liver cancer as well as colorectal cancer
serum levels of mtDNA-enriched MPs, with activation of hepatic ER stress and inflammatory
(CRC) growth. Previous human report and animal studies demonstrated that the risk of CRC-
responses. Inhibition of ER stress by gene knockout or inhibitors attenuated ethanol-induced eleva-
mediated liver metastasis is also increased by chronic alcohol consumption. However, the molecular
tion of mtDNA-enriched MPs, neutrophilia, and liver injury. Administration of mtDNA-enriched MPs
mechanisms underlying alcohol enhancement of metastatic liver tumor growth are poorly under-
isolated from chronic ethanol-fed mice caused neutrophilia in mice. In conclusion, chronic-plus-binge
stood. This study is focused on alcohol-mediated hepatocyte-derived extracellular vesicles (EVs)
ethanol consumption activates hepatic ER stress-dependent mtDNA-enriched MP release, leading
and microRNA (miRNA) regulation of HSC activation in liver metastasis. Alcohol-exposed hepato-
to neutrophilia and liver injury.
cytes enhanced production of EVs that contain pro-metastatic and pro-HSC activating miRNAs.
These miRNAs promote HSC activation and extracellular matrix production in metastatic liver
tumors. Liver metastasis model was developed by splenic injection of MC38 cells, a mouse syn-
geneic colorectal cancer cell line. Alcohol-containing liquid diet was fed on mice for six weeks before
tumor injection. Two weeks after tumor injection, mice were sacrificed. Alcohol-treated mice showed
the enhanced growth of metastatic tumors, in which HSCs were activated and hyaluronic acid (HA)
was accumulated. Hyaluronic synthase 2 (Has2) is the major enzyme to synthesize HA in the liver.
We created hepatic stellate cell (HSC)-specific HAS2 knockout (HSC-Has2 KO) mice. While liver
tumor growth was unchanged in HSC-Has2 KO mice fed with pair-fed condition compared to wild-
type mice, in the alcohol-treated condition HSC-Has2 KO mice showed reduced tumor growth, sug-
gesting alcohol-mediated tumor growth is mediated by HSCs and Has2. Moreover, we found that
that miRNAs contained in alcohol-mediated EVs promoted HSC activation and Has2 upregulation.
In summary, alcohol mediates the production of EVs and miRNAs, which enhance metastatic liver
tumor growth through HSC activation and Has2 upregulation.
ABSTRACTS-SPEACKERS
TUESDAY, JUNE 19 9:15 AM–10:45 AM
SYMPOSIUM 168–171
Functional Adaptations of Neurons Following Alcohol Exposure
Organizer: Yoshio Takashima
Chair: Chitra Mandyam
168
RECRUITMENT AND DISRUPTION OF VENTRAL PALLIDAL VALUE ENCODING IN ALCOHOL
SEEKING
J.M. Richard, A.M. Armstrong, A. Haimbaugh, P.H. Janak
Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD 21218
USA
The ventral pallidum (VP) has been suggested to act as part of a common pathway for relapse to
drug and alcohol seeking, but the specific psychological mechanisms by which it does so remain
mysterious. We previously showed that the activity of VP neurons in response to a cue predicting
reward availability encodes both the likelihood and latency of subsequent instrumental reward-seek-
ing actions (Richard et al., 2016). Here, we assessed representations of cue value and response
vigor by VP activity during cue-elicited alcohol seeking under Pavlovian versus instrumental behav-
ioral contingencies. During Pavlovian conditioning an auditory tone predicts the delivery of sucrose
or alcohol to a reward port. While delivery of the reward is not contingent on the animal’s behavior,
over conditioning the animal learns to approach the reward port during the cue. In the instrumental
task, an auditory cue (the discriminative stimulus, DS) indicates the availability of sucrose or alcohol
from the port if the animal enters the reward port during the cue period. Rats were trained in one of
these tasks until they entered the reward port on >70% of reward cue trials (CS+ or DS), and <30%
of control cue trials (CS
or NS), and were implanted with drivable microwire arrays aimed at VP.
While many (~40%) of VP neurons were excited by a cue predicting alcohol delivery (CS+), these
excitations were equally robust following the CS
, despite reliable behavioral discrimination between
these two cues and robust differences in neural responses to a sucrose CS+ versus CS
. We next
assessed VP responses to a cue predicting reward availability contingent on entry to the port during
the cue period, to determine whether the vigor of this instrumental reward seeking response would
be encoded by VP neurons equally when the reward was sucrose versus alcohol. We found that
cue-driven VP activity predicts the vigor of instrumental but not Pavlovian responses whether they
were conditioned with sucrose or alcohol. Overall, we find that VP activity contributes to reward seek-
ing in distinct ways depending on the underlying associative structure of the task and the specific
reward, and that problem alcohol seeking may be driven by biased engagement of specific decision-
making processes.
169
INVOLVEMENT OF THE ROSTROMEDIAL TEGMENTAL NUCLEUS AND ITS INPUTS IN
AVERSIVE ASPECTS OF ALCOHOL DEPENDENCE
E.J. Glover, E.M. Starr, T.C. Jhou, L.J. Chandler
Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425, USA
The negative affective state associated with alcohol withdrawal is thought to play a critical role in pro-
moting relapse. In addition, alcohol dependence is associated with tolerance to alcohol’s aversive
properties and consumption despite negative consequences. Collectively, these alterations suggest
that chronic alcohol exposure promotes plasticity in neural circuits involved in aversive signaling that
may serve to facilitate relapse and continued alcohol consumption. The rostromedial tegmental
nucleus (RMTg) exerts inhibitory control over midbrain dopamine neurons and activity within this
region has been implicated in signaling the aversive properties of various drugs of abuse. We
explored a role for the RMTg in withdrawal-induced negative affect in rats using markers of neuronal
activity in combination with behavioral indices of anxiety-like behavior and reward sensitivity. We
observed a significant increase in cFos expression in the RMTg across the time course of acute with-
drawal, with peak expression occurring 12 h after ethanol exposure (p < 0.05). This same time per-
iod was also associated with heightened anxiety-like behavior and a decrease in reward sensitivity
indicative of anhedonia. Inhibition of the RMTg attenuated withdrawal-induced anxiety-like behavior
(p < 0.05) but not reward sensitivity suggesting that activity within this region plays an important role
in mediating some symptoms that serve to promote relapse. The RMTg receives dense input from
the medial prefrontal cortex (mPFC) – a region that undergoes significant plasticity following chronic
alcohol exposure – yet the function of this pathway and its involvement in addiction is not well under-
stood. Using in vivo optogenetics we observed significant behavioral avoidance upon stimulation of
mPFC inputs to the RMTg. In addition, exposure to aversive stimuli enhanced cFos expression in
RMTg-projecting mPFC neurons relative to neutral stimuli further implicating this circuit in aversive
signaling. Ongoing studies are working to explore dependence-induced plasticity in this pathway and
its involvement in behavioral adaptations that occur following chronic alcohol exposure.
313A
170
ADAPTATIONS IN ORBITOFRONTAL CORTEX NEURONS FOLLOWING EXPOSURE TO
ETHANOL
J.J. Woodward
Department of Neuroscience, Charleston Alcohol Research Center, Charleston, SC 29425, USA
The orbitofrontal cortex (OFC) is a specialized part of the frontal cortex and is thought to be involved
in assessing value and risk associated with motivated behaviors. OFC neurons receive direct input
from a variety of sensory modalities including taste as well as limbic areas like the basolateral amyg-
dala. In humans with alcohol use disorders, alterations in OFC function are proposed to underlie the
preoccupation and craving for alcohol and individuals with alcohol use disorders often show deficits
in OFC-dependent tasks such as reversal learning. In addition, human and animal studies suggest
that the OFC dysfunction is a key determinant of obsessive-compulsive disorder that shares some
features with addiction. Despite these findings, few preclinical studies had examined the effect of
ethanol on the structure and function of OFC neurons. Using mouse models of ethanol exposure,
slice electrophysiology and dendritic spine imaging, we investigated how ethanol affects OFC neuron
structure and function. Results from these studies show that low concentrations of ethanol reduce fir-
ing of mouse OFC neurons via a novel glycine-dependent mechanism. Following repeated expo-
sures to chronic intermittent ethanol (CIE) vapor, OFC firing is enhanced and is no longer sensitive
to inhibition by acute ethanol. The enhanced firing following CIE exposure is accompanied by reduc-
tions in the after-hyperpolarization mediated by apamin-sensitive SK2 potassium channels. Imaging
studies revealed an increase in the number of long, thin spines on OFC neurons from CIE-treated
mice. We also determined that OFC neuron excitability is modulated by monoamines (DA, NE, 5HT)
via activation of Gi/o receptors coupled to G-protein, inwardly-rectifying potassium channels (GIRK).
After CIE exposure, monoamines or direct GIRK channel activators no longer reduce OFC neuron
firing. Results from recent unpublished studies show that OFC neurons from female mice are also
affected by acute and chronic ethanol although the magnitude and duration of these changes are
less than those seen in male mice. Finally, similar changes in OFC neuron excitability and ethanol
sensitivity are observed in mice undergoing voluntary intermittent ethanol drinking with effects
appearing after just 1 week of consumption. These findings suggest that changes in OFC function
following exposure to alcohol may contribute to behavioral deficits observed in alcohol-dependent
individuals.
171
FUNCTIONAL ADAPTATIONS OF PFC AND HIPPOCAMPAL NEURONS AFTER ETHANOL
EXPOSURE FOLLOWED BY PROTRACTED ABSTINENCE
Y. Takashima, M. Fannon, C. Mandyam
Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA
Alcohol use disorder (AUD) is a chronic relapsing brain disease which 16~18 million people suffer in
the United States. The process of developing AUD does not occur in a day, but over a series of
repeated cycles. The addiction cycle can be defined by three stages: binge/intoxication, withdrawal/
negative affect, and preoccupation/anticipation so called “craving” stage. Moreover, AUD is a com-
plex disorder that can directly affect the reward-, pleasure-, motivation-pathway, and memory which
are governed by many different regions of the brain. Here, we focused our attention on the prefrontal
cortex (PFC) and hippocampus, brain regions involved in preoccupation/anticipation stage which is
thought to be a key element driving propensity for relapse. Using a rat model of AUD and slice elec-
trophysiology we investigated how ethanol affects function of the PFC layer 2/3 pyramidal neurons
and hippocampal granule cell neurons (GCNs) in the dentate gyrus. Whole-cell patch-clamp record-
ings were performed in acute brain slices from rats experienced ethanol exposure via chronic inter-
mittent ethanol vapor inhalation followed by protracted abstinence (CIE-PA) and aged-matched
ethanol na€ıve controls. Spontaneous excitatory postsynaptic currents (sEPSCs) and intrinsic
excitability were recorded from the PFC neurons and GCNs. Results from our investigation showed
CIE-PA experience increased sEPSC frequency and produced larger amplitude responses in the
PFC neurons and GCNs compare to that of controls. Acute ethanol exposure on slices produced dis-
tinct alterations in sEPSCs in the PFC neurons and GCNs from na€ıve rats and CIE-PA rats. Acute
ethanol lowered frequency of sEPSC in PFC neurons, without producing significant changes in the
GCNs in na€ıve rats. CIE-PA abolished these differences. Additionally, the PFC neurons from CIE-
PA rats showed higher excitability compared to the na€ıve controls, an effect that was not evident in
GCNs. Acute ethanol exposure in na€ıve rats reduced the excitability of GCNs without producing sig-
nificant changes in PFC neurons. However, PFC neurons and GCNs from CIE-PA rats were tolerant
to acute ethanol exposure. Taken together, our results demonstrate that CIE-PA experience lead to
alterations in intrinsic spiking and spontaneous glutamatergic synaptic transmission with distinct
effects in PFC neurons and GCNs that may contribute to altered synaptic connectivity and activity in
the PFC and hippocampus and enhance propensity for relapse.
314A ABSTRACTS-SPEACKERS

TUESDAY, JUNE 19 9:15 AM–10:45 AM 174

SYMPOSIUM 172–175
Women Hold Up Half the Sky: The Evidence from Global Research on MEDICATION ASSISTED TREATMENT FOR ALCOHOL USE DISORDER TO IMPROVE THE
HIV CONTINUUM OF CARE FOR WOMEN INVOLVED IN THE CRIMINAL JUSTICE SYSTEM
Alcohol and HIV Interventions S. Springer
Organizer/Chair: Tatiana Balachova AIDS Program, Division of Infectious Diseases, Department of Medicine, Yale University School of
Chair: Wendee Wechsberg Medicine, New Haven, CT, USA

Background: Alcohol use disorders (AUD) and opioid use disorders (OUD) are highly prevalent
among persons living with HIV (PLH) within the criminal justice system (CJS) and negatively impact
172 all aspects of the HIV continuum of care. There are several FDA-approved medication assisted treat-
ments (MAT) that effectively reduce alcohol and opioid use in the community including extended-
RCT OF COMPUTER DELIVERED BRIEF ALCOHOL INTERVENTION (CBI) FOR WOMEN release naltrexone (XR-NTX) that is approved to treat both alcohol and opioid use disorders. This
ATTENDING AN URBAN STD CLINIC abstract will review how MAT can improve HIV viral suppression (VS).
G. Chander1,2,3, C. Canan1,2,3, C. Lesko1,2,3, B. Lau1,2,3, X. Xu1,2,3, M. McCaul1,2,3, H. Hutton1,2,3 Methods: The predominant results presented here are final results of a randomized double-blind
1
Department of Medicine, Johns Hopkins University, Maryland, 21205, USA, 2Bloomberg School of placebo controlled trial conducted among 100 prisoners with HIV and AUD who were transitioning to
Public Health, Johns Hopkins University, Maryland, 21205, USA and 3Department of Psychiatry and the community in Connecticut. Participants were randomized 2:1 to receive 6 monthly injections of
Behavioral Baltimore, Johns Hopkins University, Maryland, 21205, USA XR-NTX or placebo starting 1 week prior to release from prison. Primary and secondary outcomes
were the proportion with standard (<200 copies/mL) and maximal (<50 copies/mL) VS six months
Purpose: To determine if CBI with or without interactive voice response (IVR) counseling and text
post-release, respectively, using an intention to treat analysis (ITT). Multiple logistic regression anal-
messages reduced alcohol use and risky sexual behaviors compared to attention control.
yses were conducted to determine additional factors contributing to viral suppression.
Methods: We conducted a 3-arm randomized trial among women (n = 439) recruited from Balti-
Results: Compared to placebo, the ITT analyses revealed the XR-NTX group was statistically more
more City STD Clinics. Women were eligible if in the prior three months they (1) consumed an aver-
likely to achieve the primary (<200 copies/mL: 64.2% vs. 42.4%; p = 0.041) and secondary (<50
age of >7 drinks per week or (2) had ≥2 binge drinking episodes (>3 drinks on one occasion) or ≥2
copies/mL: 56.7% vs. 30.3%; p = 0.015) viral suppression outcomes six months after release. After
episodes of sex under the influence of alcohol. Alcohol use, drug use, and sexual activity (by partner)
controlling for other factors, receipt of XR-NTX remained independently predictive of standard
were assessed at baseline, 3, 6, and 12 months by intensive 30-day Timeline Followback (TLFB).
(aOR = 2.68; 95% CI = 1.01–7.09, p = 0.047) and maximal (aOR = 4.54; 95% CI = 1.43–14.43,
We ascertained drinking severity using the MINI International Neuropsychiatric Interview-DSM-IV.
p = 0.009) viral suppression. Participants receiving 3 or more injections, irrespective of allocation,
Primary alcohol outcomes included: drinking days, binge drinking days, drinks per drinking day. Sex-
were also statistically more likely to achieve both outcomes (aOR = 3.26; 95% CI = 1.26–8.47,
ual risk outcomes included number of sexual partners, days of unprotected sex, and days of unpro-
p = 0.010 and aOR = 6.34; 95% CI = 2.08–19.29, p = 0.001 respectively). Reductions in alcohol
tected sex under the influence of drugs and alcohol.
consumption (aOR = 1.43; 95% CI = 1.03–1.98, p = 0.033) and white race (aOR = 5.37; 95%
Results: The women’s median age was 31 (IQR 25–44 years), 88% were African American, 65%
CI = 1.08–27.72, p = 0.040) also predicted maximal VS.
reported illicit drug use, 49% met criteria for alcohol dependence,18% met criteria for abuse, 27%
Conclusion: Among PLH with a history of AUD transitioning from the CJS to the community, treat-
depressive symptoms,37% PTSD symptoms . At baseline, median (IQR) drinking days was 9.0
ment with XR-NTX is associated with maintaining or improving VS after release from incarceration
(5.4, 15.0); binge days was 6.0 (2.1, 11.0); and drinks per drinking day was 5.7 (3.3, 8.5) and did not
and reducing alcohol consumption. More research is needed to determine how women can access
differ among study arms. All three groups reduced all alcohol and sexual risk outcomes significantly
MAT to reduce relapse to alcohol and maintain or improve HIV VS after release from the CJS.
by 3 months with changes sustained or increased at 12 months. While women in the CBI + IVR/text
group drank with significantly less frequency compared with the control group at Visit 2, with 5.64
drinking days (95% CI 5.39–5.89) and 3.85 binge days (95% CI 3.61–4.08) over the past 30 days
compared with 6.20 drinking days (95% CI 5.95–6.41) and 4.50 binge days (95% CI 4.26–4.74), the
difference in decreased frequency of drinking did not persist. There was no difference in drinks per
drinking day nor in sexual risk outcomes among the groups.
Conclusions: Overall, there was little evidence that CBI with or without IVR reduced alcohol use or
175
sexual risk among women attending an STD. CBI was insufficient given the drinking and drug use ALCOHOL IS A FACTOR: THE EVIDENCE AND CHALLENGES OF WOMAN-FOCUSED
severity of respondents. RESEARCH IN SOUTH AFRICA
W.M. Wechsberg, F.A. Browne, J. Ndirangu, C. Peasant, B.N. Howard, W.A. Zule
RTI International, Substance Use, Gender, and Applied Research Program, Research Triangle
Park, North Carolina, 27709, USA Analyses done in the US, field work in Cape Town, South Africa

South Africa has a history of classism, sexism, and racism which contributes to the extremely high
173 HIV prevalence among women. Alcohol use is also embedded in the culture of South Africa – alcohol
was historically used as payment for labor – and contributes to HIV infection among women as it is
IMPROVING HIV EARLY IDENTIFICATION AND CARE INITIATION IN HEAVY DRINKING related to sexual risk and gender-based violence (GBV) which increase HIV risk. The HIV burden
RUSSIAN WOMEN among women is largely attributable to the intersection of sexual risk, alcohol and other drug use,
T. Balachova1,2, S. Bohora1,2, A. Shaboltas1,2 and GBV which are linked to the risk of HIV infection and reduced HIV care initiation. Based on the
1
Department of Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, need to address the intersection of sexual risk, alcohol, and other drug use, and GBV, a best-evi-
73104, USA and 2Faculty of Psychology, St. Petersburg State University, St. Petersburg, Russian dence woman-focused intervention that was developed in the U.S. was adapted in South Africa. The
Federation Women’s Health CoOp (WHC) has been evaluated during numerous randomized studies, which
continue to identify a high prevalence of alcohol consumption, intersecting with sexual risk and GBV
Early identification and initiation of care are critical for reducing HIV transmission and improving
among women in South Africa. These studies have demonstrated that many women are at risk of
health of individuals living with HIV. Drinking is prevalent in Russia, and alcohol misuse is a signifi-
HIV infection or already living with HIV at enrollment. Outcomes from these interventions have also
cant factor contributing to HIV transmission and outcomes in women. The objective of this study is to
demonstrated how the WHC is able to reduce risk behaviors. The most recent NIAAA-funded study
evaluate HIV testing behaviors and linkage to care among heavy drinking women. Effects of com-
is using an implementation science approach to assess the feasibility and effectiveness of integrating
pleting an HIV risk survey on testing decisions were also evaluated. The study was conducted in pri-
the WHC in health clinics and substance use treatment settings to decrease alcohol and other drug
mary care setting in Russia and utilized a mixed methods adaptive design and RCT. Study
use and sexual risk and increase adherence to antiretroviral medication among women living with
participants completed a brief HIV risk screening; at-risk women who had not had HIV testing in the
HIV in Cape Town, South Africa. Preliminary results from the participants who are currently enrolled
previous 12 months were randomly assigned to Opt-in or Opt-out testing conditions (N = 200),
and completed the 6-month follow-up (N = 231) demonstrated that frequency of binge drinking, as
which was followed by a more extensive survey of women’s and their partners’ sexual risk behaviors,
measured by the number of days that they binge drank in the past month, significantly decreased
alcohol and drug use, STDs, and care preferences. Then, “non-acceptors” were offered another
from baseline (M = 10.14, SD = 6.89) to 6-month follow-up (M = 7.77, SD = 6.91, p < 0.001). How-
opportunity to complete testing. Participants who chose to have HIV testing at any point during the
ever, use of alcohol and structural factors challenge consistent adherence to ARV treatment. Find-
study completed a structured interview focused on reasons for testing and barriers. A population-
ings from this study and other studies highlight the need to address alcohol use in the context of HIV
based modelling approach, i.e., Generalized Estimating Equations, was utilized to evaluate the rela-
prevention and treatment among vulnerable women in South Africa.
tionship between testing outcomes and the randomization condition over time. In addition, moderat-
ing effects of AUDIT scores and other characteristics were evaluated. Low-income and never-
married women were less likely to participate in HIV testing in the 12 months prior to the study. The
odds of acceptance to HIV testing in Opt-out were 3.1 times higher than the odds of acceptance in
Opt-in conditions in RCT. There was no significant difference between the testing conditions after
the survey, which implies increased acceptance rates in both groups and indicates the significant
effect of participating in the survey on testing decisions. While no effect of AUDIT scores on testing
acceptance was detected, education, age, and having children had significant effects on testing
behavior. Removing barriers and offering rapid testing in primary care settings is an effective strategy
to increase HIV testing uptake and care initiation among at-risk women.
ABSTRACTS-SPEACKERS
TUESDAY, JUNE 19 9:15 AM–10:45 AM
SYMPOSIUM 176–179
Determining the Risk of Drinking, Substance Use and Brain Differences in the
Ncanda Longitudinal Data Set
Organizer/Chair: Ian Colrain
176
BRAIN CHANGES ASSOCIATED WITH LIFE EVENTS AND ALCOHOL USE: A LATENT CLASS
ANALYSIS WITH THE NCANDA SAMPLE
K.B. Nooner1,2, M.D. De Bellis1,2
1 utilized a novel random forest classification procedure to explore predictors of adolescent binge
Department of Psychology, University of North Carolina Wilmington, Wilmington, NC 28409, USA
and 2Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham,
NC, 27710, USA
Purpose: Adverse life events can have a significant negative impact on the nature and manifesta-
tion of alcohol use disorders. The present study prospectively and longitudinally examines brain
changes as a possible mechanism in the relationship between adverse life events and patterns of
alcohol use. This study takes a novel person-centered approach to systematically examine life
events as they may relate to structural brain changes that have been linked to alcohol use. The pur-
pose of this inquiry is to determine how structural brain changes associated with different profiles of
life events may in turn relate to current and future alcohol use.
Methods: Participants (N = 566) were from all five sites of the National Consortium on Alcohol and
Neurodevelopment in Adolescence (NCANDA). The person-centered multivariate approach of latent
class modeling was carried out on the life events questionnaire. The latent classes were used in
analysis of covariance (ANCOVA) models comparing different life event classes on participant’s
responses on the alcohol expectancy questionnaire as well as to structural brain imaging.
Results: A four-class model of life events was developed consisting of: (1) Relational Conflict
(17.7%), (2) Financial Problems (8.7%), (3) Positive Achievement (48.4%), and (4) Adequate Func-
tioning (25.5%). Positive expectancies about alcohol were higher in classes 1 and 2 than classes 3
and 4 (F (562, 3) = 6.218, p < 0.001). Youth classes 1 and 2 had smaller frontal mid-left volumes
(p = 0.0036) and frontal right volumes (p = 0.0233) than classes 3 and 4. Youth in classes 1 and 2
also had larger parahippocampal left volumes (p = 0.0036) (p = 0.0254) than the other two classes.
Conclusion: The latent classes derived from the life events of NCANDA youth can be used to
understand expectancies about alcohol and brain structure related to alcohol use. Youth who experi-
ence more stressful life events pertaining to family financial problems or relational conflict were more
likely to have positive views about alcohol that youth without these difficulties. Youth who were in
classes indicating more negative life events were more likely to have smaller frontal regions and lar-
ger parahippocampal regions. These brain changes associated with alterations in executive function-
ing and extinction learning could make some youth more vulnerable to engaging in high-risk alcohol.
177
PSYCHOSOCIAL DYNAMICS PREDICTING SUBSTANCE USE CHANGES IN THE NCANDA
SAMPLE OVER TWO YEARS
T. Brumback, W.K. Thompson, S.A. Brown,, S.F. Tapert
Department of Psychological Science, Northern Kentucky University, Highland Heights, KY 41099,
USA
Purpose: Many psychosocial factors have been implicated as contributors to the onset and escala-
tion of substance use in adolescent populations. Typically, each identified factor explains a small
amount of the variance in substance use outcomes and is generalized across developmental peri-
ods. The NCANDA study provides a large, longitudinal sample with a wide range of psychosocial
measures along with substance use. The current study examined behavioral, cognitive, social, and
emotional competencies and their dynamic interactions that emerge across adolescence to predict
substance use 12 and 24 months later.
Methods: We evaluated the role of developmental domains including family/peer dynamics (e.g.,
parental monitoring and deviance of peers), cognitive factors (e.g., alcohol expectancies), and per-
sonality and emotional characteristics (e.g., impulsivity and typical responses to stress) in the onset
and escalation of alcohol and marijuana use across ages 12–24 (n = 831; 51% female). We
approached our analyses from a neurodevelopmental framework, characterizing biological differ-
ences related to sex, age, and pubertal development and the potential moderating effect they exhibit
on substance use. The majority of the sample exhibited no substance use at baseline.
Data: Data from the first two years of the NCANDA project were analyzed using mixed linear models
with the psychosocial and developmental factors assessed at baseline, 12, and 24 months predict-
ing alcohol and marijuana use at 12 and 24 months. We leveraged both the cross-sectional age
range as well as the 2 year longitudinal data to evaluate influences of psychosocial factors on sub-
stance use across adolescence and within individuals over time.
Results: Psychosocial variables including peer substance use, parental involvement, and sensation
seeking were associated with both alcohol and marijuana use occasions over the two years. Positive
alcohol expectancies were associated with increases in drinking occasions and this effect was stron-
ger in older adolescents (interaction: b = 0.2, p < 0.01). Endorsement of flexible cognitive style pre-
dicted less drinking among older adolescents (interaction: b =
0.7, p < 0.05), whereas
endorsement of more deliberate decision-making was predictive of less marijuana use among
younger adolescents (interaction: b = 3.6, p < 0.01).
Conclusions: These analyses point toward potentially sensitive developmental periods in adoles-
cence and help characterize the dynamic interactions of multiple domains of functioning that con-
tribute to substance use in adolescents.
315A
178
UTILIZING MACHINE LEARNING TO PREDICT THE ONSET OF BINGE DRINKING IN
ADOLESCENCE
S.J. Boyd, E. Feczko, D.A. Fair, B.J. Nagel
Department of Psychiatry, Oregon Health and Science University, Portland, OR 97239, USA
Purpose: Heavy drinking during adolescence is associated with enumerable acute consequences
and is often a precursor to alcohol use disorder. Despite these concerns, rates of binge drinking dur-
ing this developmental period remain alarmingly high. Prevention efforts are often stymied due to this
widespread use, as considerable heterogeneity exists among those who initiate binge drinking.
Advances in machine learning and exploratory data mining have revolutionized medical research by
permitting rapid analysis of large datasets to identify salient and novel risk factors. The current study
drinking, and to identify subgroups that are characterized by distinct risk profiles.
Methods: A subset of participants from all five sites of the National Consortium of Alcohol
NeuroDevelopment in Adolescence (NCANDA) study who were alcohol-na€ıve at baseline were
selected for analysis. Participants who initiated binge drinking prior to age 19 were compared to age-
and gender-matched controls who maintained abstinence from alcohol (total N = 202). A theoreti-
cally driven set of demographic, behavioral, psychological and neurocognitive variables were
entered into the model to identify the strongest predictors of binge drinking onset. Additionally, our
random forest algorithm combines community detection to identify of putative subgroups of “bingers”
or “controls” that share the same classification but present with differing etiologies.
Results: Our model achieved an overall classification accuracy of 65%, with higher accuracy for
correctly identifying bingers (67%) than controls (62%). Several variables accounted for the majority
of the predictive accuracy, including parent SES, positive alcohol expectancies, extraversion, and
general neurocognitive ability. Additionally, six subgroups of bingers and three subgroups of control
participants were identified.
Conclusion: Our novel random forest algorithm was moderately successful at differentiating ado-
lescent binge drinkers from non-drinkers using psychosocial risk factors assessed prior to drinking
onset. Highlighting the heterogeneity of adolescent binge drinking, several subgroups were identified
that were characterized by distinct patterns of psychosocial risk factors. Although the majority of ado-
lescents were correctly classified based on a few predictor measures, some of these measures var-
ied between the subgroups, suggesting that prevention programs may be most effective when
tailored to the specific risk profile of the individual.
179
PSYCHOPATHOLOGICAL TRAJECTORIES OF YOUTH WHO PROGRESS TO REGULAR
ALCOHOL USE
K.S. Bagot, A. Infante, K. Cummins, D. Clark, J. Jacobus, T. Brumback, S. Eberson, S. Tapert
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA
Background: Over 70% of adolescents with substance use disorders have comorbid psychiatric ill-
ness. Adolescent substance use and psychopathology may commonly co-occur because psy-
chopathology: (1) precedes, (2) emerges as a consequence, (3) impacts the severity, or (4)
originates from a common vulnerability as substance use. Temporal associations between psychi-
atric symptoms and substance use and their trajectories remains understudied, especially in youth.
Understanding psychopathological factors that affect risk and progression along the alcohol use tra-
jectory are important for targeted intervention efforts among those youth already at increased risk of
later use.
Methods: Linear mixed-effects models were used to analyze the longitudinal data from the yearly
in-person interviews for those participants who were below the age of 18 years at baseline
(n = 556). Participants’ trajectory intercepts are modeled as a random effect. Psychiatric symptoms
(measured by the Youth Self Report [YSR]) are modeled as the dependent variable, utilizing a zero-
inflated Poisson residual distribution. A time-varying absorbing indicator variable for regular drinking
onset is the primary exposure variable of interest. Known factors associated with subsequent psy-
chopathology will also be included in a set of models as covariates and moderators, including early
age of substance use debut, family history of substance use, early adverse childhood experiences,
access, and socioeconomic status.
Results: For each additional item endorsed by children/adolescents on YSR subscales we found
increased odds of transition to binge drinking within 2 years in the following domains: total problems
(OR = 1.67), externalizing problems (OR = 2.07), internalizing problems (OR = 1.53), aggressive
behavior (OR = 21.17), rule breaking behavior (OR = 3.77), attention problems (OR = 2.51), anx-
ious/depressed (OR = 2.35), social problems (OR = 2.87). Youth who endorsed high levels of
thought problems, withdrawn/depressed symptoms or somatic complaints were not an increased
risk.
Conclusion: Elucidating psychopathological antecedents of substance use in vulnerable adoles-
cent populations has implications on prevention and treatment interventions. Early targeted interven-
tions for youth at psychiatric risk for later substance use may improve long-term health outcomes in
these vulnerable populations.
316A
TUESDAY, JUNE 19 9:15 AM–10:45 AM
SYMPOSIUM 180–183
Towards a More Comprehensive Understanding of Relapse and Recovery:
Current Trends and Future Directions
Organizer/Chair: Brett Hagman
180
ASSOCIATION BETWEEN ALCOHOL CONSUMPTION PATTERNS DURING ALCOHOL
TREATMENT AND THREE YEAR RECOVERY OUTCOMES
K. Witkiewitz, S.A. Maisto, K.A. Hallgren, M.R. Pearson, K. SMontes, C.R. Roos, M. Kirouac,
A.D. Wilson
Department of Psychology University of New Mexico, Albuquerque, NM, USA
Treatments for alcohol use disorder (AUD) have progressed considerably over the past 30 years.
Yet, there is still lack of consensus about the prediction and prevention of returning to problematic
drinking during treatment and what factors predict longer-term recovery. Definitions of relapse and
recovery also vary and there is little empirical data to inform our understanding of long-term out-
comes following a course of evidence-based alcohol treatment. Specifically, most alcohol clinical tri-
als are limited to a 1-year follow-up assessment and few studies have examined whether reductions
in alcohol use attained during a treatment episode extend beyond the first year following treatment.
The goal of the current study was to examine the association between patterns of alcohol consump-
tion during a treatment episode and whether these patterns predict alcohol consumption and alcohol
consequences at three years following treatment among a sample of individuals who were treated in
the outpatient arm of the Project MATCH study and who completed the 3 year follow-up assessment
(n = 771; 75.7% male; 80% non-Hispanic white; average age = 40.23 (SD = 10.9)). Seven patterns
of drinking during treatment were identified: persistent heavy drinking (15.3% of the sample), increas-
ing heavy drinking (8.7%), heavy and low risk drinking (3.2%), heavy drinking alternating with absti-
nence (12.3%), low risk drinking (6.0%), increasing low risk drinking (11.8%), and abstinence
(42.7%). The patterns of drinking during treatment were significantly associated with longer-term
recovery, as defined by non-heavy drinking and improvements in consequences, at three years fol-
lowing treatment. Individuals in the increasing low risk drinking class and those who achieved absti-
nence during treatment had significantly fewer drinking consequences and lower rates of heavy
drinking at three years following treatment. There was also a significant interaction between drinking
during treatment and alcohol dependence severity in predicting 3-year outcomes. Individuals with
greater alcohol dependence severity at baseline who achieved low risk drinking or abstinence during
treatment were more likely to have better long-term outcomes at three years following treatment, as
compared to those with more severe alcohol dependence who continued to drink heavily during
treatment. Results indicate that individuals who achieve abstinence or low risk drinking during treat-
ment are likely to maintain these outcomes up to three years following treatment.
181
BEYOND ABSTINENCE: CHANGES IN INDICES OF QUALITY OF LIFE WITH TIME IN
RECOVERY IN A NATIONALLY-REPRESENTATIVE SAMPLE OF US ADULTS
J.F. Kelly, M.C. Greene, B.G. Bergman
Recovery Research Institute Massachusetts General Hospital, Harvard Medical School, Boston, MA
02114, USA
Background: Alcohol and other drug (AOD) treatment and recovery research has been criticized
for focusing too narrowly on changes in AOD use (e.g., “percent days abstinent”) and not enough on
factors related to functioning and well-being. Furthermore, little is known about if and when such
changes may occur for different groups of individuals as they progress in recovery. Greater knowl-
edge would enhance understanding of recovery milestones and timepoints associated with vulnera-
bility and growth.
Method: Cross-sectional, national probability-based sample of US adults who responded “yes” to
the screening question, “Did you used to have a problem with alcohol or drugs but no longer do?”
(63.4% response rate from 39,809 screened adults; final weighted sample n = 2,002). Controlling
for age, linear regression analyses tested the relations among years since problem resolution and
five measures of well-being: (a) quality of life; (b) happiness; (c) self-esteem; (d) recovery capital;
and e. psychological distress, over two temporal horizons: the first 40 years; and the first 5 years,
after resolving a significant AOD problem, and explored moderators of these associations (e.g., sex,
race, primary substance). Relationships were modeled with linear, spline, or quadratic terms.
Locally-weighted scatterplot and smoothing (LOWESS) was used to graphically examine turning
points.
Results: In general, across the 40 year time frame there were initially steep increases in indices of
well-being and steep drops in psychological stress particularly during the first 6 years, followed by
shallower increases. Across the first 5-year recovery timeframe, significant drops in self-esteem and
happiness were initially observed during the first year followed by substantial increases. Moderator
analyses indicated that compared to alcohol and cannabis problems, those resolving opioid or other
drug problems (e.g., stimulants) had substantially lower recovery capital in the early recovery years,
and mixed race individuals/native Americans tended to exhibit significantly poorer well-being com-
pared to Whites; women, overall, tended to report lower indices of well-being over time than men.
Conclusions: Findings suggest generally monotonic improvements in indices of well-being after
individuals resolve serious AOD problems with the exception of first year where self-esteem and hap-
piness indices initially decrease, before beginning to rise. This initial delay of positive outcomes
despite AOD problem resolution, may reflect the challenges of this early recovery phase.
ABSTRACTS-SPEACKERS
182
CHRONIC ALCOHOL-RELATED BRAIN AND PERIPHERAL STRESS RESPONSES
PREDICTIVE OF EARLY RELAPSE AND RECOVERY
R. Sinha
Department of Psychiatry, Yale University School of Medicine
Purpose: Alcohol relapse remains a significant factor jeopardizing alcoholism recovery. Chronic
alcohol alters central and peripheral stress responses, that in turn, are associated with increased
alcohol relapse risk. The goal of this presentation is to identify the chronic alcohol-related changes in
stress responses and assess their relationship to early relapse and recovery outcomes.
Methods: Data was obtained from multimodal neuroimaging and human laboratory experiments
combined with a prospective clinical outcomes design. Participants include healthy controls
(N = 65), treatment engaged 4-week abstinent inpatient (N = 93) and outpatient (N = 55) AUD indi-
viduals initiating treatment and early recovery studied in separate laboratory and repeated pre- and
post-treatment neuroimaging experiments, involving exposure to stress, alcohol cues and neutral
stimuli, and assessment of autonomic and hypothalamic pituitary adrenal (HPA axis) responses,
alcohol craving, withdrawal symptoms and alcohol use outcomes prospectively during treatment and
over a 90 day follow-up and recovery period.
Results: Findings indicate patients had hyperactive basal and neutral state autonomic and HPA
axis measures (heart rate, cortisol, cortisol/ACTH ratio), lower medial frontal brain volume, hyperac-
tive neutral state ventromedial prefrontal cortex (VmPFC) and blunted VmPFC response to stress
and alcohol cues relative to controls (p’s < 0.05, corrected), with each predicting greater risk of future
relapse and poor early recovery outcomes. With abstinence/drinking reduction at 2-month early
recovery, we found reduced craving (p < 0.01) and also reduced basal state autonomic and HPA
axis hyperactivity, and improved cue-related VmPFC response, but stress responses remained dis-
rupted with blunted VmPFC and cortisol responses to stress (p’s < 0.05), suggesting increased vul-
nerability to stress-related relapse in this early recovery period.
Conclusions: These findings identify biomarkers of early relapse and recovery in AUD patients
entering treatment and responses that show continued vulnerability to relapse. They also suggest
the need for further development and validation of these biomarkers of alcohol relapse to improve
alcoholism recovery outcomes.
183
FEELING GOOD AND STICKING WITH IT: HOW POSITIVE (AND NEGATIVE) AFFECT
CONTRIBUTE TO COMMITMENT TO SOBRIETY AND SUSTAIN ABSTINENCE
S.E. Zemore, P. Martinez, L.A. Kaskutas
Alcohol Research Group, Emeryville, CA, USA
Background: The need to cope with negative affect is thought to be central in the onset and course
of alcohol use disorders (AUDs), and studies examining emotion and relapse have focused predomi-
nantly on negative affect. Less attention has been devoted to positive affect, and very few studies
have examined positive and negative affect simultaneously. We aimed to test a conceptual model
relating positive and negative affect, abstinence motivation, and relapse. We hypothesized that
greater experiences of positive affect contribute to commitment to sobriety independently of negative
affect, and thus sustained abstinence, and that these effects are strongest early in recovery.
Methods: Data were from a community sample of abstinence-focused mutual help groups including
12-step groups, Women for Sobriety, LifeRing, and SMART. Adults with lifetime AUDs were sur-
veyed at baseline (N = 647), 6 months (81% RR) and 12 months (83% RR). Surveys included the
Positive and Negative Affect Scale (6 and 12 months only), the Commitment to Sobriety Scale, sub-
stance use measures, and other variables. We first examined bivariate associations between the 6-
month affect measures and 12-month alcohol abstinence. We then conducted multivariate, hierarchi-
cal, logistic regressions examining effects for the 6-month affect measures on 12-month abstinence
controlling for (1) baseline covariates and (2) 6-month commitment to sobriety. Sobel’s test was used
to confirm mediation, and interactions tested for moderation by length of sobriety.
Results: Both positive and negative affect at 6 months were associated with 12-month abstinence
in bivariate analyses. Yet, when entering both simultaneously, only positive affect was significant,
and this effect was robust controlling for demographics, severity, and psychiatric problems. Consis-
tent with mediation, the effect for positive affect on abstinence became nonsignificant when also con-
trolling for 6-month commitment to sobriety, and Sobel’s test supported an indirect path from 6-
month positive affect to 12-month abstinence via commitment to sobriety. Interaction tests did not
support hypothesized differences in the effects of positive affect across length of sobriety.
Conclusions: Results suggest that feeling good may motivate individuals to sustain sobriety, thus
supporting recovery. Moreover, findings that the beneficial effects of positive affect entirely
accounted for associations between negative affect and abstinence may imply that negative affect is
less important than previously thought.
ABSTRACTS-SPEACKERS
TUESDAY, JUNE 19 9:15 AM–10:45 AM
SYMPOSIUM 184–187
Addressing Alcohol Related Health Disparities on Multiple Levels
Organizers/Chairs: Kamilla Venner and Nichea Spillane
184
EXAMINING THE CONSTRUCT OF COMMUNITY WELL-BEING AND ASSOCIATIONS WITH
THE AUDIT
V. Cloud, K. Venner
Department of Psychology, Center on Alcoholism, Substance Abuse, and Addiction, University of
New Mexico, Albuquerque, NM 87106, USA
Purpose: There is a dearth of American Indian (AI) research examining the impact of socioeco-
nomic status, or the protective benefits of high ethnic identity with strong social connection on alcohol
use. This study developed and investigated a latent construct labeled community well-being (CWB)
and tested it as a predictor of scores on the Alcohol Use Disorder Identification Test (AUDIT) in a
sample of non-Hispanic White (NHW) and AI college students with consideration of self-reported
childhood social class (birth to 18).
Method: This study tested the hypothesis that CWB and AUDIT scores would be negatively associ-
ated among both AI and NHW college students. We further hypothesized that among AI college stu-
dents the relationship between CWB and AUDIT scores would be moderated by level of cultural
identity. Secondary data analysis with NHW and AI college students (N = 254) to examine a commu-
nity well-being measurement model and the relationships among CWB and AUDIT scores with con-
sideration of ethnicity and childhood social class. Finally, this study investigated the moderating
effects of cultural identity on the relationship between CWB and AUDIT scores in AI college stu-
dents.
Results: Using structural equation modeling (SEM), findings indicated increased CWB is associ-
ated with lower AUDIT scores for both NHW and AI college students. Lower levels of childhood
social class have a strengthening effect on the negative association between CWB and AUDIT
scores. Additionally, behavioral cultural identity was a near significant (p = 0.05) moderator of the
relationship between CWB and AUDIT scores for the AI sample.
Conclusions: The construct CWB accounted for a meaningful amount of variance of AUDIT scores
among AI college students. The role of socioeconomic status should be considered in future studies
and prevention efforts. Future research should validate the CWB with other populations and test its
potential role in prevention and interventions.
185
THE IMPORTANCE OF ALTERNATIVE ACTIVITIES IN ALCOHOL AND OTHER SUBSTANCE
USE BEHAVIOR AMONG FIRST NATION ADOLESCENTS LIVING IN A RESERVE COMMUNITY
N.S. Spillane, M.R. Schick, C.W. Kahler
Department of Psychology, University of Rhode Island, Kingston, RI, USA
Purpose: Behavioral theories of choice suggests that engaging in alcohol use represents a choice
among a range of possible behaviors one could choose. The purpose of the current study was to
develop and evaluate a measure of alternative behaviors that is culturally and developmentally
appropriate that Indigenous youth find important and see how that relates to substance use behav-
iors.
Methods: This was a three phase, mixed-methods study to develop a measure of culturally and
developmentally appropriate alternative behaviors to substance use. Participants for all three phases
were recruited from First Nation communities located in Eastern Canada and were between the ages
of 12–18. Phase 1, qualitative interviews and focus groups were conducted to identify relevant alter-
native behaviors. Phase 2 consisted of testing the basic psychometric properties and conducting
cognitive interviews of the new measure (N = 50). Phase 3, 106 adolescents (50% female; 100%
First Nations; mean age 14.6 years) completed questionnaires about their substance use (alcohol,
marijuana, and cigarette smoking) and importance of alternative activities. In a series of three logistic
regression analyses we examined the association between the importance of alternative activities
and past month marijuana use, cigarette smoking, and past 3-month alcohol use controlling for age
and biological sex.
Data and Results: Content analyses on the qualitative interviews and focus group suggested
themes of behaviors that are important including, cultural activities, relationships, and accessibility of
role models. Items were created to represent the themes that were found in phase 1. Psychometric
analysis suggested cutting some items from the initial measure and cognitive interviews suggested
asking about the importance of these activities to youth. In phase 3, the measure of the importance
of alternative behaviors was correlated with variables it should be correlated with (r = 0.35,
p = 0.001). After controlling for age and biological sex, the importance of alternative activities was
negatively associated with past 3-month alcohol use (p = 0.019, OR = 0.96, 95% CI [0.93, 0.99]),
past-month marijuana use (p = 0.043, OR = 0.97, 95% CI [0.94, 1.00]), and past-month cigarette
use (p = 0.021, OR = 0.97, 95% CI [0.94, 1.00]).
Conclusions: Results of this study suggest that the importance of alternative behaviors is related
to actual substance use and may be important factors to consider for prevention and/or intervention
programs.
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186
URBAN NATIVE AMERICAN PARTICIPATION IN COMMUNITY-BASED AA
J.S. Tonigan
Department of Psychology, Center on Alcoholism, Substance abuse, and Addictions (CASAA),
University of New Mexico
Urban Native Americans (UNA) with alcohol use disorders face a confusing array of off-reservation
treatment services. Evidence suggests that UNA who do enter formal treatment often receive behav-
ioral interventions with a strong 12-step emphasis and 12-step attendance is routinely encouraged.
This study (R21 AA023042, Tonigan, PI) recruited 61 UNA adults with alcohol use disorders seeking
to reduce their drinking by attending AA. Study aims focused on documenting the types of AA meet-
ings attended by UNA and how, if at all, attendance at different types of AA meetings moderated AA-
related benefit over a 6-month period. At baseline, UNA participants were divided between attending
mainstream AA meetings (n = 31) and AA meetings adapted to include native customs such as
burning sage and reciting the Indian Prayer (n = 30). Few demographic variables predicted the types
of AA meetings self-selected by UNA and cultural identity measures also did not discriminate the
types of AA meetings UNA attended. In spite of the mobile nature of UNA our follow-up rates were
good; at 3-months 82% of the sample was interviewed and 70.5% were successfully interviewed at
six-months. Large pre-post increases in alcohol abstinence (d = 0.65) and reductions in drinking
intensity (d = 0.78) were observed for the entire sample. Typically, meta-analytic works indicates
that AA attendance is associated with increased abstinence, but is unrelated to drinking intensity.
The opposite was found in this sample; in our lagged analyses frequency of AA attendance (sepa-
rately and combining both mainstream and adapted AA) was unrelated to increased abstinence but
was significantly and negatively associated with drinking intensity. Noteworthy, the types of AA meet-
ings attended by UNA did not moderate the effect of AA attendance on reduced drinking intensity.
Findings support the general practice of AA referral for UNA, but many questions remain unan-
swered. Specifically, we found that clinical referral to AA rarely included referral to adapted AA meet-
ings and, when such referral did occur, it was unrelated to the types of AA meetings actually
attended by UNA. Likewise, the finding that AA attendance impacted drinking intensity but not rates
of abstinence among URN is perplexing. Several alternative explanations for these atypical findings
will be discussed.
187
A MULTI-LEVEL APPROACH FOR PREVENTION OF UNDERAGE DRINKING ON CALIFORNIA
INDIAN RESERVATIONS: EFFICACY AND MECHANISM OF BEHAVIOR CHANGE IN ADULTS
AND ADOLESCENTS
D. Gilder, J. Geisler, J. Luna, D. Calac, J. Lee, R. Moore, C. Ehlers
Molecular and Cellular Neuroscience Department, The Scripps Research Institute, La Jolla, CA
92037, USA
Purpose: The individual and community level interventions of a successful multi-level prevention of
underage drinking program were assessed for efficacy and mechanism of behavior change in a com-
munity sample of reservation dwelling Southern California American Indian adults and adolescents.
Methods: The four interventions were: (1) youth participatory community mobilization to develop a
billboard message, (2) convenience store checks to discourage alcohol sales to minors, (3) Motiva-
tional Interviewing (MI) versus Psycho-education (PE) in 112 youth, and (4) 298 community educa-
tion and outreach events to adults and youth aimed at preventing underage drinking. One hundred
and twenty adults and 100 youth were surveyed. Frequency analysis, Wilcoxon signed rank tests,
and logistic regression were used to analyze survey results.
Data and Results: Adults (awareness of the intervention, took action to reduce teen drinking as a
result of that awareness): Billboard (49%, 75%), Store Checks (77%, 75%), MI versus PE (63%,
80%), Outreach (65%, 76%). Relative strengths of interventions (z score, p-value): Outreach > Bill-
board (2.52, 0.012), Outreach > MI versus PE (2.70, 0.007), no other differences. Mechanism of
behavior change associated with the overall program (OR, p-value): movement from Precontempla-
tion to Contemplation with awareness of problem (6.04, 0.001), from Precontemplation to Contem-
plation with considering change (1.94, NS), from Contemplation to Preparation (10.80, 0.001).
Teens (awareness of the intervention, reduced drinking as a result of that awareness, doesn’t drink):
Billboard (31%, 30%, 61%), Store Checks (68%, 32%, 52%), MI versus PE (61%, 32%, 52%), Out-
reach (74%, 29%, 58%). Relative strengths of interventions (z score, p-value): Outreach > Billboard
(2.11, 0.035), no other differences. Mechanism of behavior change associated with the overall pro-
gram (OR, p-value): movement from Precontemplation to Contemplation with awareness of problem
(18.1, 0.006), from Precontemplation to Contemplation with considering change (9.5, 0.027), and
from Contemplation to Preparation (9.5, 0.027).
Conclusions: All four interventions were associated with high levels of awareness and intervention
to reduce teen drinking (adults) and reducing drinking (teens). With some exceptions, perceived
strengths of interventions were similar. For both adults and teens, interventions were associated with
movement along the transtheoretical model of stages of behavior change. Support: National Institute
on Alcohol Abuse and Alcoholism (NIAAA) grant R01 AA023755.
318A
TUESDAY, JUNE 19 1:20 PM–2:50 PM
SYMPOSIUM 188–191
Current Advances in Alcohol-Induced Immune Dysfunction
Organizers/Chairs: Mashkoor Choudhry and Ping Zhang
188
DIMINISHED NEUTROPHIL EXTRACELLULAR TRAP (NET) FORMATION IS A NOVEL INNATE
IMMUNE DEFICIENCY INDUCED BY ACUTE ETHANOL EXPOSURE IN POLYMICROBIAL
SEPSIS
L. Jin, S. Batra, S. Jeyaseelan
Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University
1909 Skip Bertman Drive Baton Rouge, LA, 70803, USA
Polymicrobial sepsis is the result of an exaggerated host immune response to bacterial pathogens.
Animal models and human studies demonstrate that alcohol intoxication is a key risk factor for sep-
sis-induced mortality. Multiple chemokines, such as CXCL1, CXCL2 and CXCL5, are critical for neu-
trophil recruitment and proper function of neutrophils. However, it is not quite clear the mechanisms
by which acute alcohol suppresses immune responses and whether alcohol-induced immunosup-
pression can be rescued by chemokines. Thus, we assessed whether acute ethanol challenge via
gavage diminishes antibacterial host defense in a sepsis model using cecal ligation and puncture
(CLP) and whether this immunosuppression can be rescued by exogenous CXCL1. We found acute
alcohol intoxication augments mortality and enhances bacterial growth in mice following CLP. Etha-
nol exposure impairs critical antibacterial functions of mouse and human neutrophils including reac-
tive oxygen species production, neutrophil extracellular trap (NET) formation, and NET-mediated
killing in response to both Gram-negative (E. coli) and Gram-positive (Staphylococcus aureus)
pathogens. As compared with WT (C57Bl/6) mice, CXCL1 knockout mice display early mortality fol-
lowing acute alcohol exposure followed by CLP. Recombinant CXCL1 (rCXCL1) in acute alcohol
challenged CLP mice increases survival, enhances bacterial clearance, improves neutrophil recruit-
ment, and enhances NET formation (NETosis). Recombinant CXCL1 (rCXCL1) administration also
augments bacterial killing by alcohol-treated and E. coli- and S. aureus-infected neutrophils. Taken
together, our data unveils novel mechanisms underlying acute alcohol-induced dysregulation of the
immune responses in polymicrobial sepsis, and CXCL1 is a critical mediator to rescue alcohol-
induced immune dysregulation in polymicrobial sepsis. We also have done these experiments in the
context of Gram-negative pneumonia.
189
ACUTE ALCOHOL INTOXICATION SUPPRESSES EARLY IL-17 RESPONSE DURING
PNEUMOCOCCAL PNEUMONIA
G. Trevejo-Nunez,K. Chen, J. Kolls
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
In animal models, acute alcohol intoxication suppresses the host immune responses against Strep-
tococcus pneumoniae (pneumococcus). Interleukin-17 plays essential roles in host defense against
extracellular pathogens including pneumococcus. We demonstrated that IL-17 receptor signaling is
critical for the clearance of S. pneumoniae by blocking the IL-17 receptor with monoclonal antibody.
Thus, we hypothesized that alcohol impairs pneumococcal lung clearance by affecting IL-
17 production and IL-17 receptor signaling driven genes in the lung. We used a model of acute alco-
hol intoxication in mice followed by S. pneumoniae lung infection. Alcohol and control groups had
similar bacterial burden in the lungs at 5 h, however, the former group failed to clear pneumococci at
18 h post-infection. Il-17a production in the lung was decreased in the alcohol group at 5 h, suggest-
ing that the impaired clearance is, at least in part, due to the suppression of IL-17 production. Gene
expression analyses showed that both Il17a and Il17f transcripts were down-regulated in alcoholized
mice, suggesting the suppression is at transcriptional level. This notion is supported by decreased
expression of Il-17 upstream genes such as Il1b and Il23. Consequently, downstream genes such
as Csf3 and Cxcl1, which are critical in mobilizing and recruiting bacterial phagocytes, were down
regulated at 5 h compared to control mice. We also analyzed gene expression in bronchial brushes
from a group of macaques that belonged to a chronic alcohol cohort. Analysis showed a decrease in
some IL-17R dependent genes. Administration of recombinant CXCL1 or CXCL5 by oropharyngeal
aspiration decreased bacterial burden in alcoholized mice compared to wild type controls. In conclu-
sion, IL-17 dependent genes are impaired in the lung during acute alcohol intoxication and recombi-
nant chemokines could be used to counteract this defect and decrease bacterial burden.
ABSTRACTS-SPEACKERS
190
ALCOHOL POTENTIATES SYMPTOMS AND SUSCEPTIBLITY TO INFECTION IN ULCERATIVE
COLITIS
A.R. Cannon, P.V. Kuprys, M.A. Choudhry
Alcohol Research Program, Health Sciences Division, Burn & Shock Trauma Research Institute,
Loyola University Chicago, Maywood, Illinois, 60153, USA
Ulcerative colitis (UC) is a life-long disease with periods of remission and disease flares character-
ized by abdominal pain, increased weight loss, intestinal inflammation, and rectal bleeding. UC
patients are forced into treatment regimens with warnings of ‘Don’t drink alcohol’ from diagnosing
doctors. Utilizing a mouse model of binge alcohol consumption following induced colitis, we found
alcohol exacerbates weight loss, clinical scores, colonic shortening and inflammation. In this study,
we sought to elucidate whether alcohol consumption increases the susceptibility to the enteropatho-
gen C. rodentium. Male mice received DSS for 5 days. On days 5, 6, and 7 mice were gavaged with
alcohol (~3 g/kg) or water. Three hours after the last gavage on day 7, mice were orally administered
C. rodentium at 1 9 105 CFUs. Body weight and mortality were monitored. On day 11, mice were
euthanized and colons harvested to measure length and the tight junction proteins expression. Colon
sections were stained by H&E and alcian blue. C. rodentium infection in mice following DSS and
alcohol treatment resulted in increased weight loss compared to those receiving DSS alone and
C. rodentium. We observed a 50% reduction in survival in DSS alcohol treated mice following C. ro-
dentium infection compared to 100% survival with DSS and C. rodentium. This accompanied a sig-
nificant decrease in colon length in DSS alcohol treated mice following C. rodentium infection
compared to DSS and C. rodentium. Mice infected with C. rodentium following DSS and alcohol had
significant decreases in claudin 8 and occludin expression compared to all groups. H&E staining
revealed prominent colonic damage and inflammatory infiltrate in DSS alcohol plus C. rodentium
infected mice. Furthermore, a significant increase in histopathology scores was observed in DSS
alcohol and C. rodentium treated mice compared to DSS and C. rodentium. In the DSS ethanol and
C. rodentium group, 8/12 mice showed a decrease in the mucus layer along with a decrease in gob-
let cells. Along with our previous findings, these data suggest alcohol consumption potentiates the
symptoms and susceptibility to enteropathogens in mice with DSS-induced colitis.
191
ALCOHOL IMPAIRS THE GRANULOPOIETIC RESPONSE TO SEPTIC INFECTION BY
DISRUPTING SONIC HEDGEHOG SIGNALING IN HEMATOPOIETIC STEM CELLS
X. Shi, P. Zhang
Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical
University, Rootstown, OH 44272, USA
Our recent studies have demonstrated that the bone marrow hematopoietic stem cell (HSC) popula-
tion constitutes a key component of the immune defense system. Activation and reprogramming of
HSCs are critical steps for enhancing granulocyte lineage development during the granulopoietic
response to bacterial infection. Excessive alcohol exposure impairs HSC activation and the granu-
lopoietic response. The underlying cell signalling mechanisms remains elusive. In this study, we
determined the role of sonic hedgehog (SHH) signalling in the regulation of HSC activation during
the granulopoietic response to septic infection. The effect of alcohol on the SHH signalling regulation
was also examined. Acute alcohol intoxication was induced in adult mice without or with feeding on
Lieber-DeCarli low fat liquid alcohol diet for 5 weeks by intraperitoneal injection (i.p.) of alcohol (20%
alcohol in saline at a dose of 5 g alcohol/kg). Control mice without or with pair-feeding of control diet
received i.p. saline. Thirty minutes after the i.p. injection, E. coli (E11775, ATCC, 5 9 107 CFUs/
mouse) or saline was given to mice via intravenous injection. The expression of SHH by bone mar-
row cells was significantly up-regulated at both mRNA and protein levels following E. coli infection,
suggesting that the regulation of SHH expression involved transcriptional activation of the shh gene.
Murine shh promoter contains 14 predicted Sp1 binding sites. Reporter gene analysis confirmed acti-
vation of shh promoter in the presence of Sp1 binding. E. coli infection induced a significant increase
in Sp1 expression in HSCs. TLR4-ERK signaling mediates Sp1 expression. Blocking ERK1/2 activa-
tion abolished LPS-induced up-regulation of SHH expression by marrow cells. Deletion of Gli1 (the
key component of the SHH pathway) impaired HSC activation and the granulopoietic response to
E. coli infection. Alcohol intoxication suppressed both activation of ERK1/2 and up-regulation of
SHH expression in marrow cells following E. coli infection. Alcohol also impaired up-regulation of
Gli1 expression and activation of proliferation in HSCs following E. coli infection. Our results demon-
strate that disruption of SHH signaling is a novel mechanism underlying alcohol-induced impairment
of HSC activation during the granulopoietic response to serious bacterial infection. (Support by NIH
grants AA022816 and AA019676)
ABSTRACTS-SPEACKERS
TUESDAY, JUNE 19 1:20 PM–2:50 PM
SYMPOSIUM 192–195
MicroRNA Differential Expression Resulting in or from Alcohol Use
Disorders
Organizers/Chairs: Abbas Parsian and Huiping Zhang
192
GOOD (AND BAD) THINGS COME IN SMALL PACKAGES: MIRNA MEDIATED GENETIC
PREDISPOSITION TO ALCOHOL RELATED BEHAVIORS
K. Kechris, L. Saba, B. Vestal, W.J. Shi, P. Rudra, P. Russell
Department of Biostatistics and Informatics, Colorado School of Public Health, University of
Colorado Anschutz Medical Campus
There is increasing evidence that miRNAs play an important role in alcohol related behaviors. The
expression of miRNA and corresponding targets have been found to change in the brain following
acute or chronic ethanol exposure. However, the role of miRNA as mediators of the genetic effect on
alcohol phenotypes is not well understood. Therefore, our group has explored the role of miRNA reg-
ulation in the brain as a predisposing factor to alcohol responses and behavior. Within a well-charac-
terized renewable panel of mice, we have performed an unbiased analysis of behavioral data
integrated with genetic variants and high-throughput miRNA and mRNA brain expression data to
search for miRNA mediating pathways. Employing multivariate techniques such as meta-analysis,
canonical correlation analysis and Bayesian networks, we identified several miRNA networks associ-
ated with ethanol consumption, ethanol sensitivity or the sedative effects ethanol. For example, we
found a novel role of miR-106b-5p-mediated regulation of an inhibitor of CAMK2 and its downstream
targets including the GABAA and NMDA receptors, which have been previously implicated to have a
role in ethanol-induced sedation and sensitivity. In another example, miR-7057-5p was identified as
a potential mediator for low dose activation to ethanol, and target genes for this miRNA were
enriched in pathways related to cell adhesion molecules, and extracellular matrix receptor interac-
tion. Our results suggest a mechanism of how genetic variants may be affecting alcohol behaviors
through the modification of miRNA expression and their downstream targets.
Funded by NIH/R01 AA021131.
193
EXOSOME-DERIVED EXTRACELLULAR MICRORNAS: BIOLOGICAL FUNCTIONS AND
POTENTIAL MEDIATORS OF PRENATAL ALCOHOL EFFECTS
D. Chung, A. Tseng, N. Salem, A. Mahnke, R.C. Miranda
College of Medicine, Neuroscience & Experimental Therapeutics, Texas A&M University, Bryan, TX
77807, USA
Prenatal alcohol exposure (PAE) can result in a cluster of anatomical and physiological anomalies,
including brain anomalies, that are collectively termed ‘Fetal Alcohol Spectrum Disorders’ (FASD).
PAE is a leading cause of intellectual and other neurodevelopmental disabilities, and can lead to sec-
ondary disabilities that emerge over a lifespan. In 2007, we first showed that a class of small non-pro-
tein-coding regulatory RNA molecules, microRNAs, could mediate some effects of alcohol in the
developing brain. MicroRNAs are also secreted in ~200 nm diameter extracellular vesicles or exo-
somes, by a variety of cell-types, including neural stem cells (NSCs). We previously showed that
these extracellular miRNAs could predict infant birth outcomes due to PAE in human populations.
Here, we hypothesized that alcohol-affected extracellular microRNAs may be biologically active.
Using a 1st trimester-equivalent, ex vivo fetal mouse cortical neuroepithelial model, we found that
fetal NSCs secrete CD63-immunopoisitve exosomes, and that exosomes can transfer biological
function between cohorts of NSCs. This capacity to transfer information between cells suggests a
novel endocrine mechanism for functionally synchronizing NSC populations. We found that ethanol
regulated the miRNA content of exosomes, with one previously identified ethanol-sensitive miRNA,
miR-140-3p exhibiting significant elevation in exosomes derived from ethanol-exposed NSCs. More-
over, over-expression of miR-140-3p in fetal NSCs resulted in increased cell proliferation and aber-
rant elevation of astroglial mRNA transcripts. These data advance a novel endocrine, miRNA-
mediated mechanism to explain effects of PAE on early brain maturation.
319A
194
SILENCING SYNAPTIC MICRORNA-411 REDUCES VOLUNTARY ALCOHOL CONSUMPTION
IN MICE
R.D. Mayfield, D. Most, N.A. Salem, G.R. Tiwari, Y.A. Blednov, R.A. Harris
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX
78712, USA
Chronic alcohol consumption alters the levels of microRNAs and mRNAs in the brain, but the specific
microRNAs and processes that target mRNAs to affect cellular function and behavior are not known.
We examined the in vivo manipulation of previously identified alcohol-responsive microRNAs as
potential targets to reduce alcohol consumption. Knockdown of miR-411 by infusing antagomiR-411
into the prefrontal cortex of C57BL/6J mice reduced alcohol consumption and preference, without
altering total fluid consumption, saccharin consumption, or anxiety-related behaviors. AntagomiR-
411 reduced alcohol consumption when given to mice exposed to a chronic alcohol drinking para-
digm but did not affect the acquisition of consumption in mice without a history of alcohol exposure,
suggesting that antagomiR-411 has a neuroadaptive, alcohol-dependent effect. AntagomiR-411
decreased the levels of miR-411, as well as the association of immunoprecipitated miR-411 with arg-
onaute2; and, it increased levels of Faah and PpardmRNAs. Moreover, antagomiR-411 increased
the neuronal expression of glutamate receptor AMPA-2 protein, a known alcohol target and a pre-
dicted target of miR-411. These results suggest that alcohol and miR-411 function in a homeostatic
manner to regulate synaptic mRNA and protein, thus reversing alcohol-related neuroadaptations
and reducing chronic alcohol consumption.
195
SALIVARY MICRORNAS AS BIOMARKERS FOR ALCOHOL DEPENDENCE
H. Zhang, X. Chen, J. Gelernter, L.A. Farrer, D.C. Henderson
Departments of Psychiatry and Medicine (Biomedical Genetics), Boston University School of
Medicine, Boston, MA 02116, USA
Alcohol dependence (AD) is a common and complex genetic disorder. A reliable diagnostic tool that
can assess the extent of the patient’s alcohol consumption is a prerequisite for AD prevention and
treatment. Current AD diagnosis depends primarily on either questionnaires (limited by the subject’s
willingness to give a true reflection of his or her drinking patterns and attitudes) or alcohol-related bio-
chemical markers (e.g., alcohol metabolites) that may not meet the criteria for alcohol abuse or
dependence. Therefore, it is desirable to develop more sensitive, specific, and easily accessible
biomarkers for AD diagnosis. This study aimed to understand whether salivary microRNAs can
serve as biomarker for alcohol dependence, given the important role of microRNAs in regulating
gene expression at the posttranscriptional level. MicroRNA transcriptomes in the saliva of 53 African
Americans (AAs; 25 AD patients and 28 healthy controls) and 62 European Americans (EAs; 32 AD
patients and 30 healthy controls) were profiled using the small RNA sequencing technology. The
sequencing data was processed using the miRDeep2 software. MicroRNAs were detected by align-
ing them to the sequences of known microRNAs from the miRBase database. Differentially
expressed microRNAs in the saliva of AD subjects were identified using the edgeR package. The
machine learning package Caret was used to explore the possibility of using differentially expressed
microRNAs as biomarkers for AD status prediction. In AA AD subjects, four miRNA showed differen-
tial expression (>1.5 fold changes and p < 0.05). If these four microRNAs were included in machine
learning using the random forest algorithm and the train/test ratio is set at 80/20, the AD prediction
accuracy in AAs was 59.1%. In EA AD subjects, four miRNA showed differential expression (>2.0
fold changes and p < 0.05). If these four microRNAs were included in machine learning using the
random forest algorithm and the train/test ratio is set at 80/20, the AD prediction accuracy in EAs
was 68.5%. The present study demonstrated microRNA transcriptome alterations in the saliva of AD
subjects and provided evidence that AD-associated salivary microRNAs are potential biomarkers for
AD prediction. However, these findings need to be validated in a larger sample.
320A
TUESDAY, JUNE 19 1:20 PM–2:50 PM
SYMPOSIUM 196–199
Pathways That Gate or Drive Alcohol Reward and Intake: From Molecules to
Circuitries
Organizer/Chair: Dorit Ron Chair: Thomas Kash
196
PERSISTENT CONTROL OF ALCOHOL-SEEKING BEHAVIOR BY OPTOGENETIC INDUCTION
CORTICOSTRIATAL SYNAPTIC PLASTICITY IN THE DORSOMEDIAL STRIATUM OF RATS
J. Wang, E.R. Hellard, T. Ma, A. Binette
Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M
University Health Science Center, Bryan, Texas 77807, USA
Excessive alcohol consumption alters glutamatergic transmission in many brain regions, including
the dorsomedial striatum (DMS); this aberrant plasticity is thought to be responsible for alcohol-seek-
ing behavior. Recent studies reported that alcohol induced such plasticity specifically in dopamine
D1 receptor-expressing medial spiny neurons (D1-MSNs) of the DMS. However, it is unknown
whether this specific change contributes to alcohol-seeking behavior. Here, we first demonstrated
that operant alcohol self-administration increased NMDA receptor activity in DMS D1-MSNs of rats.
Next, we found that optogenetic inhibition of D1-MSNs reversibly decreased operant lever presses
for alcohol and alcohol intake. Furthermore, we reported that optogenetic stimulation of corticostriatal
inputs at low and moderate frequencies induced reliable LTD in DMS slices. Surprisingly, in vivo
delivery of the LTD-inducing protocol increased operant alcohol self-administration; this effect was
blocked by a D2 receptor antagonist. Importantly, LTD induction in the presence of both D1 and D2
receptor antagonists produced a long-lasting decrease in operant alcohol self-administration. Our
results suggest that suppressing DMS D1-MSN activity and their cortical inputs represents a novel
treatment mechanism for alcohol use disorder.
197
CORTICAL-BRAINSTEM PROJECTIONS GATE COMPULSIVE ALCOHOL DRINKING
C.A. Siciliano, X. Chen, J. Wang, H. Noamany, Y.N. Leow,E.Y. Kimchi, C.M. Vander Weele,
K.M. Tye
Department of Brain and Cognitive Sciences, The Picower Institute for Learning and Memory,
Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Over 80% of the population has used alcohol; however, only a relatively small subset of users will
develop an alcohol use disorder. Thus, understanding the neurobiological underpinnings of this wide
individual variation is of great interest. Alcohol-induced plasticity in medial prefrontal cortex (mPFC)
has been implicated in aberrant alcohol drinking behaviors; however, we have little understanding of
how neurons in mPFC are encoding alcohol related stimuli in real-time, and what downstream cir-
cuits are involved. Recently, we identified a sub-population in mPFC, neurons projecting to the dorsal
periaqueductal gray area (dPAG), which routes information related to positive and negative uncondi-
tioned stimuli. Here, we sought to dissect the role of this projection-defined subpopulation within
mPFC in associative learning and punishment-resistant alcohol drinking. Using a dual virus
approach in male C57BL/6J mice, we selectively expressed the genetically encoded calcium indica-
tor GCaMP6 m in mPFC cells projecting to dPAG. We were then able to record calcium dynamics
with single-cell resolution during a novel Pavlovian conditioning task for alcohol, or alcohol adulter-
ated with the bitter tastant quinine. Using this alcohol seeking task, where the strength of alcohol con-
ditioned cues and punishment-resistant alcohol consumption were tested before and after binge
exposure to alcohol, we found that binge drinking produced wide individual variations in the develop-
ment of punishment-resistant alcohol drinking. mPFC-dPAG activity during alcohol consumption dif-
fered between high and low drinking phenotypes whereby high drinkers showed a greater inhibitory
response to alcohol both before and after binge drinking. Further, in punishment-sensitive animals
this inhibitory response decreased when alcohol was adulterated with quinine. To determine if
mPFC-dPAG activity during drinking is causally related to punishment sensitivity, we used a closed-
loop optogenetic approach to photoinhibit mPFC-dPAG projectors during licking for alcohol with qui-
nine. We found that inhibition of this pathway conferred punishment-resistant alcohol drinking, even
in animals with minimal prior alcohol exposure. Pairing mPFC-dPAG inhibition with licking for water
did not alter water intake. Finally, photostimulation of mPFC-dPAG produced active avoidance in a
real-time place preference assay. Together, our results support a model whereby inhibitory
responses in mPFC-dPAG projectors drive alcohol reward, and compulsive alcohol drinking in a sub-
set of animals.
ABSTRACTS-SPEACKERS
198
ALCOHOL LEARNING INDUCED PLASTICITY IN THE BNST
D. Pati, M. Pina, T. Kash
Department of Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina
Chapel Hill
Contextual cues associated with drugs of abuse, such as ethanol, can trigger craving and drug seek-
ing behavior. The pavlovian model of place conditioning has been widely used to study the associa-
tion between environmental cues and drug seeking in rodents. Previous research has shown a
strong temporal relationship between ethanol and exposure to conditioned stimulus (CS): pre-CS
injection of ethanol has been found to induce conditioned place preference (CPP) whereas post CS-
injection of ethanol induces conditioned place aversion (CPA). However, the synaptic adaptations
underlying ethanol induced place conditioning has not been thoroughly investigated and the causal
link to behavior remains elusive. The bed nucleus of stria terminalis (BNST), an integral part of the
extended amygdala, is engaged by both rewarding and aversive stimuli and plays a role in cue-
induced drug seeking. The present study uses ex-vivo slice physiology to probe learning induced
synaptic plasticity in the BNST following ethanol-induced CPP and CPA as well as non-contingent
ethanol exposure. Ethanol-induced CPP was associated with increased excitability of neurons in the
ventral BNST (vBNST) as measured by rheobase (the minimum current required to elicit an action
potential), action potential threshold, and, spike firing. Conversely, ethanol-induced CPA was associ-
ated with a significant decrease in excitatory synaptic drive to neurons within vBNST as measured
by reduction in glutamatergic synaptic transmission without any changes in gabaergic transmission.
We also observed a concomitant change in presynaptic release probability at excitatory synapses
possibly indicative of negative valence induced metaplasticity at excitatory inputs to vBNST neurons.
Non-contingent exposure to ethanol did not induce any significant alterations in the synaptic proper-
ties of these neurons. These findings suggest that ethanol-induced reward learning engages neural
and synaptic plasticity changes in the vBNST which is distinct from ethanol-induced aversive learn-
ing.
199
BDNF IN THE ORBITOFRONTAL TO DORSOLATERAL STRIATUM CIRCUIT GATES KEEPS
ALCOHOL INTAKE IN MODERATION
D. Ron, S.A. Sakhai
Department of Neurology, University of California San Francisco, San Francisco, 94143, USA
We previously found that the activation of the BDNF receptor TrkB in the dorsolateral striatum (DLS)
gates the level of alcohol intake (Jeanblanc et al. 2009, 2013). The major source of BDNF in the stria-
tum is the cortex. Here, we investigated the role of BDNF in cortico-DLS circuitry in alcohol intake.
First, we determined which BDNF cortical neurons project to the DLS. To do so, we used BDNF-Cre
transgenic mice in combination with a retrograde viral strategy, and found that BDNF OFC neurons
project to the DLS. Next, we hypothesized that if BDNF in the OFC is released in the DLS, then over-
expression of BDNF in the OFC should activate BDNF signaling in the DLS. To test this, we mea-
sured the level of phosphorylation of ERK1/2, a downstream effector of BDNF/TrkB signaling. We
found that overexpression of BDNF in OFC neurons increases ERK1/2 phosphorylation in the DLS.
In contrast, ERK1/2 phosphorylation was not detected in the DMS providing evidence for the speci-
ficity of OFC to DLS BDNF signaling. We then tested whether BDNF in the OFC keeps alcohol intake
in moderation, and found overexpression of BDNF in the OFC prevents the development of exces-
sive alcohol consumption. This effect was specific to alcohol as overall fluid or saccharin intake was
unaffected by BDNF manipulation. Finally, we used a Cre-DIO viral strategy to overexpressed BDNF
only in OFC neurons that project to the DLS. We found that overexpression of BDNF in OFC to DLS
circuit maintained moderate levels of alcohol intake and preference, as compared to control GFP
infected animals. Together, our results suggest that BDNF in the OFC activates TrkB signaling in the
DLS to gate the level of alcohol consumption.
ABSTRACTS-SPEACKERS
TUESDAY, JUNE 19 1:20 PM–2:50 PM
SYMPOSIUM 200–203
Risk Factors for Alcohol Use Disorder: An Examination of Neural and
Behavioral Mechanisms from the Laboratory to the Clinic
Organizers/Chairs: Joshua Gowin and Vijay Ramchandani
200
STRIATAL DOPAMINE RECEPTORS MODULATE THE STIMULATORY AND SEDATIVE
EFFECTS OF ETHANOL
M.E. Bocarsly, V.A. Alvarez
National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, 20852, USA
Purpose: Alcohol produces both stimulatory and sedative effects in humans. The clinical literature
suggests that people who more intensely experience the stimulant effects of alcohol are more likely
to abuse the substance and develop dependency. In animal studies, stimulant and depressive
effects of alcohol can be quantified by locomotive activity. Striatal dopamine function is linked to alco-
hol sensitivity, which has been shown to be a predictor of alcohol addiction. However, a detailed
understanding of the dopamine receptor class and localization is unknown. The current study exami-
nes the contributions of specific subpopulations of dopamine D2 receptors in modulating the stimu-
lant and depressant effects of alcohol.
Methods and Results: Using genetically engineered mice lacking D2 receptors on medium spiny
neurons (MSNs) in the striatum or D2 autoreceptors on midbrain dopamine neurons, we examined
dose-dependent, alcohol-induced locomotion. Compared with littermate controls, MSN D2 knockout
mice show a significantly increased locomotor response to alcohol, while the mice lacking D2 autore-
ceptors are more sensitive to the depressive effects of alcohol. To assess differences in alcohol-
induced sedation in each of the mouse lines, we performed the Loss of Righting Reflex (LORR).
LORR data show that MSN D2 knockout mice are more resilient to the sedative effects of alcohol,
with only 50% of mice losing the righting reflex. Meanwhile, D2 autoreceptor knockout mice lose and
regain the righting reflex after a high dose of alcohol similar to control mice. To further explore the
rewarding and reinforcing aspects of alcohol in these transgenic mice, we examined intake parame-
ters. MSN D2 knockout mice showed a higher preference for alcohol than controls in a two-bottle
choice test and increased seeking in a self-administration paradigm.
Conclusions: These results suggest that MSN striatal dopamine D2 receptors may be playing an
important role in modulating the behavioral responses to alcohol. This may provide an explanation
for the variation in individuals’ responses to the stimulant effects of alcohol and the resulting suscepti-
bility to abuse and dependence.
201
COGNITIVE FLEXIBILITY AS A RISK FACTOR FOR HEAVY DRINKING IN RHESUS MONKEYS
K.A. Grant, T. Shnitko
Oregon National Primate Research Center Division of Neuroscience Oregon Health & Science
University 505 NW 185th Ave Beaverton, OR 97006, USA
Purpose: Behavioral flexibility is described as an ability to adapt to changing sets of rules governing
learned associations between conditioned stimuli and optimal responses. Cognitive flexibility relies
on high order brain functions like sensory perception, response inhibition, and associative learning.
Although there are laboratory animal and human studies to show that chronic heavy alcohol drinking
can impair cognitive flexibility, data linking pre-alcohol cognition with risk for heavy drinking is rare
and nonexistent in non human primates.
Methods: In the studies to be presented, we hypothesized that poor cognitive flexibility would pre-
dict heavy ethanol drinking. We used a set-shifting procedure to quantify cognitive flexibility in a
group of 9 late adolescent/early adult male rhesus monkeys. Following 7 training sessions, a com-
posite Performance Index (PI) was calculated for each subsequent daily session such that the per-
formance of the monkeys over the next 30 sessions could be compared. Pre-ethanol set-shifting
performance showed wide individual differences. The monkeys were then induced to drink ethanol
using a schedule-induced polydipsia procedure. Following induction, monkeys were allowed access
to ethanol and water 22 h/day, everyday, for 6 months. Under these “open-access” conditions for
alcohol consumption, there are wide individual differences in how much a monkey chooses to drink
and the monkeys can be subdivided in “heavy” and “non-heavy” alcohol drinkers using sophisticated
statistical modeling.
Results: Average ethanol intake for the non-heavy drinkers (n = 3) was 2.03  0.2 g/kg that
resulted in BEC of 29  4 mg% and for the heavy drinkers (n = 6) was 3.29  0.2 g/kg and
resulted in BEC of 102  10 mg%). Pre-ethanol set shifting performance of the future non-heavy
drinkers showed greater improvements and higher PI scores at the end of testing compared to the
future heavy drinkers (F = 13.2, p < 0.01).
Conclusions: The results demonstrate the ability to engage in flexible changes to behavioral strate-
gies governing optimal performance may be impaired in primates at risk for chronic heavy alcohol
drinking. Further, because the monkeys in this study were of an age when prefrontal cortical matura-
tion is still underway, there are implications that cortical mechanisms are mediating the risk for heavy
drinking.
321A
202
PATTERNS OF ALCOHOL CONSUMPTION AND RISK FOR ALCOHOL USE DISORDER
J.L. Gowin, M.E. Sloan, R. Janakiraman, B. Stangl, V.A. Ramchandani
National Institute on Alcohol Abuse and Alcoholism Section on Human Psychopharmacology
Bethesda, MD, 20892, USA
Purpose: Heavy drinking is usually defined by consumption patterns across weeks and months,
but few attempts have been made to characterize inter-individual differences in alcohol consumption
patterns during a single drinking session. Understanding which patterns of alcohol consumption are
associated with alcohol use disorder (AUD) vulnerability may help identify individuals who would ben-
efit from early intervention. This study sought to investigate whether rate of alcohol consumption dif-
fers between heavy drinkers and light drinkers at low or high risk for AUD, during a single 125-min
alcohol consumption session. Risk factors included male sex, family history of alcoholism, and high
levels of impulsivity as indexed by delay discounting.
Methods: Participants completed interviews to assess drinking status, psychiatric diagnosis, and
risk factors for alcohol use disorder. Participants then completed a 125-min, pharmacokinetically-
controlled, intravenous alcohol self-administration session. Between 2008 and 2017, participants
completed assessments and alcohol self-administration sessions at the National Institutes of Health
Clinical Center in Bethesda, Maryland. Two hundred eleven participants between the ages of 21 and
60 completed the study.
Data: The primary outcome of the alcohol self-administration session was rate of achieving a binge-
level intoxication (80 mg%). A secondary outcome was the amount of alcohol consumed during the
first 30 min of the session.
Results: Heavy (hazard ratio = 3.17, 95% CI 1.78, 5.64) and high-risk drinkers (hazard
ratio = 2.33, 95% CI 1.39, 3.91) were both significantly more likely to binge than low-risk drinkers.
There were no significant differences in rate of binging throughout the session between high-risk
drinkers and heavy drinkers after adjusting for covariates (hazard ratio = 0.74, 95% CI 0.42 to 1.31).
Heavy and high-risk drinkers also had a significantly greater increase in blood alcohol concentration
across the first 30 min of the session relative to low-risk drinkers.
Conclusion: Light and moderate drinkers at high risk for an AUD have an alcohol consumption pat-
tern that is similar to heavy drinkers, which is noteworthy as their drinking outside of the laboratory is
similar. Improved characterization of behavior during a single alcohol consumption session may be
useful way to identify individuals at high risk for an AUD.
203
MECHANISMS UNDERLYING RISK FOR RELAPSE AMONG INDIVIDUALS WITH ALCOHOL
USE DISORDER AND COMORBID POSTTRAUMATIC STRESS DISORDER (PTSD)
I.L. Petrakis, E. Ralevski, A. Arias, G. Yoon, T. Verplaste
Yale University School of Medicine VACT Healthcare System 950 Campbell Avenue, #116A West
Haven, CT 06516, USA
Purpose: There is evidence to suggesting that PTSD is a risk factor for alcohol use disorder (AUD),
since AUD and PTSD are highly comorbid. Understanding mechanisms that lead to heavy drinking
and relapse is important among those with comorbidity. Information about the antecedents of drink-
ing behavior in this population can be obtained using laboratory studies or data from clinical trials.
The purpose of this presentation is to describe data from 2 types of studies: one laboratory study of
stress and trauma reactivity and the second is data from a randomized placebo controlled clinical trial
evaluating prazosin-both in individuals with alcohol use disorder and PTSD. The studies will shed
light on the link between trauma exposure and PTSD symptoms to alcohol craving and consump-
tion.
Methods: Individuals with AUD and comorbid PTSD who were recruited to a clinical trial were also
recruited to undergo laboratory testing prior to randomization (n = 25). Subjects were interviewed
about a stressful event and an index trauma during baseline sessions in order to develop personal-
ized scripts. During the laboratory session, subjects were exposed to neutral, stressful and trauma
scripts randomly assigned. The outcomes included alcohol craving, anxiety, mood symptoms and
cardiovascular responses. A secondary analysis also is being conducted using data from a medica-
tion clinical trial for PTSD and AUD (n = 98); data will be analyzed for the interaction on CAPS
scores and drinking outcomes using mixed models.
Results: Data from the laboratory using personalized scripts showed that while both stress and
trauma scripts produced significantly stronger craving for alcohol than neutral cues, trauma scripts
produced stronger craving and greater cardiovascular reactivity than stress scripts (p = 0.0001).
Further, clinical trial data in comorbidity from two medication clinical trials for PTSD and AUD
(n = 98) can shed light on the relationship between PTSD symptoms and alcohol consumption.
Conclusions: Data suggest traumatic memories and PTSD symptoms are more salient cues than
stress cues that promote craving and drinking behavior. These data have practical and clinical impli-
cations for treatment of dual diagnosis, and how to develop interventions to treat these disorders will
be discussed.
322A
TUESDAY, JUNE 19 1:20 PM–2:50 PM
SYMPOSIUM 204–207
New Findings on Alcohol and Injury from Emergency Room Studies
Organizer/Chair: Cheryl Cherpitel
204
ALCOHOL AND ROAD TRAFFIC INJURIES IN AFRICA
C. Staton1,2, J. Vissoci1,2, S. Galson1,2, Y. Ye1,2
1
Division of Emergency Medicine, Department of Surgery, Duke University Medical Center, 27707,
Durham, USA and 2Duke Global Health Institute Duke University, 27710, Durham, USA
Purpose: Globally, alcohol is the leading risk factor for injury. Africa has the second highest rates of
binge drinking and alcohol dependence and the highest road traffic fatality rate. The purpose of this
study was to determine the role of alcohol consumption in road traffic injuries (RTIs) in three sub-
saharan African countries.
Methods: The proportion of emergency department (ED) patients presenting with RTIs who are
breathalyzer positive, as an estimate of blood alcohol concentration (BAC), and who reported drink-
ing within 6 h prior to the injury are analyzed. The dose-response risk of RTI from self-reported con-
sumption was determined for Tanzania (the only country to have these data) using the case-
crossover method, with multiple control periods of the day prior to injury and the week prior.
Data: ED data on injured patients 18 years and older from Mozambique (Moz), South Africa (SA)
and Tanzania (Tz) were analyzed, using the International Collaborative Alcohol and Injury Study
(ICAIS). Of the 1,439 patients, 33% (581) suffered RTIs (25% Moz, 20% SA, 73% Tz).
Results: Overall 31% of RTI patients were BAC positive (24% Moz, 42% SA, 29% Tz), and 29%
were positive for self-report (24% Moz, 40% SA, 26% Tz). In Tanzania, risk of RTI increased six-fold
(OR = 6.53; CI 3.98–10.71) for any alcohol consumption, with a dose-dependent response. Those
with injuries related to both motorcycles and cars/trucks had an increased odds of RTI for any alcohol
(OR = 5.31; CI 2.24–12.57 and OR = 4.53; CI 3.98–10.71, respectively), but motorcyclists had the
highest increased odds at 3–4 drinks (OR = 5.60; CI 2.22–14.10).
Conclusions: RTIs were most prevalent in Tanzania. Overall, nearly a third of RTI patients were
BAC positive on arrival to an ED and reported drinking prior to the injury event, however, the propor-
tion differed by country. While any alcohol consumption prior to injury can increase the risk for a RTI,
motorcyclists are at greater risk of an RTI at lower levels of consumption.
205
ACUTE ALCOHOL USE AND CHRONIC ALCOHOL PROBLEMS PRECEEDING A RECENT
SUICIDE ATTEMPT
C.L. Bagge, A.K. Littlefield
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson
MS 39216, USA
Objective: Risk factors for suicide attempt include acute alcohol use (drinking immediately prior to
the attempt) and chronic alcohol use (a history of problematic drinking). However, it is important to
disaggregate acute and chronic alcohol associations with correlates of suicide attempt (e.g., history
of previous attempt). The aim of the current study was to examine main and interactive effects of
acute alcohol use and chronic problematic alcohol use on previously identified correlates of suicide
attempt.
Method: Participants included 166 recent suicide attempters presenting to a Level 1 trauma hospi-
tal. Acute alcohol use (A) was coded positive for participants who drank within 6 h of their suicide
attempt (measured by the Timeline Follow Back for Suicide Attempts) and chronic problematic alco-
hol use (PAU) was coded positive for participants with scores >8 on the Alcohol Use Identification
Test. Dependent variables included gender, history of previous attempt, prior psychological hospital-
ization, short proximal suicide contemplation, depressive symptoms, past year negative life events,
quality of life, and trait aggression.
Results: PAU had a positive main effect on depressive symptoms. Disordinal interactions between
A and PAU were identified for both quality of life and short proximal suicidal ideation; A had a positive
relation with both quality of life and short proximal suicide premeditation for those who were PAU-
but a negative relation to these outcomes for those who were PAU+. No other significant main or
interactive effects were identified.
Conclusions: These findings highlight the importance of disaggregating acute and chronic effects
of alcohol on suicide-related characteristics to inform suicide prevention and treatment.
ABSTRACTS-SPEACKERS
206
MULTI-LEVEL ANALYSIS OF ALCOHOL-RELATED INJURY, SOCIETAL DRINKING PATTERN
AND ALCOHOL CONTROL POLICY: EMERGENCY DEPARTMENT DATA FROM 28
COUNTRIES
C.J. Cherpitel, R.A. Korcha, J. Witbrodt
Alcohol Research Group, Public Health Institute, Emeryville, CA 94608, USA
Purpose: While alcohol is known to be strongly associated with injury, the magnitude of the relation-
ship has been found to vary across studies and countries. The aim of this study is to examine the role
of societal-level drinking pattern and alcohol control policy on this observed heterogeneity.
Methods: Cross-study variation in the rate of alcohol-related injury (self-reported drinking prior to
the event and causal attribution of injury to drinking) is examined using multilevel modeling of individ-
ual-level drinking variables, country level detrimental drinking pattern (DDP) and a policy measure,
the International Alcohol Policy and Injury Index (IAPII), which includes the four regulatory domains
of availability, vehicular, advertising and drinking context.
Data: Emergency department (ED) data on 14,933 injured patients from 28 countries is analyzed,
using the International Collaborative Alcohol and Injury Study (ICAIS), which includes four collabora-
tive ED studies on alcohol and injury, all using a similar methodology.
Results: Controlling for demographic characteristics, individual-level volume and pattern of drink-
ing, and study-level volume, the IAPII significantly predicted cross-study variation in rates of both
self-reported drinking (p < 0.001) and causal attribution (p < 0.05), and DDP did not alter this affect.
Three of the four domains were significantly predictive of self-reported drinking (p < 0.01), with the
domain of drinking context (community mobilization and server training) being marginally significant
(p < 0.10), while only the vehicular domain was significantly predictive of cross-study variation in
rates of causal attribution (p < 0.05).
Conclusions: The more restrictive the alcohol policy in a country, the lower the rate of alcohol-
related injury, with country-level drinking pattern having little effect on this relationship.
207
AN ASSESSMENT OF METHODOLOGIES TO ESTIMATE THE BURDEN OF INJURIES
ATTRIBUTABLE TO ALCOHOL CONSUMPTION
K. Shield, Y. Ye,A. Sherk,J. Manthey, J. Rehm
Institute for Mental Health Policy, Centre for Addiction and Mental Health, Toronto, Ontario, M5S
3M1, Canada
Purpose: To investigate the accuracy and precision of estimating the number of injuries which are
attributable to alcohol consumption using (1) emergency room (ER) studies, versus (2) the current
method of combining population-level alcohol consumption data with relative risk (RR) data, in both
cases using data for Canada, the United States, Ireland, Poland, Spain, Sweden and Switzerland.
Methods: Firstly, population-attributable fractions (PAFs) of injuries due to alcohol were estimated
by means of a secondary analysis of data from ER studies. Subsequently, using the current Levin
methodology, the same PAFs were estimated using data on alcohol consumption obtained from the
Global Information System on Alcohol and Health for 2014. RRs taking into account drinking vol-
umes and patterns were estimated using data from the National Health Interview Survey, which sur-
vey is linked to the United States’ Vital Records registry (stratified by volume and binge alcohol
consumption). Mortality and population data were obtained from the Global Health Data Exchange.
Results: The PAFs for alcohol attributable-injuries which were estimated using data from ER stud-
ies varied from 8.5% for Poland to 19.7% for Ireland. Conversely, the PAFs for alcohol-attributable
injuries which were estimated using 2014 population data on alcohol consumption combined with
RR data ranged from 10.8% for Poland to 20.4% for Ireland. On average, results from the ER studies
were 1.07 times greater than the results obtained using the population-level data approach, how-
ever, on the country level this ratio ranged from 0.79 to 1.48.
Conclusions: Attributable-injury estimates from ER studies and from population-level alcohol con-
sumption statistics combined with RR data may produce different burden estimates. Such differ-
ences may stem from the nature of the injuries outlined in ER studies, which may not be
representative of the entire population, and from the biases introduced by using the same injury RR
function across countries, despite hypothesized differences in these countries’ drinking contexts.
ABSTRACTS-SPEACKERS
TUESDAY, JUNE 19 1:20 PM–2:50 PM
SYMPOSIUM 208–211
The Adolescent Brain Cognitive Development (ABCD) Study: Emerging
Findings on Substance Use, Risk and Protective Factors, and Neuroimaging
Organizer/Chair: Mary Heitzeg Chair: Sandra Brown
208
ADOLESCENT BRAIN COGNITIVE DEVELOPMENT (ABCD): AN OVERVIEW OF THE STUDY
AND DESCRIPTION OF THE SAMPLE
S. Tapert, M. Hernandez
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093-0603, USA
Purpose: The NIH-funded Adolescent Brain and Cognitive Development (ABCD) Consortium aims
to be the largest longitudinal multi-site study of brain and behavioral development to date. It seeks to
determine how childhood experiences, including adolescent alcohol use, influence brain develop-
ment and behavior.
Methods: The ABCD study was launched in 2015 and data collection began in Fall 2016. This
prospective, longitudinal, multi-site study will combine developmental psychology, neuroimaging,
cognitive neuroscience, genetics, and epidemiology with advanced techniques in bioassays, bioin-
formatics, and mobile technology-based assessments. ABCD is enrolling 11,500 9-to-10 year-old
singleton and twin participants who represent the United States population from 21 sites around the
country (>6,000 enrolled as of 11/14/2017). Participants are recruited primarily from schools, and
twins from twin registries. This diverse, representative cohort includes children from all races, ethnici-
ties, and family education and income levels, as well as those living in rural, urban, and suburban
environments with selection weighted to approximate the true demographic characteristics of the
United States. This cohort will be followed through adolescence and into young adulthood. Partici-
pants and their families complete comprehensive behavioral assessments of mental health, sub-
stance use, neurocognition, social function, and personality as well as a 2-h brain imaging protocol
that includes structural, diffusion tensor, resting-state, and task-based scans.
Results: This presentation will outline the design of the study, and will provide descriptive character-
istics of the sample at baseline, to date. The sample is roughly half female, and half 9-year-olds. The
most common mental health disorders are attention deficit hyperactivity disorder, followed by opposi-
tional defiant disorder, and then general and social anxiety disorders.
Conclusions: One goal of ABCD is to create a unique data resource for the entire scientific com-
munity using an open science model. The ABCD Study will release curated, anonymized data along
with the computational workflows used to produce the data annually, beginning in December 2017.
Findings from ABCD are expected to increase the ability to distinguish environmental, sociocultural,
and genetic factors relevant to substance use and brain development and to inform prevention, treat-
ment, and public health strategies.
209
SUBSTANCE USE RATES AND RISK FACTORS IN 9 AND 10 YEAR OLDS: INITIAL FINDINGS
FROM THE ABCD STUDY
M.M. Heitzeg, K.M. Lisdahl
Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, USA
Purpose: Although the initiation of drinking and drug use typically begins during the teen years,
early sipping of alcohol and experimentation with nicotine can occur in late childhood. Still, little is
known about substance use patterns in children, as current national surveys typically begin in ado-
lescence. The ABCD study will be the first to provide detailed characterization of substance initiation,
experimentation and use patterns in 9 and 10 year olds, as well as the risk and protective factors
influencing trajectories of substance use throughout adolescence.
Methods: The ABCD study is enrolling 11,500 children (ages 9–10) at baseline. The substance use
module focuses on assessment of knowledge and use of all major drug categories. Important predic-
tors of substance use are also captured, including peer use, intention to use, availability of sub-
stances, and parent rules about use. Additional risk and protective factors are captured in the culture
and environment module of the ABCD protocol. Baseline data is currently available for 4,516 partici-
pants. Initial analyses are focused on comparisons between high-risk (42% of participants) and low-
risk groups formed based on externalizing and negative affect symptoms.
Results: High-risk youth were more likely than low-risk youth to report having heard of marijuana
(p = 0.028) and inhalants (p = 0.009), but not alcohol, tobacco or prescription drug misuse. Of youth
having knowledge of alcohol, 26% reported having sipped alcohol and 0.3% (n = 13) reported hav-
ing a full drink; these rates did not differ by risk group (p = 0.060). Of youth having knowledge of
tobacco, 0.6% (n = 25) reported having tried a puff; this rate was higher in high-risk than low-risk
youth (p = 0.002). High-risk youth also reported having friends who use alcohol and tobacco more
than low-risk youth (p’s < 0.05). Peer drinking was significantly associated with the endorsement of
sipping (p < 0.001).
Conclusions: The ABCD study will be able to provide detailed characterization of substance initia-
tion, experimentation and use patterns in a large, diverse sample of 9 and 10 year olds. The collec-
tion of these data along with the assessment of risk and protective factors and psychological and
neurobiological development over 10 years will allow the ABCD study to identify the effects of sub-
stance use trajectories on brain maturation, and behavioral, health, and psychological outcomes.
323A
210
GENERAL FACTOR ANALYSIS REVEALS LATENT VARIABLES CONNECTING MEDIA
ACTIVITY TO PSYCHOPATHOLOGY IN THE ABCD COHORT
M.P. Paulus, W. Thompson, S.F. Tapert, F. Breslin, A. Sheffield Morris
Laureate Institute for Brain Research 6655 S Yale Ave Tulsa, OK 74136-3326, USA
Purpose: Media activity is among the most important recreational behavior adolescents engage in.
98.9% of young individuals report current internet use (Rikkers et al., 2016), however, its impact on
development, the risk and resilience contributions to the development of high risk behaviors is not
well understood. In extreme cases media activity can result in internet addiction, which has also been
associated attention deficit hyperactivity disorder and suicidal behavior (Ha et al., 2007; Yen et al.,
2007). This investigation aimed to establish the latent variables that link internet activity to psy-
chopathology in the ABCD cohort.
Methods: This analysis was conducted with the first publically available data set from the ABCD
cohort. Briefly, 4,524 male and female subjects age 9–10, which had been recruited between
September 2016 and August 2017 were eligible for this analysis. Group factor analysis (GFA) was
used to identify the latent variables (LV) that relate media activity.
Results: GFA identified 6 robust LVs accounting for approximately 50% of the variance. Notably,
these LVs revealed: (1) a relationship between low scores on socio-economic variables, high scores
on media activity and psychopathology, as well as low scores on cognitive task performance, (2)
gender-specific performance on cognitive task, high media activity, and high psychopathology, and
(3) gender-specific differences in media activity. In preliminary analyses, the subset of the cohort
identified at high risk for future substance use (n = 1,876) relative to those at lower risk for substance
use (n = 2,633) showed greater loading on the LV 1 (t =
7.0994, df = 3,949.7, p-
value = 1.479e
12).
Conclusions: These results show that (1) media activity is complex and cannot be described by a
single variable, (2) a specific combination of socio-demographics, cognitive function, and media
activity is related to increased psychopathology, and (3) substance use risk status can be related to
a specific aspect of media activity. These findings have important implications for public education,
identification of children at risk, and future, more in-depth investigations of media activity and psy-
chopathology.
211
TASK-BASED NEUROIMAGING PROBES OF THE DEVELOPING BRAIN IN THE ABCD STUDY
M.T. Sutherland, M.C. Riedel, A.S. Dick
Departments of Psychology and Physics, Florida International University, Miami, FL 33199, USA
Purpose: As alcohol and drug use often begin in adolescence, the ABCD longitudinal design, with
baseline assessments in late childhood, can facilitate delineation of the antecedents and conse-
quences of substance use (SU) and addiction. Such efforts may provide insight into neurobiological
risk and resiliency factors influencing SU trajectories. Here, we provide an initial characterization of
neuroimaging task outcomes from children 9–10 years old.
Methods: The ABCD protocol’s neuroimaging module involves T1-, T2-, and diffusion-weighted
scans assessing brain structure and resting-state and task-based scans assessing brain function.
The neuroimaging tasks probe psychological constructs and brain regions previously implicated in
SU and thought to be feasibly implemented across development. The stop signal task (SST) probes
inhibitory control required to countermand a prepotent motor response and provides brain activation
maps of inhibition and error detection. A monetary incentive delay (MID) task probes aspects of
reward processing and provides functional maps for anticipation and outcome phases associated
with high- and low-value wins and losses. A variant of the n-back task contains emotional-face and
neutral-place stimuli and provides activation maps of emotional processing and working memory
load.
Results: Initial behavioral (n = 965) and brain (n = 88) assessments demonstrate the feasibility
and developmental appropriateness of these tasks. Regarding MID performance, hit rates were
higher for win (59  0.2%) versus loss (56  0.2%) and neutral trials (48  0.4%) (p’s < 0.001).
Contrasting successful versus unsuccessful win trials identified expected reward outcome-related
activity notably in the ventral striatum. Regarding the SST, participants succeeded on 82  0.5% of
go trials and 55  0.3% of stop trials. RT on failed stop trials (456  3 ms) was faster than that on
successful go trials (522  3 ms) (p < 0.001). Contrasting successful stop versus successful go tri-
als identified expected inhibitory-related activity notably in lateral prefrontal regions. N-Back accuracy
was higher and RT lower in the low-load (0-back: 83  0.5%, 921  5 ms) versus the high-load
condition (2-back: 76  0.5%, 1,050  4 ms) (p’s < 0.001). Contrasting low- versus high-load con-
ditions identified working memory-related activity notably in lateral prefrontal cortices.
Conclusions: These expected outcomes suggest high participant compliance with protocol
demands, which will yield baseline neuroimaging data critical for assessing the impact of SU trajecto-
ries on brain maturation. Subsequent analyses will focus on cross-sectional comparisons of sub-
stance-na€ıve participants at elevated risk for SU versus those at low risk.
324A
TUESDAY, JUNE 19 1:20 PM–2:50 PM
SYMPOSIUM 212–215
Antecedents of Alcohol and Other Substance Use: Examining Commonalities
Across Substances Using Ecological Momentary Assessment
Organizer: Ryan Carpenter Organizer/Chair: Rachel Tomko
212
NATURALISTIC ASSESSMENT OF DUAL CUE ATTENTIONAL BIAS IN MODERATE TO
HEAVY-DRINKING SMOKERS
R.R. MacLean1,2, A.J. Waters1,2, M. Sofuoglu1,2
1 endorse substance use as a means of coping. However, due to the persistent nature of the stressor,
VA Connecticut Healthcare System Psychology West Haven, CT 06516, USA and 2Yale University
School of Medicine, New Haven, CT 06510, USA
Purpose: Over time and repeated use, substance-related cues acquire incentive-motivational prop-
erties that serve to grab an individual’s attention (“attentional bias” or AB) in a variety of situations.
Despite high prevalence of substance co-use and frequent exposure to drug-related stimuli in daily
life, AB tasks typically focus on one substance and are often measured in a laboratory environment.
The present study evaluated contemporaneous AB to alcohol and cigarette stimuli in daily smokers
who regularly consume alcohol using ecological momentary assessment (EMA).
Methods: Recruitment included daily smokers (>5 cigarettes/day) that endorsed moderate to heavy
drinking in the past year. Participants were given a personal digital assistant (PDA) that randomly
administered assessments of environment, craving, and substance use four times per day. Each
assessment also included a dot probe task to measure AB. Briefly, a smoking or alcohol-related and
neutral stimuli are presented side by side for 500 ms, and then a probe immediately replaces the
location previously occupied by one of the stimuli. Participants are asked to respond to the location
of the probe and AB is defined as a faster reaction time when the probe replaces the drug-related rel-
ative to the neutral picture.
Results: Preliminary analysis of recruited participants (n = 16) initiated provided complete self-
report data on 428 of those assessments with 422 assessments containing complete AB task data.
When excluding extreme smoking and alcohol bias scores (<1st percentile, >99th percentile) mean
smoking AB = 5.40 ms (SD = 25.03), p = 0.03, d = 0.62 and mean alcohol AB = 15.90 ms
(SD = 42.46), p = 0.15, d = 0.37. Smoking AB and alcohol AB were not significantly different from
one another. Using linear mixed models, mean craving for cigarettes was associated with craving for
alcohol, PE = 0.96, SE = 0.12, t = 8.32, p < 0.001 (between-person association). Within-person
analysis revealed that higher than average (person-centered) craving for cigarettes was also associ-
ated with craving for alcohol, PE = 0.18, SE = 0.06, t = 3.14, p = 0.007.
Conclusion: Individuals that regularly use alcohol and smoke cigarettes demonstrate similar AB to
both drugs. There is also evidence that craving for cigarettes is related to craving for alcohol across
individuals, but also at a single time point. Future analyses will evaluate lagged relationships
between alcohol and cigarette craving and AB.
213
DAILY LIFE ASSOCIATIONS BETWEEN NEGATIVE AFFECT AND ALCOHOL AND CANNABIS
USE IN OUTPATIENTS WITH EMOTION DYSREGULATION
A.M. Wycoff, J.G. Kerns, T.J. Trull
Department of Psychological Sciences, University of Missouri, Columbia, MO 65211, USA
Affective motivational models of substance addiction posit that problematic use stems from using
substances for the purpose of relieving negative affect (NA). Individuals with emotion dysregulation
may be particularly susceptible to this pattern due to increased NA and lack of adaptive regulation
strategies. We sought to examine this pattern in daily life, hypothesizing that individuals would be
more likely to use substances (alcohol or cannabis) following higher levels and instability of NA, and
that individuals would report lower levels and instability of NA following use. A sample of outpatient
women (N = 32) aged 18–38 with diagnoses of mood, anxiety, or borderline personality disorders
carried smartphones for 14 days that randomly prompted them 6 times per day to report on recent
affective states and substance use. Data were analyzed using generalized estimating equations and
multilevel models. Results partially supported hypotheses, revealing most consistent associations
for hostility and cannabis such that hostility at one prompt predicted cannabis use at the next prompt
(Est. = 0.53, SE = 0.11, p < 0.001), day-level instability of hostility predicted next-day cannabis use
(Est. = 1.76, SE = 0.64, p < 0.01), and day-level cannabis use predicted decreased same-day
instability of hostility (Est. =
0.84, SE = 0.38, p < 0.05). This pattern of results suggests a negative
reinforcement effect for cannabis use in terms of hostility specifically, while less consistent results
were found for alcohol use and for additional types of NA.
ABSTRACTS-SPEACKERS
214
USING ALCOHOL, TOBACCO, AND CANNABIS TO COPE WITH NEGATIVE AFFECT BEFORE
A STRESSFUL EXAMINATION
S.P. Lane
Department of Psychological Sciences, Purdue University, West Lafayette, IN 47907, USA
Substance use is a common means of coping with negative emotional reactions brought on by
stressful life experiences, particularly among those with stronger learned associations with respect
to its negatively reinforcing effects. However, it may not be an effective coping mechanism insofar as
it does not mitigate such negative emotions or the stressor that caused them. The current study
sought to examine the hypothesis that substance use would be more likely on days characterized by
greater morning negative affect leading up to an acute stressor, particularly among those who
it was expected that substance use would not alleviate subsequent negative affect. A sample of 232
undergraduate students preparing for an important premedical examination were recruited to partici-
pate in a 14-day diary study in which they completed morning and evening measures for approxi-
mately 7 days before the exam and 7 days including and after the exam. Each morning and evening
individuals reported on their negative affect. In the evening individuals also indicated if they had used
alcohol, tobacco, and cannabis that day. At baseline participants completed a battery of scales,
which included a measure of substance use directed coping. Multivariate multilevel logistic mediation
models indicated that morning negative affect was associated with a greater likelihood of drinking on
days prior to the exam, especially for those who endorsed greater substance use coping. Morning
negative affect was associated with pre-exam cannabis use, but only among high substance use
coping individuals, and was not associated with tobacco use. Importantly, while drinking was then
associated with lower evening negative affect in the days after the exam, it was not associated with
pre-exam evening negative affect. Simultaneously, tobacco use was associated with lower pre-exam
evening negative affect, but only among high substance use coping individuals, and cannabis was
not associated with evening negative affect. These results suggest that alcohol and cannabis use
may be ineffective at alleviating negative affect brought on by acute stress. This may relate to cogni-
tive impairments resulting from alcohol/cannabis use, in contrast to tobacco use, that otherwise
impede preparation for the exam stressor.
215
PHYSICAL PAIN AS AN AVERSIVE STIMULUS: NEGATIVE REINFORCEMENT OF ALCOHOL
AND OPIOID USE IN DAILY LIFE IN CHRONIC PAIN PATIENTS
R.W. Carpenter, P.K. Wood, T.J. Trull
Department of Psychiatry & Human Behavior, Brown University, Providence, RI, 02912, USA
Negative reinforcement models of addiction have generally focused on negative affect. However,
negative reinforcement can refer to the removal of any aversive stimulus. Physical pain is one par-
ticularly unpleasant, and commonly experienced, stimulus. Though increasingly controversial, opi-
oids are frequently prescribed to individuals with chronic pain. Many individuals may also manage
their pain through alcohol use. Similar to opioids, alcohol has analgesic effects, via stimulation of
the endogenous opioid system. However, little research has examined the association of alcohol
and pain, and none has done so in the natural environment. Thus, it is unknown to what extent
individuals with chronic pain drink in response to pain, and what, if any, pain relief they experience
following consumption. Additionally, while the analgesic properties of opioids are well-established,
no work has examined the association of pain and opioid use in daily life. The present study used
ecological momentary assessment (EMA) to examine negative reinforcement of alcohol and opioid
use via pain in a sample of patients with chronic low back pain. Participants either drank alcohol at
least twice per week (n = 27) or took daily or every-other-day prescribed opioids (n = 27). Partici-
pants reported on their momentary pain and alcohol and/or opioid use multiple times daily for two
weeks (nobservations = 4,954). Findings found inconsistent support for negative reinforcement of
alcohol use. Pain largely did not predict consequent alcohol use, but alcohol use was associated
with reductions in pain. In particular, faster rate of consumption was associated with greater reduc-
tions in pain across the drinking episode. In contrast, findings strongly supported negative rein-
forcement of opioid use, with participants more likely to take opioids, and at higher doses, at
moments of elevated pain. Opioid use was also associated with next-moment decreases in pain.
Findings suggest that pain should be considered in negative reinforcement models of addiction.
However, while both alcohol and opioid use were associated with analgesia, there was stronger
evidence for the negative reinforcement of opioid use. Despite this, given the analgesic effects of
alcohol, there is a risk that the prevalence of pain-related alcohol use may increase as access to
legally prescribed opioids becomes more regulated.
ABSTRACTS-SPEACKERS
TUESDAY, JUNE 19 1:20 PM–2:50 PM
SYMPOSIUM 216–219
Recent Advances in Technology Based Alcohol Intervention Approaches
Organizer/Chair: Jenni Teeters
216
AN INTERACTIVE TEXT-MESSAGE BASED BRIEF INTERVENTION IS ASSOCIATED WITH
REDUCTIONS IN ALCOHOL-IMPAIRED DRIVING AMONG COLLEGE DRINKERS
J.B. Teeters, J.G. Murphy
University of Memphis, Psychology, Memphis, TN, 38152, USA
Purpose: Alcohol-Impaired Driving (AI-driving) among college students remains a significant public
health concern and is perhaps the single riskiest drinking-related behavior. Counselor-delivered and
web-based Brief Alcohol Interventions (BAIs) have been shown to reduce AI-driving among college
students, but to date no study has evaluated the efficacy of an interactive text-message based BAI
specific to AI-driving. The present study examined whether an AI-driving specific BAI delivered via
text-messaging would significantly decrease AI-driving among college students compared to an
informational control.
Method: Participants were 84 college students (67.1% women; average age = 23; 52.4% Cau-
casian) who endorsed driving after drinking two or more drinks at least twice in the past three
months. After completing baseline measures, participants were randomly assigned to receive either:
(1) alcohol information or (2) an AI-driving specific personalized feedback intervention. Participants
completed outcome measures at 3-month follow-up.
Results: Repeated measures mixed modeling analyses revealed that students receiving the Al-
driving intervention reported significantly greater reductions in the number of times driving after drink-
ing and the number of drinks consumed prior to driving than students in the information condition at
3-month follow-up.
Conclusions: The findings of this study provide preliminary support for the short-term efficacy of an
interactive text-message based intervention for reducing alcohol-impaired driving.
217
WHICH TEXT MESSAGE COMPONENTS ARE NECESSARY FOR DRINKING REDUCTIONS IN
YOUNG ADULTS?
B.P. Suffoletto, T. Chung, D. Clark
Department of Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
15221, USA
We sought to understand which components of a text message (TM)-based intervention are neces-
sary to reduce alcohol consumption in young adults. We enrolled 149 non-treatment seeking young
adults who screened positive for hazardous drinking in an urban emergency department. Following a
2-week TM assessment-only run-in, 125 subjects were randomized to 5 different 12-week TM Inter-
vention Arms: Assessment Control (AC); Drinking Cognition Feedback (DCF); Drinking Performance
Feedback (DPF); Adaptive Goal Support (AGS); and COMBO. All subjects received TM queries
3 days per week (based on typical drinking days) on drinking plans and desire to get drunk and fol-
lowing days on number of drinks consumed. AC received no feedback based on TM reports. DCF
received TM feedback on drinking plans and desire to get drunk. DPF received TM feedback on
number of drinks consumed. AGS received additional TM prompts and feedback related to drinking
limit goal commitment. COMBO received a combination of AC + DCF + DPF + AGS. Response
rates to TM were, on average, 66% for pre-drinking and 60% for post-drinking queries over
14 weeks, with significant declines in response rates over time. COMBO had lowest response rates
(60% pre & 54% post) whereas DPF had highest response rates (75% pre & 69% post). Qualitative
feedback indicated acceptability of TM interventions, with no significant differences between Arms.
Using TM data, controlling for covariates, odds of reporting a binge drinking episode and drinks con-
sumed on drinking days was lower in all Arms compared with AC. COMBO was the only Arm associ-
ated with lower ratings of desire to get drunk. Preliminary evidence suggests that non-treatment
seeking young adult hazardous drinkers find different features of TM interventions similarly accept-
able, with higher response burden producing lower engagement. A larger study is needed to validate
findings and explore heterogeneity of response.
325A
218
ONLINE INTERVENTIONS FOR NON-TREATMENT SEEKING YOUNG ADULTS:
INGREDIENTS FOR LOWERING MOTIVATION, ENGAGEMENT, AND EFFICACY
C. Neighbors, L.M. Rodriguez, M. Tomkins,L. Garey
University of Houston, 126 Heyne Building, Houston, TX 77204,USA
Brief personalized feedback interventions for non-treatment seeking young adults, especially college
students, have become increasingly delivered electronically. A large proportion of peer-reviewed
evaluations of these interventions suffer from at least two potentially confounding motivational factors
which may result in biases related to recruitment, retention, and intervention efficacy. Two specific
questions which have remained largely unaddressed include (1) whether the effectiveness of elec-
tronically delivered interventions depends on the location in which they are completed, and (2) what
is the optimal incentive structure to balance recruitment with motivational biases in intervention trials.
Some evidence indicates that remotely-delivered web-based personalized feedback interventions
are less effective than the same interventions completed in a lab setting or specific location associ-
ated with the study. However, the evidence is not conclusive because no study provides a direct
comparison between delivery methods based on random assignment within the same study. The
present research randomly assigned 498 heavy drinking college students to a 2 9 2 9 2 repeated
measures design. Conditions included in-lab PNF, remote PNF, in-lab attention control, or remote
attention control. Participants were also randomly assigned to receive no incentive ($0) or an incen-
tive ($30) for participation. Follow-up assessments occurred at 3-months and 6-months post-base-
line/intervention. Results provided overall support for PNF across conditions. Incentives were
associated with higher retention but also more drinking. Participants were initially more likely to par-
ticipate in remote conditions, especially when provided an incentive, but were more than twice as
likely to drop out after baseline. Participants were less likely to complete interventions in person but
this was not affected by incentives. Results provide theoretical and practical improvements to feed-
back-based intervention strategies.
219
ADAPATING TRANSDERMAL ALCOHOL MONITORING PROCEDURES FROM EVIDENTIARY
TO TREATMENT APPLICATIONS
C.W. Mathias, N. Hill-Kapturczak, T. Karns-Wright, J. Mullen, J.D. Roache, J.C. Fell, T.J. Moon,
D.M. Dougherty
Department of Psychiatry, The University of Texas Health Science Center at San Antonio, San
Antonio, TX, 78229, USA
Transdermal alcohol monitoring technology has been available for over 25 years and the largest
market for these devices has been for criminal justice application. Ankle bracelet transdermal alcohol
monitors are widely adopted in jurisdictions across the US and internationally for detecting heavy
alcohol use in violation of bond stipulation. However, forensic procedures for evidentiary applications
of this technology are not always suitable for use in therapeutic treatments contexts. This presenta-
tion describes translation and development of procedures for using transdermal alcohol monitoring
for clinical care of a criminal justice involved population: adults arrested for alcohol impaired driving.
Baseline data are described for 86 adults enrolled in an 8-week contingency management (CM) pro-
gram informed by transdermal alcohol monitoring. Under transdermal-informed CM conditions alco-
hol use occurred in about 25% of cases, monitor tamper were rare (1%), and treatment completion
was over 80%. Discussion focuses on considerations in adapting procedures for using transdermal
alcohol monitoring for treatment purposes. Considerations include: adapting cut-off levels for identi-
fying drinking events, procedures for rapidly processing the large quantity of data available from
transdermal alcohol monitoring, and provisions for instructing patients on how best to comply with
the monitoring treatment program. There will also be discussion of ethical considerations around: vol-
untary transdermal monitoring, confidentiality in the criminal justice context, and coercion protections
for criminal justice involved treatment seeking patients. Technological innovation opens new oppor-
tunities for use of transdermal alcohol monitoring to inform health care aimed at reducing alcohol
use. As these tools are applied to new treatment settings, continued work is required for establishing
procedures and best-practices around integration of transdermal alcohol monitoring into practice.
326A
TUESDAY, JUNE 19 3:10 PM–4:40 PM
SYMPOSIUM 220–223
Novel Players of Alcohol Mediated Inflammation and Organ Injury
Organizer/Chair: Pranoti Mandrekar
Organizer: Ashwani Singal
220
INTESTINAL INFLAMMATION AS TARGET FOR ALCOHOLIC LIVER DISEASE
B. Schnabl
Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
Alcoholic liver disease is associated with changes in the intestinal microbiota (dysbiosis) and
increased intestinal permeability. Dysbiosis-induced intestinal inflammation and TNF-receptor
(TNFR)1 signaling on intestinal epithelial cells are mediating a disruption of the intestinal barrier fol-
lowing chronic alcohol feeding. The mechanism by which microbiota results in intestinal inflammation
is not known. Using metagenomics and targeted metabolomics, we have recently demonstrated that
alcohol-associated dysbiosis leads to changes in intestinal bile acid profiles and lower farnesoid X
receptor (FXR) activity in the intestine of the host. To restore bile acid homeostasis, we used a phar-
macological intervention with the intestine-specific FXR agonist fexaramine, which is not absorbed
after oral gavage and does not show any systemic FXR stimulation. Fexaramine reduced intestinal
inflammation, restored gut barrier function and protected mice from liver disease following chronic
ethanol administration in mice. Our results suggest that alcohol-associated changes in bile acids are
mediating intestinal inflammation and increased intestinal permeability.
221
NADPH OXIDASES IN STELLATE CELL-MEDIATED ALCOHOLIC LIVER INJURY
€der1,2,3,
A. Dehnad1,2,3, J.X. Jiang1,2,3, S. Fish1,2,3, S. Das1,2,3, Y. Sasaki1,2,3, A. Sato1,2,3, K. Schro
€ ro
N.J. To €k1,2,3
1
Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA,
95817, USA, 2VA Northern California Health Care System, Mather, CA, 95655, USA and 3Wolfgang
Goethe University, Frankfurt am Main, Germany
Oxidative radicals play a key role in disease progression in alcoholic liver disease, and NADPH (ni-
cotine amide adenine dinucleotide reduced form) oxidases have emerged as major inducible
sources of superoxide and/or hydrogen peroxide. We show that of the seven NADPH oxidase
(NOX) homologues, the phagocytic NOX2 and the non-phagocytic NOX4 have important roles in
stellate cell activation to myofibroblasts the key producers of extracellular matrix. NOX2 and NOX4
were highly activated in patients with alcoholic liver disease and they colocalized with myofibroblasts.
NOX-mediated hydrogen peroxide production induced the transcriptional activity of the collagen I
promoter in primary stellate cells, and deposition of extracellular matrix, directly contributing to fibro-
sis. To study NOX4 induction, Chip assays were performed on the livers of EtOH and pair fed mice,
and revealed a significant activation of the NOX4 promoter by Smad3. In NOX4
/
mice on the EtOH
diet we observed improved redox stress, lipid peroxidation and TNFa converting enzyme activity. In
order to study NOX4 in stellate cells we generated HSCNOX4Ko mice, and these and fl/fl mice were
pair-fed by the NIAAA diet. Triglyceride content, lipid peroxidation and inflammatory markers have
significantly improved in HSCNOX4Ko mice. Furthermore, we observed decreased expression of colla-
gen 1(a)I, and CCR2/CCL2 had significantly reduced expression. NOX4 in stellate cells has signifi-
cantly increased the mRNA stability of CCR2 and its ligand CCL2 by modulating HuR
phosphorylation and nucleo-cytoplasmic shuttling. Taken together, NOX4 in stellate cells plays an
immunomodulatory role in early pre-fibrotic alcoholic injury by dysregulating CCR2/CCL2 cascades
whereas later it has a direct profibrogenic role by activating the collagen 1(a)I promoter. Thus reduc-
ing NOX4 activation could be an important therapeutic goal in alcoholic liver disease.
ABSTRACTS-SPEACKERS
222
ALCOHOL-INDUCED ADIPOSE TISSUE INFLAMMATION IS INDEPENDENT OF MYELOID
TOLL-LIKE RECEPTOR 4 EXPRESSION
M.A. Fulham, E.A. Kurt-Jones, P. Mandrekar
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
Alcoholic liver injury involves a combination of immune and metabolic pathogenic events. In addition
to liver injury, chronic alcohol consumption also causes adipose tissue inflammation. However, the
precise immune cells and cytokine profiles involved in alcohol-induced adipose tissue inflammation
are not yet clearly identified. Further, the specific immune mechanisms that drive this process are
unknown. In this study, we first sought to use flow cytometry to characterize the immune cells, mye-
loid and lymphoid, in the adipose tissue of alcohol-fed mice. Next we hypothesized that toll-like
receptor 4 (TLR4), an important driver of inflammation, is crucial in alcohol-induced adipose tissue
inflammation. To characterize the immune cells in the adipose tissue and determine the role of TLR4
we subjected C57BL/6J (WT), global/whole-body TLR4KO mice (TLR4KO), and myeloid-specific
TLR4KO (LysMCre+/
Tlr4f/f, M-TLR4KO) mice to a chronic, multiple-binge model of alcohol expo-
sure, modified from an early stage alcoholic steatohepatitis model, which has been recently reported.
Mice received the Lieber-DeCarli alcohol diet (5% v/v ethanol) for 10 days followed by alcohol gav-
age (5 g/kg alcohol) once a week for five subsequent weeks, followed by euthanasia 9 h after the
last gavage. Perigonadal adipose tissue, blood samples, and liver were collected. Adipose tissue
was minced and digested to collect the stromal vascular fraction (SVF), comprised of adipose
immune cells, endothelial cells, and pre-adipocytes, and subjected to flow cytometric analysis and
real-time PCR. Our results show that chronic-multiple binge alcohol increased accumulation of pro-
inflammatory adipose tissue macrophages (ATMs), neutrophils, dendritic cells, and B cells as well as
CD4+ T cells. On the other hand, the higher frequency of ATMs, dendritic cells, B cells and CD4+ T
cells was absent in alcohol-fed global-TLR4 knockout mice compared to their WT/littermate controls.
Interestingly, pro-inflammatory cytokine/chemokine expression in adipose SVF occurred indepen-
dently of global-TLR4 expression. Further, pro-inflammatory macrophage accumulation did not
depend on macrophage TLR4 expression; LysMCre-driven deletion of Tlr4 from myeloid cells did
not affect the accumulation of M1 macrophages in the adipose tissue following alcohol exposure.
Together, this data indicates that TLR4 expression on cells, other than classical myeloid cells, is
important for the alcohol-induced increase in pro-inflammatory adipose tissue macrophages and
cytokine production.
223
MIRNA REGULATION OF MACROPHAGE M1/M2 POLARIZATION OF KUPFFER CELLS AND
PBMCS IN ALCOHOLIC LIVER DISEASE
A. Kim, P. Saikia, M. McMullen,R. McCullough,L.E. Nagy
Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio, 44106, USA
Kupffer cells, the resident macrophage of livers, are critical to the progression of alcoholic liver dis-
ease (ALD). In response to chronic ethanol, they become sensitized to bacterial lipopolysaccharides
(LPS), express more pro-inflammatory cytokines and exhibit M1 polarization. We recently discov-
ered that 35kD hyaluronic acid (HA35) decreased sensitivity to LPS in Kupffer cells from chronic
ethanol-fed rats. Here we use miRNA sequencing to understand the regulation of M1 polarization
after chronic ethanol and a potential role for HA35 in promoting anti-inflammatory M2 polarization.
Method: Kupffer cells were isolated from male rats fed a Lieber-Decarli diet or pair-fed control diet.
Cells were cultured HA35 for 5 or 24 h and then challenged LPS for 1 h. Small RNAs were iso-
lated, libraries generated and sequenced using an Illumina HiSeq. We used Bowtie to align reads
and EdgeR to calculate differential expression. PBMCs were also isolated from AH patients with a
MELD score >20 and healthy controls then treated HA35 and LPS.
Results: Differential expression analyses revealed 105 misregulated miRNAs in Kupffer cells from
the chronic ethanol-fed rats compared to pair-fed (FDR<0.2). 39/105 miRNAs clustered in 9 distinct
regions of the genome. Each cluster contained at least 3 differentially expressed miRNAs, where 8/9
clusters had decreased expression in chronic ethanol. Three downregulated clusters contained miR-
NAs with known roles in M2 polarization, including miR125a, let-7c, miR221, and miR222. Treatment
with HA35 for 5 h lead to increased Arg-1 and decreased iNOS expression, indicating a potential
anti-inflammatory effect. This result was supported by decreased expression of CD86 (M1 marker)
and increased expression of CD206 (M2 marker) after 24 h of HA35 treatment. PBMCs from AH
patients, compared to healthy controls, were protected from LPS stimulation after pre-treatment with
HA35, associated with an increase in M2 markers.
Conclusion: Taken together, these data suggest that increased M1 polarization of Kupffer cells
after chronic ethanol is caused by global repression of miRNAs associated with M2 polarization.
HA35 decreased the pro-inflammatory effect of LPS and increased M2 polarization in both Kupffer
cells from ethanol-fed rats and PBMCs from AH patients. These data support HA35 as a potential
anti-inflammatory therapy in ALD.
ABSTRACTS-SPEACKERS 327A

TUESDAY, JUNE 19 3:10 PM–4:40 PM 226

Workshop 224–227
Workshop: Using Alcohol Biosensor Hardware and Software in Research: EXPERIENCES USING THREE TRANSDERMAL ALCOHOL BIOSENSORS FOR ALCOHOL
USE MONITORING AND INTERVENTION: BENEFITS AND LIMITATIONS
Options and Applications Y. Wang, E. Porges, R.F. Leeman, R.L. Cook
Organizer/Chair: Susan Luczak Department of Epidemiology, University of Florida, Gainesville, FL, 32610, USA
Organizer: Nancy Barnett
Transdermal alcohol biosensors can provide noninvasive, continuous monitoring of alcohol use by
detecting ethanol diffused through the skin. The SCRAM CAM anklet is the most widely used monitor
but mainly designed for law enforcement. The new wrist worn alcohol biosensors intended for com-
224 mercial use have the potential for wider application in research. However, there is no existing data
on these new devices. To address this gap, this presentation will (1) describe experiences of using
ALCOHOL BIOSENSORS: PRINCIPLES, APPLICATIONS AND DEVELOPMENT HISTORY three different transdermal alcohol biosensors (SCRAM CAM bracelet, Quantac wrist sensor, and
R.M. Swift BACtrack Skyn sensor) in research, (2) review their strengths and limitations with examples from our
Brown University Center for Alcohol and Addiction Studies and Providence VA Medical Center, studies, and (3) highlight needs for advancing this line of research. We are currently applying trans-
Providence, RI, USA dermal alcohol biosensors in three ongoing studies. In the first study, SCRAM ankle bracelet is used
for alcohol monitoring in a clinical trial that investigates the effects of experimentally-induced drinking
The accurate and reliable determination of alcohol consumption over long time periods is important
reduction on cognitive functions and clinical outcomes among persons living with HIV. Participants
for monitoring individuals in research studies, those undergoing alcoholism treatment and for foren-
are asked to wear the anklet for four weeks for continuous monitoring. The second study is a fixed-
sic monitoring. Common methods used to estimate alcohol consumption include self-report mea-
dose laboratory alcohol administration. Young adults are asked to wear a wrist biosensor (Quantac
sures (e.g. timeline follow back) and ecological momentary assessment and biochemical markers,
or Skyn) while they consumed two beers. The third study includes using ecological momentary
including liver function tests, carbohydrate deficient transferrin and ethyl glucuronide. Methods com-
assessment and alcohol biosensor (both SCRAM and wrist sensors or just wrist sensor) to measure
monly used to estimate current alcohol consumption include direct measurement of alcohol in
alcohol use among drinkers (HIV+ or
) for a 2-week period. Several benefits and limitations of each
venous blood, urine, saliva, expired air and perspiration. These current methods have limitations in
device emerged in terms of wearability/acceptability to participants, cost-efficiency, ease of operation
accuracy, reliability and burden and a specified time interval is typically represented by a single mea-
and maintenance by researchers, fail rates and influential factors, and data storage and access for
surement. In the past decade, advances in technology have led to the development of devices that
research. Briefly, the SCRAM bracelet has been extensively validated, but the major limitations
can passively detect and/or quantitate real-time alcohol use and then store or transmit alcohol data
include large size (5.8 oz), high cost (device + daily fee), social stigma (perceived as house
for later analysis. At the heart of these devices is a sensor that detects alcohol in body fluid or in air
arrested), large sample intervals (30 min), and no real-time data display. The wrist biosensors are
that is expired or perspired. The sensor must be sensitive enough to detect alcohol over the range of
smaller, more affordable, with minimized social stigma, sample up to every second, and use a smart-
physiological alcohol concentrations and must be highly specific for ethyl alcohol. Ideally, the sensor
phone App for real-time data display. Their limitations include relatively high fail rates in high humid-
has a response to alcohol that is linear. The devices also contain hardware and integrated software
ity, difficulty to pair with the App, requirement of some technology efficiency (in participants), and
to collect and to organize the sensor output over time, to store the data and to output the data either
relative fragility compared to SCRAM.
through a direct (e.g. USB) or remote (e.g. Bluetooth or Wi-Fi) connection. Finally, additional soft-
ware is used to convert the data to established measurement units (e.g. mg/dL), and to interpret the
data in tables, graphs and/or narrative. In this presentation, Dr. Swift will discuss how the clinical
pharmacology of alcohol in the body provides both opportunities and challenges for determining
alcohol consumption and blood alcohol concentration. He will discuss the history of alcohol measure-
ment, including the recent development of electrochemical and infrared based sensors and their
application to continuous, real-time remote alcohol measurement.
227
USING TRANSDERMAL TECHNOLOGY TO UNDERSTAND ALCOHOL-RELATED EMOTIONAL
REINFORCEMENT AMONG HEAVY DRINKERS IN EVERYDAY DRINKING CONTEXTS
C.E. Fairbairn
Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA

225 In the current project, we employed transdermal alcohol technology to assess effects of alcohol use
in everyday drinking contexts. Research indicates that differences in emotional reward from alcohol
A REVIEW OF ALCOHOL BIOSENSOR HARDWARE AND SOFTWARE AND THEIR USE IN can help explain vulnerability for Alcohol Use Disorder (AUD). Here, we examined the extent to which
ALCOHOL RESEARCH drinking in specific contexts might be associated with enhanced emotional reward from alcohol and
S.E. Luczak, N.P. Barnett, I.G. Rosen thus potentially confer risk for heavy drinking. Forty-eight heavy social drinkers engaged in a 7-day
Department of Psychology, University of Southern California, Los Angeles, CA 90089-1061, USA ambulatory assessment period during which they took photographs of their current contexts and fur-
ther self-reported on their mood in response to random prompts. Also during this period, participants
Recent advancements in alcohol biosensor development have produced novel tools for obtaining
wore the Secure Continuous Remote Alcohol Monitor (SCRAM) ankle bracelet to assess their drink-
real-time alcohol consumption data in the field. Here we review biosensor devices and software pro-
ing. The SCRAM was calibrated for each participant through breathalyzer readings taken within a
grams currently available or under development that are designed to record and consolidate real-
laboratory-based alcohol-administration session, and then translated into estimates of BrAC (eBrAC)
time alcohol data, and offer suggestions for researchers to consider when selecting devices and soft-
using BrAC Estimator Software. Our 7-day period of ambulatory assessment captured heavy levels
ware to best address their research needs. The most well-established biosensor device is the breath
of consumption, including binge drinking episodes for more than half of our participants (N = 25,
analyzer, which obtains the well-understood metric of breath alcohol concentration (BrAC). In addi-
52%) and extreme binge drinking episodes for a subset of participants (N = 8; 17%), and thus pro-
tion to medical grade devices traditionally used in research, there are now commercially available
vided a rich dataset within which to better understand the dynamic relationship between BAC and
breath analyzer devices geared toward lay users; with data storage via smartphone apps, these por-
mood. The relationship between continuous eBrAC and mood emerged as quite complex—we found
table devices become potentially useful research tools. To obtain drinking data in a manner requiring
significant quadratic (p’s < 0.04) and also cubic (p’s < 0.03) components to the relationship between
less participant burden, passive alcohol biosensors have been developed that only require partici-
eBrAC and both positive and negative mood, with the correlation between eBrAC and mood becom-
pants to wear them while drinking. Among these devices, the most well-developed have been those
ing significantly weaker as eBrACs increased. Furthermore, results revealed significant interactions
measuring transdermal alcohol concentration (TAC), the amount of alcohol diffusing through the
between alcohol consumption and context in predicting mood, with results indicating that the relation-
skin. A number of TAC devices have been available to researchers for over a decade, and others
ship between (transformed) eBrAC and mood was more pronounced when participants were drink-
are under development to be commercially available. Several other non-invasive methodologies
ing in the company of strangers (vs. familiar individuals), b =
0.002, SE = 0.001, p = 0.019. Our
including chemical, electronic, infrared, and photothermal devices are being investigated as possible
study included several measures intended to assess the validity of transdermal data, and we will dis-
real-time alcohol monitors, as well as microneedle technology, a more invasive technique to record
cuss our experience of both the strengths and also the weaknesses of current transdermal alcohol
alcohol concentration below the surface of the skin. As companies develop alcohol biosensor
technology and BAC conversion software. We will further discuss our own experience of the advan-
devices that are more reliable, precise, durable, inexpensive, and appealing to the wearer, the need
tages of transdermal measures specifically within investigations focusing on the relationship between
to consolidate large amounts of data and to adapt these data into meaningful metrics becomes criti-
psychosocial constructs and drinking behaviors.
cal. A number of physics-/physiological-based models, statistical algorithms, and integrative software
systems are being created to consolidate biosensor data (e.g., peak levels, duration of drinking,
absorption and elimination rates), and to convert TAC data into interpretable quantitative estimates
of BrAC/BAC. Some of these models are applicable to any biosensor device that measures alcohol
content in body-water on or in the body, thus broadening their utility to numerous hardware technolo-
gies. Researchers will need to weigh the costs and benefits of using each method to obtain data at
the required resolution to address their research questions.
328A ABSTRACTS-SPEACKERS

TUESDAY, JUNE 19 3:10 PM–4:40 PM 230

SYMPOSIUM 228–231
Making Go/No-Go Decisions About Novel Addiction Pharmacotherapies: EVALUATING MEDICATIONS FOR COCAINE OR METHAMPHETAMINE USE DISORDER IN
THE HUMAN LAB
Insightsfrom Human Laboratory Studies R. De La Garza, II
Organizers/Chairs: Lara Ray and Spencer Bujarski Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine,
Houston, TX 77030, USA

228
PREDICTIVE VALUE OF A HUMAN LABORATORY PARADIGM FOR SCREENING
MEDICATIONS TO TREAT ADOLESCENT ALCOHOL MISUSE
R. Miranda Jr., H. Treloar Padovano
Brown University Center for Alcohol and Addiction Studies, Providence, Rhode Island, 02912, USA
Adolescence is a key period for the pathogenesis of alcohol use disorder (AUD). Alcohol use typically
begins during the adolescent years, and prevalence rates for AUD peak before age 21 with nearly 1
million teenagers in the U.S. developing AUD each year. Yet, despite clinical demand, treatments for
youth rely on psychosocial interventions that yield only modest benefits. One potential way to
improve adolescent alcohol treatment is to augment the best available psychosocial interventions
with pharmacotherapy. At present, however, no medication is indicated for adolescents, and there is
strong evidence that the safety and efficacy of medications for adolescents cannot be inferred from
adult data. Thus, there is a clear need for screening tools for evaluating medications for AUD among
teenagers. This study leveraged a human laboratory paradigm to evaluate the viability of naltrexone
for treating adolescent problem drinkers. New data will be presented that directly tests whether
endophenotypes sampled among teenagers in the laboratory predict medication effects on drinking
outcomes in real-world settings. Specifically, we tested whether medication effects on cue reactivity
in the laboratory predict its effects on drinking in real-world settings. Participants were 22 teenager
problem drinkers, ages 15–19 years (M = 18.36, SD = 0.95, 12 females), randomized to naltrexone
(50 mg/day) and placebo in a double-blind cross-over study. Each arm lasted 10 days and included
an alcohol cue reactivity paradigm, where adolescents’ subjective and physiological reactivity to
alcohol cues was measured. Generalized estimating equations showed that naltrexone treatment
reduced percent drinking days in the natural environment (b =
6.96, SE = 3.44, p = 0.043) and
blunted cue-elicited craving in the laboratory (b =
0.15, SE = 0.05, p = 0.008). Moreover, cue-eli-
cited craving predicted percent drinking days (b = 21.47, SE = 8.66, p = 0.013). A formal test of
mediation suggested that naltrexone’s effects on drinking, in part, could be explained by how it
affected cue-elicited craving in the human laboratory (p = 0.071). These findings present the first evi-
dence that medication effects on cue reactivity among adolescents in human laboratory predict drink-
ing real-world outcomes, and support the utility of this paradigm for screening medications for
treating AUD among teenagers.
229
FROM THE LAB TO THE CLINIC: A NOVEL TRANSLATIONAL META-ANALYTIC APPROACH
TO ALCOHOLISM MEDICATION DEVELOPMENT
S. Bujarski, R. Green, D.J.O. Roche, L.A. Ray
Department of Psychology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
Our laboratory has evaluated dozens of compounds as potential treatments for cocaine- or metham-
phetamine-use disorder. In each instance, a randomized, double-blind, placebo-controlled trial is
conducted to evaluate the effects of a given medication on the effects produced by cocaine or
methamphetamine administered in the lab. The FDA is most interested in safety data derived from
these studies, including adverse events, and changes in cardiovascular outcomes (EKG, blood pres-
sure, heart rate). As addiction researchers, we are most interested in data from subjective effects
(e.g., self-report of “high”, “desire”, etc) and self-administration (number of choices for the drug).
Additional data routinely captured from our lab include computerized tests of cognitive function and
collection of blood for genetic testing. The majority of our published data show reductions in subjec-
tive effects by candidate medications, but we have seldom reported reductions in self-administration.
The primary reason for this disconnect is very likely the very short treatment regimen used in these
studies – specifically, taking a medicine for several days cannot be expected to change a recalcitrant
behavior (drug taking) that has been in place for 10–15 years. Specific data outputs from recently
completed studies will be discussed. In our view, a “go” decision for candidate medications can be
made on (1) A favorable side effect profile and (2) A significant reduction in key positive subjective
effects. A “no-go” decision should be made if either or both of the above are negative.
231
DEVELOPING MEDICATIONS FOR OPIOID USE DISORDER IN THE HUMAN LABORATORY
S.D. Comer, J.D. Jones, V. Metz, S. Mogali, J.M. Manubay
Department of Psychiatry, The New York State Psychiatric Institute, Columbia University, 1051
Riverside Drive, Unit 120 New York, NY 10032, USA
The United States is currently in the midst of an opioid crisis. Although several medications are cur-
rently approved for treating Opioid Use Disorder (OUD), rates of relapse to opioid use are high and
deaths due to opioid overdose continue to rise. Therefore, the continued search for new and
improved medications for treating OUD is important. Dr. Comer will discuss development of medica-
tions for treating OUD using a laboratory model of opioid self-administration and subjective
responses in human research volunteers. She will provide an overview of studies of approved treat-
ments for OUD, including buprenorphine, methadone, and naltrexone. For comparison, studies that
examined novel medications and/or mechanisms of action as potential targets for the treatment of
OUD, including N-methyl-D-aspartate, serotonin, and neurokinin antagonists, as well as inhibitors of
glial activation, will be discussed. The go/no go decision points for further development of each of
these medications will be described.

Human laboratory paradigms have been advanced as integral tools for the efficient development of
AUD pharmacotherapies. However, the concordance between human laboratory outcomes and clin-
ical efficacy has never been subject to rigorous quantitative analysis. Thus, at present it is not known
whether human laboratory paradigms actually predict treatment efficacy in randomized clinical trials
(RCTs), a necessary precursor for their wide-spread implementation as go/no-go decision-making
tools. To address this central question in medications development research, Dr. Bujarski will pre-
sent a novel translational meta-analytic approach to testing the predictive utility of human laboratory
research vis-a-vis clinical efficacy. Based on a Monte-Carlo simulations, statistical power for this
approach is high when effect size uncertainty is low (power ≥0.97) however as effect size uncertainty
increases power deteriorates. Proof-of-concept results will be presented testing whether medication
effects on subjective responses to alcohol in the human laboratory predict treatment efficacy in
RCTs. Human laboratory data were culled from 51 studies, including 24 medications and 1,862 total
subjects. RCT data were culled from 109 studies, including 17 medications and 20,567 total sub-
jects.
ABSTRACTS-SPEACKERS
TUESDAY, JUNE 19 3:10 PM–4:40 PM
SYMPOSIUM 232–235
Noradrenergic Mechanisms at the Intersection of Alcohol Dependence and
Stress
Organizers/Chairs: Florence Varodayan and Marisa Roberto
232
NORADRENERGIC REGULATION OF CENTRAL AMYGDALA GABA SYNAPSES IS ALTERED
BY ALCOHOL DEPENDENCE
F.P. Varodayan, R.R. Patel, S. Khom, M. Roberto
Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA
The locus coeruleus noradrenergic system is a major brain stress response system that innervates
several addiction-related brain regions, including the central nucleus of the amygdala (CeA). It is acti-
vated by arousal, stress and alcohol, and its dysfunction is implicated in anxiety, chronic stress, and
alcoholism. Both norepinephrine and its adrenergic receptors (a1, a2, and b) are abundantly
expressed in the CeA, a primarily GABAergic nucleus that acts as a hub for negative emotional
responses. Here we investigated whether alcohol dependence and withdrawal alter noradrenergic
regulation of CeA GABAergic synapses. Male Sprague Dawley rats were housed under control con-
ditions, subjected to chronic intermittent alcohol vapor exposure, or withdrawn from alcohol for two
weeks, and whole-cell voltage-clamp electrophysiology was performed in the medial CeA. We found
that norepinephrine increases GABA release in the CeA of na€ıve rats, but has mixed effects (in-
creases or decreases it) in alcohol-dependent animals. Norepinephrine’s dual effects stem from dif-
ferences in adrenergic receptor subtypes (a1 receptor activity increases GABA release and b
receptor activity decreases it). After two weeks withdrawal, norepinephrine consistently increases
CeA GABA release, as observed in na€ıve rats. These findings identify subtype-specific activation of
adrenergic receptors throughout the time course of alcohol dependence and highlight the importance
of the CeA noradrenergic system as a key site of dysregulation with chronic ethanol exposure. Sup-
ported by NIH/NIAAA K99 AA025408 (FPV), R01 AA015566 (MR), P60 AA006420 (MR), R37
AA017447 (MR), U01 AA013498 (MR), R01 AA021491 (MR).
233
NORADRENERGIC FUNCTION AFTER CHRONIC STRESS AND ETHANOL EXPOSURE
C.R. den Hartog, D.E. Moorman, E.M. Vazey
Department of Biology, University of Massachusetts Amherst, Amherst, MA, 01003, USA
Purpose: Stress is implicated in the transition to alcohol dependence, as well as in relapse following
abstinence. Chronic stress increases ethanol consumption in rodents with a history of ethanol
dependence. Identifying the neural circuits and behaviors disrupted by concomitant stress and etha-
nol may help identify new treatments for alcohol use disorders. Candidate circuits include those
within the locus coeruleus (LC) norepinephrine (NE) system, a stress sensitive nucleus that is dys-
regulated in addiction. Candidate behaviors include cognitive control and anxiety, both of which can
be influenced by LC-NE. The goal of these studies was to investigate the role of the LC-NE system
in cognition and anxiety after chronic stress and ethanol exposure.
Methods: Adult male and female C57BL/6J mice were trained to drink ethanol (15%, v/v, 1 h/day).
Mice were then exposed to weekly cycles of chronic intermittent ethanol (CIE) or air-control vapor
exposure (Air), followed by test cycles of 1 h/day ethanol drinking. Mice were split into non-stress
control (NS) or 10 min of forced swim stress (FSS) groups 4 h before each drinking test, resulting in
four experimental groups (Air/NS, CIE/NS, Air/FSS, and CIE/FSS). After stress and ethanol history
was established, all animals received cognitive testing using object/context recognition (OCR) and
tests for anxiety-like behavior using a marble burying test (MBT) with or without prazosin (0.75 mg/
kg). After behavioral testing we recorded single unit LC activity before and after alcohol administra-
tion.
Results: Combined stress and ethanol history disrupted cognition (disrupted OCR) and increased
anxiety (increased MB). Prazosin treatment impacted cognitive function in males but not females.
Prazosin decreased anxiety in animals with CIE/FSS history in both sexes. During in-vivo recording,
ethanol and stress history altered baseline activity and sensory responsiveness of LC neurons, with
a bias towards increased LC activity in alcohol and/or stress groups. Treatment with systemic alcohol
ameliorated some changes in LC activity.
Conclusions: Noradrenergic function is sensitive to stress and ethanol history, although impact
varies between males and females. Addressing LC-NE function, either through manipulation of LC-
NE neurons or pharmacological treatment at specific NE receptor targets, may be a future therapeu-
tic strategy for alcohol use disorders, particularly in cases of interactions between chronic stress and
alcohol use.
329A
234
EFFECTS OF NORADRENERGIC TARGETS ON ALCOHOL CRAVING, WITHDRAWAL,
NEURAL AND PERIPHERAL STRESS RESPONSES AND ALCOHOL TREATMENT
OUTCOMES
H.C. Fox1,2, S. Wemm1,2, V. Milivojevic1,2, G. Hermes1,2, R. Sinha1,2
1
Department of Psychiatry, School of Medicine, Yale University and 2Department of Psychiatry,
School of Medicine, Stonybrook University
Purpose: Chronic alcohol alters central norepinephrine and related stress biology to increase alco-
hol withdrawal, craving, loss of control drinking and relapse risk. We evaluated noradrenergic agents
that decrease norepinephrine centrally, Prazosin, an a1 antagonist, and Guanfacine, an a2 agonist,
for their effects on stress physiology, alcohol craving and withdrawal, cognitive function and alcohol
use outcomes.
Methods: In separate randomized, placebo controlled double blind laboratory studies we assessed
whether 3-week treatment of Prazosin (16 mg/day; N = 40) and also Guanfacine (3 mg/day;
N = 40) reversed chronic alcohol-related effects on stress, cognitive and alcohol craving responses.
With Prazosin, we also assessed alcohol withdrawal, craving and drinking outcomes over a 12-week
trial (N = 94). Finally, we assessed Prazosin/Placebo effects on fMRI stress circuits affected by
chronic alcohol abuse (N = 24).
Results: Findings show that Guanfacine decreases alcohol craving and improves cognitive flexibil-
ity in a sex-specific manner (p < 0.05), where effects are seen in only women. On the other hand,
we found Prazosin treatment reduced stress-induced craving in the laboratory and also weekly alco-
hol craving relative to placebo in the 12-week trial. Prazosin also improved stress-related HPA axis
and autonomic arousal and was beneficial in reducing alcohol withdrawal symptoms (p’s < 0.05).
Finally, Prazosin relative to placebo was effective in reducing drinks per drinking day and heavy
drinking during the 12-week trial in those reporting alcohol withdrawal symptoms at treatment entry
(p < 0.05). Finally, Prazosin treatment significantly improved neural responses to stress and cue-
induced craving and neutral state hyperactivity in key regions of the hypothalamus, amygdala/hip-
pocampal complex, dorsal striatum and ventromedial and dorsolateral prefrontal cortices (p < 0.01,
corrected).
Conclusions: These findings suggest further development of noradrenergic targets in the treat-
ment of AUDs, and especially for identifying subgroups who are most affected by such alcohol-
related stress pathophysiology and who can most benefit from noradrenergic treatments for AUDs.
235
ADMINISTRATION OF THE NORADRENERGIC-SELECTIVE ANTIDEPRESSANT REBOXETINE
ALONG ALCOHOL WITHDRAWAL INCREASES ALCOHOL SELF-ADMINISTRATION AFTER
RELAPSE
F.R. de Fonseca, J. Suarez, A. Ballesta, A. Serrano, M. Anton, R. Gomez, L. Orio, F. Alen
Unidad de Gestion Clinica de Salud Mental, Laboratorio de Medicina Regenerativa, Hospital
Regional Universitario de Malaga, 29010 Malaga, Spain
It has been described that selective serotonin reuptake inhibitors administered along alcohol with-
drawal increases net alcohol intake after relapse to alcohol self-administration in rodents. In the pre-
sent study we investigated whether this consequence of antidepressant treatment along alcohol
withdrawal occurs when the selective noradrenaline reuptake inhibitor Reboxetine (15 mg/kg i.p. for
14 days) is used. Reboxetine treatment along withdrawal in rats with a history of alcohol consump-
tion resulted in a clear escalation on alcohol self-administration after cessation of reboxetine treat-
ment and subsequent relapse to alcohol self-administration. However, when a dopamine uptake
inhibitor (Bupropion, 20 mg/kg for 14 days) was used, no effects on alcohol relapse were observed.
The effects of Reboxetine were associated with specific changes in endocannabinoid, PPARalfa and
glutamatergic signaling in the prefrontal Cortex, hippocampus and central amygdala. These results
stresses the importance of avoiding abrupt cessation of Serotonin/Noradrenalin antidepressant treat-
ment along alcohol withdrawal for avoiding a potential recrudescence of alcohol consumption after
relapse. They also suggests that the escalation of alcohol self-administration derived of antidepres-
sant treatment is associated to a dysregulation of endocannabinoid/glutamatergic signaling.
330A
TUESDAY, JUNE 19 3:10 PM–4:40 PM
SYMPOSIUM 236–239
Novel Mechanisms Regulating Alcohol Seeking and Relapse: The View from
Latin-America
Organizers/Chairs: C. Fernando Valenzuela and Ricardo Pautassi
236
FETAL PROGRAMMING OF HEIGHTENED ETHANOL PREFERENCE AND NEONATAL
BREATHING DISRUPTIONS: COMMON DENOMINATORS BASED ON ETHANOL-RELATED
LEARNING PROCESSES
1,2, G. D0 Aloisio1,2, F. Anunziata1,2, V. Trujillo1,2,
A.F. Macchione1,2, M.B. Acevedo1,2, S. Castello
J.C. Molina1,2
1
n Me
Instituto de Investigacio dica Mercedes y Martın Ferreyra, Friuli 2434, Co  rdoba-5016,
Argentina and 2Facultad de Psicologıa, Universidad Nacional de Co rdoba, Ciudad Universitaria,
Cordoba-5000, Argentina
Beyond the well known teratological effects of ethanol, preclinical studies have systematically
demonstrated that moderate ethanol doses recruit sensory and learning capabilities of the near term
fetus. When ethanol accumulates in the amniotic fluid, the unborn organism processes its
chemosensory cues. Familiarization with ethanol0 s sensory attributes results in later recognition and
acceptance of the odor and taste of the drug. This memory is modulated by different physiological
consequences of the state of intoxication. Relative to this issue, a series of studies have been con-
ducted in rats and humans. Preclinical approaches have dealt with functional learning capabilities of
the near term fetus and during neonatal life (stages that in terms of brain synaptogenesis are analo-
gous to the 2nd and 3rd human gestational trimesters; respectively). Brief experiences with moder-
ate ethanol doses (0.5–2.0 g/kg) were sufficient to sensitize the developing organism to ethanol0 s
reinforcing effects. The studies also demonstrated an early capability of associating ethanol0 s sen-
sory cues with the reinforcing effects of the drug. The associative memory enhances subsequent
ethanol drinking patterns and exacerbates operant-mediated ethanol seeking behaviors. The motiva-
tional effects of ethanol coexist with other physiological consequences of the state of intoxication;
particularly with a significant respiratory depression. Sequential exposure to the drug also sensitizes
the organism towards its disruptive effects upon respiratory neuroplasticity. In turn, the sensitization
process favors associative learning mechanisms that comprise the contingency existing between
chemosensory perception of ethanol and its depressant respiratory effects. Two additional studies
have been conducted in human neonates delivered by infrequent, moderate or frequent drinkers.
We employed the Neonatal Facial Coding System to evaluate facial expressions elicited by ethanol
odor or a novel scent (lemon). Babies prenatally exposed to the drug exhibited significantly higher
appetitive responses to ethanol odor when compared with babies delivered by infrequent drinkers. In
a second study, respiratory, cardiac and oxygen saturation parameters were assessed in babies
exposed to ethanol odor or lemon. Ethanol odor was found to significantly depress respiratory fre-
quencies in neonates delivered by frequent drinkers. These studies demonstrate that fetal ethanol
exposure recruits analogous non-associative (sensitization) and associative learning processes
related with the establishment of ethanol preferences and with physiological disruptions of the respi-
ratory system.
237
A PERSISTENT REDOX IMBALANCE UNDERLIES MALADAPTIVE BEHAVIOR IN
ADOLESCENT OFFSPRING EXPOSED PRE- AND POST-NATALLY TO ETHANOL
P. Haeger, M. Contreras, W. Plaza, S. Vargas-Roberts, E. de la Fuente-Ortega
Departamento de Ciencias Biome  dicas, Facultad de Medicina, Universidad Cato
lica Del Norte,
Coquimbo, 1781421, Chile
Ethanol intake during pregnancy may generate severe effects in the cognitive development of the
offspring. Prenatal ethanol exposure (PEE) in both human as well as animal models alters cognitive
behaviors including learning and memory, and also increases susceptibility to developing alcohol
and substance use disorders. Here, we tested the hypothesis that PEE induces a long-lasting
increase in oxidative stress in the brain that can be correlated with cognitive deficits. We also hypoth-
esized that antioxidant treatment would ameliorate PEE-induced cognitive deficits in adolescent rats.
We quantified the levels of antioxidant-enzyme mRNAs in mesocorticolimbic brain regions- pre-
frontal cortex (PFC), ventral tegmental area (VTA) and hippocampus (Hip)- and tested the particular
role NADPH oxidase 2 (NOX2) (postsynaptic superoxide generator) on impairment of hippocampal
long term plasticity (LTP) or spatial memory acquisition as well as in the increased ethanol seeking
behavior of rats developmentally-exposed to ethanol (during pregnancy and 7 days of nursing)
(DEE). We observed that DEE reduced mRNA levels for antioxidant-enzymes in PFC and Hip,
besides NOX2 in VTA during early adolescence (postnatal day 21). In contrast, during late adoles-
cence (postnatal day 70), reduced NOX2 mRNA levels are observed in PFC and Hip, and of antioxi-
dant-enzymes in VTA. Moreover, inhibition of NOX2, restored long-term potentiation in the CA1
hippocampal region and rescued spatial learning deficits in DEE rats. Finally, inhibition of NOX2 into
the VTA blocked alcohol-seeking behavior. We are currently performing studies to further character-
ize the specific mechanisms by which NOX2 is contributing to the memory impairments and vulnera-
bility to alcohol abuse in DEE rats. Funded by FONDECYT grant No 1140855.
ABSTRACTS-SPEACKERS
238
THE PRELIMBIC CORTEX NEURONAL ENSEMBLES ENCODE ASSOCIATIVE MEMORIES
BETWEEN ALCOHOL REWARDING EFFECTS AND CONTEXTUAL CUES
F.C. Cruz, P. Palombo, P.C. Bainchi, C.R. Zaneboni, S.A. Engi, P.E. Carneiro de Oliveira,
C.S. Planeta, R.M. Leao
Pharmacology Department, Sa ~o Paulo Federal University, Sao Paulo, Sao Paulo, 040023062,
Brazil
Environmental contexts previously associated with drug use provoke relapse to drug use in humans
and reinstatement of drug seeking in animal models of drug relapse. We examined, whether context-
induced reinstatement of alcohol seeking is mediated by activation of neuronal ensembles of the pre-
limbic cortex. We also evaluated changes in gene expression related to alcohol seeking. To assess
a causal role for the prelimbic neuronal ensembles in context-induced reinstatement of alcohol seek-
ing, we used the Daun02 procedure to selectively inactivate these neurons. We trained c-fos-lacZ
transgenic rats to self-administer alcohol in Context A and extinguished their lever-pressing in Con-
text B. On induction day, we exposed rats to either Context A or a novel Context C for 30 min and
injected Daun02 or vehicle into prelimbic cortex 60 min later. On test day, 3 d after induction day, the
ability of Context A to reinstate alcohol seeking was attenuated when Daun02 was previously
injected after exposure to Context A (active lever presses: 16.0  4.0 Vehicle drug context vs
4.0  2.0 Daun02 drug context; n = 6; p < 0.05). In addition, we assessed whether context-induced
reinstatement was associated with molecular alterations selectively induced within context-activated
Fos-expressing neurons. We used fluorescence-activated cell sorting to selectively-isolate reinstate-
ment-activated Fos-positive neurons and Fos-negative neurons in the prelimbic cortex and used
quantitative PCR to assess gene expression within these two populations of neurons. Context-
induced reinstatement was associated with increased expression of GABAa5 GABAA receptor sub-
unit mRNA (3.04  1.09 in Fos-positive, and 1  1.15 in Fos-negative; n = 4–6; p < 0.05) and a
decrease in GluA1 (0.16  0.65 and 1  0.33; respectively; n = 4–6; p < 0.05) and GluA2
(
0.3  1.41 and 0.99  0.89; respectively; n = 4–6; p < 0.05) AMPA receptor subunit mRNAs in
only Fos-positive neurons. Our results demonstrate an important role of the prelimbic cortex neu-
ronal ensembles in context-induced reinstatement of alcohol seeking and that this reinstatement is
associated with unique gene alterations in Fos-expressing neurons.
239
EXPRESSION OF ETHANOL SENSITIVE GLYCINE RECEPTORS IN SEVERAL BRAIN
REGIONS IN WILD TYPE AND ALPHA1 KI MICE
L.G. Aguayo1, S. Gallegos1, B. Mun~oz1, R. Viveros1, D.M. Lovinger2, G.E. Homanics3
1
University of Concepcion, Concepcion, Chile, 2National Institute on Alcohol Abuse and Alcoholism,
National Institutes of Health, Bethesda, MD, USA and 3University of Pittsburgh, Pittsburgh, PA
15261, USA
Synaptic glycine receptors (GlyR) are expressed primarily in spinal cord and brain stem neurons.
GlyRs are sensitive to general anesthetics, neurosteroids, Zn2+ and ethanol. Recently, GlyRs were
also found in other supratentorial regions, but their properties are largely unknown. Mesolimbic
regions, such as ventral tegmental area (VTA) and nucleus accumbens (nAc), were also found to
express GlyRs of a still unidentified molecular nature. This information is of interest because these
areas might be important for the rewarding effects of drugs of abuse. The aim of this work was to
identify the presence of GlyRs in regions of the reward system (prefrontal cortex, PFC, NAc and
VTA) and to characterize electrophysiological properties and sensitivity to ethanol in WT and KI mice
with ethanol insensitive alpha1 subunits. Using western blot, we detected the GlyR a1 subunit in
PFC, VTA and NAc in C57BL/6J mice. These results were corroborated with immunohistochemistry
studies in coronal brain slices containing the regions of interest from adult WT (C57BL/6J). Confocal
microscopy analysis suggests the presence of both synaptic and non-synaptic GlyRs in the three
areas. Recordings from acutely dissociated neurons showed that most neurons displayed a large
current (>500 pA at 1 mM of glycine). The currents had different sensitivities in the three cell types
examined. For instance, PFC had a glycine EC50 value of 130 mM while in NAc and VTA the values
were close to 40 mM. Interestingly in WT mice, glycine-induced current in VTA and NAc neurons
was potentiated by 50 mM ethanol whereas PFC neurons were insensitive. Glycine-induced cur-
rents in VTA and NAc neurons in alpha1 KI mice were not affected by ethanol supporting the idea
that these brain regions express a1 subunits. The results suggest that the receptor conformation and
sensitivity to glycine and ethanol are different in distinct brain areas. Supported by NIH U01
AA017875, RO1 AA025718 and Fondecyt DPI 20140008 grants
ABSTRACTS-SPEACKERS 331A

TUESDAY, JUNE 19 3:10 PM–4:40 PM 242

SYMPOSIUM 240–243
Explaining the Dynamics of Population Alcohol Use Over Long Time MODELING SOCIAL NETWORK SELECTION AND INFLUENCE MECHANISMS ON ALCOHOL
USE AT LARGE SCALE: AN EXPLORATORY AGENT-BASED MODEL
Horizonsusing Calibrated, Systems-Based Computer Modeling A.E. Nielsen, R.C. Purshouse
Organizer/Chair: Robin Purshouse Alcohol Research Group, Public Health Institute, Emeryville, CA 94608, USA
Organizers: William Kerr and Juergen Rehm
Purpose: Social contagion is a metaphor used to explain apparent transmission of behaviors
through populations, as individuals influence the beliefs and choices of their family members and
peers. Small empirical network studies show that individuals influence each others’ behaviors, but
240 that they also select peers that behave similarly to themselves. In this study, trends in larger, popula-
tion-level drinking behaviors for San Diego County from 1980 to the present are hypothesized to
A CONCEPTUAL FRAMEWORK FOR MODELING ALCOHOL USE DYNAMICS OVER arise due to influence mechanisms on peer and family networks and homophily on peer networks.
OPULATION HEALTH TIME HORIZONS Methods: An agent-based model was implemented in RepastHPC to simulate the apparent trans-
R.C. Purshouse, A. Nielsen, A. Brennan mission of alcohol use behaviors through social networks. The simulation was initialized with syn-
University of Sheffield, Department of Automatic Control and Systems Engineering, Sheffield, South thetic familial networks based on census data, and synthetic peer networks based on geographic
Yorkshire, S1 3JD, UK proximity and empirically derived network statistics. Demographic developments of the agent popu-
lation were modeled using a microsimulation of San Diego County. Individual agents develop pat-
Purpose: The development of a systems-based formulation of alcohol use requires the synthesis of a con-
terns of drinking through time as they are influenced by how their family and peers drink, and as they
stellation of determinants and mechanisms that have been developed from distinct disciplinary perspectives,
select peers based on shared drinking behaviors. The model was calibrated to reproduce drinking
including anthropology, sociology, economics, social psychology and neuroscience. A key challenge is how
trends in San Diego County, 1980–2000 using an Approximate Bayesian Computation framework.
these distinct perspectives can be brought together to form a coherent, unified systems perspective that can
The ability of the calibrated model to reproduce population trends to 2015 was also assessed.
form the basis for future quantitative policy analyses over preventative health time horizons.
Data: The agent-based model was parameterized using the 1980 US Census and cross-sectional
Methods: The mechanism-based approach of analytical sociology offers a potential solution to this
data from the National Alcohol Survey (NAS) from eight assessments between 1979 and 2012. Fer-
challenge by abstracting mechanisms from arbitrary disciplines into three different types: “action
tility, mortality and migration rates for the microsimulation were taken from the Statistical Abstract of
mechanisms” that explain behaviors based on observed or unobserved characteristics of individuals;
the United States. Network statistics were derived from The National Longitudinal Study of Adoles-
“transformational mechanisms” that explain how individual behaviors, in concert, act to change social
cent to Adult Health. The model calibration used population-level alcohol use data from NAS and
structures; and “situational mechanisms” that explain how individual characteristics are affected by
National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).
social structures. The process by which these abstract mechanisms interact can be represented con-
Results: The calibration process was able to identify model parameterizations that could reproduce
veniently using agent-based modeling methods and adapted to an alcohol systems context.
population-stratified trends in drinking behaviors to a good degree of approximation, but confidence
Data: A variety of existing, discipline-specific, mechanisms that are relevant to a systems-based for-
intervals for model fit were large, with similar results for the 2000–2015 model validation period.
mulation of alcohol use are extracted from the literature and set within the context of the analytical
Conclusions: Social influence and homophily can be useful in developing understanding on popu-
sociology framework. These include examples from role theory, theories of reasoned action, norma-
lation level trends in alcohol use over long time periods with large populations even in the absence of
tive theory, and social contagion theory. The success of any set of mechanisms is judged by their
fully described social network data.
ability to reproduce trends in drinking patterns (or associated alcohol-related harms) within a jurisdic-
tion over a defined period. In this example, data for San Diego County is extracted from census data
and repeated cross-sections of the National Alcohol Survey.
Results: Mechanisms from different disciplinary perspectives are successfully translated to the new
conceptual framework. Comparison results show the relative ability of the different sets of mecha-
nisms – realized as agent-based models – to reproduce trends in per capita alcohol consumption
and rates of heavy episodic drinking, given the available supporting data for San Diego County.
243
Conclusions: The conceptual framework, adapted from analytical sociology, is a useful unifying PLATFORM FOR CALIBRATED, SYSTEM-BASED MODELS OF ALCOHOL USE DYNAMICS
device for comparing different disciplinary perspectives on alcohol consumption. Further research is T. Broomhead, R. Purshouse, M. Strong, A. Brennan, W. Kerr, T. Greenfield, A. Nielsen, C. Probst
needed to enable the abstracted action, situational and transformational mechanisms to be inte- Department of Automatic Control and Systems Engineering, The University of Sheffield, Sheffield,
grated into a single systems-based model. South Yorkshire, S1 3JD, UK

Purpose: Quantitative realizations of systems-based formulations of alcohol use behaviors require

a computational platform. Such a platform has three main objectives: (1) simulate the system dynam-
ics, given a particular set of model equations and parameters; (2) calibrate the model to a particular
jurisdiction over a particular historical period, accounting for uncertainties in the evidence available
241 for that setting; (3) perform integrated calibration and simulation activities within reasonable
research timeframes. No such platform exists within the alcohol use field, although previous
CAN NORMATIVE MECHANISMS EXPLAIN THE CHANGES IN FEMALE DRINKING PATTERNS research efforts have produced a systems-based simulation platform (Holder and colleagues’ Sim-
OVER THE PAST DECADES? AN AGENT-BASED MODEL Com) and a calibration platform for social network data analysis (Snijders and colleagues’ Siena).
C. Probst SimCom is legacy software, whilst Siena is available and maintained. A new platform is needed that
Centre for Addiction and Mental Health, Institute for Mental Health Policy Research, Toronto will deliver all of the required objectives.
Ontario, M5S 2S1, Canada Methods: An individual-level model (or ‘microsimulation’) was designed to simulate core demo-
graphic dynamics of a population (births, deaths, and migration flows) and implemented in C++ using
Purpose: Alcohol use is one of the major risk factors for morbidity and mortality in the United States.
the RepastHPC agent-based modeling platform. Individuals in the microsimulation were cross-tabu-
Over the past decades, a convergence between male and female drinking patterns has been observed in
lated by sex, age and ethnicity – with parameters estimated using iterative proportional fitting. To deli-
the United States, with increases in alcohol use among women. The objective of the present study was to
ver objective 1, this microsimulation was extended with theory-specific mechanisms that relate
test the ability of social norms mechanisms to explain converging patterns of alcohol use between men
individual and environmental characteristics to alcohol use behaviors. To deliver objective 2, the
and women over the previous three decades using San Diego County as an example jurisdiction.
microsimulation was integrated with existing software for model calibration – the EasyABC package
Methods: An agent-based model was implemented in RepastHPC in order to simulate dynamic
for the R statistical system. EasyABC provides implementations of the Approximate Bayesian Com-
normative processes underlying drinking behavior over time. The model encompassed mechanisms
putation framework for model calibration, a state-of-the-art method for calibrating complex simulation
of descriptive as well as injunctive drinking norms and their impact on frequency and quantity of alco-
models.
hol use. Core demographic developments of the agent population were represented using a
Data: The microsimulation and theory-specific mechanisms were calibrated for the population of
microsimulation of the population of San Diego County. The model was calibrated to the population
San Diego County, 1980–2000 (with subsequent validation to 2015). Data were extracted from the
of San Diego County using data for the period 1980–2000 using the Approximate Bayesian Compu-
US Census and repeated cross-sections of the National Alcohol Survey.
tation framework. The ability of the calibrated model to reproduce population-level trends in alcohol
Results: The RepastHPC and EasyABC platform was able to satisfy the simulation and calibration
use was then tested over the period 2000–2015.
objectives needed to support systems-based alcohol use modeling. Execution times for a county-
Data: The agent-based model was parameterized using the 1980 US Census and cross-sectional
scale model were feasible, given the availability of dedicated high-performance computing
data from the National Alcohol Survey (NAS) from eight assessments between 1979 and 2012. Fer-
resources.
tility, mortality and migration rates for the microsimulation were taken from the Statistical Abstract of
Conclusions: The new computational platform for systems-based modeling delivers the core
the United States. The model calibration used population-level alcohol use data from NAS and
objectives needed for population health policy models at community-level. Further research is
National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).
needed to understand the scalability of the method to larger populations and more advanced sys-
Results: The model calibration process identified model parameterizations that were able to approxi-
tems-level calibration approaches.
mately reproduce trends in male and female population-level alcohol use estimates over the period 1980–
2000. Partial model validation was achieved for the period 2000–2015, but confidence intervals around
model estimates were wider than desirable for the model to be used for harm reduction purposes.
Conclusions: Normative processes around alcohol use likely contributed to the observed changes
in female drinking patterns. Future research should test the model in different jurisdictions and inte-
grate further mechanisms, for example relating to social roles, to improve the model’s ability to cap-
ture trends in population-level alcohol use with increased confidence.
332A
TUESDAY, JUNE 19 3:10 PM–4:40 PM
SYMPOSIUM 244–247
Advances in Clarifying Alcohol’s Role in HIV Acquisition in Sub-Sahara Africa
Organizer/Chair: Robert Freeman
Chair: Sarah Feldstein-Ewing
244
ALCOHOL USE AND OTHER PSYCHOSOCIAL CORRELATES OF SELF-REPORTED HIV
AMONG YOUTH LIVING IN THE SLUMS OF KAMPALA, UGANDA
M.H. Swahn,R. Culbreth,R. Kasirye,I. Obot,L.F. Salazar, N. Tumwesigye
School of Public Health, Georgia State University, Atlanta, Georgia, 30302, USA
Purpose: HIV rates are high in Uganda (6.7%) and of great concern, particularly in vulnerable youth
living in the Kampala slums. The purpose of this study was to assess the psychosocial correlates,
particularly alcohol use, associated with HIV among youth in the slums.
Methods: Analyses are based on cross-sectional survey data collected in 2014. Participants com-
prised a convenience sample (N = 1,134; ages 12–18 years) of urban service-seeking youth who par-
ticipated in one of five Uganda Youth Development Link drop-in center cross the Kampala slums (56.1%
female and 43.9% male). Logistic regression analyses were used to determine the association between
demographic characteristics, psychosocial covariates (i.e., alcohol use, gender-based violence, paren-
tal living status and depressive symptoms) and HIV. Chi-square tests were used to determine differ-
ences in alcohol use patterns between HIV-positive and HIV-negative youth. IRB approvals were
obtained from Georgia State University and the Uganda National Council for Science and Technology.
Results: Among youth who had ever had sex (n = 593), 49.8% (n = 292) of youth reported alcohol
use in the past 12 months and 13.8% (n = 81) reported being HIV-positive. Among youth living with
HIV, most were female (61.7%), reported alcohol use in the past 12 months (63.0%), had only one
parent living (44.4%), were 17–18 years of age (69.1%), experienced gender-based violence
(76.1%), and reported depressive symptoms (74.1%). In the multivariable model, HIV was associ-
ated with alcohol use (AOR: 1.84; 95% CI: 1.05, 3.20) and experiencing gender-based violence
(AOR: 2.64; 95% CI: 1.45, 4.79). A higher percentage of HIV-positive youth reported drinking 3 or
more drinks on a typical occasion (40.7%) compared to HIV-negative youth (18.8%) (v2 = 19.7,
df = 1, p < 0.001). Additionally, a higher percentage of HIV-positive youth reported having sex with
multiple partners while drinking alcohol during the past 12 months (35.8%) compared to HIV-nega-
tive youth (16.6%) (v2 = 16.5, df = 1, p < 0.001).
Conclusion: Sexually active youth living in the slums have a very high prevalence of HIV, which in
turn was associated with higher levels of alcohol use and gender-based violence. Prevention efforts
that seek to delay alcohol use among underage youth and that reduce risky alcohol use among drin-
kers are urgently needed to reduce HIV acquisition and transmission and other harm in these high-
risk communities.
245
SOCIAL DESIRABILITY AND REPORTED ALCOHOL USE AMONG PERSONS WITH HIV IN
UGANDA
J. Adong, R. Fatch, N.I. Emenyonu, D.M. Cheng, A. Kekibiiina, C. Ngabirano, W.R. Muyindike,
J.H. Samet, J.A. Hahn
Mbarara University of Science and Technology, Mbarara, Uganda University of California, San
Francisco, CA 94143, USA
Introduction: Self-report remains a widely used method for assessing and quantifying alcohol use,
albeit subject to social desirability (SD) bias. We explored the relationship between SD and self-
reported alcohol use, while controlling for phosphatidylethanol (PEth), an alcohol biomarker.
Methods: This cross-sectional study included HIV-infected patients attending a regional HIV Clinic
in Mbarara, Uganda. We assessed self-reported recent alcohol use (prior 3 months), the primary
outcome, using the AUDIT-C, and assessed SD using the Marlowe-Crowne Social Desirability Scale
Short Form C. We used multivariable logistic regression to assess the relationship between SD (low,
medium, and high, based on tertiles) and any reported recent alcohol use, among those who were
PEth-positive (≥8 ng/mL) – presumed current drinkers. In secondary analyses, we used multivariable
linear regression to assess the relationship between SD and continuous AUDIT-C score, among
those reporting any recent alcohol use. Models controlled for PEth level, age, sex, education, eco-
nomic assets, marital status, religion, spirituality/religiosity, and social support.
Results: Of 751 participants, 59% were female; the mean age was 33 years (Interquartile range
[IQR]: 26–39). Median SD score was 9 [range: 1–13; IQR: 4–10]. Two-thirds (62%) reported any
recent alcohol use and 57% were PEth-positive. Among those who were PEth-positive (n = 430),
13% (55/430) reported no recent alcohol use; in bivariate analysis, those with the highest SD tertile
had decreased odds of reporting recent alcohol. However, the association was not statistically signifi-
cant in adjusted analyses (adjusted odds ratios 0.72 (95% confidence interval (CI): 0.35, 1.48) and
0.55 (95% CI: 0.25, 1.23) for the medium and high SD tertiles compared to the lowest, respectively).
Among participants self-reporting any recent alcohol use, higher SD was associated with lower
AUDIT-C scores (adjusted b:
0.70 (95% CI:
1.19,
0.21) and
1.42 (95% CI:
2.05,
0.78) for
those with medium and high versus low SD tertiles, respectively).
Conclusion: Social desirability was not significantly associated with recent self-reported alcohol
use, but higher social desirability (SD) was associated with lower levels of self-reported alcohol use
among those reporting any use, even when adjusting for a biomarker of alcohol use. Methods are
needed to improve the accuracy of alcohol self-report, which might include use of sensitive biomark-
ers and SD measures.
ABSTRACTS-SPEACKERS
246
YOUNG MEN’S ATTITUDES ABOUT AN ALCOHOL SCREENING AND BRIEF INTERVENTION
DURING HIV POST-TEST COUNSELING IN THREE FISHING VILLAGES OF RAKAI, UGANDA
J.A. Wagman, E. Bonnevie, N. Nakyanjo, C. Breuer, C. Ssekyewa, W. Ddaaki, G. Kigozi
Rakai Health Sciences Program, Department of Medicine, Uganda Virus Research Institute Kalisizo,
University of California San Diego Rakai District, Uganda
Purpose: Uganda has one of the highest global rates of alcohol use. Men, especially adolescents
and young adults, drink more and at more hazardous levels than women, particularly in fishing areas.
Findings from 8 Ugandan fishing sites suggest 64% of HIV incidence is attributed to alcohol, implying
a need to integrate alcohol reduction approaches in HIV programs. Alcohol screening and brief inter-
ventions (SBI) have reduced alcohol risk in many health settings. There is limited knowledge, how-
ever, about SBI’s acceptability and impact in resource poor settings. This study aimed to assess
young men’s attitudes about alcohol and willingness to participate in an HIV counseling-based alco-
hol SBI in fishing areas.
Methods: Twelve (12) in-depth interviews and 3 focus groups were conducted (Oct 2016–Jan
2017) with men 15 to 24 years in 3 fishing villages in Rakai, Uganda. Participants described trends
and reasons for drinking, and perceived barriers and facilitators to participating in an alcohol SBI
delivered during HIV counseling.
Results: Of the 39 participants, most did fishing work or casual labor for pay (in addition to or
instead of school); 8% were HIV-positive. Participants drank frequently, regularly and in large quanti-
ties. They recognized their use as “excessive” and potentially problematic, but believed many factors
explained their behaviors. Most felt free to drink because they were young and unburdened by fami-
lies/relationships; and had money so felt entitled to spend it. Many suggested alcohol helped cope
with stress and hardship of working long hours, often alone in harsh weather. Further, a prevailing
“life is short” attitude was voiced. Many narrated how early death (from HIV/AIDS or drowning) was
imminent. Other than time constraints, men felt an alcohol SBI during HIV post-test counseling was
acceptable. There was skepticism, however, that it would change behavior as alcohol use is deeply
engrained. While most had no idea what moderate or hazardous drinking was, the majority would try
an SBI to see if it helped them become more healthy/strong or “respectable.”
Conclusion: Integrating alcohol SBIs into HIV counseling procedures could be a feasible, accept-
able and cost-effective approach for reducing hazardous alcohol use and HIV incidence among
young men in Uganda’s fishing communities.
247
USING PARTICIPATORY METHODOLOGIES TO UNDERSTAND ADOLESCENTS
EXPERIENCES WITH ALCOHOL AND SEX IN URBAN TANZANIA
M.S. Sommer1,2, M. Ibitoye1,2, S. Likindikoki1,2, S. Kaaya1,2, R. Parker1,2
1
Mailman School of Public Health, Columbia University, New York, New York 10032, USA and
2
Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania
Purpose: This study used a methodological toolkit aimed at gaining an in-depth understanding of
urban Tanzanian adolescent girls’ and boys’ experiences and perspectives on alcohol use within
their local environments, their gendered patterns of use, and related sexual behaviors. The aim was
to contribute to filling the gap in the evidence on young people’s alcohol use and unsafe sexual
behaviors in sub-Saharan Africa, including the ways in which their social and physical environments
influence alcohol uptake and use, and increase their vulnerability to HIV. Conducting research with
adolescents on sensitive topics, such as alcohol use and risky sexual behaviors, presents method-
ological challenges. A key one is the ability to capture valid descriptions of self-reported behaviors
around their own and their peers drinking behaviors, and subsequent engagement in sex. Using par-
ticipatory methodologies can encourage honesty and demonstrate respect for young people’s own
abilities to identify solutions to the challenges they face.
Methods: The 2-year qualitative research study combined multiple methodologies, including partici-
patory methodologies with young people (aged 15–19) in diverse sites across urban Tanzania. We
conducted key informant interviews with policy makers and adolescent health experts, in-depth inter-
views with adults and adolescents, and systematic mapping around secondary schools and youth
centers of alcohol availability and advertising. A range of participatory methods were conducted with
groups of in and out of school youth.
Results: The various participatory methodologies utilized, such as stories youth wrote detailing their
experiences with alcohol and with sex, revealed the intensity of alcohol’s presence in youth’s lives,
occasions of violence in relation to sex, peer pressure dynamics around alcohol use at ceremonies,
interpersonal aspects of evolving relationships that include discordant feelings about sexual engage-
ment, and alcohol’s role in increasing unsafe sex. Such findings go beyond with might emerge
through the use of traditional qualitative methods, and provide critical insights into the realities of
youth’s individual perspectives but also the social and structural influences shaping their beliefs and
behaviors.
Conclusion: The application of participatory methodologies identified the social and physical fac-
tors impacting youth alcohol uptake and use, along with recommendations for structural interventions
to prevent or reduce youth consumption and related unsafe sexual behaviors, and reduce vulnerabil-
ity to HIV.
ABSTRACTS-SPEACKERS 333A

WEDNESDAY, JUNE 20 9:15 AM–10:45 AM 250

SYMPOSIUM 248–251
Brain Reward and Brain Stress System Cross-Talk in Alcohol Addiction ALCOHOL DEPENDENCE IMPACTS MIDBRAIN PROJECTIONS TO CENTRAL AMYGDALA
E.M. Avegno, L.K. Kelley, T.D. Lobell, J.W. Middleton, N.W. Gilpin
Organizer/Chair: Nicholas Gilpin Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA
70112, USA

248 The neural adaptations that define excessive alcohol drinking in alcohol-dependent individuals may
include interactions between mesolimbic reward circuits and brain stress circuits. Here, we focused
CENTRAL AMYGDALA CORTICOTROPIN RELEASING FACTOR NEURONS ENCODE AND on dopaminergic and non-dopaminergic projections from the ventral tegmental area (VTA) to the
MODULATE BINGE DRINKING central nucleus of the amygdala (CeA), regions important for mediating acute alcohol reinforcement
J. Irving, S. Aroni, D.R. Sparta and dependence-induced escalation of alcohol drinking, respectively. Our overarching hypotheses
Department of Anatomy and Neurobiology, School of Medicine, University of Maryland, Baltimore, are that (1) chronic alcohol produces neuroadaptations in VTA dopamine neurons projecting to the
MD 21201, USA CeA, and (2) these adaptations are critical for escalation of alcohol drinking in alcohol-dependent ani-
mals. Little is known about the VTA-CeA circuit, even under basal conditions; therefore, we com-
Alcohol misuse costs the United States more than $200 billion every year, with excessive alcohol bined retrograde tracing and immunohistochemical experiments in rats to demonstrate that the CeA
consumption accounting for three-quarters of this cost. Binge alcohol drinking is a severe public receives both dopaminergic and non-dopaminergic projection neurons from VTA and the neighbor-
health problem and has been shown to cause progressive neuroplastic alterations in numerous brain ing substantia nigra (SN). We then used slice electrophysiology and cFos immunohistochemistry to
regions. Although the extended amygdala mediates binge drinking, the study of selective circuit test the effects of alcohol dependence on activity and activation profiles of CeA-projecting neurons in
mechanisms within this region are poorly understood. Corticotropin releasing factor (CRF) neurons VTA and SN; this work revealed distinct effects of alcohol dependence on TH+ and TH
neurons
in the central amygdala (CeA) have been shown to affect binge drinking through pharmacological projecting to CeA from VTA and SN. Our data indicate that alcohol dependence perturbs midbrain
methods, although their precise circuit mechanisms remain unclear. To close this knowledge gap, projections to the amygdala, raising the possibility that this circuit is involved in mediating behaviors
we examined the role of CeA CRF neurons and their projection to the ventral tegmental area (VTA) (e.g., escalated alcohol drinking) associated with alcohol dependence. These studies were sup-
on binge drinking. In our first set of experiments, we combined optogenetics with in vivo electrophysi- ported by NIH grants R01 AA023305, R01 AA026531, T32 AA007577, and F32 AA025831.
ology to identify and record from CeA CRF neurons in mice during a repeated binge drinking task.
We observed that CeA CRF neurons displayed a heterogeneous spike profile in response to a lick of
ethanol. Next, we found that pharmacogenetic inhibition of CeA CRF neurons decreased binge
drinking. In another set of studies, we found that repeated optogenetic stimulation of CeA CRF neu-
rons did not alter binge drinking. However, it did increase binge drinking during context reinstatement
sessions. In our last series of experiments, we examined the role of the CRF CeA to VTA circuit on 251
binge drinking. Using, ex vivo electrophysiology, we observed that CeA CRF neurons form functional
KETAMINE INOCULATION REGULATES EXCITATORY DRIVE IN THE BNST AND PREVENTS
synapses on VTA GABA neurons. Finally, we found that optical stimulation of this pathway increased
THE MANIFESTATION OF AFFECTIVE DISTURBANCES DURING ETHANOL FORCED
binge drinking, whereas pharmacogenetic inhibition resulted in a decrease. These data indicate that
ABSTINENCE
CeA CRF neurons play a complex and critical role in binge ethanol drinking. Additionally, the CRF
D.G. Winder, G. Winkler, O. Vranjkovic, S. Centanni
CeA-VTA projection may be necessary for the manifestation of this behavior. Thus, taken together,
Vanderbilt Center for Addiction Research Vanderbilt School of Medicine Nashville, TN 37232
these data indicate a novel circuit that could be a potential target for the treatment of alcohol use dis-
order. Alcohol use disorders (AUDs) are strongly comorbid with depression, and alcohol withdrawal is asso-
ciated with the manifestation of affective disturbances. The interaction between AUDs and depres-
sion represents an understudied area of research that could yield therapeutics aimed at treating
alcohol abstinence-induced affective behaviors. Using a two-bottle choice mouse model of chronic
ethanol drinking followed by forced abstinence (CDFA), we assessed the development of depres-
249 sive-like phenotypes and alterations in extended amygdala circuit function in C57Bl/6J mice. We
observed a time-dependent development of depressive-like behaviors that was associated with an
CORTICOTROPHIN RELEASING FACTOR ALTERS KAPPA OPIOID RECEPTOR FUNCTION IN increase in excitatory drive onto BNST CRF neurons and neuronal activation in the BNST and insula.
A SUBSET OF DOPAMINE NEURONS IN THE VENTRAL TEGMENTAL AREA We previously demonstrated that the NMDA receptor antagonist ketamine could acutely reverse
E.B. Margolis depressive-like behavior if administered immediately prior to testing. Here we found that ketamine
Department of Neurology, UCSF, San Francisco, CA, 94143, USA administered at the onset of forced abstinence, but curiously not at intermediate time points closer to
the behavioral testing day, prevented the development of both early anxiety-like and later depres-
Stress can activate neural circuits associated with fear, anxiety, attention, motivation, and memory, sive-like behavior. Moreover, we found that ketamine administered at the onset of forced abstinence
and lead to relapse to alcohol seeking. Depending on the degree or type, stress can be associated substantially augmented the potential for plasticity at excitatory synapses in the BNST. Collectively,
with either rewarding or aversive outcomes. During stress, corticotrophin releasing factor (CRF) is these data suggest a critical period for interventions during the initial phases of forced abstinence
released into the ventral tegmental area (VTA; Wang et al., 2005), increasing dopamine release in that have implications for therapeutic strategies. Moreover, as the extended amygdala is a key inte-
VTA terminal regions including the nucleus accumbens (NAc; Holly et al., 2015). CRF also leads to grator of stress information that regulates motivated behavior through outputs to mesolimbic, striatal
kappa opioid receptor (KOR) activation in brain areas involved in stress, resulting in conditioned and hypothalamic systems, these data suggest the possibility that the alterations in excitatory signal-
place aversion (Land et al. 2008; Bruchas et al. 2009). Understanding the interaction of CRF and the ing observed could drive altered alcohol seeking behavior.
KOR system may help dissociate the deleterious aspects of stress from those that promote positive
adaptation. We previously showed that the KOR agonist U69593 hyperpolarizes VTA dopamine
neurons. Furthermore, this effect was seen in neurons that project to the amygdala or prefrontal cor-
tex but not to the NAc (Margolis et al., 2006, 2008). Here we used whole cell ex vivo electrophysiol-
ogy to examine CRF modulation of U69593 responses in VTA neurons. In current clamp (I = 0 pA),
baseline U69593 (1 lM) responses were measured, then CRF was bath applied for 5–7 min and
washed out for at least 5 min before a second U69593 application. Surprisingly, 8/19 neurons that
showed initial U69593 hyperpolarizations later showed U69593 induced depolarizations following
CRF application. This switch in signaling did not correlate with the neural response to CRF. Excita-
tions were also independent of the magnitude of the U69593 response prior to CRF application. In a
second set of recordings, where neurons were not selected based on their initial sensitivity to
U69593, 8/28 neurons were excited by U69593 after CRF exposure and 12/28 were inhibited. We
are currently investigating if in vivo stress is sufficient to drive the same change in KOR signaling,
and the signaling pathways responsible for this change in signaling. In summary, CRF exposure
robustly altered KOR induced signaling in a subset of VTA neurons, causing a switch from inhibition
to excitation. These results provide insight into how stress may profoundly alter neuronal responses
to KOR activation in mesolimbic neurons, including during stress induced relapse to alcohol con-
sumption.
334A
WEDNESDAY, JUNE 20 9:15 AM–10:45 AM
SYMPOSIUM 252–255
Astrocytes & Alcohol: Beyond Neuroinflammation
Organizer/Chair: Marina Guizzetti
Chair: Mary-Louise Risher
252
STRITAL ADENOSINE SIGNALING AND NEURON-ASTROCYTE INTERACTION IN ALCOHOL
USE DISORDER
S.I. Hong, P. Starski, S. Choi, A. Oliversos, D.S. Choi
Mayo Clinic College of Medicine, Department of Molecular Pharmacology and Experimental
Therapeutics, Rochester, Minnesota, 55905, USA
Adenosine as an inhibitory neurotransmitter attenuates neuronal activity through receptor-mediated
signaling in the brain. Equilibrative nucleoside transporter 1 (ENT1) is an ethanol-sensitive adeno-
sine transporter and regulates adenosine levels. Mice lacking ENT1 displayed elevated ethanol
drinking with decreased ethanol sensitivity. Previously, we demonstrated that ENT1 deficiency
dampens astrocyte function, which decreases adenosine A2A receptor (A2AR) function in the dorso-
medial striatal (DMS) and increases ethanol-seeking goal-directed behavior in random ratio (RR)
paradigm of the nose-poke operant chamber. However, the precise role of striatal astrocyte and ade-
nosine signaling depending on behavioral contexts remains to be examined. Our findings show that
ENT1 ablation dampens glial fibrillary acidic protein (GFAP; astrocyte marker) and aldehyde dehy-
drogenase 1 family member A1 (ALDH1A1; dopaminergic axon terminal marker) in the striatum of
na€ıve mice. Mice with increased goals toward alcohol displayed the reduction of GFAP, aquaporin-4
(AQP4), and c-Fos levels in the DMS. Next, using dopamine receptor D2 (D2R) promoter-driven
ENT1 overexpression virus, we investigated whether adenosine dynamics in D2R-expressing med-
ium spiny neurons (D2-MSNs) of the striatum contribute to alcohol goal-directed behaviors. Viral
D2R promoter-inducible ENT1 increases astrocytic glutamate transporter (GLT1) and A2AR mRNA
levels in the DMS. In contrast to our initial hypothesis, ENT1 overexpression in the DMS D2R-
expressing cells promotes alcohol-seeking behaviors and goal-directed behaviors. Viral-mediated
DMS ENT1 overexpression increases ALDH1A1 and adenosine receptors in the DMS and dorsolat-
eral striatum (DLS) but not GFAP and glutamate decarboxylase-65 (GAD65; GABAergic neuronal
marker) after expression of ethanol goal-directed behaviors. Interestingly, DMS/DLS ALDH1A1 and
DMS A1R have correlations with the expression of goal-directed behaviors, while DLS A2AR corre-
lates with not goal-oriented behaviors but ethanol-seeking behaviors. Taken together, our results
demonstrate that striatal ENT1-regulated adenosine signaling plays an essential role in goal-directed
and alcohol-seeking behaviors through for neuron-astrocyte interaction.
253
ADOLESCENT INTERMITTENT ETHANOL EXPOSURE: ELUCIDATING THE ROLE OF
ASTROCYTES IN THE MODULATION OF NEURONAL FUNCTION
M.-L. Risher1,2, Q. Li1,2, R.C. Klein1,2, H.G. Sexton1,2, C.E. Eroglu1,2, S.D. Moore1,2
1 life. Neuronal plasticity and connectivity are affected by in utero alcohol exposure and may play a
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC,
27710, USA and 2Neurobiology Research Laboratory, Durham VA Medical Center, Durham, NC,
27705, USA
Astrocytes, the major glial cells in the brain, play an essential role in establishing and maintaining
neuronal connectivity throughout development and into adulthood. The ability of astrocytes to
ensheathe synapses and associate with multiple neurons places them in the ideal position to tightly
regulate the initiation, formation, maturation, and maintenance of neuronal synapses throughout life.
When astrocyte signaling goes awry, dysregulated synaptogenesis can occur resulting in neuronal
circuit remodeling. These regulatory processes occur through the secretion of a variety of astrocyte
signaling factors and contact-mediated signals. Despite significantly increased awareness in the last
decade of the role of astrocytes in synaptic function, dysfunction and formation, much less is known
about how acute and long-term ethanol exposure influences these non-neuronal cells. In addressing
this question, we use a rat model of adolescent intermittent ethanol (AIE) exposure (5 g/kg ethanol
(i.g.) 10 times across 14 days beginning PND30) to investigate the impact of astrocytes on post-
binge neuronal structure and function. Using astrocyte-related RNAseq gene expression, immuno-
histochemistry, and morphological data collected from hippocampal tissue, we demonstrate that AIE
alters astrocyte capacity to regulate glutamate uptake through acute dysregulation of astrocyte gluta-
mate transporter GLT1 and through protracted disruption of glutamine synthetase expression. We
hypothesize that the inability of astrocytes to effectively regulate glutamate contributes to astroglial
reactivity and release of extracellular matrix proteins involved in neuronal and synaptic remodeling
events.
ABSTRACTS-SPEACKERS
254
ASTROCYTE-MEDIATED CONTROL OF NEURON REDOX HOMEOSTASIS: A HIGHLY
EVOLVED MECHANISM OF NEUROPROTECTION AGAINST ALCOHOL AND OTHER
PROOXIDANTS
G. Henderson, M. Narasimhan, M. Rathinam, D. Patel, L. Mahimainathan
Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center,
Lubbock, TX, 79430, USA
Ethanol (E) is a teratogen that elicits damage to the developing brain via disruption of redox circuits
which are maintained by thiol disulfide couples including GSH/GSSG and Cys/CYSS. This, com-
bined with damage to cellular macromolecules is a refined definition of “oxidative stress” and has
been termed the redox hypothesis of teratogenesis. Astrocytes (Ast) play a central role in maintain-
ing neuron redox homeostasis (RH), however mature Ast are not apparent in the developing brain
until the third trimester, likely in preparation for the immature brain entering the higher oxygen post-
birth environment. Ast have evolved highly effective mechanisms to maintain neuron RH which can
strikingly prevent E-mediated neuron apoptotic death. Our laboratory has focused on mechanisms
underlying neuronal RH control both in the individual neuron and in the presence of Ast, the former
modeling E exposure during the second trimester and the latter modeling the third trimester and
thereafter. Ast-related regulation of neuron RH in response to oxidative stressors such as E, can be
tightly connected to regulation of neuron GSH homeostasis. In studies, E reduced cultured fetal corti-
cal neuron (PCN) and cerebral cortical GSH (binge model) and cysteine (cys) up to 50%. The
reduced GSH could be blocked by administration of N-acetylcysteine. This prevented E-related
apoptotic death of PCN. Co-culture with Ast also prevented the E-related decrease in GSH and strik-
ingly reduced toxic responses to E, including apoptotic death. This is due in large part to Ast contribu-
tion to the gamma-glutamyl cycle supplying GSH synthesis precursors to neurons combined with
neuronal regulation of the rate-limiting availability of cys. In the immature neuron, cys availability is
maintained by inward cys transport via the excitatory amino acid transporter (EAAT3/EAAC1) and its
synthesis by the transsulfuration pathway. Both of these systems are negatively impacted by E
in vivo (fetal brain in utero) and in PCN. A central player in these homeostasis systems is the tran-
scription factor Nrf2 which functions as a redox switch in both cell types, but much more robustly in
Ast. In summary, the presented studies demonstrate the neuroprotective role of Ast-mediated main-
tenance of neuron redox homeostasis via supply of GSH precursors to preserve GSH homeostasis
in the presence of E.
255
THE REMODELING OF ASTROCYTE EXTRACELLULAR MATRIX BY ETHANOL DURING
BRAIN DEVELOPMENT
M. Guizzetti, J.G. Hashimoto, C.J. Wilhelm, M.L. Roberts, C.M. Goeke, S.H. Bloom
Oregon Health & Science University and VA Portland Health Care System Portland, OR 97239,
USA
In utero alcohol exposure can cause fetal alcohol spectrum disorders (FASD), characterized by
structural brain abnormalities and behavioral and cognitive dysfunction that affect FASD individuals
throughout life. The vast majority of individuals with FASD develop mental health problems later in
major role in the cognitive and behavioral dysfunction in FASD. Neuronal plasticity in the developing
brain can be modulated by extracellular proteolysis. Plasmin is a major extracellular serine-protease
whose activation from its zymogen plasminogen is tightly regulated by the plasminogen activator
(PA) system. Major targets of plasmin proteolytic activity are extracellular matrix (ECM) proteins,
such as laminin and fibronectin, which are involved in neuronal development and plasticity. We
explored the effect of ethanol on the expression of the main components of the brain PA system in
sex-specific cortical astrocyte primary cultures in vitro and in the cortex and hippocampus of PD 9
male and female rats. We find that ethanol alters the PA system in astrocytes and in the developing
brain. In particular, the expression of tissue-type PA (tPA), encoded by the gene Plat, is consistently
upregulated by ethanol in astrocytes in vitro and in the cortex and hippocampus in vivo. Astrocytes
exhibit endogenous plasmin activity that is increased by ethanol and recombinant tPA and inhibited
by tPA silencing. We also find that tPA is expressed by astrocytes of the developing cortex and hip-
pocampus in vivo. All components of the PA system investigated, with the exception of Neuroserpin/
Serpini1, are expressed at higher levels in astrocyte cultures than in the developing brain, suggesting
that astrocyte PA system plays a major role in the modulation of the brain extracellular matrix and
neuronal plasticity. Changes in plasmin extracellular proteolysis in astrocytes due to changes in the
expression of components of the PA system may be therefore responsible for altered plasticity after
developmental ethanol exposure. In conclusion, ethanol-induced upregulation of tPA levels and plas-
min activity in astrocytes may be partially responsible for altered neuronal plasticity in FASD. This
work was supported by VA Merit Review Award # I01BX001819 and by NIH/NIAAA R01AA021468
and R01AA022948.
ABSTRACTS-SPEACKERS 335A

WEDNESDAY, JUNE 20 9:15 AM–10:45 AM 258

SYMPOSIUM 256–259
Engineered Biomimetic Models for Studying Mechanisms of Alcohol-Induced RAPID 3D BIOPRINTING: AN ENABLING PLATFORM FOR MICROPHYSIOLOGICAL SYSTEMS
S. Chen
Tissue Injury Department of NanoEngineering, University of California, San Diego, 9500 Gilman Drive, La Jolla
Organizers/Chairs: Srivatsan Kidambi and Rajanikanth Vadigepalli CA, 92093, USA

256
DISEASE IN A DISH: ENGINEERING TISSUE MICROENVIRONMENT TO RECREATE
SNAPSHOT OF DISEASE PROGRESSION
S. Kidambi
Chemical Engineering, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA
Engineering in vitro models that reproduce tissue microenvironment and mimic functions and
responses of tissues that is more physiologically relevant represents a potential bridge to cover the
gap between animal models and clinical studies. Dr. Kidambi’s group aims to engineer in vitro mod-
els of tissues including liver, and brain in an effort to understand the role of the tissue microenviron-
ment (physical attributes, cell-cell communication, and ligand density) on the underlying biology of
healthy and diseased tissues. These platforms provide an ideal model to delineate the critical but
unexplored areas of tissue microenvironment in which the cells reside. This presentation will discuss
about the matrix-based platforms developed that recreate the various components (mechanical stim-
uli, cell-cell interaction) of the tissue microenvironment to provide a snapshot of physiologically rele-
vant disease stages of the tissues. Using this strategy in situ models of tissues such as liver, and
brain has been engineered. The technologies will have tremendous potential applications in under-
standing several diseases including alcohol disorders in liver and brain and development of several
classes of therapeutic compounds (drugs, biologics).
257
A NOVEL 3D-LIVER-ON-A-CHIP MODEL FOR EX VIVO LIVER STUDIES
M.J. Bouchard
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine,
Philadelphia PA, 19102, USA
In this talk, we will present our laboratory’s recent research efforts in rapid continuous projection 3D
bioprinting to create 3D scaffolds using a variety of biomaterials. These 3D biomaterials are function-
alized with precise control of micro-architecture, mechanical (e.g. stiffness and Poisson’s ratio),
chemical, and biological properties. Design, fabrication, and experimental results will be discussed.
Such functional biomaterials allow us to investigate cell-microenvironment interactions at nano- and
micro-scales in response to integrated physical and chemical stimuli. From these fundamental stud-
ies, we can create both in vitro and in vivo microphysiological systems such as a human liver tissue
for tissue regeneration, disease modeling, and drug discovery.
259
IN SILICO BIOMIMETIC MODELS OF MULTICELLULAR INTERACTION NETWORK DYNAMICS
R. Vadigepalli
Department of Pathology, Philadelphia PA, 19107, USA
Technological advancements are rapidly increasing the scale, speed and precision with which bio-
logical systems can be manipulated and measured, partly due to the advent of engineered models of
the kind presented earlier in this session. At the same time, bridging the insights derived from the bio-
mimetic and pathomimetic models across the wide spectrum of in vitro, ex vivo and in vivo platforms
continues to remain a challenge, constraining the translational utility to unravel human disease
mechanisms. This presentation will make the case for in silico modeling as an essential integrating
platform for combining and contrasting the mechanistic insights from engineered systems, in vivo
models, and human studies. The salient features of an in silico model-based integrative inquiry will
be demonstrated via case studies using network models of liver regeneration and of neuroinflamma-
tion. A generalized framework for development and analysis of the in silico biomimetic models of mul-
tiscale molecular, cellular and physiological interactions will be presented with potential application to
study alcohol-induced injury response in a broad range of tissues.

Long term ex vivo maintenance of differentiated, cultured primary hepatocytes remains a challenge.
Once removed from the liver environment and cultured in traditional formats, primary hepatocytes
quickly de-differentiate, restricting their use as ex vivo models to a short time period. Unfortunately,
most of the co-culture systems do not re-create the 3D structure of parenchymal and non-parenchy-
mal cells in the liver, potentially limiting the biological relevance of studies in these systems. We have
been using micro-fluidic and micro-fabrication technologies to create layered co-cultures of primary
hepatocytes and liver sinusoidal endothelial cells in micro-channels with continuous fluid flow. This
system more closely mimics the micro-architecture and micro-fluid environment of the liver. This
system also allows for long-term maintenance of differentiated hepatocytes and facilitates their use
in assays that test effects of toxins or infectious agents on hepatocytes. We are continuing to modify
our device to incorporate stellate and Kupffer cells with the long-term goal of creating a fully human-
primary-liver-cell composed, novel 3D liver-on-a-chip model that can be used for testing chronic con-
sequences of exposure to alcohol, toxins, and hepatotropic infectious agents.
336A
WEDNESDAY, JUNE 20 9:15 AM–10:45 AM
SYMPOSIUM 260–263
Alcohol-Associated Immune Dysfunction and Lung Disease: New Therapeutic
Horizons
Organizers/Chairs: Samantha Yeligar and Ellen Burnham
260
ALCOHOL BIOMARKERS FOR IDENTIFICATION OF ALCOHOL MISUSE IN TRAUMA
PATIENTS
M. Afshar1,2,3, E.L. Burnham1,2,3, J. Corral1,2,3, J.M. Mueller1,2,3, R. Gonzalez1,2,3, E.M. Lowery1,2,3,
E.J. Kovacs1,2,3
1 epithelial respectively.
Department of Medicine, Loyola University Chicago, Maywood, IL 60153, 2Department of Surgery,
Loyola University Chicago, Maywood, IL 60153 and 3Colorado Pulmonary-Alcohol Research
Consortium (CoPARC), University of Colorado School of Medicine, Aurora, CO, USA
Purpose: Patients with alcohol misuse arriving to the hospital develop more complications and
develop organ dysfunction more frequently. Tools to facilitate prompt identification of alcohol misuse
would be helpful in prognostication of outcomes among hospitalized patients. Self-report tools to
quantify alcohol consumption, such as the Alcohol Use Disorder Identification Test (AUDIT), are the
current standard for identifying alcohol misuse. However, self-report AUDIT is often difficult to obtain
routinely due to barriers in patient communication and hospital staffing. We aim to examine the dis-
crimination of alcohol biomarkers for the detection of alcohol misuse in the trauma setting.
Methods: This was a prospective study of 36 adult patients enrolled between June 7, 2017 and
September 19, 2017 at a Level 1 trauma center. Blood and urine samples were obtained within 24 h
of emergency department presentation and the follow biomarkers were evaluated: (1) dried whole
blood spot phosphatidylethanol (PEth); (2) urine ethyl glucuronide (EtG); (3) urine ethyl sulfate (EtS);
(4) serum gamma-glutamyl-transpeptidase (GGT); and (5) serum carbohydrate deficient transferrin
(CDT). The AUDIT questionnaire was collected on all enrolled patients to identify cases of alcohol
misuse. The lower risk limit of alcohol misuse was defined as an AUDIT score ≥5 and ≥8 for females
and males, respectively. Discrimination of the biomarkers were evaluated using the area under the
receiver operating characteristic (ROC) curve.
Results: The proportion of patients with alcohol misuse was 33.6% (n = 12). The area under the
ROC was greatest for PEth (0.95; 95% CI 0.88–0.99) followed by EtG and EtS (0.77; 95% CI 0.61–
0.94), GGT (0.75; 95% CI 0.55–0.096) and CDT (0.53; 95% CI 0.32–0.74). PEth had better discrimi-
nation for detecting alcohol misuse than any other biomarker (p < 0.05 for all comparisons). The
combination of PEth with the urinary biomarkers EtG and EtS did not improve the discrimination for
detecting alcohol misuse over PEth alone (p = 0.30). The median PEth level in patients with alcohol
misuse was 740 ng/mL (IQR 170–1780) and those without alcohol misuse was 0 ng/mL (IQR 0–22).
Conclusions: PEth was a strong predictor and had good discrimination for alcohol misuse in
trauma patients. Screening with PEth may be used in patients with barriers to self-report.
261
DIFFERENTIAL EPIGENETIC EFFECTS OF ALCOHOL EXPOSURE AND THE TRANSIENT
ANTI-OXIDANT PROTECTIVE EFFECT OF TRICHOSTATIN A, IN HUMAN DENDRITIC CELLS
T. Parira, S. Granado, J. Napuri, G. Figueroa, M. Agudelo*
Department of Immunology, Herbert Wertheim College of Medicine, Florida International University,
Miami, FL 33190, USA
Alcohol has been known to upregulate reactive oxygen species (ROS) production thereby causing
increased oxidative stress leading to the development of alcohol-related organ damage. In general,
alcohol consumption alters immune responses including function of innate immune cells and histone
deacetylases (HDACs) inhibitors have been shown to exhibit anti-inflammatory and neuro-protective
properties. We have previously published the role of alcohol towards modulation of histone deacety-
lases (HDACs) in both human neuronal and peripheral immune cells treated acutely with alcohol.
However, innate immune system cells which are known to be compromised by alcohol abuse remain
to be understudied in the areas of oxidative stress and epigenetics. Our previous findings have
demonstrated that acute alcohol or binge drinking increases histone deacetylases while chronic alco-
hol use exerts a differential epigenetic effect by enhancing histone quantity and acetylation. Further,
we have demonstrated that HDAC inhibitors (HDACi) blocked alcohol-induction of class I HDACs
and modulated alcohol-induced oxidative stress related genes expressed by monocyte-derived den-
dritic cells (MDDCs) treated acutely with alcohol. Therefore, in the current study, we developed a
method combining single cell imaging flow cytometry and fluorometric microplate reading to measure
intra-cellular, extra-cellular, and total levels of ROS produced by MDDCs after chronic alcohol expo-
sure for 5 days and to measure the long term ability of trichostatin A (TSA) to protect MDDCs from
alcohol-induced ROS production. Our results demonstrate that alcohol increases ROS production
over time and this effect is only transiently blocked by TSA. Therefore, other epigenetic mechanisms
might be playing a role on the anti-oxidant regulation of alcohol-induced effects on this innate
immune cells exposed chronically to alcohol. In summary, this study provides insights on the differ-
ential epigenetic effects induced by acute and chronic alcohol exposure and highlights single cell
imaging flow cytometry as a novel tool to detect ROS and histone modifications at the single cell
level.
ABSTRACTS-SPEACKERS
262
CATHELICIDIN RECOVERY VIA ORGANOSULFUR-MEDIATED CYP2E1 INHIBITION IN
ETHANOL-TREATED HUMAN PULMONARY CELLS
P. Sriyotha, T. Burns, H. Odinga, M. McCaskill
Tulane University School of Public Health and Tropical Medicine Global Environment Health
Sciences, New Orleans, LA 70122, USA
Rationale: Chronic over-consumption of ethanol has been observed to increase the frequency and
severity of respiratory infections in humans. We have shown that this reduction in infection resistance
is at least partially mediated by ethanol-induced pulmonary tissue and cell reductions in levels of
active vitamin D and associated antimicrobial peptide, Cathelicidin. Treatment of naturally occurring
CYP2E1 inhibitor Diallyl Disulfide (DADS), has been effective in recovering pulmonary levels of
active vitamin D and Cathelicidin in chronic ethanol-fed/treated mice and immortalized pulmonary
Methods: Immortalized pulmonary epithelial cells (Nuli-1) were categorized into two treatment
groups: sub-chronic-binge exposure to ethanol and control. The sub-chronic exposure group was
treated with 50 mM ethanol, while the control group was remained in the recommended media. After
60 h of sub-chronic-binge exposure, both groups were given a respective acute treatment for 12 h
with all following compounds: 70 mM Ethanol, 10 mM DADS and 20 mg/mL Poly (I:C). After
the completion of treatment, cells were harvested and quantified level of Cathelicidin using ELISA
assay. Simultaneously, in the parallel experiment, cells were cultured and treated in the identical
manner of the previous described experiment. Upon the completion of treatment, cells were
immune-stained with anti-Cathelicidin (Alexa Fluor 647; pink) and observed by immunofluorescence
microscopy.
Results: Ethanol exposure significantly (30%–40%) decreased levels of Cathelicidin. DADS treat-
ment of Nuli-1 attenuated this ethanol effect and recovered approximately 35%–40% levels of Cathe-
licidin. This phenomenon was also observed to be similar in Poly (I:C) immune-stimulated groups.
Subchronic-binge exposure to ethanol posed more critical and persistent effects than acute expo-
sure. Immunofluorescence confocal imaging showed comparable effects of ethanol and Cathelicidin
recovery by DADS as in ELISA assay – Cathelicidin was found to be reduced in ethanol-exposed
groups and this effect was reversed by DADS treatment according to noticeably higher fluorescence
of Cathelicidin presented in ethanol-matched groups.
Conclusions: These findings suggest that ethanol plays a pivotal role in Cathelicidin dysregulation
via vitamin D metabolism and the organosulfur compounds, DADS can reverse the effects of ethanol
on Cathelicidin recovery.
263
ROLE OF ACQUIRED CFTR DYSFUNCTION IN ALCOHOL IMPAIRMENT OF MUCUS
CLEARANCE
L. Rasmussen1, D. Stafford1, J. LaFontaine1, S.M. Rowe1, T.R. Schoeb2, W.E. Swords1,
S. MBailey3, E.L. Burnham4, S.V. Raju1
1
Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA,
2
3
Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA,
Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA and
4
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of
Medicine, Denver, CO, USA
Introduction: Impairment of mucociliary clearance (MCC) is considered to increase risk of respira-
tory infections among excessive alcohol users. Here, we test the hypothesis that alcohol-induced
CFTR dysfunction reduces airway surface hydration and mucus transport thereby impairing airway
defense against inhaled bacterial pathogens, in particular Klebsiella pneumoniae, to which alcohol
users are susceptible.
Methods: Age and gender-matched rats (CFTR+/+) were pair-fed with Lieber-DeCarli alcohol diet
or isocaloric control diet for 4 weeks and with K. pneumoniae (KP, ATCC 43816). CFTR activity was
measured with nasal potential difference (NPD) and MCC was assayed with radiographic clearance
of Tc99. Airway surface liquid (ASL), periciliary layer (PCL), and ciliary beat frequency (CBF) of
excised trachea were quantified with micro-optical coherence tomography (lOCT). Expression of
CFTR and MUC5B were assessed in bronchoalveolar lavage (BAL) and bronchial brushings from
healthy participants and those with a history of alcohol use disorders (AUDs) per Alcohol Use Disor-
ders Identification Test (AUDIT).
Results: Alcohol administration reduced CFTR ion transport by NPD (DCl-free + forskolin in mV,

13.7  1.0 Alcohol vs.
21.0  2.4 Control, p ≤ 0.01). Clearance of Tc99 label in 30 min indi-
cated delayed MCC in alcohol-treated rats (22.7%  4.4 Alcohol vs. 39.1  4.8% Control,
p ≤ 0.01). Trachea excised from alcohol-treated rats exhibited decreased PCL depth (3.3  0.05
Alcohol vs. 4.7  0.5 lm Control, p ≤ 0.01), but no meaningful differences in ASL or CBF. Analysis
of lung tissues indicated reduced expression of CFTR mRNA and protein and increased AB-PAS
mucus staining and Muc5b protein expression. Compared to controls, histopathological examination
of lung sections from alcohol-treated animals exhibited more severe evidence of multifocal pneumo-
nia with edema, fibrin deposition and numerous bacteria in alveolar spaces. Expression studies were
supported by decreased CFTR mRNA expression in bronchial biopsies and elevated MUC5B protein
in BAL from AUD subjects.
Conclusions: Alcohol-induced defects in CFTR ion transport resulted in reduced airway surface
hydration and delayed mucus clearance in rat airways that was associated with mucus hypersecre-
tion and diminished ability to clear bacterial pathogens. These data implicate a role for CFTR as a
proximate cause of compromised lung mucosal defense leading to an increased incidence of pneu-
monia among alcohol abusers.
ABSTRACTS-SPEACKERS
WEDNESDAY, JUNE 20 9:15 AM–10:45 AM
SYMPOSIUM 264–267
Out with the Old, in with the New: Methodological Advances in Assessing
Risky Drinking
Organizers/Chairs: Daniel Fridberg and Andrea King
264
APPLICATIONS OF A HUMAN LABORATORY MODEL OF IMPAIRED CONTROL OVER
ALCOHOL USE TO TESTS OF NEW INTERVENTIONS FOR HEAVY DRINKING YOUNG
ADULTS
R.F. Leeman1,2
1 cebo beverage in two sessions at initial testing and then were invited back for re-examination testing
Department of Health Education & Behavior, University of Florida, Gainesville, FL, 32611, USA and
2 5 and 10 years later. From the original sample, 90% of those eligible (n = 163/180) participated in
Department of Psychiatry, Yale School of Medicine, New Haven, CT 06510, USA
A human alcohol self-administration paradigm was developed to model individual differences in
impaired control over alcohol use. The paradigm includes moderate drinking guidelines meant to
model limits on alcohol consumption, which are typically exceeded by people with impaired control.
Possible payment reductions designed to model negative consequences of alcohol use provide a
disincentive for excessive drinking. Alcohol use above the guideline despite possible pay reductions
is considered indicative of impaired control. Sessions are conducted in small groups of unacquainted
participants with a 3-h ad libitum drinking period when they may self-administer non-alcoholic and
alcoholic beverages. The paradigm has been implemented in a proof of concept study (N = 39, 69%
male) and two studies testing new, technology-based interventions: one testing automatic action ten-
dency retraining incorporating a joystick (N = 72, 54% male) and another testing devices/apps pro-
viding feedback on breath/blood alcohol concentration (BAC) (N = 49, 54% male). All studies have
enrolled non-treatment-seeking, heavy drinking young adults ages 21–25. For instance, participants
in the automatic action tendency retraining study reported baseline means of 8.85 (4.5) heavy drink-
ing days and 5.18 (1.72) drinks per drinking day in the past 30 days. Ability to elicit a range of
response is a critical aspect of laboratory paradigms. Accordingly, participants have displayed a
range of drinking behavior in the lab. For instance, participants in the BAC feedback study self-admi-
nistered 1–8 alcoholic drinks (4.17 + 1.6). Participants have also demonstrated a range of behavior
in terms of drinking topography and behaviors indicative of moderate drinking strategies in the lab. In
the proof of concept study, inter-drink intervals ranged from 1 to 64 min (14.5 + 14.7) and 60% of
participants self-administered at least one non-alcoholic beverage. Greater alcohol self-administra-
tion in the impaired control paradigm has also been related significantly to baseline external validity
measures including recent alcohol consumption and related problems; lower initial subjective
response to alcohol; earlier age of alcohol use onset and less frequent use of protective behavioral
strategies to limit alcohol use and/or related problems (all p values <0.05). Given observed variability
in alcohol self-administration behavior; measures of internal and external validity across multiple
studies, the impaired control laboratory paradigm has utility for initial tests of novel interventions to
reduce alcohol use.
265
UNDERSTANDING THE RECIDIVIST DUI OFFENDER BY STUDYING THEIR ACUTE
REACTION TO ALCOHOL
M.T. Fillmore
Department of Psychology, University of Kentucky, Lexington, KY 40506-0044, USA
Alcohol-related traffic fatality and injury continue to be a major public health problem, prompting the
need for research aimed at identifying characteristics of DUI drivers in efforts to improve treatment
and prevention. Despite considerable economic resources dedicated to these efforts, DUI remains
one of the most frequently repeated offenses, with over one-third of offenders being charged with a
second DUI offense within 5 years. The limited efficacy of DUI prevention programs has prompted
research to focus on the characteristics of individuals who have been arrested for DUI. DUI offenders
report traits of impulsivity, a characteristic that can heighten sensitivity to the impairing effects of alco-
hol. Dr. Fillmore will describe research conducted in his laboratory that supports this working hypoth-
esis. Laboratory studies are described that compare the acute responses to alcohol displayed by
DUI offenders (n = 20) and non-offender control subjects (n = 20). Analyses of the acute effects of
0.65 g/kg alcohol (peak BAC  0.08%) versus placebo on the Two-choice Impulsivity task measured
subjects’ preference for smaller, sooner rewards (impulsive choices) versus larger, delayed rewards
(non-impulsive choices). Results showed that alcohol selectively increased impulsive responding in
DUI offenders (p = 0.01), but not in controls (p > 0.05). Offenders also estimated their BACs to be
lower than BAC self-estimations of control subjects (p < 0.05). Moreover, we showed that the ten-
dency to underestimate BAC is associated with greater risk-taking behavior during a simulated driv-
ing test. The findings are important because they indicate that the offender’s risk awareness is
diminished in the intoxicated state, when critical decisions are made about whether or not to drive.
The presentation concludes with a discussion about how such evidence can guide promising new
treatment approaches that reinforce the offender’s risk awareness during intoxication and reduce
recidivism of DUI.
337A
266
 A
DEJ  BREW? SUBJECTIVE ALCOHOL RESPONSES IN HEAVY DRINKERS OVER A DECADE
OF RE-EXAMINATION TESTING
A.C. King
Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL,
60637, USA
Our group and others have shown that young nonalcoholic heavy drinkers (HD) show greater subjec-
tive stimulation and reward, and lower sedation compared with light drinkers (LD). As most research
incorporates cross-sectional designs, it is unknown whether these alcohol response differences
change over time or are stable. The present study reports on repeated alcohol challenge testing from
the Chicago Social Drinking Project. Participants were young adults (mean age 25.6 yrs) who were
either HD (n = 104 HD or 86 LD (n = 86) at enrollment. They consumed alcohol (0.8 g/kg) and pla-
re-examination through the decade. Results showed that HD (vs. LD) exhibited higher alcohol stimu-
lation and reward (liking and wanting), and lower sedation, and this was evident at initial testing and
persisted at both the 5- and 10-year re-examination testing (all ps<0.01). Stimulating and rewarding
alcohol effects were more pronounced in HD with exacerbated drinking over the decade as evi-
denced by greater binge drinking frequency and intermediate-to-high AUD symptoms (averaging 2.6
and 5.0 annual symptoms, respectively) compared with HD who moderated their drinking over time
with low AUD (<1 symptom over time). LD who progressed with heavier drinking by the end of the
decade (12%; mean 2.9 AUD symptoms) showed increases in alcohol stimulation, liking and wanting
by the 10-year re-examination compared to their initial responses and to LD who remained with low-
risk drinking (88%) and persisted with low positive-like alcohol responses. In sum, this research
demonstrates the importance of longitudinal alcohol response research to elucidate factors underly-
ing progression and/or regression of risky drinking and AUD. Results support the early stage of
allostasis, with high alcohol stimulation and reward that continues throughout the development of
AUD in the transition from the 20 to 30s, when excessive drinking becomes less normative. The
study is the first to employ an alcohol response re-examination paradigm in the same individuals over
a substantial period of time. Results challenge the conventional notion of low level responses and tol-
erance as the driving force in the progression of AUD.
267
INTO THE WILD: MOBILE SMARTPHONE ASSESSMENT OF REAL-WORLD BINGE DRINKING
D.J. Fridberg
Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL
60637, USA
Laboratory alcohol challenges are the “gold standard” to measure subjective alcohol responses, but
the degree to which responses to an intoxicating dose of alcohol administered in the laboratory
resemble those elicited during real-world binge drinking events is unclear. Thus, we conducted a
proof-of-concept study assessing the validity, feasibility, and safety of measuring real-world subjec-
tive alcohol responses in young adult binge drinkers. Participants used smartphones to record their
alcohol use and subjective responses during the first 3 h of a real-world binge drinking episode. Par-
ticipants also completed a separate laboratory alcohol challenge during which identical subjective
effects measures were assessed for 3 h following an intoxicating dose (0.8 g/kg) of alcohol. Primary
outcomes were estimated BrAC (eBrAC)/BrAC and subjective alcohol effects (well-validated mea-
sures of stimulation, sedation, feeling, liking, and wanting) for the mobile and laboratory assess-
ments, and acceptability and safety of the mobile procedure. Preliminary analyses in n = 35
participants (MSD age = 24.9  2.6 years; 37% female; 7.6  2.7 binge days/month) examined
the association between subjective responses measured in the natural environment and laboratory.
eBrAC increased steadily to 0.16  0.09 mg% during the 3-h mobile assessment, versus a peak of
0.09  0.02 mg% in the laboratory. Response rates in the natural environment were excellent (293/
315 assessments completed; 93%). At comparable eBrAC/BrAC (~0.08 mg%, 1 h after initiating
drinking in both settings), subjective alcohol stimulation, liking, and wanting in the natural environ-
ment were higher than in the laboratory (ps < 0.05), with lower sedation (p < 0.05) and no difference
in alcohol liking. Stimulation and sedation correlated positively between settings (rs > 0.46,
ps < 0.01). Overall satisfaction with the mobile response assessment procedure (rated 1–5;
5 = highest) was very high (4.5  0.70), and intrusiveness was low (2.0  0.90). Low energy (74%)
and mild hangover (71%) were the most common consequences of the mobile assessment. In sum,
assessing real-world alcohol responses using smartphones is feasible and safe. Positive-like alcohol
responses are generally higher in the real-world versus the laboratory, with real-world and laboratory
stimulation and sedation correlated at eBrac/BrAC ~0.8 g/kg. Smartphones are a practical tool to
assess alcohol effects in the natural environment, and may facilitate research on alcohol responses
and vulnerability to AUD and hazardous drinking in at-risk groups.
338A
WEDNESDAY, JUNE 20 9:15 AM–10:45 AM
SYMPOSIUM 268–271
Understanding and Preventing Impaired Driving and Riding with an Impaired
Driver
Organizers/Chairs: Brittney Hultgren and Mary Larimer
268
DWI OFFENDERS AND DRIVING BEHAVIOR
A.R. Manning1,2, T.H. Nochajski2, C.F. Scott2, R.B. Voas1, E. Romano1, E. Taylor1,P. Marques1,
M. Scherer1
1 about driving after drinking are made. y classified as either a rational, compensatory strategy (i.e.,
Pacific Institute for Research and Evaluation, University at Buffalo and 2The State University of
New York
Purpose: Ignition interlock devices (IID) is a sanction for DWI offenders that prevents them from
starting their vehicle if they are impaired. This study examines driving accommodations DWI offend-
ers use to manage driving with the IID.
Methods: The sample consisted of 99 individuals who completed interviews for the period before
the IID (T1) and during IID (T2). Information collected included; demographics, driving environments,
transportation needs, and driving during each time period.
Results: Demographics: Sex 56% male, 83% White, not Hispanic, 53% single – never married,
78% employed, 48% with an associate degree or higher. Sixty percent began drinking at age 15 or
below, with 38% indicating first drunk at aged 15 or younger. Driving environment: At T1, interlock
cost was a problem for 56%, 86% reported access to additional vehicles, 25% indicated others were
not available to provide transportation, 25% drove more than the national average. Driving being
important to work was reported by 85%, with 42% needing to drive for work, and 14% driving a com-
pany vehicle. Other types of transportation use varied; 15% used a bicycle, 16% used public trans-
portation, with 28% reporting no access to public transit. Comparing driving prior to and while on the
interlock: At T1, 77% acknowledged owning 86 cars, with 17% driving a vehicle registered to some-
one else. At T2, 83% acknowledged owning 98 cars, with 21% driving a vehicle registered to some-
one else. While 74% reported driving daily before the interlock was installed, 81% reported driving
daily while on the interlock. Late night driving, was reported as a daily occurrence, or several times
per week, for 35% of the participants before the interlock compared to 41% while the device was on
their car. Use of other types of transportation varied, 14% indicated travel by bicycle before the inter-
lock and 15% while on the interlock. At T1, only 55% indicated public transportation was available,
while at T2 72% indicated that public transit had been available.
Conclusions: Consistent with expectations, 78% of the sample were employed and 85% felt that
driving was extremely important to working, or the process of finding a job. While T1 and T2 differ-
ences were small, being on the interlock increased awareness of potential transportation solutions.
Further analyses will consider the relationship between driving and drinking.
269
PSYCHOSOCIAL AND BEHAVIORAL DECISION-MAKING PREDICTORS OF RIDING WITH AN
IMPAIRED DRIVER AND IMPAIRED DRIVING BEHAVIORS IN COLLEGE STUDENTS
B.A. Hultgren1,2, R. Turrisi1,2, M.E. Larimer1,2
1 Unique to this effort was its success in reaching and retaining participation of undocumented immi-
Department of Psychiatry and Behavioral Sciences, Center for the Study of Health and Risk
Behaviors, University of Washington, Seattle WA, 98105, USA and 2Edna Bennett Pierce
Prevention Research Center, Pennsylvania State University, University Park, PA, 16801, USA
Background: Motor-vehicle crashes remain the number one cause of death in the United States
among emerging adults (ages 18–24). Many of these crashes are due to an alcohol-impaired driver.
Older college students may be particularly at risk, as past research has shown they ride with
impaired drivers (RWI) more often than their non-college peers, and show increased rates of driving
while impaired (DWI) after turning 21. Prevention efforts have focused on reducing DWI; however,
by comparison far less is known about decisions to accept or decline rides from impaired drivers.
The current study aimed to address this gap by examining both psychosocial and behavioral deci-
sion-making factors as predictors of riding with an impaired driver (RWI), declining a ride from an
impaired driver (Decline) and DWI in a sample of older college students.
Methods: College students (N = 791) from 3 large and diverse universities completed online sur-
veys during the fall semester of their 3rd and 4th years of college assessing psychosocial variables
(e.g., norms and attitudes), behavioral decision-making factors (e.g., willingness and intentions), and
RWI, Decline and DWI behavior. Zero-inflated Poisson regression analyses were conducted in
Mplus.
Results: A total of 13% of students reported RWI and 8.1% reported DWI when they thought the dri-
ver or they, themselves, had too much to drink to be driving; 28.9% reported Decline. Predictors var-
ied based on the outcome. Willingness to RWI and peer descriptive norms increased likelihood of
RWI. Positive prototype for using safe alternatives was associated with less DWI and parental injunc-
tive norms about RWI were associated with increased DWI. Self-efficacy to use safe alternatives
and peer and parental descriptive norms about RWI predicting increased likelihood of Decline.
Conclusions: Findings suggest that while RWI, DWI and Decline are related behaviors they differ
on factors that predict each behavior. This indicates that prevention and intervention programs may
need to have a multifaceted approach to increase safe travel decision for college students. Findings
specifically highlight the importance of both peer and parental norms, suggesting normative feed-
back approaches may be helpful in reducing RWI and DWI and increasing Decline behaviors.
ABSTRACTS-SPEACKERS
270
MODELING THE DECISION TO DRIVE AFTER DRINKING
D.M. McCarthy, C.P. Davis-Strober
Department of Psychological Sciences, University of Missouri, Columbia, MO 65211, USA
The vast majority of individuals in the U.S. recognize drinking and driving as a significant public
health risk, and hold highly negative views of this behavior. Despite this, it is estimated that more
than 120 million impaired driving events occur each year in the U.S. Previous research from our lab
and others have used laboratory alcohol administration designs to explore mechanisms for the dis-
crepancy between the negative perceptions of impaired driving and the persistence of this behavior.
In this presentation, data will be presented from a series of studies using quantitative models of deci-
sion making under risk (Kahneman & Tversky, 1979) to explore the process by which decisions
incorporating all relevant information) or a non-compensatory strategy (i.e., following simple heuris-
tics). In a preliminary study (n = 126), individuals who followed a classically rational (i.e., compen-
satory) strategy for monetary gambles were more likely to report driving after drinking. In a set of
studies using college students (n = 63, n = 56) and a community sample (n = 67), we reframed
these gambles as a series of decisions about whether to drive (or not) under conditions that varied
relevant aspects of the drinking situation (e.g., amount consumed, convenience/cost of alternative
transportation, distance from destination). Across studies, drinking and driving was associated with
using a compensatory strategy for these decisions. These result suggests that the use of simple
heuristics (e.g., setting a drink cut-off and ignoring information such as taxi cost) may lead to safer
driving decisions. Finally, data will be presented from an alcohol administration study (current
n = 18, enrollment ongoing) designed to test the effect of intoxication on decision making strategy.
Previous studies using classical monetary gambles (Davis-Stober et al., in press) found little effect of
intoxication on strategy use. In addition, data from this study will test how subjective states (e.g., per-
ceived impairment, perceived risk of driving) are incorporated into driving decision making. Future
directions for this line of research include extending these models to driving after use of cannabis
and adaptation of these models to analyze real-world driving decisions.
271
IMPAIRED DRIVING AMONG RECENT LATINO IMMIGRANTS TO SOUTHERN FLORIDA
E. Romano1,2, M. Sa  nchez1,2, M. de la Rosa1,2
1
Pacific Institute for Research and Evaluation, Calverton, Maryland, USA and 2Florida International
University, Miami, Florida, USA
Purpose: Latinos have been consistently overinvolved in alcohol-related motor-vehicle fatal
crashes. While Latinos do not drink and drive more often than their White counterparts, they have
higher rates of driving-while-intoxicated (DWI) arrests and alcohol-related fatal crashes. Of particular
relevance is the role that immigration in the prevalence of Latinos in DWI events However, research
is limited on how Latinos, in particular recent immigrants, perceive the risks of driving impaired and
how this may translate into actual DWI. The current study examined pre- and post-immigration fac-
tors as predictors of DWI and riding with an impaired driver (RWI) among recent Latino immigrants
to Florida.
Methods: This study took advantage of a 5-year longitudinal assessment of pre- and post-immigra-
tion factors that influence alcohol and drug use of recent Latino immigrants to Florida (aged 18–34).
grants. Respondent-driven sampling (RDS) was the primary recruitment strategy. The current study
examined the association between pre- and post-immigration factors and DWI and RWID.
Results: Compared with permanent residents, undocumented drivers are more likely to binge drink,
and less likely to understand DWI laws and perceive risks associated with DWI. Undocumented
immigrants showed low DWI rates, partly due to their limited amount of driving. Regarding risk per-
ceptions, immigrants who utilized negative religious coping more often were less likely to view DWI
as a risk. Post-immigration rates of DWI (and drug driving—DWID) were strongly influenced by pre-
immigration DWID and DWI. Of concern was the prevalence of RWI.
Conclusions: Differences in risk perceptions and DWI between Latino immigrants of different resi-
dency statuses suggest the possibility of early interventions to reduce DWI among Latino immi-
grants. Importantly, because it is not affected by driving limitations, RWI for these Latino immigrants
is perhaps a more immediate risk than DWI. Addressing RWI among recent Latino immigrants
should be a priority for traffic safety. Future interventions should make efforts to (1) identify immi-
grants who had DWI and DWID in their country of origin, given they may be at higher risk; and (2)
design and deliver specific and culturally-relevant messages to prevent engaging in those risk behav-
iors in the host country.
ABSTRACTS-SPEACKERS
WEDNESDAY, JUNE 20 9:15 AM–10:45 AM
SYMPOSIUM 272–275
Leveraging National Epidemiological Data to Advance an Empirical
Understanding of Substance Misuse in LGBT Sub-Populations
Organizers/Chairs: Amelia Talley and Paul Gilbert
272
SEXUAL MINORITY YOUTH ARE AT ELEVATED RISK FOR RECENT USE OF MULTIPLE
SUBSTANCES
S.S. Dermody
School of Psychological Science, Oregon State University, Corvallis, OR, 97331, USA
Purpose: Sexual minority youth (SMY) are at an increased risk for substance use compared to
heterosexual youth. The risk of polysubstance use, which magnifies drug-related harms, remains lar-
gely unexamined among SMY relative to heterosexual youth. The purpose of this investigation was
to use a national epidemiological dataset to describe disparities between SMY and heterosexual
youth with regard to risk of polysubstance use.
Methods: The study used the 2015 CDC’s Youth Risk Behavior Surveillance System (YRBS;
N = 15,624). Latent mixture modeling was carried out using the 3-step method in MPlus v8.0 to iden-
tify relatively homogenous subgroups of adolescents based on their reported past-month use of alco-
hol, cigarettes, chewing tobacco/snus/snuff, cigars/cigarillos/little cigars, e-cigarettes, or marijuana,
as well as past-month binge drinking (all dichotomized: 0 = none; 1 = at least one time in the past
30 days). Adjusting for participant race, gender, and age, empirically-identified clusters based on
multiple substance use patterns were compared on the basis of self-reported sexual identity (gay/les-
bian, bisexual, “not sure,” heterosexual [reference group]).
Results: When comparing solutions with up to six classes, the five-class solution exhibited optimal
fit and the most interpretable classes. Most youth were in the “non-users” class (68%). Other classes
included: “alcohol users” (13%; elevated probabilities (>50%) for recent alcohol use and binge drink-
ing), “nicotine and marijuana co-users” (6%; elevated probabilities for recent nicotine and marijuana
use), “poly-substance/e-cigarette users” (5%; elevated probabilities on all substances except for all
tobacco-containing products), and “polysubstance/tobacco users” (8%; elevated probabilities for
recent use of all substances). Relative to heterosexual youth, gay/lesbian-identified youth were at
risk for being “nicotine and marijuana co-users”, bisexual youth were at risk for being in all four sub-
stance-using classes, and individuals who reported being “not sure” of their sexual identity were at
risk for being in the “polysubstance/tobacco users” class. Race and gender moderated some of the
aforementioned disparities.
Conclusions: SMY, particularly bisexual youth, were at an increased risk relative to heterosexual
youth for being identified as polysubstance users, relative to a “non-users.” SMY are at risk for poly-
substance use, which warrants attention in substance use interventions, especially those tailored for
this community of at-risk youth.
273
EMPIRICAL IDENTIFICATION OF SEXUAL MINORITY SUBGROUPS AND THEIR RISK FOR
PERSISTENT ALCOHOL, MARIJUANA, AND TOBACCO USE IN ADOLESCENCE
A.E. Talley, B. Turner, A.M. Foster, G. Phillips II
Department of Psychological Sciences, Texas Tech University, Lubbock, TX 79409, USA
Background: Adolescents who identify as non-heterosexual or report same-gender sexual attrac-
tions and behavior are at risk of substance use, relative to their heterosexual-identified counterparts.
Equivocal findings in the literature may reflect the sample characteristics or varying operationaliza-
tions of sexual orientation; examinations of identity-related characteristics that potentiate risk of sub-
stance misuse are necessary to further understand how sexual orientation may predict risk of
persistent substance use in adolescence.
Methods: Youth Behavior Risk Surveillance (YRBS) datasets were pooled across national jurisdic-
tions (city, state) and years (biennially from 2005 to 2015). Students were excluded if they were miss-
ing any of the sexual orientation variables or primary demographic variables of interest, resulting in a
sample size of 348,175 students. Latent drinker classes were identified on the basis of student-
reported sexual identity and behavior. Two items for each substance (i.e., alcohol, marijuana,
tobacco), respectively, were used to assess persistent substance use. Students users were consid-
ered persistent users if they reported any lifetime use and any past 30 days use.
Results: Five-class solutions fit the data well among both male and female youth. Female clusters
were primarily defined by self-identification (e.g., lesbian, bisexual), whereas male clusters were pri-
marily defined by sexual behavior (e.g., partners of both sexes). Disparities among female youth sub-
groups were not reliably shown when predicting persistent alcohol use. By contrast, classes of
female youth who self-identified as bisexual (8.7%) or lesbian (4.7%) were at heightened risk of
reporting persistent tobacco (OR 1.97, OR 1.52, respectively) and marijuana use (OR 1.53, OR
1.31, respectively), compared to their sexually active heterosexual peers (38%). Male youth report-
ing partners of both sexes (2%) reported more persistent alcohol (OR 1.95), marijuana (OR 2.27),
and tobacco use (OR 2.69) than their sexually active heterosexual peers (49%). Male youth with a
history of only same-sex partners (2.1%) were at equal risk of reporting persistent substance use, rel-
ative to sexually active heterosexual youth.
Conclusions: The study was ground-breaking in that it highlights the importance of lesbian or
bisexual identity in female youths’ marijuana and tobacco use behavior, as well as the key considera-
tion of bisexual behavior for male youths’ risk of alcohol and other drug use.
339A
274
TRENDS IN TOBACCO AND MARIJUANA USE ACROSS SEXUAL IDENTITY GROUPS:
NATIONAL ALCOHOL SURVEY 2000–2015
K.F. Trocki, L.A. Drabble, K. Karriker-Jaffe, J. Klinger, R. Korcha, T.L. Hughes, C. Velhuis,
P.A. Gilbert
Alcohol Research Group, Emeryville, CA 94608, USA
Purpose: Population-based studies have found higher risk of tobacco and marijuana use among
sexual minority compared to heterosexual persons (e.g., Trocki, Drabble and Midanik, 2009). In a
changing policy context, where tobacco prevention efforts have flourished and state laws permitting
legal access to marijuana have increased, there is a need to examine how disparities in risk may
change over time. We sought to extend earlier work using multiple cohorts from the National Alcohol
Survey to compare differences, and changes over time, in the prevalence of tobacco and marijuana
use by sexual identity.
Methods: This study analyzed cross-sectional datasets from the National Alcohol Survey – col-
lected at 5-year intervals (2000, 2005, 2010 and 2015). Separate analyses, by gender, compare
rates of past-year use of tobacco and marijuana by sexual identity: lesbian/gay, bisexual, and hetero-
sexual respondents.
Results: The main comparisons of interest were trends in use over the 15-year period from 2000 to
2015. Among women, there were significant differences across sexual identity groups in all four sub-
sets of data as well as in the combined dataset. For the combined data, 19% of heterosexual women
reported tobacco use compared to 44% of bisexual- and 36% of lesbian-identified women
(v2 = 74.62, p < 0.001). Marijuana use generally increased from 2000 to 2015 among all women,
but remained higher among SMW (37.8% to 46.35 among bisexuals and 21.1% to 23.8% among les-
bians) compared to heterosexual (5% to 8.9%) women. Overall, prevalence of tobacco use
decreased among heterosexual women (from 21% in 2000 to 17% in 2015), yet increased among
lesbian women (from 29% to 36%). Rates among bisexual women remained the same (54% in both
2000 and 2015). Among men, there were no significant differences in tobacco use across the sexual
identity groups in all years, except 2005, and a drop in tobacco use was shown among all sexual
identity groups between the first two survey points and the last. Marijuana use among was greater
among bisexual (26.7%) and gay men (24.8%) compared to heterosexual men (11%), and this use
generally increased between 2000 and 2015 across all groups.
Conclusion: Disparities in risk of tobacco and marijuana use continue and are most pronounced
among women.
275
WHO’S AT-RISK OF WHAT? A LATENT CLASS ANALYSIS OF MEN’S DRINKING BY SEXUAL
ORIENTATION
P.A. Gilbert, L. Drabble, K.J. Conron, J. Daniel-Ulloa, K.F. Trocki
Department of Community and Behavioral Health, The University of Iowa, Iowa City, IA, 52242, USA
Background: Gay and bisexual men are often presumed to drink more and be at higher risk of alco-
hol-related problems than heterosexual men; however, the empirical literature is inconsistent, at
times suggesting higher, equivalent, and lower risk. Seeking clarification, we conducted a latent class
analysis to identify underlying drinker groups and assess probability of class membership by sexual
orientation.
Methods: This study analyzed data from a subset of White (n = 8,235), Black (n = 3,061), and
Latino (n = 2,969) men in the National Epidemiological Study of Alcohol and Related Outcomes-III.
Latent drinker classes were identified on the basis of four lifetime and four past-year alcohol use indi-
cators, as well as past-year cannabis use. After establishing a baseline model, an exogenous indica-
tor of sexual orientation (derived from self-reported sexual identity, behavior, and attraction) was
used to predict class membership. Post-hoc analyses examined variations in sexual orientation
effects by self-reported race/ethnicity. All analyses were completed using PROC LCA in SAS v9.4.
Results: A six-class solution fit the data best, with classes labeled as infrequent drinkers (35%),
non-problem heavy drinkers (20%), non-problem moderate drinkers (16%), current problem drinkers
(15%), resolved problem drinkers (7%), and lifetime abstainers (7%). Gay identity was associated
with lower odds of membership in current problem, non-problem heavy, and non-problem moderate
drinker classes (OR 0.27, OR 0.43, and OR 0.25, respectively). Bisexual identity was associated with
higher odds of membership in the infrequent drinker class (OR 3.13). Heterosexual-identified men
who reported same-sex partners (i.e., behaviorally discordant men) had higher odds of membership
in both non-problem heavy and problem drinker classes (OR 3.64 and OR 4.94, respectively). Post-
hoc analyses revealed few racial/ethnic differences in class membership by sexual orientation;
among conditional associations, gay-identified White men had higher odds of membership in the
infrequent drinker class, compared to gay-identified Black and Latino men. Compared to their Black
and Latino counterparts, behaviorally discordant heterosexual White men had lower odds of mem-
bership in the lifetime abstainer class.
Conclusions: This study found little evidence of greater heavy and hazardous drinking among gay
and bisexual men; in contrast, behaviorally discordant heterosexual men appeared to be at greatest
risk. Findings shed light on subgroups of men to target for alcohol risk-reduction interventions.
340A
WEDNESDAY, JUNE 20 9:15 AM–10:45 AM
SYMPOSIUM 276–279
The Boon and Bane of Social Living: Novel Takes on Social Processes in
Predicting and Intervening to Reduce Alcohol Use
Organizers/Chairs: Allecia Reid and Helle Larsen
276
A DEVELOPMENTAL PERSPECTIVE ON PARENTING: LONGITUDINAL EFFECTS OF
AUTOMATIC AND EXPLICIT PARENTING ON ADOLESCENTS’ ALCOHOL USE
I.M. Koning, S.M. Doornwaard, V.van. der Rijst, J. De Houwer, W. Vollebergh
Utrecht University, Interdisciplinary Social Science, Youth Studies
Purpose: Commonly, parenting behaviors are assessed in an explicit way, usually by means of
self-reports. Yet, under suboptimal conditions it is expected that parents act more automatically.
Therefore, the aim of the present empirical study was to investigate the influence of automatic and
explicit parenting cognitions on alcohol use in adolescents and whether this relationship was depen-
dent on adolescents’ age.
Methods: A sample of 111 parent-child dyads (71.9% mothers; M age = 47.4, SD = 5.3) with chil-
dren between 12 and 18 years (55.2% boys; M age = 14.8 years, SD = 1.6) completed the Rela-
tional Responding Task (RRT) twice (6 month interval) to assess automatic parenting prior to an
online questionnaire that assessed explicit parenting (rules and attitudes about alcohol use). The
RRT assessed parents’ automatic responses to strict (10 statements) and tolerant (10 statements)
statements regarding their child’s alcohol use in relation to their behavior (e.g. if I catch my child
drinking, I will get angry) and to their attitudes (I find it unacceptable if my child comes home tipsy).
The effects of automatic and explicit parenting at T1 on two drinking outcomes at T2 were analyzed;
average number of glasses per week (weekly drinking) and life-time prevalence of drinking.
Results: Regarding to lifetime prevalence of drinking, stricter explicit parenting cognitions predicted
a lower likelihood of children ever having consumed alcohol at T2. This effect was particularly rele-
vant for older adolescents. Automatic parenting cognitions were not predictive of lifetime prevalence
of alcohol use. For weekly drinking, no main effects for automatic and explicit parenting cognitions
were identified. However, the significant protective effect of stricter automatic parenting cognitions
on weekly drinking was significant for older adolescents.
Conclusions: This study is the first to demonstrate longitudinally that automatic parenting behav-
iors as measured by the RRT can be used as a predictor of level of drinking among older adoles-
cents, even after controlling for explicit parenting behaviors. This study provides the starting point of
a much broader research program aimed at uncovering the relationship between automatic parent-
ing behaviors and offspring behavior, also beyond the domain of alcohol use.
277
PEERS, COGNITIONS AND ALCOHOL: AN EXPERIMENTAL STUDY ON THE INTERACTION
BETWEEN PEER CONTEXT AND COGNITIVE-MOTIVATIONAL PROCESSES
H. Larsen, A. Hagen, B. Van Bockstaele, R.W. Wiers
Department of Psychology, University of Amsterdam, Amsterdam, The Netherlands. Research
Priority Area Yield
There is an abundance of scientific evidence suggesting that the initiation and progression of alcohol
use is influenced by peers, but the underlying processes remain to be elucidated. Until now, peer
context and automatically activated cognitive-motivational processes have been investigated sepa-
rately. In this study, we took first steps to investigate the interplay between peer influence and auto-
matically activated cognitive-motivational processes. In an experimental lab-study we examined
whether drinking identity changed under the influence of peers. Moderating effects of gender, alcohol
use and alcohol problems were also tested.
Methods: A sample of 220 students from the University of Amsterdam (Mage = 20.71, SD = 1.27;
75% females) participated. To manipulate peer influence, we used a simulated internet chatroom
experiment in which participants were asked to chat with a peer about what they do with their friends
in their leisure time. Participants were randomized into one of three conditions: 1. Active Control (i.e.,
no-alcohol content chat with confederate peer), 2. Control (i.e., writing about leisure time, no interac-
tion with confederate peer), 3. Alcohol (i.e., alcohol content chat with confederate peer). Directly after
this manipulation, participants completed the Drinking Identity Implicit Association Task (IAT;
me + drinker associations), a self-reported drinking identity questionnaire, AUDIT, and Rutgers Alco-
hol Problem Index.
Results: While controlling for self-reported drinking identity, no main effect of peer chat condition on
IAT drinking identity was found. The three-way interaction between peer chat condition, gender, and
alcohol problems was significant F(1, 141) = 4.06, p = 0.04. Post-hoc analyses showed that for
female participants, the interaction between chat condition and alcohol problems was significant F(1,
110) = 3.87, p = 0.05, demonstrating that in the alcohol chat condition the IAT drinking identity was
stronger for females with high levels of alcohol problems compared to females with low alcohol prob-
lem levels. The interaction between chat condition, gender, and AUDIT showed the same pattern but
at a trend level (p = 0.07).
Conclusion: This study was a first step examining the complex interaction between peer context
and cognitive-motivational processes. If replicated, findings suggest that automatically activated
drinking identity might be easier triggered by peers in women with higher levels of alcohol problems,
making this group vulnerably for the development of alcohol misuse.
ABSTRACTS-SPEACKERS
278
DO FRIENDS MATTER? CLOSE FRIENDS AND PARTICIPATION IN YOUTH ALCOHOL
INTERVENTIONS
K.G. Anderson
Adolescent Health Research Program, Department of Psychology, Reed College, Portland, OR
97202, USA
Little is known about how co-participation with a close friend in group alcohol interventions may
impact engagement and outcomes for youth. In this research, we examined demographic differ-
ences in rates of participation with a close peer and the impact of attendance with friends on group
satisfaction and intervention outcomes. Project Options (PO) is a voluntary, school-based, brief alco-
hol intervention integrating cognitive-behavioral skills building approaches with motivational
enhancement techniques. PO was tested in 11 high schools in three cities in the United States. One
thousand seventy-one students completed at least one session of the group intervention (59% girls;
24.1% African-American, 23.4% White, 39.3% Hispanic; Mage = 16.1 [SD = 1.4]) randomized into
two conditions: standard PO administration and didactic control. Preliminary findings suggest that
attendance with a close friend did not vary by condition, t(1,160) =
0.40, p = 0.69, and that teens
commonly participated in groups with a close friend (74% of sessions). Girls more frequently
attended PO with a close peer (0.78) as compared with boys (0.68; t[1,145] = 4.78, p < 0.0001),
and African-American and Hispanic students participated in groups with a close friend more often
than peers categorized as “Other” in terms of race and ethnicity, F(4, 1,153) = 3.17, p = 0.01.
Twelfth grade students reported having a close friend in group more frequently than freshmen, F(93,
1,143) = 2.96, p = 0.03, and current drinkers attended groups with friends at a higher rate than
those who had not consumed alcohol in the past 30 days, t[1,073] =
2.98, p = 0.003. Youth
expressed greater satisfaction with the intervention when participating with a close friend, r = 0.08,
p = 0.005, but peer impacts were not supported on a categorical index of treatment outcome, F(3,
948) = 1.75, p = 0.16. In sum, girls, current drinkers, and some racial minority groups evidenced
higher rates of close friend co-attendance than their opposing counterparts, and co-attendance was
associated with higher intervention satisfaction. While experimental research is needed to explicitly
test the impact of friends on group processes, if validated, such findings could provide insights into
how peer participation may be leveraged to improve youth engagement with alcohol interventions.
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ENCOURAGING THE ROAD LESS TRAVELED: TESTING SELF-AFFIRMATION AS A
STRATEGY FOR REDUCING CONFORMITY TO PEER ALCOHOL USE
A.E. Reid, M. Field, A. Jones, L.C.G. DiLemma, E. Robinson
Department of Psychological Sciences, University of Liverpool, Liverpool L69 7ZA, UK
Purpose: Although myriad studies have demonstrated that peers strongly influence young adults’
alcohol use, little research has examined strategies that might weaken the influence of peers. Self-
affirmation, in which affirmed individuals reflect on important characteristics and values, has been
shown to both decrease concerns about belonging and enhance availability of self-regulatory
resources. These processes may disrupt the motivations that underlie conformity to peer behavior.
We therefore hypothesized that self-affirmation would reduce conformity to peer alcohol use.
Methods: Utilizing an experimental medicine, laboratory-based approach, participants (N = 153)
were randomly assigned to one of four conditions in a 2 (self-affirmed vs. not) 9 2 (heavy vs. light
drinking peer confederate) design. Following the self-affirmation task, potential mechanisms—desire
to affiliate with a stranger and inhibitory control—were assessed. Participants were then served an
alcoholic beverage and interacted with a confederate who engaged in heavy or light alcohol con-
sumption. The amount of alcohol consumed by the participant was recorded.
Results: Participants who interacted with a heavy drinking confederate, relative to a light drinking
confederate, consumed significantly more alcohol (p = 0.003, g2 = 0.06). Self-affirmation did not
moderate this effect (p = 0.47) and also had no effect on either of the proposed mechanisms, desire
to affiliate and inhibitory control (p’s > 0.31). A follow-up study demonstrated an effect of self-affirma-
tion on a precursor to self-regulation, private self-awareness (p = 0.03, g2 = 0.04); self-affirmed par-
ticipants reported higher levels of private self-awareness. However, neither self-affirmation nor
private self-awareness (p’s > 0.22) moderated the strong effect of consumption condition on partici-
pants’ consumption (p < 0.001, g2 = 0.13).
Conclusions: Our results highlight a novel method for studying strategies that may limit conformity
and further support the robust effect of peer behavior on alcohol consumption. Though its effect on
private self-awareness is promising, self-affirmation may alter additional mechanisms that ultimately
limit its impact on conformity. Additional research is therefore needed on strategies that may weaken
the influence of peers, in service of the development of more efficacious risk-reduction interventions
for young adults. As peers also strongly influence use of other substances, strategies that weaken
peer influence may be consequential for a range of risky behaviors.