CNS Drugs 2004; 18 (15): 1105-1118

REVIEW ARTICLE 1172-7047/04/0015-1105/$31.00/0

 2004 Adis Data Information BV. All rights reserved.

Role of the Serotonergic System in the

Neurobiology of Alcoholism
Implications for Treatment
Bankole A. Johnson
University of Virginia Health System, Charlottesville, Virginia, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1105
1. Serotonin Pathways: Anatomical Distribution and Functional Correlates . . . . . . . . . . . . . . . . . . . . . . 1106
2. SSRIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107
3. 5-HT1 Partial Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108
4. 5-HT2 Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1109
5. 5-HT3 Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1109
6. Other 5-HT Receptor Subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1112
7. Combining Serotonergic Agents with Other Types of Medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1112
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1114

Abstract Preclinical studies have contributed greatly to our understanding of the

neurochemical pathways associated with the development and maintenance of
alcohol-seeking behaviour. These studies have demonstrated the important role of
serotonin pathways, particularly as they relate to dopaminergic function, which
mediates alcohol-induced reward associated with its abuse liability. Naturally, this
has led to the study of serotonergic agents as treatments for alcoholism.
SSRIs do not appear to be effective treatment for a heterogeneous alcoholic
group. However, they may be useful as treatment for late-onset alcoholics, or
alcoholism complicated by comorbid major depression. Buspirone, a serotonin
5-HT1A partial agonist, does not appear to be an effective treatment for alcoholics
without comorbid disease. Buspirone may, however, have some utility for treating
alcoholics with comorbid anxiety disorder. The 5-HT2 antagonist ritanserin, at
pharmacologically relevant clinical doses, does not appear to be an effective
treatment for alcoholism. Ondansetron, a 5-HT3 antagonist, is an efficacious and
promising medication for the treatment of early-onset alcoholism. Preliminary
evidence suggests that combining the mu antagonist naltrexone with the 5-HT3
antagonist ondansetron promises to be more effective for treating alcoholism than
either alone.
The differential treatment effect of SSRIs and ondansetron among various
subtypes of alcoholic is intriguing. Future research is needed to understand more
clearly the molecular genetic differences and the interactions of such differences
with the environment that typify a particular alcoholic subtype. Such an under-
standing could enable us to make comfortable predictions as to which alcoholic
1106
subtype might respond best to a particular serotonergic agent, which could then be
provided.
Serotonergic agents have been studied for more
than 20 years as potential treatments for alcoholism.
Preclinical studies have implicated the serotonin
system, and especially its interaction with midbrain
and cortical dopamine pathways, as being central to
the expression and appreciation of the rewarding
effects of alcohol. Such studies have increased
knowledge about the bio-behavioural basis of alco-
holism and have provided the foundation for testing
medications that interact with specific serotonin re-
ceptor subtypes as treatment for particular types of
alcoholic, with or without comorbid psychiatric dis-
order.
The sections of this review are organised first to
provide the scientific rationale for testing a particu-
lar class of serotonergic medication for treating al-
coholism and, subsequently, to evaluate the reported
efficacy of these agents in clinical studies. Finally,
the rationale of ongoing studies that combine sero-
tonergic medications with other agents to provide an
added or synergistic therapeutic treatment effect is
discussed. These augmentation strategies hold the
promise of developing more efficacious treatments
for alcoholism.
1. Serotonin Pathways: Anatomical
Distribution and Functional Correlates
Mesocorticolimbic dopamine pathways do not
mediate the rewarding effects of alcohol in isolation.
Importantly, there is solid evidence that midbrain
dopamine is itself modulated by a variety of neuro-
transmitters, including serotonin. Indeed, these mid-
brain dopamine fibres are under the tonic inhibitory
control of serotonin. Research has dramatically in-
creased our understanding of serotonin receptors
and pathways and has improved knowledge of how
the serotonin system mediates the expression of
numerous physiological and behavioural conditions,
including alcohol dependence. Of the nine serotonin
nuclei, the median and dorsal raphe and the centralis
posterior provide the most dense serotonin innerva-
 2004 Adis Data Information BV. All rights reserved.
Johnson
tion of the cortico-midbrain regions. Coarse, thick
beaded fibres with varicosed projections from the
median raphe innervate the hippocampus and septal
regions. Fine dorsal raphe projections typically in-
nervate the limbic (including the nucleus accum-
bens), striatal and cortical regions.[1,2]
This organisational delineation of ascending pro-
jections from serotonin cell bodies is interesting in
terms of morphology and topological distribution.[3]
That is, not only do these projections differ morpho-
logically, but also they vary in sensitivity and re-
sponsiveness to various neurochemicals, an effect
that may be due to their possessing different distri-
butions of serotonin receptor subtypes. Although
identification of serotonin receptor subtypes is in-
creasing, this review focuses on those that have been
the targets of medications for altering alcohol-seek-
ing behaviour in both animals and humans. These
include the serotonin 5-HT1 class (divided into four
additional subclasses A–D), which consists of both
postsynaptic receptors and the presynaptic
autoreceptor.
The 5-HT1A receptor type is seen both post-
synaptically and as the autoreceptor. Postsynaptic
5-HT1 receptors (subclasses A, B and D) express
their function by increasing cyclic adenosine mono-
phosphate (cAMP) turnover; in contrast, the 5-HT1C
receptor is linked with phosphatidyl inositol. 5-HT2
and 5-HT3 class receptors are all postsynaptic; how-
ever, they are functionally different. 5-HT2 recep-
tors are mediated by increasing turnover of the
second messenger phosphatidyl inositol. Serotonin
projections from the raphe synapse on dopamine
cells,[4,5] and 5-HT2 receptors are tonic inhibitors of
dopamine burst firing. 5-HT3 receptors exert their
effects through ligand-gated ion channels and are
positive modulators of dopamine function. 5-HT3
receptors also express their activity through co-lo-
calised neurotransmitters such as GABA and chole-
cystokinin, both of which also have indirect effects
on dopamine function.[6] Finally, 5-HT4 receptors
CNS Drugs 2004; 18 (15)
Alcoholism and the Serotonergic System
are coupled positively to adenylate cyclase[7-9] and
are distributed densely in the limbic system, includ-
ing the nucleus accumbens.[10-13] 5-HT4 receptors
facilitate serotonin-associated neurotransmission in
hippocampal pyramidal cells,[11,14,15] thereby modu-
lating striatal dopamine release.[16,17]
2. SSRIs
Lesions or pharmacological manipulations that
result in serotonin depletion have been associated
with decreased ethanol preference.[18,19] Preference
and operant ethanol-reinforced behaviour paradigms
have been used to examine the effects of SSRIs in
animal drinking models.
Generally, SSRIs decrease voluntary ethanol
consumption in preference paradigms.[20-24] Al-
though SSRIs suppress ethanol consumption, there
is debate as to whether suppression of ethanol intake
is due to a reduction in the reinforcing effects of
ethanol, or to a generalised decrease in consumma-
tory behaviour.[25,26] The impact of SSRIs on food
intake and fluid consumption is complex.[27] Typi-
cally, SSRIs decrease food intake,[28,29] fluid con-
sumption,[27] and palatability;[30] they may also de-
crease motivation toward consummatory behav-
iours.[31] Effects of SSRIs on food intake also appear
to be greater in well nourished compared with
malnourished rats.[32] Notably, not only do SSRIs
enhance satiety,[26] but also they selectively reduce
preference for sweet items and carbohydrates.[33-35]
Food is, therefore, perceived as being less palatable
and rewarding.[36-38] Decreased general consumma-
tory behaviour may, at least partially, mediate the
effects of SSRIs on ethanol consumption in animals.
Operant studies have also shown that SSRIs exert
their effects on ethanol consumption through a com-
bination of CNS and peripheral effects. Haraguchi
and colleagues[39] showed that same-day pretreat-
ments with fluoxetine dose-dependently decreased
ethanol responding. Thus, in animals for which etha-
nol serves as a reinforcer, classical extinction pat-
terns should be evident with abstinence. Corre-
spondingly, Murphy and colleagues[40] showed that
single-day fluoxetine infusion produced a signif-
icant decrease in ethanol-reinforced responding be-
 2004 Adis Data Information BV. All rights reserved.
1107
ginning on day 1 of treatment and increasing on
subsequent days of the 7-day treatment regimen.
Levels of responding for ethanol returned to base-
line when fluoxetine treatment was stopped. Initial
suppression of food intake also returned to baseline
on subsequent treatment days. Thus, in animal
drinking models, fluoxetine reduces both alcohol
reinforcement and general consummatory beha-
viour.
Despite these positive preclinical results, the
clinical data on SSRIs as single agents for the treat-
ment of alcoholics without major depressive disor-
der have been inconsistent. Early studies with small
sample sizes showed that SSRIs can produce short-
term (1–4 weeks) reductions in alcohol consumption
among problem drinkers.[41-45] However, these stud-
ies had three additional limitations. Firstly, they
were conducted predominantly in men,[41-43] thereby
reducing the generalisability of the results. Second-
ly, standardised psychosocial treatments, which can
reduce the apparent effectiveness of putative thera-
peutic medications, were used infrequently; hence,
nonspecific factors may be responsible for at least
some of the clinical improvement. Thirdly, the short
treatment period did not allow for determination of
whether SSRI-related clinical improvement in prob-
lem drinkers can be sustained. With longer SSRI
treatment periods and an alcohol-dependent popula-
tion, there has been no clear evidence of efficacy.
For example, while Gorelick and Paredes[46] ob-
served an initial dramatic decrease in alcohol con-
sumption (approximately 15%) during the first of 4
weeks in a clinical trial, the overall treatment effect
with fluoxetine was no better than that with placebo.
Naranjo et al.[47] were unable to demonstrate differ-
ences in drinking between patients taking the SSRI
citalopram 40 mg/day or placebo after 12 weeks of
treatment. Kabel and Petty[48] also did not find
fluoxetine 60 mg/day treatment for 12 weeks to be
superior to placebo for reducing drinking among 28
alcohol-dependent men. Furthermore, Kranzler and
colleagues,[49] in a well executed 12-week study, did
not find fluoxetine 60 mg/day to be superior to
placebo in treating alcoholism. Interestingly, predi-
cated on the findings of human laboratory studies
CNS Drugs 2004; 18 (15)
1108
that alcoholics with an early onset of disease may
have reduced serotonin levels,[50-53] Kranzler and
colleagues[54] re-examined their data. Presumably,
their premise was that if type B (i.e. early-onset)
alcoholics were deficient in serotonin, then SSRIs
would be expected to be particularly beneficial for
this alcoholic subtype. Paradoxically, they found
that fluoxetine worsened rather than improved the
clinical benefit of adjunctive cognitive behavioural
therapy, and was certainly no better than placebo. In
contrast, Pettinati and colleagues[55] have shown that
sertraline appears to benefit type A (i.e. late-onset)
alcoholics. Early-onset alcoholics differ from their
late-onset counterparts by having a stronger family
history of alcoholism and greater propensity for
impulse-dyscontrol, serotonergic dysfunction and
antisocial behaviours.[56,57] It is therefore tempting
to speculate that the relationship between serotonin
dysfunction and the onset of alcoholism might not
be a simple deficiency state but rather due to differ-
ential expression of genotypic differences in the
serotonin system. This topic is revisited (see below)
in section 5 on 5-HT3 receptor antagonists.
Although outside the scope of this review article,
SSRIs may be useful in treating alcoholics with
suicidal tendencies and severe comorbid depres-
sion;[58] however, further studies are needed to con-
firm these results. Among alcoholics with more
moderate levels of comorbid depression, TCAs re-
duce dysphoric symptoms significantly; neverthe-
less, these decreases in dysphoric symptoms are not
accompanied by similar or significant rates of dimi-
nution of drinking behaviour.[59-61]
In conclusion, SSRIs do not appear to be effec-
tive treatment for a heterogeneous alcoholic group.
SSRIs may, however, be useful as treatment for late-
onset alcoholics, or for alcoholism complicated by
comorbid major depression.
3. 5-HT1 Partial Agonists
Buspirone, a 5-HT1A partial agonist, reduces eth-
anol consumption in a variety of animal paradigms.
Collins and Myers[62] have shown that buspirone
decreases volitional alcohol consumption by
30–60% in macaque monkeys; however, there was
 2004 Adis Data Information BV. All rights reserved.
Johnson
considerable inter-individual variation. Privette and
colleagues[63] also have reported that buspirone sig-
nificantly reduced ethanol intake in Sprague-Daw-
ley rats induced to drink by repeated brain stem
injection of tetrahydropapaveroline. In a group of
medium alcohol-preferring rats, buspirone
(0.0025–0.63 mg/kg) suppressed, while buspirone
(>2.5 mg/kg) increased, alcohol consumption with-
out affecting water consumption.[64] Finally, bus-
pirone may reduce stimulus-conditioned responding
for ethanol.[65] Mechanistically, these effects are
supported by the finding that the relatively seroto-
nin-deficient fawn-hooded rat is predisposed to eth-
anol consumption;[66] correspondingly, alcohol-pre-
ferring rats, compared with their non-alcohol-prefer-
ring counterparts, have reduced cortical and
subcortical grey matter serotonin content (see
Gongwer et al.[67] and McBride et al.[68] compared
with Korpi et al.[69]). Thus, enhancing serotonin
neurotransmission should decrease ethanol con-
sumption. 5-HT1A receptors exhibit differential sen-
sitivity, the greater effect being seen at the post-
synaptic receptor compared with the autoreceptor.
Therefore, long-term buspirone administration aug-
ments serotonin function and down-regulates
autoreceptor function.[70] For these reasons, and de-
spite the paucity of operant dose-response studies
examining the effects of buspirone on ethanol drink-
ing, there appears to be some foundation for testing
its efficacy as a treatment agent for alcoholism.
Generally, clinical studies have not found bus-
pirone to be efficacious at treating alcoholics with-
out concurrent comorbid anxiety disorder. For ex-
ample, Malcolm and colleagues[71] did not find that
buspirone was superior to placebo at reducing either
the symptoms of anxiety or drinking among anxious
alcoholics. In a similarly well executed trial (n =
61), Kranzler and colleagues[72] did not find a signif-
icant effect of buspirone for reducing the amount of
alcohol consumed, the number of drinks per day, or
the number of drinking days; however, there was an
effect of buspirone to increase significantly the in-
terval to the first heavy drinking day following
randomisation. In a review of five published studies,
buspirone was found to have no convincing effect in
CNS Drugs 2004; 18 (15)
Alcoholism and the Serotonergic System
alcoholics; however, alcoholics with comorbid anxi-
ety appeared to derive some benefit.[73,74] Finally,
George et al.[75] showed that the younger the age of
onset, the lower the CSF level of 5-hydroxyindole-
acetic acid (5-HIAA), the major metabolite of sero-
tonin. Despite the likelihood of serotonin facilitation
by long-term buspirone treatment, buspirone was
not superior to placebo at improving drinking out-
comes in early-onset alcoholics. Again, this demon-
strates that the apparent serotonin dysfunction
among early-onset alcoholics is not a simple defi-
ciency but rather may be the result of other complex
interactions within the serotonin system (see section
5 on 5-HT3 antagonists below for additional details).
In sum, buspirone does not appear to be an effec-
tive treatment for alcoholics without comorbid dis-
ease. Buspirone may, however, have some utility for
treating alcoholics with comorbid anxiety disorder.
4. 5-HT2 Antagonists
In a series of animal studies, ritanserin, a 5-HT2
receptor antagonist, has been shown to attenuate
ethanol consumption (see Meert et al.[76] and Myers
et al.[77] compared with Svensson et al.[78]). Also, the
5-HT2 antagonists amperozide[79-81] and FG
5974[82,83] significantly suppress ethanol intake
without affecting water consumption. The magni-
tude of amperozide-induced ethanol suppression ap-
peared relatively larger than that reported previously
for naltrexone.[81] Both amperozide and naltrexone
diminish food palatability; hence, these medications
may, at least in part, also cause general decreases in
consummatory behaviour. Mechanistically, 5-HT2
receptor antagonist-mediated acute anti-drinking be-
haviour may be due to substitution for the
pharmacobehavioural effects of alcohol by in-
creased levels of burst firing in mesocorticolimbic
dopaminergic neurons[84] and, later, through recipro-
cal feedback inhibition of dopaminergic activity.[85]
We were the first to examine the efficacy of
ritanserin for the treatment of alcoholism.[86] In a
rigorous multicentre clinical trial, 423 alcoholics
received 12 weeks of ritanserin (2.5 mg/day or 5 mg/
day) or placebo as adjunctive medication to cogni-
tive behavioural therapy. Significant reductions in
 2004 Adis Data Information BV. All rights reserved.
1109
alcohol consumption were seen at study end in all
treatment groups. Ritanserin was, however, not su-
perior to placebo at improving drinking outcomes. A
later study using a similar methodology demonstra-
ted that even using a higher ritanserin dose (10 mg/
day) did not improve drinking outcome compared
with placebo.[87] Although it is plausible that even
higher ritanserin doses may show effectiveness in
treating alcoholism, the potential to test this para-
digm is limited by the ability of ritanserin to produce
dose-dependent prolongation of the corrected QT
(QTc) interval on the ECG,[86] thereby increasing the
potential for cardiac arrhythmias and the risk of
sudden death.
In conclusion, ritanserin at pharmacologically
relevant clinical doses does not appear to be an
effective treatment for alcoholism. There are, at
present, no clinical data on the use of other 5-HT2
antagonists as a treatment for alcoholism.
5. 5-HT3 Antagonists
Of the numerous serotonergic agents that have
been suggested as pharmacotherapies for alcohol-
ism, the 5-HT3 antagonist ondansetron appears to be
particularly promising.[88] Preclinical studies using
cloned cells and animals show that 5-HT3 receptors
modulate important neurochemical and behavioural
effects of alcohol associated with its abuse liability.
These studies laid the foundation for testing 5-HT3
antagonists for the treatment of alcoholism. For
instance, neurophysiological experiments show that
ethanol potentiates 5-HT3 receptor-mediated ion
currents in NCB-20 neuroblastoma cells[89,90] and
human embryonic kidney 293 cells transfected with
5-HT3RA complementary DNA.[91] 5-HT3 receptor
antagonists block these effects.[92] Hence, the 5-HT3
receptor is a site of action for ethanol in the
brain.[93,94]
The rewarding effects of alcohol, and those of
other abused substances, are mediated by mesocor-
ticolimbic dopamine pathways.[6,95-98] 5-HT3 recep-
tors are densely distributed in the terminals of
mesocorticolimbic dopamine-containing neurons,
where they regulate dopamine release in these brain
regions.[99-101] Thus, the rewarding effects of alcohol
CNS Drugs 2004; 18 (15)
1110
can be modulated by interactions between dopamine
and 5-HT3 receptors in the midbrain and cor-
tex.[6,96,97,102,103] Demonstration that 5-HT3 receptor
blockade reduces dopamine activity and, therefore,
the rewarding effects of alcohol and other abused
drugs is derived from at least three different animal
paradigms. Firstly, 5-HT3 receptor antagonists at-
tenuate hyperlocomotion in the rat induced by dop-
amine or ethanol injection into the nucleus accum-
bens.[104] Secondly, 5-HT3 receptor antagonists sup-
press DiMe-C7 (a neurokinin)-induced hyper-
locomotion, an effect also diminished by the dop-
amine antagonist fluphenazine.[105,106] Thirdly,
5-HT3 receptor antagonists reduce alcohol con-
sumption in a variety of animal models and across
different species (see Meert,[64] Barnes and
Sharp,[102] Costall et al.,[107] Hodge et al.,[108] Fadda
et al.,[109] Rodd-Henricks et al.,[110] McBride and
Li,[111] and Tomkins et al.,[112] compared with
Beardsley et al.[113]). Essentially, the results of
preclinical studies show that ondansetron is a prom-
ising medication for treating alcoholism.
Human laboratory studies also have mainly sup-
ported a role for 5-HT3 antagonists in the treatment
of alcoholism. In two independent studies, we were
the first to show that ondansetron pretreatment at-
tenuates low-dose alcohol-induced positive subjec-
tive effects, including the desire to drink.[103,114] That
is, ondansetron reduced the rewarding effects of
alcohol associated with its abuse liability. Swift and
colleagues,[115] using much higher alcohol and
ondansetron doses, also observed that ondansetron
pretreatment, compared with placebo, decreased al-
cohol preference; however, a mixture of both stimu-
lant and sedative interactions between ondansetron
and alcohol was also reported. In contrast, Doty and
coworkers[116] did not find an effect of ondansetron
on alcohol-induced mood. These investigators may
have failed to detect the effects of ondansetron be-
cause administration of ondansetron via the intrave-
nous rather than the oral route, together with use of a
group rather than an individual experimental setting,
may have reduced the sensitivity of their mood
assessments. Thus, although three human laboratory
studies had suggested that ondansetron would be a
 2004 Adis Data Information BV. All rights reserved.
Johnson
beneficial treatment for alcoholism, rigorous doub-
le-blind clinical studies were needed to establish its
efficacy.
Clinical trial evidence supports the efficacy of
ondansetron for treating alcoholism. In a 6-week
double-blind trial of non-severely alcohol-depen-
dent males (n = 71), Sellers and colleagues[117]
showed that the 0.5-mg/day dose but not the 4-mg/
day dose of ondansetron was associated with a non-
significant trend (p = 0.06) toward a reduction in
alcohol consumption. Secondary data analysis to
exclude those who consumed more than ten drinks
per drinking day (n = 11) yielded a significant
difference (p = 0.001) between the ondansetron 0.5
mg/day and placebo groups. Excluding this group
can be justified by the fact that such individuals
would typically not be enrolled in contemporary
clinical trials (and are more likely to have received
inpatient treatment) because their persistent level of
intoxication may have reduced the validity of their
self-reported drinking. Nevertheless, as with other
preliminary studies, there are some limitations that
should be taken into consideration when evaluating
these results. Firstly, ondansetron was provided for a
relatively short treatment period (6 weeks rather
than the typical 12 weeks). Since the therapeutic
effects of ondansetron appear to take several weeks
to emerge, there may have been insufficient time to
demonstrate the full magnitude of the medication’s
effects. Secondly, the relatively low subject num-
bers would have decreased statistical power; hence,
the treatment differences observed in this small co-
hort may have been even more striking with a larger
study population. Thirdly, the study cohort was lim-
ited to mostly white males, thereby limiting the
generalisability of the results. Despite these limita-
tions, these results were supportive of a treatment
effect for ondansetron that required testing in a
large-scale clinical trial. Further, the study of Sellers
and colleagues[117] indicated the need for future
studies to determine whether ondansetron had an
inverted U-shaped dose-response curve. Prospective
empirical characterisation of what type of alcoholic
responds best to ondansetron treatment was also
CNS Drugs 2004; 18 (15)
Alcoholism and the Serotonergic System
needed, given that psychosocial factors in the cohort
had important effects on treatment outcome.
In a recent large-scale (n = 321), randomised,
double-blind, placebo-controlled, 12-week clinical
trial, we tested the efficacy of ondansetron (1, 4 and
16 µg/kg twice daily) in alcohol-dependent men and
women receiving weekly cognitive behavioural
therapy.[118] The first treatment week consisted of
single-blind placebo followed by 11 weeks of doub-
le-blind treatment. Thus, double-blind treatment
was not provided until study week 2. The cohort was
about equally divided between early- and late-onset
alcoholics. The results of this study showed that
early-onset alcoholics who received ondansetron (1,
4 and 16 µg/kg twice daily), compared with those
who were administered placebo, had fewer drinks
per day (1.89, 1.56 and 1.87 vs 3.30; p = 0.03, p =
0.01 and p = 0.02, respectively) and fewer drinks/
drinking day (4.75, 4.28 and 5.18 vs 6.90; p = 0.03, p
= 0.004 and p = 0.03, respectively). Ondansetron (4
µg/kg twice daily) was superior to placebo at in-
creasing the percentage of days abstinent (70.10 vs
50.20; p = 0.02) and total days abstinent per study
week (6.74 vs 5.92; p = 0.03). Among early-onset
alcoholics, there also was a significant difference in
the mean log carbohydrate-deficient transferrin ratio
(a biochemical marker of heavy alcohol consump-
tion) between those who received ondansetron (1
and 4 µg/kg twice daily) and those who received
placebo (–0.17 and –0.19 vs 0.12; p = 0.03 and p =
0.01, respectively).[118] Of the 321 subjects in this
study, we identified a cohort (n = 253) who had at
least 1 week of randomised medication (i.e. had
completed at least study week 2). In this group, we
examined whether ondansetron also had a differ-
ential effect on the craving dimension derived by
factor analysis of seven visual analogue scales. We
found that ondansetron (4 µg/kg twice daily), com-
pared with placebo, was associated with a signif-
icant decrease in the craving dimension.[119] More
recently, Kranzler and colleagues[120] have also
shown that early-onset alcoholics treated with
ondansetron (4 µg/kg twice daily) had significantly
better drinking outcomes and fewer alcohol-related
 2004 Adis Data Information BV. All rights reserved.
1111
problems compared with their late-onset alcoholic
counterparts.
In sum, our results show that ondansetron is
efficacious in treating early- but not late-onset al-
coholics, as exemplified by improved drinking out-
comes and decreased alcohol craving.
The differential effects of specific medication
treatment for a particular subtype of alcoholic are
intriguing. Ondansetron improves the drinking out-
comes of early-onset alcoholics but has no effect on
late-onset alcoholics.[118] In contrast, SSRIs improve
the drinking outcomes of late-onset[55] but not early-
onset[49] alcoholics. We have proposed an hypo-
thesis, as yet untested, that these treatment differ-
ences may be related to variations in the interaction
between allelic variants of the serotonin transporter
(SERT) and alcohol drinking in subtypes of alcohol-
ic. Genotypic variation of the SERT 5′regulatory
promoter region (5′-HTTLPR) on chromosome
17p12 consists of three types,[121-123] the long (LL),
short (SS) and heterozygous (SL) forms. While nor-
mal individuals with the LL genotype experience
facilitated serotonin uptake,[124,125] the converse ap-
pears to be the case among chronic heavy drinkers.
We have hypothesised that because (i) early-onset
alcoholics may have greater likelihood of possess-
ing the LL variant of the SERT transporter (see
Johnson[126] for a review); (ii) those with the LL
form of 5′-HTTLPR are more vulnerable to chronic
alcohol-induced reductions in SERT density;[127]
and (iii) decreased somatodendritic SERT density
and function in early-onset alcoholics with the LL
variant of 5′-HTTLPR can be associated with re-
duced serotonin firing rates (i.e. by increasing ex-
tracellular serotonin levels and correspondingly in-
creasing autoreceptor-mediated inhibition), it is rea-
sonable to predict that chronically drinking early-
onset alcoholics would have reduced trans-synaptic
serotonin neurotransmission and up-regulated
5-HT3 receptors. The therapeutic effects of ondanse-
tron may, therefore, be associated with blockade and
normalisation of these up-regulated 5-HT3 recep-
tors.[126,128] My colleagues and I recognise that alco-
holism is a multifactorial and complex disease and
that it is likely that other genotypes (even those not
CNS Drugs 2004; 18 (15)
1112
in the serotonin system) and environmental circum-
stances also may contribute to ondansetron respon-
siveness among early-onset alcoholics. However,
what we have proposed is a theoretical starting point
from which to launch future research.
6. Other 5-HT Receptor Subtypes
5-HT4 receptor antagonists may play a role in
alcohol-induced brain reward mechanisms.[129] It is,
therefore, of interest that Panocka and col-
leagues[130] have shown that subcutaneous injection
of the 5-HT4 antagonist GR113808 (1, 3 or 10 mg/
kg) significantly reduced volitional ethanol intake.
Additional animal studies are, however, needed to
establish this result. To date, no human studies on
the effects of 5-HT4 antagonists on alcohol con-
sumption have been conducted. Relatively little is
known about the effects of medications that affect
other serotonin receptor subtypes and drinking be-
haviour.
7. Combining Serotonergic Agents with
Other Types of Medication
Recently, there has been intense scientific and
clinical interest in combining therapeutic agents for
the treatment of alcohol dependence. This is based
upon the hypothesis that multiple neurochemical
pathways may be dysregulated as either ‘state’ or
‘trait’ effects of the drinking behaviour, and com-
bining effective medications working at different
neurotransmitters may produce a synergistic or at
least an added therapeutic response. Although this
hypothesis is intriguing, knowledge about how the
various neurotransmitters interact in the living brain
of alcohol-dependent individuals and how this may
differ under different stages of the addiction is not
well known. Hence, at present, the practical option
is to combine medications with some demonstrated
effectiveness in the clinical setting and determine
the treatment response.
Of the medications reviewed, perhaps the most
intriguing rationale for a combination has been de-
veloped for the addition of naltrexone (a mu opiate
antagonist) to the 5-HT3 antagonist ondansetron in
the treatment of early-onset alcoholism. This ratio-
 2004 Adis Data Information BV. All rights reserved.
Johnson
nale is supported by four streams of scientific evi-
dence. Firstly, early-onset alcoholics may have ab-
normalities at both the opioid and serotonergic sys-
tems;[57] thus, treating each of these abnormalities
with a selective agent can be expected to be asso-
ciated with a superior improvement in drinking out-
comes compared with treatment with either agent
alone.
Secondly, evidence from preclinical research
shows that there might be synergistic interactions
between the 5-HT3 and endogenous opioids in the
mesocorticolimbic dopamine reward system.[57]
Binding studies demonstrate that 5-HT3 receptors
are highly concentrated within the mesocor-
ticolimbic system, including the nucleus accum-
bens,[99,131,132] which receives its serotonergic inner-
vation from the dorsal raphe nucleus.[133] The re-
warding effects of alcohol through enhancement of
dopamine release in the nucleus accumbens are me-
diated through activation of 5-HT3 receptors.[134] It
is also known that alcohol stimulates the release of
β-endorphins and enkephalins,[135] which also pro-
duce dopamine release through activation of mu and
delta opioid receptors. Importantly, morphine can
increase ethanol intake,[136-138] and morphine-in-
duced increases in extracellular dopamine levels and
place preference are attenuated by 5-HT3 antagon-
ists.[139-142] Ondansetron also attenuates morphine-
or TAN-67 (a selective delta opioid agonist)-in-
duced enhancement of alcohol place preference, an
effect that appears greater at the mu than at the delta
opioid receptors.[143] Alcohol-induced increases in
dopamine levels can also be attenuated by both mu
and delta opioid receptor antagonists.[144] Taken to-
gether, these data suggest that 5-HT3 receptors may
themselves mediate alcohol reward via activation of
the endogenous opioid system. Additionally, the
augmentation of this effect may be due to the fact
that the opioid and 5-HT3 systems also show a
distribution that, combined, results in more exten-
sive dopaminergic modulation throughout the
mesocorticolimbic system, rather than more selec-
tively at the centrally located nucleus accumbens.
For example, while ondansetron has additional anti-
dopaminergic actions in more rostral structures such
CNS Drugs 2004; 18 (15)
Alcoholism and the Serotonergic System
as the frontal cortex, dopamine release may also be
effectively modulated at the more caudally located
ventral tegmental area through endogenous opioids.
In effect, the net result of combining ondansetron
and naltrexone would be to diminish dopamine
function across the mesocorticolimbic system axis,
thereby resulting in a synergistic effect on attenuat-
ing alcohol-induced reward. Indeed, the result of a
recent animal study demonstrates that the combina-
tion of ondansetron and naltrexone might be more
effective than either alone at reducing ethanol in-
take.[145]
Thirdly, the clinical efficacy of naltrexone is
dependent upon high levels of compliance. Com-
pliance is reduced, particularly in the early days of
treatment, by the ability of naltrexone to induce
nausea.[146] Ondansetron has both anti-nausea and
anti-emetic properties.[147,148] Therefore, it would be
reasonable to expect that the addition of ondansetron
would improve the tolerability of naltrexone.
Fourthly, apart from its actions on the mesocor-
ticolimbic system, naltrexone has other nonspecific
effects, such as those that reduce general consum-
matory behaviours. The impact of these nonspecific
naltrexone-induced reductions in general consum-
matory behaviours may play a greater role in de-
creasing alcohol consumption under conditions of
increased compliance. Hence, the combination of
ondansetron and naltrexone might be associated
with both specific and nonspecific neurobiological
changes that work together to reduce alcohol con-
sumption. As a preliminary exploration of this con-
cept, my group compared the drinking outcomes of
individuals who received ondansetron plus naltrex-
one (n = 10) with those who received placebo (n =
10). Despite the small sample size, the medication
combination was superior to placebo at reducing the
self-reported drinking outcomes of drinks per day,
drinks per drinking day, and percentage of days
abstinent,[149] an effect that was corroborated by
differentially greater decreases for the biochemical
marker among those who took the medication com-
bination.[118,150] Importantly, the treatment effect
sizes for the medication combination were large; in
contrast, effect sizes reported for ondansetron alone
 2004 Adis Data Information BV. All rights reserved.
1113
have been in the moderate range.[118] There are,
however, two important caveats to this interpreta-
tion. Firstly, the independent effects of ondansetron
versus the combination of ondansetron and naltrex-
one were not tested in the same experiment. There-
fore, even though these studies were conducted by
the same experimental group, we cannot control for
the possibility that nonspecific factors might ac-
count for these differential treatment effects. We are
not aware of any studies that have examined the
effects of naltrexone in treating early-onset al-
coholics. Secondly, although our data do not offer
direct proof that the ondansetron plus naltrexone
combination will have an additive or synergistic
effect, these results would suggest that the med-
ication combination is likely to be superior to either
alone. A large-scale study testing the independent
effects of ondansetron and naltrexone is now needed
to build upon these promising preliminary results.
Mechanistically, there are, of course, other po-
tential combinations worthy of scientific explora-
tion. For instance, animal studies suggest that while
naltrexone may reduce alcohol consumption in non-
stressed conditions, fluoxetine administration is
associated with blockade of stress-induced reinstate-
ment.[151] Although the current preclinical evidence
does not suggest that a combination of naltrexone
and fluoxetine would be superior to either alone,[152]
it is possible that the provision of these medications
in combination may be particularly useful in
humans, since fluoxetine may assist with the initial
period of post-cessation craving and anxiety, there-
by allowing more time for naltrexone to establish its
drinking-reductive effects. Obviously, the combina-
tion of an SSRI and naltrexone might be an interest-
ing area of investigation for the treatment of al-
coholics with concurrent comorbid major depres-
sion.
In sum, studying the effectiveness of combina-
tions of serotonergic agents with other types of
medication, both alone and together, is a growth
area in the pharmacotherapy field because it affords
us the potential to improve our understanding of the
biological underpinnings of alcoholism as a disease,
CNS Drugs 2004; 18 (15)
1114
and may provide promising new treatment strate-
gies.
8. Conclusions
Preclinical studies have contributed greatly to our
understanding of the neurochemical pathways asso-
ciated with the development and maintenance of
alcohol-seeking behaviour. These studies have dem-
onstrated the important role of serotonin pathways,
particularly as they relate to dopaminergic function,
which mediates alcohol-induced reward associated
with its abuse liability. Naturally, this has led to the
study of serotonergic agents as treatments for alco-
holism.
Serotonergic agents remain an intense area of
pharmacological study as treatments for alcoholism.
SSRIs do not appear to be effective treatment for a
heterogeneous alcoholic group. However, they may
be useful as treatment for late-onset alcoholics, or
alcoholism complicated by comorbid major depres-
sion. Buspirone, a 5-HT1A partial agonist, does not
appear to be an effective treatment for alcoholics
without comorbid disease. Buspirone may, how-
ever, have some utility for treating alcoholics with
comorbid anxiety disorder. The 5-HT2 antagonist
ritanserin at pharmacologically relevant clinical
doses does not appear to be an effective treatment
for alcoholism. Ondansetron, a 5-HT3 antagonist, is
an efficacious and promising medication for the
treatment of early-onset alcoholism.
The differential treatment effect of SSRIs and
ondansetron among various subtypes of alcoholic is
intriguing. Future research is needed to understand
more clearly the molecular genetic differences and
the interactions of these differences with the envi-
ronment that typify a particular alcoholic subtype.
Such an understanding could enable us to make
comfortable predictions as to which alcoholic sub-
type might respond best to a particular serotonergic
agent, which could then be provided. Relatively
little is known about the effects that medications
acting on serotonin receptor subtypes other than
those described have on drinking behaviour.
Research into adding other types of medication to
enhance the efficacy of serotonergic agents is in its
 2004 Adis Data Information BV. All rights reserved.
Johnson
infancy. Nevertheless, there appears to be promise
in combining naltrexone with ondansetron for the
treatment of early-onset alcoholism.
Acknowledgements
This work was supported by grants #AA10522-05 and
AA10522-0551 from the National Institute on Alcohol Abuse
and Alcoholism. I would also like to thank the following
colleagues affiliated with my group (alphabetical order) – Drs
N. Ait-Daoud, M. Devous, J. Hensler, M. Javors, R. Lamb,
and J. Roache – for their comments in developing this hypo-
thesis for the differential effectiveness of specific sero-
tonergic agents in treating alcoholic subtypes. I also am
grateful to Mr Robert Cormier BA for his skilled assistance in
the preparation of this manuscript. The author has no poten-
tial conflicts of interest directly related to the contents of this
review.
References
1. Audet MA, Descarries L, Doucet G. Quantified regional and
laminar distribution of the serotonin innervation in the anterior
half of adult rat cerebral cortex. J Chem Neuroanat 1989; 2:
29-44
2. Dahlstrom A, Fuxe K. Evidence for the existence of monoam-
ine-containing neurons in the central nervous system: I. Dem-
onstration of monoamines in the cell bodies of brain stem
neurons. Acta Physiol Scand 1964; 62 Suppl. 232: 1-55
3. Molliver ME. Serotonergic neuronal systems: what their ana-
tomic organization tells us about function. J Clin Psycho-
pharmacol 1987; 7: 3S-23S
4. Herve D, Pickel VM, Joh TH, et al. Serotonin axon terminals in
the ventral tegmental area of the rat: fine structure and synaptic
input to dopaminergic neurons. Brain Res 1987; 435: 71-83
5. Nedergaard S, Hopkins C, Greenfield SA. Do nigro-striatal
neurones possess a discrete dendritic modulatory mechanism?
Electrophysiological evidence from the actions of amphetam-
ine in brain slices. Exp Brain Res 1988; 69: 444-8
6. Hemby SE, Johnson BA, Dworkin SI. Neurobiological basis of
drug reinforcement. In: Johnson BA, Roache JD, editors. Drug
addiction and its treatment: nexus of neuroscience and behav-
ior. Philadelphia: Lippincott-Raven, 1997: 137-69
7. Bockaert J, Sebben M, Dumuis A. Pharmacological characteri-
zation of 5-hydroxytryptamine4 (5-HT4) receptors positively
coupled to adenylate cyclase in adult guinea pig hippocampal
membranes: effect of substituted benzamide derivatives. Mol
Pharmacol 1990; 37: 408-11
8. Ford AP, Baxter GS, Eglen RM, et al. 5-Hydroxytryptamine
stimulates cyclic AMP formation in the tunica muscularis
mucosae of the rat oesophagus via 5-HT4 receptors. Eur J
Pharmacol 1992; 211: 117-20
9. Monferini E, Gaetani P, Rodriguez y Baena R, et al. Pharmaco-
logical characterization of the 5-hydroxytryptamine receptor
coupled to adenylyl cyclase stimulation in human brain. Life
Sci 1993; 52: PL61-5
10. Grossman CJ, Kilpatrick GJ, Bunce KT. Development of a
radioligand binding assay for 5-HT4 receptors in guinea-pig
and rat brain. Br J Pharmacol 1993; 109: 618-24
CNS Drugs 2004; 18 (15)
Alcoholism and the Serotonergic System
11. Roychowdhury S, Haas H, Anderson EG. 5-HT1A and 5-HT4
receptor colocalization on hippocampal pyramidal cells.
Neuropharmacology 1994; 33: 551-7
12. Waeber C, Sebben M, Grossman C, et al. [3H]-GR113808
labels 5-HT4 receptors in the human and guinea-pig brain.
Neuroreport 1993; 4: 1239-42
13. Waeber C, Sebben M, Nieoullon A, et al. Regional distribution
and ontogeny of 5-HT4 binding sites in rodent brain. Neuro-
pharmacology 1994; 33: 527-41
14. Andrade R, Chaput Y. 5-Hydroxytryptamine4-like receptors
mediate the slow excitatory response to serotonin in the rat
hippocampus. J Pharmacol Exp Ther 1991; 257: 930-7
15. Chaput Y, Araneda RC, Andrade R. Pharmacological and func-
tional analysis of a novel serotonin receptor in the rat hippo-
campus. Eur J Pharmacol 1990; 182: 441-56
16. Steward LJ, Brown DC, Stokes PR, et al. Antagonism of the (S)-
zacopride-induced increase in dopamine release from rat
striatal slices by the 5-HT receptor antagonist SDZ 205-557
[abstract]. Third International Union of Pharmacology Satel-
lite Meeting on Serotonin; 1994 Jul 30-Aug 3; Chicago: 84
17. Steward LJ, Barnes NM. The 5-HT4 receptor agonists
renzapride and (S)-zacopride stimulate dopamine release from
rat striatal slices [abstract]. Br J Pharmacol 1994; 111 Suppl.:
155P
18. Myers RD, Veale WL. Alcohol preference in the rat: reduction
following depletion of brain serotonin. Science 1968; 160:
1469-71
19. Nachman M, Lester D, Le Magnen J. Alcohol aversion in the
rat: behavioral assessment of noxious drug effects. Science
1970; 168: 1244-6
20. Daoust M, Chretien P, Moore N, et al. Isolation and striatal
(3H) serotonin uptake: role in the voluntary intake of ethanol
by rats. Pharmacol Biochem Behav 1985; 22: 205-8
21. Geller I. Effects of para-chlorophenylalanine and 5-hydroxy-
tryptophan on alcohol intake in the rat. Pharmacol Biochem
Behav 1973; 1: 361-5
22. Gill K, Amit Z, Koe BK. Treatment with sertraline, a new
serotonin uptake inhibitor, reduces voluntary ethanol con-
sumption in rats. Alcohol 1988; 5: 349-54
23. Gill K, Filion Y, Amit Z. A further examination of the effects of
sertraline on voluntary ethanol consumption. Alcohol 1988; 5:
355-8
24. Zabik JE, Binkerd K, Roache JD. Serotonin and ethanol aver-
sion in the rat. In: Naranjo CA, Sellers EM, editors. Research
advances in new psychopharmacological treatments for alco-
holism: proceedings of the symposium; 1984 Oct 4-5; Toronto.
Amsterdam: Excerpta Medica, 1985
25. Blundell JE, Latham CJ. Behavioural pharmacology of feeding.
In: Silverstone T, editor. Drugs and appetite. London: Aca-
demic Press, 1982
26. Blundell JE. Serotonin and appetite. Neuropharmacology 1984;
23: 1537-51
27. Gill K, Amit Z. Serotonin uptake blockers and voluntary alcohol
consumption: a review of recent studies. Recent Dev Alcohol
1989; 7: 225-48
28. Gottfries CG. Influence of depression and antidepressants on
weight. Acta Psychiatr Scand Suppl 1981; 290: 353-6
29. Simpson RJ, Lawton DJ, Watt MH, et al. Effect of zimelidine, a
new antidepressant, on appetite and body weight. Br J Clin
Pharmacol 1981; 11: 96-8
30. Leander JD. Fluoxetine suppresses palatability-induced inges-
tion. Psychopharmacology 1987; 91: 285-7
 2004 Adis Data Information BV. All rights reserved.
1115
31. Stellar JR, Stellar E. The neurobiology of motivation and re-
ward. New York: Springer-Verlag, 1985
32. Barreto Medeiros JM, Cabral Filho JE, De Souza SL, et al.
Early malnourished rats are not affected by anorexia induced
by a selective serotonin reuptake inhibitor in adult life. Nutr
Neurosci 2002; 5: 211-4
33. Wurtman JJ, Wurtman RJ. Fenfluramine and fluoxetine spare
protein consumption while suppressing caloric intake by rats.
Science 1977; 198: 1178-80
34. Wurtman JJ, Wurtman RJ. Drugs that enhance central sero-
toninergic transmission diminish elective carbohydrate con-
sumption by rats. Life Sci 1979; 24: 895-903
35. Li ET, Anderson GH. 5-Hydroxytryptamine control of meal to
meal composition chosen by rats. Fed Proc 1983; 42: 542-8
36. Smith GP. The physiology of the meal. In: Silverstone T, editor.
Drugs and appetite. London: Academic Press, 1982
37. Fantino M. Role of sensory input in the control of food intake. J
Auton Nerv Syst 1984; 10: 347-58
38. Wise RA, Raptis L. Effects of pre-feeding on food-approach
latency and food consumption speed in food deprived rats.
Physiol Behav 1985; 35: 961-3
39. Haraguchi M, Samson HH, Tolliver GA. Reduction in oral
ethanol self-administration in the rat by the 5-HT uptake
blocker fluoxetine. Pharmacol Biochem Behav 1990; 35:
259-62
40. Murphy JM, Waller MB, Gatto GJ, et al. Effects of fluoxetine
on the intragastric self-administration of ethanol in the alcohol
preferring P line of rats. Alcohol 1988; 5: 283-6
41. Naranjo CA, Sellers EM, Roach CA, et al. Zimelidine-induced
variations in alcohol intake by nondepressed heavy drinkers.
Clin Pharmacol Ther 1984; 35: 374-81
42. Naranjo CA, Sellers EM, Sullivan JT, et al. The serotonin
uptake inhibitor citalopram attenuates ethanol intake. Clin
Pharmacol Ther 1987; 41: 266-74
43. Naranjo CA, Sellers EM. Serotonin uptake inhibitors attenuate
ethanol intake in problem drinkers. Recent Dev Alcohol 1989;
7: 255-66
44. Naranjo CA, Kadlec KE, Sanhueza P, et al. Fluoxetine differen-
tially alters alcohol intake and other consummatory behaviors
in problem drinkers. Clin Pharmacol Ther 1990; 47: 490-8
45. Naranjo CA, Poulos CX, Bremner KE, et al. Citalopram de-
creases desirability, liking, and consumption of alcohol in
alcohol-dependent drinkers. Clin Pharmacol Ther 1992; 51:
729-39
46. Gorelick DA, Paredes A. Effect of fluoxetine on alcohol con-
sumption in male alcoholics. Alcohol Clin Exp Res 1992; 16:
261-5
47. Naranjo CA, Bremner KE, Lanctot KL. Effects of citalopram
and a brief psycho-social intervention on alcohol intake, de-
pendence and problems. Addiction 1995; 90: 87-99
48. Kabel DI, Petty F. A placebo-controlled, double-blind study of
fluoxetine in severe alcohol dependence: adjunctive pharma-
cotherapy during and after inpatient treatment. Alcohol Clin
Exp Res 1996; 20: 780-4
49. Kranzler HR, Burleson JA, Korner P, et al. Placebo-controlled
trial of fluoxetine as an adjunct to relapse prevention in al-
coholics. Am J Psychiatry 1995; 152: 391-7
50. Buydens-Branchey L, Branchey MH, Noumair D. Age of alco-
holism onset: I. Relationship to psychopathology. Arch Gen
Psychiatry 1989; 46: 225-30
51. Linnoila M, Virkkunen M. Biologic correlates of suicidal risk
and aggressive behavioral traits. J Clin Psychopharmacol
1992; 12 (2 Suppl.): 19S-20S
CNS Drugs 2004; 18 (15)
1116
52. Linnoila M, De Jong J, Virkkunen M. Family history of alcohol-
ism in violent offenders and impulsive fire setters. Arch Gen
Psychiatry 1989; 46: 613-6
53. Fils-Aime ML, Eckardt MJ, George DT, et al. Early-onset
alcoholics have lower cerebrospinal fluid 5-hydroxy-
indoleacetic acid levels than late-onset alcoholics. Arch Gen
Psychiatry 1996; 53: 211-6
54. Kranzler HR, Burleson JA, Brown J, et al. Fluoxetine treatment
seems to reduce the beneficial effects of cognitive-behavioral
therapy in type B alcoholics. Alcohol Clin Exp Res 1996; 20:
1534-41
55. Pettinati HM, Volpicelli JR, Kranzler HR, et al. Sertraline
treatment for alcohol dependence: interactive effects of med-
ication and alcoholic subtype. Alcohol Clin Exp Res 2000; 24:
1041-9
56. Johnson BA, Cloninger CR, Roache JD, et al. Age of onset as a
discriminator between alcoholic subtypes in a treatment-seek-
ing outpatient population. Am J Addict 2000; 9: 17-27
57. Johnson BA, Ait-Daoud N. Neuropharmacological treatments
for alcoholism: scientific basis and clinical findings. Psycho-
pharmacology 2000; 149: 327-44
58. Cornelius JR, Salloum IM, Ehler JG, et al. Fluoxetine in
depressed alcoholics: a double-blind, placebo-controlled trial.
Arch Gen Psychiatry 1997; 54: 700-5
59. Mason BJ, Kocsis JH, Ritvo EC, et al. A double-blind, placebo-
controlled trial of desipramine for primary alcohol dependence
stratified on the presence or absence of major depression.
JAMA 1996; 275: 761-7
60. McGrath PJ, Nunes EV, Stewart JW, et al. Imipramine treat-
ment of alcoholics with primary depression: a placebo-control-
led clinical trial. Arch Gen Psychiatry 1996; 53: 232-40
61. Pettinati HM, Volpicelli JR, Luck G, et al. Double-blind
clinical trial of sertraline treatment for alcohol dependence. J
Clin Psychopharmacol 2001; 21: 143-53
62. Collins DM, Myers RD. Buspirone attenuates volitional alcohol
intake in the chronically drinking monkey. Alcohol 1987; 4:
49-56
63. Privette TH, Hornsby RL, Myers RD. Buspirone alters alcohol
drinking induced in rats by tetrahydropapaveroline injected
into brain monoaminergic pathways. Alcohol 1988; 5: 147-52
64. Meert TF. Effects of various serotonergic agents on alcohol
intake and alcohol preference in Wistar rats selected at two
different levels of alcohol preference. Alcohol Alcohol 1993;
28: 157-70
65. Wilson AW, Costall B, Neill JC. Manipulation of operant re-
sponding for an ethanol-paired conditioned stimulus in the rat
by pharmacological alteration of the serotonergic system. J
Psychopharmacol 2000; 14: 340-6
66. Rezvani AH, Overstreet DH, Janowsky DS. Genetic serotonin
deficiency and alcohol preference in the fawn hooded rats.
Alcohol Alcohol 1990; 25: 573-5
67. Gongwer MA, Murphy JM, McBride WJ, et al. Regional brain
contents of serotonin, dopamine and their metabolites in the
selectively bred high- and low-alcohol drinking lines of rats.
Alcohol 1989; 6: 317-20
68. McBride WJ, Bodart B, Lumeng L, et al. Association between
low contents of dopamine and serotonin in the nucleus accum-
bens and high alcohol preference. Alcohol Clin Exp Res 1995;
19: 1420-2
69. Korpi ER, Paivarinta P, Abi-Dargham A, et al. Binding of
serotonergic ligands to brain membranes of alcohol-preferring
AA and alcohol-avoiding ANA rats. Alcohol 1992; 9: 369-74
 2004 Adis Data Information BV. All rights reserved.
Johnson
70. Blier P, Ward NM. Is there a role for 5-HT1A agonists in the
treatment of depression? Biol Psychiatry 2003; 53: 193-203
71. Malcolm R, Anton RF, Randall CL, et al. A placebo-controlled
trial of buspirone in anxious inpatient alcoholics. Alcohol Clin
Exp Res 1992; 16: 1007-13
72. Kranzler HR, Burleson JA, Del Boca FK, et al. Buspirone
treatment of anxious alcoholics: a placebo-controlled trial.
Arch Gen Psychiatry 1994; 51: 720-31
73. Bruno F. Buspirone in the treatment of alcoholic patients.
Psychopathology 1989; 22 Suppl. 1: 49-59
74. Malec TS, Malec EA, Dongier M. Efficacy of buspirone in
alcohol dependence: a review. Alcohol Clin Exp Res 1996; 20:
853-8
75. George DT, Rawlings R, Eckardt MJ, et al. Buspirone treatment
of alcoholism: age of onset, and cerebrospinal fluid 5-hydroxy-
indolacetic acid and homovanillic acid concentrations, but not
medication treatment, predict return to drinking. Alcohol Clin
Exp Res 1999; 23: 272-8
76. Meert TF, Awouters F, Niemegeers CJ, et al. Ritanserin reduces
abuse of alcohol, cocaine, and fentanyl in rats. Pharmacop-
sychiatry 1991; 24: 159-63
77. Myers RD, Lankford M, Bjork A. Selective reduction by the
5-HT antagonist amperozide of alcohol preference induced in
rats by systemic cyanamide. Pharmacol Biochem Behav 1992;
43: 661-7
78. Svensson L, Fahlke C, Hard E, et al. Involvement of the
serotonergic system in ethanol intake in the rat. Alcohol 1993;
10: 219-24
79. Myers RD, Lankford MF. Suppression of alcohol preference in
high alcohol drinking rats: efficacy of amperozide versus
naltrexone. Neuropsychopharmacology 1996; 14: 139-49
80. Myers RD, Lankford M. Action of the 5-HT2A antagonist
amperozide on alcohol-induced poikilothermia in rats.
Pharmacol Biochem Behav 1998; 59: 91-5
81. Biggs TA, Myers RD. Naltrexone and amperozide modify choc-
olate and saccharin drinking in high alcohol-preferring P rats.
Pharmacol Biochem Behav 1998; 60: 407-13
82. Overstreet DH, McArthur RA, Rezvani AH, et al. Selective
inhibition of alcohol intake in diverse alcohol-preferring rat
strains by the 5-HT2A antagonists amperozide and FG 5974.
Alcohol Clin Exp Res 1997; 21: 1448-54
83. Lankford MF, Bjork AK, Myers RD. Differential efficacy of
serotonergic drugs FG5974, FG5893, and amperozide in re-
ducing alcohol drinking in P rats. Alcohol 1996; 13: 399-404
84. Ugedo L, Grenhoff J, Svensson TH. Ritanserin, a 5-HT2 recep-
tor antagonist, activates midbrain dopamine neurons by block-
ing serotonergic inhibition. Psychopharmacology 1989; 98:
45-50
85. Awouters F, Niemegeers CJ, Megens AA, et al. The pharmaco-
logical profile of ritanserin, a very specific central serotonin-
S2 antagonist. Drug Dev Res 1988; 15: 61-73
86. Johnson BA, Jasinski DR, Galloway GP, et al. Ritanserin in the
treatment of alcohol dependence: a multi-center clinical trial.
Ritanserin Study Group. Psychopharmacology 1996; 128:
206-15
87. Wiesbeck GA, Weijers HG, Chick J, et al. Ritanserin in relapse
prevention in abstinent alcoholics: results from a placebo-
controlled double-blind international multicenter trial. Ritan-
serin in Alcoholism Work Group. Alcohol Clin Exp Res 1999;
23: 230-5
88. LeMarquand D, Pihl RO, Benkelfat C. Serotonin and alcohol
intake, abuse, and dependence: clinical evidence. Biol Psychi-
atry 1994; 36: 326-37
CNS Drugs 2004; 18 (15)
Alcoholism and the Serotonergic System
89. Lovinger DM, White G. Ethanol potentiation of 5-hydroxy-
tryptamine3 receptor-mediated ion current in neuroblastoma
cells and isolated adult mammalian neurons. Mol Pharmacol
1991; 40: 263-70
90. Zhou Q, Lovinger DM. Pharmacologic characteristics of poten-
tiation of 5-HT3 receptors by alcohols and diethyl ether in
NCB-20 neuroblastoma cells. J Pharmacol Exp Ther 1996;
278: 732-40
91. Lovinger DM, Zhou Q. Alcohols potentiate ion current medi-
ated by recombinant 5-HT3RA receptors expressed in a mam-
malian cell line. Neuropharmacology 1994; 33: 1567-72
92. Lovinger DM. Inhibition of 5-HT3 receptor-mediated ion cur-
rent by divalent metal cations in NCB-20 neuroblastoma cells.
J Neurophysiol 1991; 66: 1329-37
93. Lovinger DM. Ethanol potentiates ion current mediated by
5-HT3 receptors on neuroblastoma cells and isolated neurons.
Alcohol Alcohol Suppl 1991; 1: 181-5
94. Lovinger DM. 5-HT3 receptors and the neural actions of alco-
hols: an increasingly exciting topic. Neurochem Int 1999; 35:
125-30
95. Di Chiara G, Imperato A. Drugs abused by humans preferential-
ly increase synaptic dopamine concentrations in the
mesolimbic system of freely moving rats. Proc Natl Acad Sci
U S A 1988; 85: 5274-8
96. Koob GF. Neural mechanisms of drug reinforcement. Ann N Y
Acad Sci 1992; 654: 171-91
97. Wise RA, Bozarth MA. A psychomotor stimulant theory of
addiction. Psychol Rev 1987; 94: 469-92
98. Bloom FE, Morales M. The central 5-HT3 receptor in CNS
disorders. Neurochem Res 1998; 23: 653-9
99. Kilpatrick GJ, Jones BJ, Tyers MB. Identification and distribu-
tion of 5-HT3 receptors in rat brain using radioligand binding.
Nature 1987; 330: 746-8
100. Kilpatrick GJ, Hagan RM, Gale JD. 5-HT3 and 5-HT4 receptors
in terminal regions of the mesolimbic system. Behav Brain Res
1996; 73: 11-3
101. Oxford AW, Bell JA, Kilpatrick GJ, et al. Ondansetron and
related 5-HT3 antagonists: recent advances. Prog Med Chem
1992; 29: 239-70
102. Barnes NM, Sharp T. A review of central 5-HT receptors and
their function. Neuropharmacology 1999; 38: 1083-152
103. Johnson BA, Cowen PJ. Alcohol-induced reinforcement: dop-
amine and 5-HT3 receptor interactions in animals and humans.
Drug Dev Res 1993; 30: 153-69
104. Bradbury AJ, Costall B, Domeney AM, et al. Laterality of
dopamine function and neuroleptic action in the amygdala in
the rat. Neuropharmacology 1985; 24: 1163-70
105. Hagan RM, Jones BJ, Jordan CC, et al. Effect of 5-HT3
receptor antagonists on responses to selective activation of
mesolimbic dopaminergic pathways in the rat. Br J Pharmacol
1990; 99: 227-32
106. Eison AS, Iversen SD, Sandberg BE, et al. Substance P analog,
DiMe-C7: evidence for stability in rat brain and prolonged
central actions. Science 1982; 215: 188-90
107. Costall B, Domeney AM, Naylor RJ, et al. Effects of the 5-HT3
receptor antagonist, GR38032F, on raised dopaminergic ac-
tivity in the mesolimbic system of the rat and marmoset brain.
Br J Pharmacol 1987; 92: 881-94
108. Hodge CW, Samson HH, Lewis RS, et al. Specific decreases in
ethanol- but not water-reinforced responding produced by the
5-HT3 antagonist ICS 205-930. Alcohol 1993; 10: 191-6
109. Fadda F, Garau B, Marchei F, et al. MDL 72222, a selective
5-HT3 receptor antagonist, suppresses voluntary ethanol con-
 2004 Adis Data Information BV. All rights reserved.
1117
sumption in alcohol-preferring rats. Alcohol Alcohol 1991; 26:
107-10
110. Rodd-Henricks ZA, McKinzie DL, Li T-K, et al. Intracranial
self-administration of ethanol into the posterior VTA of Wistar
rats is mediated by 5-HT3 receptors [abstract]. Alcohol Clin
Exp Res 1999; 23 Suppl. 5: 49A
111. McBride WJ, Li TK. Animal models of alcoholism: neurobiolo-
gy of high alcohol-drinking behavior in rodents. Crit Rev
Neurobiol 1998; 12: 339-69
112. Tomkins DM, Le AD, Sellers EM. Effect of the 5-HT3 ant-
agonist ondansetron on voluntary ethanol intake in rats and
mice maintained on a limited access procedure. Psycho-
pharmacology 1995; 117: 479-85
113. Beardsley PM, Lopez OT, Gullikson G, et al. Serotonin 5-HT3
antagonists fail to affect ethanol self-administration of rats.
Alcohol 1994; 11: 389-95
114. Johnson BA, Campling GM, Griffiths P, et al. Attenuation of
some alcohol-induced mood changes and the desire to drink by
5-HT3 receptor blockade: a preliminary study in healthy male
volunteers. Psychopharmacology 1993; 112: 142-4
115. Swift RM, Davidson D, Whelihan W, et al. Ondansetron alters
human alcohol intoxication. Biol Psychiatry 1996; 40: 514-21
116. Doty P, Zacny JP, de Wit H. Effects of ondansetron pretreat-
ment on acute responses to ethanol in social drinkers. Behav
Pharmacol 1994; 5: 461-9
117. Sellers EM, Toneatto T, Romach MK, et al. Clinical efficacy of
the 5-HT3 antagonist ondansetron in alcohol abuse and de-
pendence. Alcohol Clin Exp Res 1994; 18: 879-85
118. Johnson BA, Roache JD, Javors MA, et al. Ondansetron for
reduction of drinking among biologically predisposed alcohol-
ic patients: a randomized controlled trial. JAMA 2000; 284:
963-71
119. Johnson BA, Roache JD, Ait-Daoud N, et al. Ondansetron
reduces the craving of biologically predisposed alcoholics.
Psychopharmacology 2002; 160: 408-13
120. Kranzler HR, Pierucci-Lagha A, Feinn R, et al. Effects of
ondansetron in early- versus late-onset alcoholics: a prospec-
tive, open-label study. Alcohol Clin Exp Res 2003; 27: 1150-5
121. Heils A, Teufel A, Petri S, et al. Allelic variation of human
serotonin transporter gene expression. J Neurochem 1996; 66:
2621-4
122. Heils A, Mossner R, Lesch KP. The human serotonin transport-
er gene polymorphism: basic research and clinical implica-
tions. J Neural Transm 1997; 104: 1005-14
123. Lesch KP, Meyer J, Glatz K, et al. The 5-HT transporter gene-
linked polymorphic region (5-HTTLPR) in evolutionary per-
spective. Alternative biallelic variation in rhesus monkeys:
rapid communication. J Neural Transm 1997; 104: 1259-66
124. Greenberg BD, Tolliver TJ, Huang SJ, et al. Genetic variation
in the serotonin transporter promoter region affects serotonin
uptake in human blood platelets. Am J Med Genet 1999; 88:
83-7
125. Lesch KP, Bengel D, Heils A, et al. Association of anxiety-
related traits with a polymorphism in the serotonin transporter
gene regulatory region. Science 1996; 274: 1527-31
126. Johnson BA. Serotonergic agents and alcoholism treatment:
rebirth of the subtype concept: an hypothesis. Alcohol Clin
Exp Res 2000; 24: 1597-601
127. Heinz A, Jones DW, Mazzanti C, et al. A relationship between
serotonin transporter genotype and in vivo protein expression
and alcohol neurotoxicity. Biol Psychiatry 2000; 47: 643-9
CNS Drugs 2004; 18 (15)
1118
128. Enoch M-A, Schuckit MA, Johnson BA, et al. Genetics of
alcoholism using intermediate phenotypes. Alcohol Clin Exp
Res 2003; 27: 169-76
129. Bisaga A, Sikora J, Kostowski W. The effect of drugs interact-
ing with serotonergic 5HT3 and 5HT4 receptors on morphine
place conditioning. Pol J Pharmacol 1993; 45: 513-9
130. Panocka I, Ciccocioppo R, Polidori C, et al. The 5-HT4 receptor
antagonist, GR113808, reduces ethanol intake in alcohol-pre-
ferring rats. Pharmacol Biochem Behav 1995; 52: 255-9
131. Barnes JM, Barnes NM, Champaneria S, et al. Characterisation
and autoradiographic localisation of 5-HT3 receptor recogni-
tion sites identified with [3H]-(S)-zacopride in the forebrain of
the rat. Neuropharmacology 1990; 29: 1037-45
132. Perry DC. Autoradiography of [3H]quipazine in rodent brain.
Eur J Pharmacol 1990; 187: 75-85
133. Yoshimoto K, McBride WJ. Regulation of nucleus accumbens
dopamine release by the dorsal raphe nucleus in the rat.
Neurochem Res 1992; 17: 401-7
134. Campbell AD, McBride WJ. Serotonin-3 receptor and ethanol-
stimulated dopamine release in the nucleus accumbens.
Pharmacol Biochem Behav 1995; 51: 835-42
135. Gianoulakis C. The effect of ethanol on the biosynthesis and
regulation of opioid peptides. Experientia 1989; 45: 428-35
136. Reid LD, Hunter GA. Morphine and naloxone modulate intake
of ethanol. Alcohol 1984; 1: 33-7
137. Hubbell CL, Czirr SA, Reid LD. Persistence and specificity of
small doses of morphine on intake of alcoholic beverages.
Alcohol 1987; 4: 149-56
138. Hubbell CL, Czirr SA, Hunter GA, et al. Consumption of
ethanol solution is potentiated by morphine and attenuated by
naloxone persistently across repeated daily administrations.
Alcohol 1986; 3: 39-54
139. Carboni E, Acquas E, Leone P, et al. 5-HT3 receptor antagon-
ists block morphine- and nicotine-induced place-preference
conditioning. Eur J Pharmacol 1988; 151: 159-60
140. Carboni E, Acquas E, Frau R, et al. Differential inhibitory
effects of a 5-HT3 antagonist on drug-induced stimulation of
dopamine release. Eur J Pharmacol 1989; 164: 515-9
141. Imperato A, Angelucci L. 5-HT3 receptors control dopamine
release in the nucleus accumbens of freely moving rats.
Neurosci Lett 1989; 101: 214-7
142. Pei Q, Zetterstrom T, Leslie RA, et al. 5-HT3 receptor antagon-
ists inhibit morphine-induced stimulation of mesolimbic dop-
 2004 Adis Data Information BV. All rights reserved.
Johnson
amine release and function in the rat. Eur J Pharmacol 1993;
230: 63-8
143. Matsuzawa S, Suzuki T, Misawa M, et al. Roles of 5-HT3 and
opioid receptors in the ethanol-induced place preference in rats
exposed to conditioned fear stress. Life Sci 1999; 64: PL241-9
144. Widdowson PS, Holman RB. Ethanol-induced increase in en-
dogenous dopamine release may involve endogenous opiates. J
Neurochem 1992; 59: 157-63
145. Le AD, Sellers EM. Interaction between opiate and 5-HT3
receptor antagonists in the regulation of alcohol intake. Alco-
hol Alcohol Suppl 1994; 2: 545-9
146. Volpicelli JR, Rhines KC, Rhines JS, et al. Naltrexone and
alcohol dependence: role of subject compliance. Arch Gen
Psychiatry 1997; 54: 737-42
147. Gale JD. Serotonergic mediation of vomiting. J Pediatr Gas-
troenterol Nutr 1995; 21 Suppl. 1: S22-8
148. Wilde MI, Markham A. Ondansetron: a review of its pharmacol-
ogy and preliminary clinical findings in novel applications.
Drugs 1996; 52: 773-94
149. Johnson BA, Ait-Daoud N, Prihoda TJ. Combining ondansetron
and naltrexone effectively treats biologically predisposed al-
coholics: from hypotheses to preliminary clinical evidence.
Alcohol Clin Exp Res 2000; 24: 737-42
150. Ait-Daoud N, Johnson BA, Javors M, et al. Combining ondan-
setron and naltrexone treats biological alcoholics: corrobora-
tion of self-reported drinking by serum carbohydrate deficient
transferrin, a biomarker. Alcohol Clin Exp Res 2001; 25:
847-9
151. Le AD, Poulos CX, Harding S, et al. Effects of naltrexone and
fluoxetine on alcohol self-administration and reinstatement of
alcohol seeking induced by priming injections of alcohol and
exposure to stress. Neuropsychopharmacology 1999; 21:
435-44
152. Gardell LR, Whalen CA, Chattophadyay S, et al. Combination
of naltrexone and fluoxetine on rats’ propensity to take alco-
holic beverage. Alcohol Clin Exp Res 1997; 21: 1435-9
Correspondence and offprints: Dr Bankole A. Johnson, De-
partment of Psychiatric Medicine, University of Virginia,
PO Box 800623, Charlottesville, VA 22908-0623, USA.
E-mail: bankolejohnson@virginia.edu
CNS Drugs 2004; 18 (15)