FOSB

Protein fosB, also known as FosB and G0/G1 switch

regulatory protein 3 (G0S3), is a protein that in humans is
encoded by the FBJ murine osteosarcoma viral oncogene
homolog B (FOSB) gene.[5][6][7]
The FOS gene family consists of four members: FOS, FOSB,
FOSL1, and FOSL2. These genes encode leucine zipper
proteins that can dimerize with proteins of the JUN family
(e.g., c-Jun, JunD), thereby forming the transcription factor
complex AP-1. As such, the FOS proteins have been
implicated as regulators of cell proliferation, differentiation,
and transformation.[5] FosB and its truncated splice variants,
ΔFosB and further truncated Δ2ΔFosB, are all involved in
osteosclerosis, although Δ2ΔFosB lacks a known
transactivation domain, in turn preventing it from affecting
transcription through the AP-1 complex.[8]
FOSB
Identifiers
Aliases FOSB (https://www.genenames.org/cgi-bin/gene_symb
ol_report?hgnc_id=3797), AP-1, G0S3, GOS3, GOSB,
FosB, ΔFosB, FosB proto-oncogene, AP-1
transcription factor subunit
External MGI: 95575 (http://www.informatics.jax.org/marker/MG
IDs I:95575) HomoloGene: 31403 (https://www.ncbi.nlm.ni
h.gov/entrez/query.fcgi?cmd=Retrieve&db=homologen
e&dopt=HomoloGene&list_uids=31403) GeneCards:
FOSB (https://www.genecards.org/cgi-bin/carddisp.pl?
gene=FOSB)
Gene location (Human)

The ΔFosB splice variant has been identified as playing a

central, crucial (necessary and sufficient)[9][10] role in the
development and maintenance of addiction.[9][11][12] ΔFosB
overexpression (i.e., an abnormally and excessively high
level of ΔFosB expression which produces a pronounced
Chr. Chromosome 19 (human)[1]
gene-related phenotype) triggers the development of
addiction-related neuroplasticity throughout the reward
system and produces a behavioral phenotype that is
characteristic of an addiction.[9][12][13] ΔFosB differs from
the full length FosB and further truncated Δ2ΔFosB in its Band 19q13.32 Start 45,467,995 bp[1]
capacity to produce these effects, as only accumbal ΔFosB End 45,475,179 bp[1]
overexpression is associated with pathological responses to
Gene location (Mouse)
drugs.[14]

Contents
DeltaFosB
Role in addiction
Chr. Chromosome 7 (mouse)[2]
Plasticity in cocaine addiction
Summary of addiction-related plasticity
Other functions in the brain
See also
Band 7 A3|7 9.56 cM Start 19,302,696 bp[2]
Notes
References
End 19,310,051 bp[2]

Further reading RNA expression pattern

External links

DeltaFosB
DeltaFosB – more commonly written as ΔFosB – is a
truncated splice variant of the FOSB gene.[15] ΔFosB has
been implicated as a critical factor in the development of
virtually all forms of behavioral and drug
addictions.[10][11][16] In the brain's reward system, it is
linked to changes in a number of other gene products, such as
CREB and sirtuins.[17][18][19] In the body, ΔFosB regulates
the commitment of mesenchymal precursor cells to the
adipocyte or osteoblast lineage.[20]
In the nucleus accumbens, ΔFosB functions as a "sustained
molecular switch" and "master control protein" in the
development of an addiction.[9][21][22] In other words, once
"turned on" (sufficiently overexpressed) ΔFosB triggers a
series of transcription events that ultimately produce an
addictive state (i.e., compulsive reward-seeking involving a
particular stimulus); this state is sustained for months after
cessation of drug use due to the abnormal and exceptionally
long half-life of ΔFosB isoforms.[9][21][22] ΔFosB expression
in D1-type nucleus accumbens medium spiny neurons
directly and positively regulates drug self-administration and
reward sensitization through positive reinforcement while
decreasing sensitivity to aversion.[9][12] Based upon the
accumulated evidence, a medical review from late 2014
argued that accumbal ΔFosB expression can be used as an
addiction biomarker and that the degree of accumbal ΔFosB
induction by a drug is a metric for how addictive it is relative
to others.[9]
More reference expression data (http://biogps.org/gene/2354/)
Gene ontology
Molecular • DNA binding (http://amigo.geneontology.org/amig
function o/term/GO:0003677)
• sequence-specific DNA binding (http://amigo.gene
ontology.org/amigo/term/GO:0043565)
• transcription factor activity, sequence-specific
DNA binding (http://amigo.geneontology.org/amigo/t
erm/GO:0003700)
• transcriptional activator activity, RNA polymerase
II core promoter proximal region sequence-specific
binding (http://amigo.geneontology.org/amigo/term/
GO:0001077)
• transcription factor binding (http://amigo.geneontol
ogy.org/amigo/term/GO:0008134)
• double-stranded DNA binding (http://amigo.geneo
ntology.org/amigo/term/GO:0003690)
• RNA polymerase II core promoter proximal region
sequence-specific DNA binding (http://amigo.geneo
ntology.org/amigo/term/GO:0000978)
• RNA polymerase II transcription factor activity,
sequence-specific DNA binding (http://amigo.geneo
ntology.org/amigo/term/GO:0000981)
• transcriptional activator activity, RNA polymerase
II transcription regulatory region sequence-specific
binding (http://amigo.geneontology.org/amigo/term/
GO:0001228)
Cellular • intracellular membrane-bounded organelle (http://
component amigo.geneontology.org/amigo/term/GO:0043231)
• cell nucleus (http://amigo.geneontology.org/amigo/
term/GO:0005634)
• nucleoplasm (http://amigo.geneontology.org/amig
o/term/GO:0005654)
Biological • cellular response to calcium ion (http://amigo.gene
process ontology.org/amigo/term/GO:0071277)
• regulation of transcription, DNA-templated (http://a
migo.geneontology.org/amigo/term/GO:0006355)
• regulation of transcription from RNA polymerase II
promoter (http://amigo.geneontology.org/amigo/ter
m/GO:0006357)
• response to progesterone (http://amigo.geneontol
ogy.org/amigo/term/GO:0032570)
 • female pregnancy (http://amigo.geneontology.org/
amigo/term/GO:0007565)
• response to corticosterone (http://amigo.geneontol
ogy.org/amigo/term/GO:0051412)
• response to mechanical stimulus (http://amigo.gen
eontology.org/amigo/term/GO:0009612)
• negative regulation of transcription from RNA
polymerase II promoter (http://amigo.geneontology.
org/amigo/term/GO:0000122)
• transcription from RNA polymerase II promoter (ht
tp://amigo.geneontology.org/amigo/term/GO:000636
6)
• response to morphine (http://amigo.geneontology.
org/amigo/term/GO:0043278)
• cellular response to hormone stimulus (http://amig
o.geneontology.org/amigo/term/GO:0032870)
• response to cAMP (http://amigo.geneontology.org/
amigo/term/GO:0051591)
• response to drug (http://amigo.geneontology.org/a
migo/term/GO:0042493)
• positive regulation of transcription from RNA
polymerase II promoter (http://amigo.geneontology.
org/amigo/term/GO:0045944)
Sources:Amigo (http://amigo.geneontology.org/) / QuickGO (http
s://www.ebi.ac.uk/QuickGO/)

Orthologs
Species Human Mouse
Entrez
2354 (https://www.ncbi.nlm. 14282 (https://www.ncbi.nl
nih.gov/entrez/query.fcgi?d m.nih.gov/entrez/query.fcg
b=gene&cmd=retrieve&dop i?db=gene&cmd=retrieve&
t=default&list_uids=2354&r dopt=default&list_uids=142
n=1) 82&rn=1)

Ensembl
ENSG00000125740 (http://
www.ensembl.org/Homo_s
apiens/geneview?gene=EN
SG00000125740;db=core)
ENSMUSG00000003545
(http://www.ensembl.org/M
us_musculus/geneview?ge
ne=ENSMUSG000000035
45;db=core)

UniProt
P53539 (https://www.unipro P13346 (https://www.unipro
t.org/uniprot/P53539) t.org/uniprot/P13346)

RefSeq
NM_001114171 (https://ww
(mRNA)
w.ncbi.nlm.nih.gov/entrez/vi
ewer.fcgi?val=NM_001114
171)
NM_006732 (https://www.n
cbi.nlm.nih.gov/entrez/view
er.fcgi?val=NM_006732)
NM_008036 (https://www.n
cbi.nlm.nih.gov/entrez/view
er.fcgi?val=NM_008036)
NM_001347586 (https://ww
w.ncbi.nlm.nih.gov/entrez/vi
ewer.fcgi?val=NM_001347
586)
 RefSeq
NP_001107643 (https://ww
(protein)
w.ncbi.nlm.nih.gov/entrez/vi
ewer.fcgi?val=NP_0011076
43)
NP_006723 (https://www.n
cbi.nlm.nih.gov/entrez/view
er.fcgi?val=NP_006723)
NP_001334515 (https://ww
w.ncbi.nlm.nih.gov/entrez/vi
ewer.fcgi?val=NP_0013345
15)
NP_032062 (https://www.n
cbi.nlm.nih.gov/entrez/view
er.fcgi?val=NP_032062)

Location Chr 19: 45.47 – 45.48 Mb Chr 7: 19.3 – 19.31 Mb (ht

(UCSC) (https://genome.ucsc.edu/
cgi-bin/hgTracks?org=Hu
man&db=hg38&position=c
hr19:45467995-45475179)
PubMed [3]
tps://genome.ucsc.edu/cgi
-bin/hgTracks?org=Mouse
&db=mm0&position=chr7:
19302696-19310051)
[4]

search
Wikidata

View/Edit Human View/Edit Mouse

Role in addiction
Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic
Addiction and dependence
projection, which arise through transcriptional and epigenetic mechanisms.[10][32][33] The most
glossary[12][23][24][25]
important transcription factors that produce these alterations are ΔFosB, cyclic adenosine
monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B
addiction – a brain disorder
(NF-κB).[10] ΔFosB is the most significant biomolecular mechanism in addiction because the
characterized by compulsive
overexpression of ΔFosB in the D1-type medium spiny neurons in the nucleus accumbens is
engagement in rewarding stimuli
necessary and sufficient for many of the neural adaptations and behavioral effects (e.g.,
despite adverse consequences
expression-dependent increases in drug self-administration and reward sensitization) seen in
addictive behavior – a behavior
drug addiction.[9][10][12] ΔFosB overexpression has been implicated in addictions to alcohol
that is both rewarding and
(ethanol), cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol,
reinforcing
and substituted amphetamines, among others.[9][10][32][34][35] ΔJunD, a transcription factor, and
G9a, a histone methyltransferase, both oppose the function of ΔFosB and inhibit increases in its addictive drug – a drug that is
expression.[10][12][36] Increases in nucleus accumbens ΔJunD expression (via viral vector- both rewarding and reinforcing
mediated gene transfer) or G9a expression (via pharmacological means) reduces, or with a large dependence – an adaptive state
increase can even block, many of the neural and behavioral alterations seen in chronic drug associated with a withdrawal
abuse (i.e., the alterations mediated by ΔFosB).[13][10] syndrome upon cessation of
repeated exposure to a stimulus
ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such (e.g., drug intake)
as palatable food, sex, and exercise.[10][16] Natural rewards, similar to drugs of abuse, induce
drug sensitization or reverse
gene expression of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards
tolerance – the escalating effect
can result in a similar pathological addictive state through ΔFosB overexpression.[10][11][16]
of a drug resulting from repeated
Consequently, ΔFosB is the key mechanism involved in addictions to natural rewards (i.e.,
administration at a given dose
behavioral addictions) as well;[10][11][16] in particular, ΔFosB in the nucleus accumbens is
drug withdrawal – symptoms
critical for the reinforcing effects of sexual reward.[16] Research on the interaction between
that occur upon cessation of
natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and
repeated drug use
sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus
accumbens and possess bidirectional reward cross-sensitization effects[note 1] that are mediated physical dependence –
through ΔFosB.[11][37] This phenomenon is notable since, in humans, a dopamine dysregulation dependence that involves
syndrome, characterized by drug-induced compulsive engagement in natural rewards persistent physical–somatic
(specifically, sexual activity, shopping, and gambling), has also been observed in some withdrawal symptoms (e.g.,
individuals taking dopaminergic medications.[11] fatigue and delirium tremens)
ΔFosB inhibitors (drugs or treatments that oppose its action or reduce its expression) may be an psychological dependence –
effective treatment for addiction and addictive disorders.[38] Current medical reviews of dependence that involves
research involving lab animals have identified a drug class – class I histone deacetylase emotional–motivational
inhibitors[note 2] – that indirectly inhibits the function and further increases in the expression of withdrawal symptoms (e.g.,
accumbal ΔFosB by inducing G9a expression in the nucleus accumbens after prolonged dysphoria and anhedonia)
use.[13][36][39][40] These reviews and subsequent preliminary evidence which used oral reinforcing stimuli – stimuli that
administration or intraperitoneal administration of the sodium salt of butyric acid or other class I increase the probability of
HDAC inhibitors for an extended period indicate that these drugs have efficacy in reducing repeating behaviors paired with
addictive behavior in lab animals[note 3] that have developed addictions to ethanol, them
psychostimulants (i.e., amphetamine and cocaine), nicotine, and opiates;[36][40][41][42] however,
rewarding stimuli – stimuli that
as of August 2015, few clinical trials involving human addicts and any HDAC class I inhibitors
the brain interprets as intrinsically
have been conducted to test for treatment efficacy in humans or identify an optimal dosing
positive and desirable or as
regimen.[note 4]
something to approach
sensitization – an amplified
Plasticity in cocaine addiction response to a stimulus resulting
ΔFosB levels have been found to increase upon the use of cocaine.[44] Each subsequent dose of from repeated exposure to it
cocaine continues to increase ΔFosB levels with no ceiling of tolerance. Elevated levels of substance use disorder – a
ΔFosB leads to increases in brain-derived neurotrophic factor (BDNF) levels, which in turn condition in which the use of
increases the number of dendritic branches and spines present on neurons involved with the substances leads to clinically and
nucleus accumbens and prefrontal cortex areas of the brain. This change can be identified rather functionally significant impairment
quickly, and may be sustained weeks after the last dose of the drug. or distress

Transgenic mice exhibiting inducible expression of ΔFosB primarily in the nucleus accumbens tolerance – the diminishing effect
and dorsal striatum exhibit sensitized behavioural responses to cocaine.[45] They self-administer of a drug resulting from repeated
cocaine at lower doses than control,[46] but have a greater likelihood of relapse when the drug is administration at a given dose
withheld.[22][46]
ΔFosB increases the
expression of AMPA
receptor subunit
GluR2[45] and also
decreases expression of
dynorphin, thereby
enhancing sensitivity
to reward.[22]
 Signaling cascade in the nucleus accumbens that results in psychostimulant addiction
Note: colored text
contains article links.
[Color legend 1]
Cav1.2

NMDAR CaMKII
CaM

PP2B PP1 CREB

AMPAR

DARPP-32 ΔFosB
DRD1 JunD c-Fos
Gs
SIRT1
DRD5 AC PKA
HDAC1

DRD2 Gi/o Nuclear pore

cAMP

DRD3 Nuclear membrane

DRD4

Plasma membrane

cAMP

This diagram depicts the signaling events in the brain's reward center that are induced by chronic
high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like
amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and
glutamate co-release by such psychostimulants,[26][27] postsynaptic receptors for these
neurotransmitters trigger internal signaling events through a cAMP-dependent pathway and a calcium-
dependent pathway that ultimately result in increased CREB phosphorylation.[26][28][29] Phosphorylated
CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of
corepressors;[26][21][30] c-Fos repression acts as a molecular switch that enables the accumulation of
ΔFosB in the neuron.[31] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons
for 1–2 months, slowly accumulates following repeated high-dose exposure to stimulants through this
process.[21][30] ΔFosB functions as "one of the master control proteins" that produces addiction-related
structural changes in the brain, and upon sufficient accumulation, with the help of its downstream
targets (e.g., nuclear factor kappa B), it induces an addictive state.[21][30]
 ΔFosB accumulation from excessive drug use

Top: this depicts the initial effects of high dose exposure to an

addictive drug on gene expression in the nucleus accumbens for
various Fos family proteins (i.e., c-Fos, FosB, ΔFosB, Fra1, and
Fra2).
Bottom: this illustrates the progressive increase in ΔFosB expression
in the nucleus accumbens following repeated twice daily drug
binges, where these phosphorylated (35–37 kilodalton) ΔFosB
isoforms persist in the D1-type medium spiny neurons of the nucleus
accumbens for up to 2 months.[22][30]

Neural and behavioral effects of validated ΔFosB transcriptional targets[9][17]

Target Target
Neural effects Behavioral effects
gene expression

Molecular switch enabling the chronic

c-Fos ↓ –
induction of ΔFosB[note 5]

↓
dynorphin [note 6] • Downregulation of κ-opioid feedback loop • Increased drug reward

• Expansion of Nacc dendritic processes • Increased drug reward

NF-κB ↑ • NF-κB inflammatory response in the NAcc • Increased drug reward
• NF-κB inflammatory response in the CP • Locomotor sensitization

GluR2 ↑ • Decreased sensitivity to glutamate • Increased drug reward

• GluR1 synaptic protein phosphorylation • Decreased drug reward

Cdk5 ↑
• Expansion of NAcc dendritic processes (net effect)

Summary of addiction-related plasticity

 Form of Type of reinforcer
neuroplasticity Physical
High fat or Sexual Environmental Sources
or behavioral Opiates Psychostimulants exercise
plasticity sugar food intercourse enrichment
(aerobic)
ΔFosB expression
in [11]
↑ ↑ ↑ ↑ ↑ ↑
nucleus accumbens
D1-type MSNs
Behavioral plasticity

Escalation of intake Yes Yes Yes [11]

Psychostimulant [11]
Yes Not applicable Yes Yes Attenuated Attenuated
cross-sensitization

Psychostimulant [11]
↑ ↑ ↓ ↓ ↓
self-administration

Psychostimulant
conditioned place ↑ ↑ ↓ ↑ ↓ ↑ [11]
preference
Reinstatement of
drug-seeking ↑ ↑ ↓ ↓ [11]
behavior
Neurochemical plasticity
CREB
phosphorylation [11]
↓ ↓ ↓ ↓ ↓
in the
nucleus accumbens
Sensitized
dopamine response [11]
No Yes No Yes
in the
nucleus accumbens
↑DRD1,
Altered striatal ↓DRD2, ↑DRD1, ↓DRD2, [11]
↓DRD2, ↑DRD2 ↑DRD2
dopamine signaling ↑DRD3 ↑DRD3
↑DRD3
No change
Altered striatal or ↑μ-opioid receptors ↑μ-opioid ↑μ-opioid [11]
No change No change
opioid signaling ↑μ-opioid ↑κ-opioid receptors receptors receptors
receptors
↑dynorphin
Changes in striatal No [11]
↑dynorphin ↓enkephalin ↑dynorphin ↑dynorphin
opioid peptides change:
enkephalin
Mesocorticolimbic synaptic plasticity
Number of
dendrites in the ↓ ↑ ↑ [11]
nucleus accumbens
Dendritic spine
density in [11]
↓ ↑ ↑
the
nucleus accumbens

Other functions in the brain

Viral overexpression of ΔFosB in the output neurons of the nigrostriatal dopamine pathway (i.e., the medium spiny neurons in the dorsal
striatum) induces levodopa-induced dyskinesias in animal models of Parkinson's disease.[47][48] Dorsal striatal ΔFosB is overexpressed in
rodents and primates with dyskinesias;[48] postmortem studies of individuals with Parkinson's disease that were treated with levodopa have also
observed similar dorsal striatal ΔFosB overexpression.[48] Levetiracetam, an antiepileptic drug which has been demonstrated to reduce the
severity of levodopa-induced dyskinesias, has been shown to dose-dependently decrease the induction of dorsal striatal ΔFosB expression in rats
when co-administered with levodopa;[48] the signal transduction involved in this effect is unknown.[48]

ΔFosB expression in the nucleus accumbens shell increases resilience to stress and is induced in this region by acute exposure to social defeat
stress.[49][50][51]

Antipsychotic drugs have been shown to increase ΔFosB as well, more specifically in the prefrontal cortex. This increase has been found to be
part of pathways for the negative side effects that such drugs produce.[52]

See also
AP-1 (transcription factor)

Notes
1. In simplest terms, this means that when either amphetamine or sex is perceived as "more alluring or desirable" through reward
sensitization, this effect occurs with the other as well.
2. Inhibitors of class I histone deacetylase (HDAC) enzymes are drugs that inhibit four specific histone-modifying enzymes:
HDAC1, HDAC2, HDAC3, and HDAC8. Most of the animal research with HDAC inhibitors has been conducted with four drugs:
butyrate salts (mainly sodium butyrate), trichostatin A, valproic acid, and SAHA;[39][40] butyric acid is a naturally occurring
short-chain fatty acid in humans, while the latter two compounds are FDA-approved drugs with medical indications unrelated to
addiction.
3. Specifically, prolonged administration of a class I HDAC inhibitor appears to reduce an animal's motivation to acquire and use
an addictive drug without affecting an animals motivation to attain other rewards (i.e., it does not appear to cause motivational
anhedonia) and reduce the amount of the drug that is self-administered when it is readily available.[36][40][41]
4. Among the few clinical trials that employed a class I HDAC inhibitor, one utilized valproate for methamphetamine addiction.[43]
5. In other words, c-Fos repression allows ΔFosB to accumulate within nucleus accumbens medium spiny neurons more rapidly
because it is selectively induced in this state.[12]
6. ΔFosB has been implicated in causing both increases and decreases in dynorphin expression in different studies;[9][17] this
table entry reflects only a decrease.

Image legend

1. Ion channel
G proteins & linked receptors
(Text color) Transcription factors

References
1. GRCh38: Ensembl release 89: ENSG00000125740 (http://May2017.archive.ensembl.org/Homo_sapiens/Gene/Summary?db=c
ore;g=ENSG00000125740) - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000003545 (http://May2017.archive.ensembl.org/Mus_musculus/Gene/Summar
y?db=core;g=ENSMUSG00000003545) - Ensembl, May 2017
3. "Human PubMed Reference:" (https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Link&LinkName=gene_pubmed&from
_uid=2354).
4. "Mouse PubMed Reference:" (https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Link&LinkName=gene_pubmed&from_
uid=14282).
5. "Entrez Gene: FOSB FBJ murine osteosarcoma viral oncogene homolog B" (https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gen
e&Cmd=ShowDetailView&TermToSearch=2354).
6. Siderovski DP, Blum S, Forsdyke RE, Forsdyke DR (October 1990). "A set of human putative lymphocyte G0/G1 switch genes
includes genes homologous to rodent cytokine and zinc finger protein-encoding genes". DNA and Cell Biology. 9 (8): 579–87.
doi:10.1089/dna.1990.9.579 (https://doi.org/10.1089%2Fdna.1990.9.579). PMID 1702972 (https://www.ncbi.nlm.nih.gov/pubme
d/1702972).
 7. Martin-Gallardo A, McCombie WR, Gocayne JD, FitzGerald MG, Wallace S, Lee BM, Lamerdin J, Trapp S, Kelley JM, Liu LI
(April 1992). "Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3". Nature Genetics.
1 (1): 34–9. doi:10.1038/ng0492-34 (https://doi.org/10.1038%2Fng0492-34). PMID 1301997 (https://www.ncbi.nlm.nih.gov/pub
med/1301997).
8. Sabatakos G, Rowe GC, Kveiborg M, Wu M, Neff L, Chiusaroli R, Philbrick WM, Baron R (May 2008). "Doubly truncated FosB
isoform (Delta2DeltaFosB) induces osteosclerosis in transgenic mice and modulates expression and phosphorylation of Smads
in osteoblasts independent of intrinsic AP-1 activity" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674536). Journal of Bone
and Mineral Research. 23 (5): 584–95. doi:10.1359/jbmr.080110 (https://doi.org/10.1359%2Fjbmr.080110). PMC 2674536 (http
s://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674536). PMID 18433296 (https://www.ncbi.nlm.nih.gov/pubmed/18433296).
9. Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". The American Journal of
Drug and Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840 (https://doi.org/10.3109%2F00952990.2014.933
840). PMID 25083822 (https://www.ncbi.nlm.nih.gov/pubmed/25083822). "
ΔFosB as a therapeutic biomarker
The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in
addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed
from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress
into a new era – the use of ΔFosB as a biomarker. If ΔFosB detection is indicative of chronic drug exposure (and is at least
partly responsible for dependence of the substance), then its monitoring for therapeutic efficacy in interventional studies is a
suitable biomarker (Figure 2). Examples of therapeutic avenues are discussed herein. ...

Conclusions
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated
drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1
complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to
some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100).
Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral
changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles
of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and
histones, truly as a ‘‘molecular switch’’ (34). As a consequence of our improved understanding of ΔFosB in addiction, it is
possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the
efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their
infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much
needed in addiction."
10. Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction" (https://www.ncbi.nlm.nih.
gov/pmc/articles/PMC3272277). Nature Reviews. Neuroscience. 12 (11): 623–37. doi:10.1038/nrn3111 (https://doi.org/10.103
8%2Fnrn3111). PMC 3272277 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277). PMID 21989194 (https://www.ncbi.nl
m.nih.gov/pubmed/21989194). "ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or
viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated
transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both
necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-
type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where
it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and
perhaps during pathological addictive-like states."
11. Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions" (https://www.ncbi.nlm.nih.gov/pmc/arti
cles/PMC3139704). Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010 (https://doi.org/10.1016%2F
j.neuropharm.2011.03.010). PMC 3139704 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704). PMID 21459101 (https://
www.ncbi.nlm.nih.gov/pubmed/21459101). "Cross-sensitization is also bidirectional, as a history of amphetamine administration
facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual
experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased
in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b).
This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and
NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression
of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al.,
2009). ... In some people, there is a transition from “normal” to compulsive engagement in natural rewards (such as food or
sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans,
the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a
dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a
medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans
et al, 2006; Aiken, 2007; Lader, 2008)."
Table 1 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704/table/T1/?report=objectonly)
12. Nestler EJ (December 2013). "Cellular basis of memory for addiction"
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681). Dialogues Clin. Neurosci. 15 (4): 431–443. PMC 3898681 (https://w
ww.ncbi.nlm.nih.gov/pmc/articles/PMC3898681). PMID 24459410 (https://www.ncbi.nlm.nih.gov/pubmed/24459410). "Despite
the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of
repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of
drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that
such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural
rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB
target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch
whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that,
despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long
periods of time can transform someone who has relatively lower genetic loading into an addict."
13. Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug
addiction". Annals of Agricultural and Environmental Medicine. 19 (3): 491–6. PMID 23020045 (https://www.ncbi.nlm.nih.gov/pu
bmed/23020045). "For these reasons, ΔFosB is considered a primary and causative transcription factor in creating new neural
connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased,
stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of
abstinence. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further
taken ... In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for
dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial
factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression,
i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of
G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects
caused by cocaine by means of this feedback which blocks ΔFosB transcription"
14. Ohnishi YN, Ohnishi YH, Vialou V, Mouzon E, LaPlant Q, Nishi A, Nestler EJ (January 2015). "Functional role of the N-terminal
domain of ΔFosB in response to stress and drugs of abuse" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268105).
Neuroscience. 284: 165–70. doi:10.1016/j.neuroscience.2014.10.002 (https://doi.org/10.1016%2Fj.neuroscience.2014.10.002).
PMC 4268105 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268105). PMID 25313003 (https://www.ncbi.nlm.nih.gov/pubme
d/25313003).
15. Nakabeppu Y, Nathans D (February 1991). "A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional
activity". Cell. 64 (4): 751–9. doi:10.1016/0092-8674(91)90504-R (https://doi.org/10.1016%2F0092-8674%2891%2990504-R).
PMID 1900040 (https://www.ncbi.nlm.nih.gov/pubmed/1900040).
16. Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll:
hypothesizing common mesolimbic activation as a function of reward gene polymorphisms" (https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC4040958). Journal of Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112 (https://doi.org/10.1
080%2F02791072.2012.662112). PMC 4040958 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040958). PMID 22641964 (h
ttps://www.ncbi.nlm.nih.gov/pubmed/22641964).
17. Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB" (https://www.ncbi.nlm.nih.gov/
pmc/articles/PMC2607320). Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 363
(1507): 3245–55. doi:10.1098/rstb.2008.0067 (https://doi.org/10.1098%2Frstb.2008.0067). PMC 2607320 (https://www.ncbi.nl
m.nih.gov/pmc/articles/PMC2607320). PMID 18640924 (https://www.ncbi.nlm.nih.gov/pubmed/18640924). "Recent evidence
has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several
short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug
exposure—cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos expression is
complex and is covered below. ...
Examples of validated targets for ΔFosB in nucleus accumbens ... GluR2 ... dynorphin ... Cdk5 ... NFκB ... c-Fos"
Table 3 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607320/table/tbl3/)
18. Renthal W, Nestler EJ (August 2008). "Epigenetic mechanisms in drug addiction" (https://www.ncbi.nlm.nih.gov/pmc/articles/P
MC2753378). Trends in Molecular Medicine. 14 (8): 341–50. doi:10.1016/j.molmed.2008.06.004 (https://doi.org/10.1016%2Fj.m
olmed.2008.06.004). PMC 2753378 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753378). PMID 18635399 (https://www.nc
bi.nlm.nih.gov/pubmed/18635399).
19. Renthal W, Kumar A, Xiao G, Wilkinson M, Covington HE, Maze I, Sikder D, Robison AJ, LaPlant Q, Dietz DM, Russo SJ,
Vialou V, Chakravarty S, Kodadek TJ, Stack A, Kabbaj M, Nestler EJ (May 2009). "Genome-wide analysis of chromatin
regulation by cocaine reveals a role for sirtuins" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779727). Neuron. 62 (3): 335–
48. doi:10.1016/j.neuron.2009.03.026 (https://doi.org/10.1016%2Fj.neuron.2009.03.026). PMC 2779727 (https://www.ncbi.nlm.
nih.gov/pmc/articles/PMC2779727). PMID 19447090 (https://www.ncbi.nlm.nih.gov/pubmed/19447090).
20. Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, Bouali Y, Mukhopadhyay K, Ford K, Nestler EJ, Baron R
(September 2000). "Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis".
Nature Medicine. 6 (9): 985–90. doi:10.1038/79683 (https://doi.org/10.1038%2F79683). PMID 10973317 (https://www.ncbi.nlm.
nih.gov/pubmed/10973317).
21. Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction" (https://www.ncbi.nlm.nih.
gov/pmc/articles/PMC3272277). Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111 (https://doi.org/10.1038%2Fnrn31
11). PMC 3272277 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277). PMID 21989194 (https://www.ncbi.nlm.nih.gov/p
ubmed/21989194). "ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also
represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene
activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors,
including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression."
Figure 4: Epigenetic basis of drug regulation of gene expression (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277/figur
e/F4/)
22. Nestler EJ, Barrot M, Self DW (September 2001). "DeltaFosB: a sustained molecular switch for addiction" (https://www.ncbi.nl
m.nih.gov/pmc/articles/PMC58680). Proceedings of the National Academy of Sciences of the United States of America. 98
(20): 11042–6. doi:10.1073/pnas.191352698 (https://doi.org/10.1073%2Fpnas.191352698). PMC 58680 (https://www.ncbi.nlm.
nih.gov/pmc/articles/PMC58680). PMID 11572966 (https://www.ncbi.nlm.nih.gov/pubmed/11572966).
23. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY
(eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical.
pp. 364–375. ISBN 9780071481274.
24. "Glossary of Terms" (http://neuroscience.mssm.edu/nestler/glossary.html). Mount Sinai School of Medicine. Department of
Neuroscience. Retrieved 9 February 2015.
25. Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". N.
Engl. J. Med. 374 (4): 363–371. doi:10.1056/NEJMra1511480 (https://doi.org/10.1056%2FNEJMra1511480). PMID 26816013
(https://www.ncbi.nlm.nih.gov/pubmed/26816013). "Substance-use disorder: A diagnostic term in the fifth edition of the
Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes
clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at
work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss
of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term
addiction is synonymous with the classification of severe substance-use disorder."
26. Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression" (https://www.ncbi.nlm.nih.go
v/pmc/articles/PMC2834246). Dialogues Clin. Neurosci. 11 (3): 257–268. PMC 2834246 (https://www.ncbi.nlm.nih.gov/pmc/arti
cles/PMC2834246). PMID 19877494 (https://www.ncbi.nlm.nih.gov/pubmed/19877494). "[Psychostimulants] increase cAMP
levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP
response element binding protein (CREB), the phosphorylation of which induces its association with the histone
acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on
many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic
psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits
HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal
cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK
(calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5."
Figure 2: Psychostimulant-induced signaling events (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834246/figure/DialoguesC
linNeurosci-11-257-g002/)
27. Broussard JI (January 2012). "Co-transmission of dopamine and glutamate" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC32
50102). J. Gen. Physiol. 139 (1): 93–96. doi:10.1085/jgp.201110659 (https://doi.org/10.1085%2Fjgp.201110659).
PMC 3250102 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250102). PMID 22200950 (https://www.ncbi.nlm.nih.gov/pubme
d/22200950). "Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates
processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as
projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative
process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing
PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc
synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate
co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs
bias or filter either limbic or cortical inputs to guide goal-directed behavior."
28. Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)" (http://www.genome.jp/kegg-bin/show_pat
hway?hsa05031+2354). KEGG Pathway. Retrieved 31 October 2014. "Most addictive drugs increase extracellular
concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of
mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in
extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique
transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain."
29. Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine
addiction and withdrawal: evidence from a long-access self-administration model in the rat" (https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC4359351). Mol. Neurobiol. 51 (2): 696–717. doi:10.1007/s12035-014-8776-8 (https://doi.org/10.1007%2Fs12035-0
14-8776-8). PMC 4359351 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359351). PMID 24939695 (https://www.ncbi.nlm.ni
h.gov/pubmed/24939695). "Figure 1 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359351/figure/Fig1/)"
30. Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3
569166). Clin. Psychopharmacol. Neurosci. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136 (https://doi.org/10.9758%2Fcpn.2
012.10.3.136). PMC 3569166 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569166). PMID 23430970 (https://www.ncbi.nl
m.nih.gov/pubmed/23430970). "The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their
extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after
cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB
to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other
repressive proteins such as a repressive histone methyltransferase"
31. Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB" (https://www.ncbi.nlm.nih.gov/
pmc/articles/PMC2607320). Philos. Trans. R. Soc. Lond., B, Biol. Sci. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067 (htt
ps://doi.org/10.1098%2Frstb.2008.0067). PMC 2607320 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607320).
PMID 18640924 (https://www.ncbi.nlm.nih.gov/pubmed/18640924). "Recent evidence has shown that ΔFosB also represses
the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute
drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure"
32. Hyman SE, Malenka RC, Nestler EJ (2006). "Neural mechanisms of addiction: the role of reward-related learning and
memory". Annual Review of Neuroscience. 29: 565–98. doi:10.1146/annurev.neuro.29.051605.113009 (https://doi.org/10.114
6%2Fannurev.neuro.29.051605.113009). PMID 16776597 (https://www.ncbi.nlm.nih.gov/pubmed/16776597).
33. Steiner H, Van Waes V (January 2013). "Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other
psychostimulants" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525776). Progress in Neurobiology. 100: 60–80.
doi:10.1016/j.pneurobio.2012.10.001 (https://doi.org/10.1016%2Fj.pneurobio.2012.10.001). PMC 3525776 (https://www.ncbi.nl
m.nih.gov/pmc/articles/PMC3525776). PMID 23085425 (https://www.ncbi.nlm.nih.gov/pubmed/23085425).
34. Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)" (http://www.genome.jp/kegg-bin/show_pathw
ay?hsa05034+2354). KEGG Pathway. Retrieved 31 October 2014.
35. Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (February 2009). "Methylphenidate-induced dendritic spine
formation and DeltaFosB expression in nucleus accumbens" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650365).
Proceedings of the National Academy of Sciences of the United States of America. 106 (8): 2915–20.
doi:10.1073/pnas.0813179106 (https://doi.org/10.1073%2Fpnas.0813179106). PMC 2650365 (https://www.ncbi.nlm.nih.gov/pm
c/articles/PMC2650365). PMID 19202072 (https://www.ncbi.nlm.nih.gov/pubmed/19202072).
36. Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC376638
4). Neuropharmacology. 76 Pt B: 259–268. doi:10.1016/j.neuropharm.2013.04.004 (https://doi.org/10.1016%2Fj.neuropharm.2
013.04.004). PMC 3766384 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766384). PMID 23643695 (https://www.ncbi.nlm.n
ih.gov/pubmed/23643695). "Short-term increases in histone acetylation generally promote behavioral responses to the drugs,
while sustained increases oppose cocaine’s effects, based on the actions of systemic or intra-NAc administration of HDAC
inhibitors. ... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates,
whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced
downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress
(Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with
increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in
the synaptic plasticity associated with addiction (Maze et al., 2010).
G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback
loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler,
2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a). ... Also, G9a is induced in NAc
upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine’s behavioral effects seen under these
conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this
feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which
is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to
cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of
GABAA receptor and IPSC regulation."
37. Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on
common neural plasticity mechanisms with ΔFosB as a key mediator"
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865508). The Journal of Neuroscience. 33 (8): 3434–42.
doi:10.1523/JNEUROSCI.4881-12.2013 (https://doi.org/10.1523%2FJNEUROSCI.4881-12.2013). PMC 3865508 (https://www.
ncbi.nlm.nih.gov/pmc/articles/PMC3865508). PMID 23426671 (https://www.ncbi.nlm.nih.gov/pubmed/23426671).
38. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and addictive disorders". In Sydor A, Brown RY
(eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical.
pp. 384–385. ISBN 9780071481274.
39. McCowan TJ, Dhasarathy A, Carvelli L (February 2015). "The Epigenetic Mechanisms of Amphetamine" (https://www.ncbi.nlm.
nih.gov/pmc/articles/PMC4955852). J. Addict. Prev. 2015 (Suppl 1). PMC 4955852 (https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC4955852). PMID 27453897 (https://www.ncbi.nlm.nih.gov/pubmed/27453897). "Epigenetic modifications caused by
addictive drugs play an important role in neuronal plasticity and in drug-induced behavioral responses. Although few studies
have investigated the effects of AMPH on gene regulation (Table 1), current data suggest that AMPH acts at multiple levels to
alter histone/DNA interaction and to recruit transcription factors which ultimately cause repression of some genes and
activation of other genes. Importantly, some studies have also correlated the epigenetic regulation induced by AMPH with the
behavioral outcomes caused by this drug, suggesting therefore that epigenetics remodeling underlies the behavioral changes
induced by AMPH. If this proves to be true, the use of specific drugs that inhibit histone acetylation, methylation or DNA
methylation might be an important therapeutic alternative to prevent and/or reverse AMPH addiction and mitigate the side
effects generate by AMPH when used to treat ADHD."
40. Walker DM, Cates HM, Heller EA, Nestler EJ (February 2015). "Regulation of chromatin states by drugs of abuse" (https://www.
ncbi.nlm.nih.gov/pmc/articles/PMC4293340). Curr. Opin. Neurobiol. 30: 112–121. doi:10.1016/j.conb.2014.11.002 (https://doi.or
g/10.1016%2Fj.conb.2014.11.002). PMC 4293340 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293340). PMID 25486626
(https://www.ncbi.nlm.nih.gov/pubmed/25486626). "Studies investigating general HDAC inhibition on behavioral outcomes have
produced varying results but it seems that the effects are specific to the timing of exposure (either before, during or after
exposure to drugs of abuse) as well as the length of exposure"
41. Primary references involving sodium butyrate:

• Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E, Chaudhury D, Damez-Werno DM, Haggarty SJ, Han MH,
Bassel-Duby R, Olson EN, Nestler EJ (April 2013). "Class I HDAC inhibition blocks cocaine-induced plasticity by targeted
changes in histone methylation" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609040). Nat. Neurosci. 16 (4): 434–440.
doi:10.1038/nn.3354 (https://doi.org/10.1038%2Fnn.3354). PMC 3609040 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609
040). PMID 23475113 (https://www.ncbi.nlm.nih.gov/pubmed/23475113). "While acute HDAC inhibition enhances the
behavioral effects of cocaine or amphetamine1,3,4,13,14, studies suggest that more chronic regimens block psychostimulant-
induced plasticity3,5,11,12. ... The effects of pharmacological inhibition of HDACs on psychostimulant-induced plasticity appear
to depend on the timecourse of HDAC inhibition. Studies employing co-administration procedures in which inhibitors are given
acutely, just prior to psychostimulant administration, report heightened behavioral responses to the drug1,3,4,13,14. In contrast,
experimental paradigms like the one employed here, in which HDAC inhibitors are administered more chronically, for several
days prior to psychostimulant exposure, show inhibited expression3 or decreased acquisition of behavioral adaptations to
drug5,11,12. The clustering of seemingly discrepant results based on experimental methodologies is interesting in light of our
present findings. Both HDAC inhibitors and psychostimulants increase global levels of histone acetylation in NAc. Thus, when
co-administered acutely, these drugs may have synergistic effects, leading to heightened transcriptional activation of
psychostimulant-regulated target genes. In contrast, when a psychostimulant is given in the context of prolonged, HDAC
inhibitor-induced hyperacetylation, homeostatic processes may direct AcH3 binding to the promoters of genes (e.g., G9a)
responsible for inducing chromatin condensation and gene repression (e.g., via H3K9me2) in order to dampen already
heightened transcriptional activation. Our present findings thus demonstrate clear cross talk among histone PTMs and suggest
that decreased behavioral sensitivity to psychostimulants following prolonged HDAC inhibition might be mediated through
decreased activity of HDAC1 at H3K9 KMT promoters and subsequent increases in H3K9me2 and gene repression."

• Simon-O'Brien E, Alaux-Cantin S, Warnault V, Buttolo R, Naassila M, Vilpoux C (July 2015). "The histone deacetylase
inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals". Addict Biol. 20 (4): 676–689.
doi:10.1111/adb.12161 (https://doi.org/10.1111%2Fadb.12161). PMID 25041570 (https://www.ncbi.nlm.nih.gov/pubmed/25041
570). "Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and
support the hypothesis that HDACi may have a potential use in alcohol addiction treatment."

• Castino MR, Cornish JL, Clemens KJ (April 2015). "Inhibition of histone deacetylases facilitates extinction and attenuates
reinstatement of nicotine self-administration in rats" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399837). PLoS ONE. 10
(4): e0124796. doi:10.1371/journal.pone.0124796 (https://doi.org/10.1371%2Fjournal.pone.0124796). PMC 4399837 (https://w
ww.ncbi.nlm.nih.gov/pmc/articles/PMC4399837). PMID 25880762 (https://www.ncbi.nlm.nih.gov/pubmed/25880762). "treatment
with NaB significantly attenuated nicotine and nicotine + cue reinstatement when administered immediately ... These results
provide the first demonstration that HDAC inhibition facilitates the extinction of responding for an intravenously self-
administered drug of abuse and further highlight the potential of HDAC inhibitors in the treatment of drug addiction."
42. Kyzar EJ, Pandey SC (August 2015). "Molecular mechanisms of synaptic remodeling in alcoholism" (https://www.ncbi.nlm.nih.g
ov/pmc/articles/PMC4506731). Neurosci. Lett. 601: 11–9. doi:10.1016/j.neulet.2015.01.051 (https://doi.org/10.1016%2Fj.neule
t.2015.01.051). PMC 4506731 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506731). PMID 25623036 (https://www.ncbi.nl
m.nih.gov/pubmed/25623036). "Increased HDAC2 expression decreases the expression of genes important for the
maintenance of dendritic spine density such as BDNF, Arc, and NPY, leading to increased anxiety and alcohol-seeking
behavior. Decreasing HDAC2 reverses both the molecular and behavioral consequences of alcohol addiction, thus implicating
this enzyme as a potential treatment target (Fig. 3). HDAC2 is also crucial for the induction and maintenance of structural
synaptic plasticity in other neurological domains such as memory formation [115]. Taken together, these findings underscore
the potential usefulness of HDAC inhibition in treating alcohol use disorders ... Given the ability of HDAC inhibitors to potently
modulate the synaptic plasticity of learning and memory [118], these drugs hold potential as treatment for substance abuse-
related disorders. ... Our lab and others have published extensively on the ability of HDAC inhibitors to reverse the gene
expression deficits caused by multiple models of alcoholism and alcohol abuse, the results of which were discussed above
[25,112,113]. This data supports further examination of histone modifying agents as potential therapeutic drugs in the treatment
of alcohol addiction ... Future studies should continue to elucidate the specific epigenetic mechanisms underlying compulsive
alcohol use and alcoholism, as this is likely to provide new molecular targets for clinical intervention."
43. Kheirabadi GR, Ghavami M, Maracy MR, Salehi M, Sharbafchi MR (2016). "Effect of add-on valproate on craving in
methamphetamine depended patients: A randomized trial" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025910). Advanced
Biomedical Research. 5: 149. doi:10.4103/2277-9175.187404 (https://doi.org/10.4103%2F2277-9175.187404). PMC 5025910
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025910). PMID 27656618 (https://www.ncbi.nlm.nih.gov/pubmed/27656618).
44. Hope BT (May 1998). "Cocaine and the AP-1 transcription factor complex". Annals of the New York Academy of Sciences. 844:
1–6. doi:10.1111/j.1749-6632.1998.tb08216.x (https://doi.org/10.1111%2Fj.1749-6632.1998.tb08216.x). PMID 9668659 (http
s://www.ncbi.nlm.nih.gov/pubmed/9668659).
45. Kelz MB, Chen J, Carlezon WA, Whisler K, Gilden L, Beckmann AM, Steffen C, Zhang YJ, Marotti L, Self DW, Tkatch T,
Baranauskas G, Surmeier DJ, Neve RL, Duman RS, Picciotto MR, Nestler EJ (September 1999). "Expression of the
transcription factor deltaFosB in the brain controls sensitivity to cocaine". Nature. 401 (6750): 272–6. doi:10.1038/45790 (http
s://doi.org/10.1038%2F45790). PMID 10499584 (https://www.ncbi.nlm.nih.gov/pubmed/10499584).
46. Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW (March 2003). "Striatal cell type-specific overexpression of DeltaFosB
enhances incentive for cocaine". The Journal of Neuroscience. 23 (6): 2488–93. PMID 12657709 (https://www.ncbi.nlm.nih.gov/
pubmed/12657709).
47. Cao X, Yasuda T, Uthayathas S, Watts RL, Mouradian MM, Mochizuki H, Papa SM (May 2010). "Striatal overexpression of
DeltaFosB reproduces chronic levodopa-induced involuntary movements" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888
489). The Journal of Neuroscience. 30 (21): 7335–43. doi:10.1523/JNEUROSCI.0252-10.2010 (https://doi.org/10.1523%2FJNE
UROSCI.0252-10.2010). PMC 2888489 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888489). PMID 20505100 (https://ww
w.ncbi.nlm.nih.gov/pubmed/20505100).
48. Du H, Nie S, Chen G, Ma K, Xu Y, Zhang Z, Papa SM, Cao X (2015). "Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia
in Hemiparkinsonian Rats Inducing Critical Molecular Changes in the Striatum" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC
4322303). Parkinson's Disease. 2015: 253878. doi:10.1155/2015/253878 (https://doi.org/10.1155%2F2015%2F253878).
PMC 4322303 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322303). PMID 25692070 (https://www.ncbi.nlm.nih.gov/pubme
d/25692070). "Furthermore, the transgenic overexpression of ΔFosB reproduces AIMs in hemiparkinsonian rats without chronic
exposure to L-DOPA [13]. ... FosB/ΔFosB immunoreactive neurons increased in the dorsolateral part of the striatum on the
lesion side with the used antibody that recognizes all members of the FosB family. All doses of levetiracetam decreased the
number of FosB/ΔFosB positive cells (from 88.7 ± 1.7/section in the control group to 65.7 ± 0.87, 42.3 ± 1.88, and 25.7 ±
1.2/section in the 15, 30, and 60 mg groups, resp.; Figure 2). These results indicate dose-dependent effects of levetiracetam on
FosB/ΔFosB expression. ... In addition, transcription factors expressed with chronic events such as ΔFosB (a truncated splice
variant of FosB) are overexpressed in the striatum of rodents and primates with dyskinesias [9, 10]. ... Furthermore, ΔFosB
overexpression has been observed in postmortem striatal studies of Parkinsonian patients chronically treated with L-DOPA
[26]. ... Of note, the most prominent effect of levetiracetam was the reduction of ΔFosB expression, which cannot be explained
by any of its known actions on vesicular protein or ion channels. Therefore, the exact mechanism(s) underlying the antiepileptic
effects of levetiracetam remains uncertain."
49. "ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS" (http://neuroscience.mssm.edu/nestler/deltaFosB.html). Mount Sinai
School of Medicine. NESTLER LAB: LABORATORY OF MOLECULAR PSYCHIATRY. Retrieved 6 September 2014.
50. Furuyashiki T, Deguchi Y (August 2012). "[Roles of altered striatal function in major depression]". Brain and Nerve = Shinkei
Kenkyū No Shinpo (in Japanese). 64 (8): 919–26. PMID 22868883 (https://www.ncbi.nlm.nih.gov/pubmed/22868883).
51. Nestler EJ (April 2015). "∆FosB: a transcriptional regulator of stress and antidepressant responses" (https://www.ncbi.nlm.nih.g
ov/pmc/articles/PMC4380559). European Journal of Pharmacology. 753: 66–72. doi:10.1016/j.ejphar.2014.10.034 (https://doi.o
rg/10.1016%2Fj.ejphar.2014.10.034). PMC 4380559 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380559).
PMID 25446562 (https://www.ncbi.nlm.nih.gov/pubmed/25446562). "In more recent years, prolonged induction of ∆FosB has
also been observed within NAc in response to chronic administration of certain forms of stress. Increasing evidence indicates
that this induction represents a positive, homeostatic adaptation to chronic stress, since overexpression of ∆FosB in this brain
region promotes resilience to stress, whereas blockade of its activity promotes stress susceptibility. Chronic administration of
several antidepressant medications also induces ∆FosB in the NAc, and this induction is required for the therapeutic-like
actions of these drugs in mouse models. Validation of these rodent findings is the demonstration that depressed humans,
examined at autopsy, display reduced levels of ∆FosB within the NAc. As a transcription factor, ΔFosB produces this behavioral
phenotype by regulating the expression of specific target genes, which are under current investigation. These studies of ΔFosB
are providing new insight into the molecular basis of depression and antidepressant action, which is defining a host of new
targets for possible therapeutic development."
52. Dietz DM, Kennedy PJ, Sun H, Maze I, Gancarz AM, Vialou V, Koo JW, Mouzon E, Ghose S, Tamminga CA, Nestler EJ
(February 2014). "ΔFosB induction in prefrontal cortex by antipsychotic drugs is associated with negative behavioral outcomes"
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895248). Neuropsychopharmacology. 39 (3): 538–44.
doi:10.1038/npp.2013.255 (https://doi.org/10.1038%2Fnpp.2013.255). PMC 3895248 (https://www.ncbi.nlm.nih.gov/pmc/article
s/PMC3895248). PMID 24067299 (https://www.ncbi.nlm.nih.gov/pubmed/24067299).

Further reading
Schuermann M, Jooss K, Müller R (April 1991). "fosB is a transforming gene encoding a transcriptional activator". Oncogene. 6
(4): 567–76. PMID 1903195 (https://www.ncbi.nlm.nih.gov/pubmed/1903195).
Brown JR, Ye H, Bronson RT, Dikkes P, Greenberg ME (July 1996). "A defect in nurturing in mice lacking the immediate early
gene fosB". Cell. 86 (2): 297–309. doi:10.1016/S0092-8674(00)80101-4 (https://doi.org/10.1016%2FS0092-8674%2800%2980
101-4). PMID 8706134 (https://www.ncbi.nlm.nih.gov/pubmed/8706134).
 Heximer SP, Cristillo AD, Russell L, Forsdyke DR (December 1996). "Sequence analysis and expression in cultured
lymphocytes of the human FOSB gene (G0S3)". DNA and Cell Biology. 15 (12): 1025–38. doi:10.1089/dna.1996.15.1025 (http
s://doi.org/10.1089%2Fdna.1996.15.1025). PMID 8985116 (https://www.ncbi.nlm.nih.gov/pubmed/8985116).
Liberati NT, Datto MB, Frederick JP, Shen X, Wong C, Rougier-Chapman EM, Wang XF (April 1999). "Smads bind directly to
the Jun family of AP-1 transcription factors" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC21779). Proceedings of the
National Academy of Sciences of the United States of America. 96 (9): 4844–9. doi:10.1073/pnas.96.9.4844 (https://doi.org/10.
1073%2Fpnas.96.9.4844). PMC 21779 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC21779). PMID 10220381 (https://www.n
cbi.nlm.nih.gov/pubmed/10220381).
Yamamura Y, Hua X, Bergelson S, Lodish HF (November 2000). "Critical role of Smads and AP-1 complex in transforming
growth factor-beta -dependent apoptosis". The Journal of Biological Chemistry. 275 (46): 36295–302.
doi:10.1074/jbc.M006023200 (https://doi.org/10.1074%2Fjbc.M006023200). PMID 10942775 (https://www.ncbi.nlm.nih.gov/pub
med/10942775).
Bergman MR, Cheng S, Honbo N, Piacentini L, Karliner JS, Lovett DH (February 2003). "A functional activating protein 1 (AP-
1) site regulates matrix metalloproteinase 2 (MMP-2) transcription by cardiac cells through interactions with JunB-Fra1 and
JunB-FosB heterodimers" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1223099). Biochemical Journal. 369 (Pt 3): 485–96.
doi:10.1042/BJ20020707 (https://doi.org/10.1042%2FBJ20020707). PMC 1223099 (https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC1223099). PMID 12371906 (https://www.ncbi.nlm.nih.gov/pubmed/12371906).
Milde-Langosch K, Kappes H, Riethdorf S, Löning T, Bamberger AM (February 2003). "FosB is highly expressed in normal
mammary epithelia, but down-regulated in poorly differentiated breast carcinomas". Breast Cancer Research and Treatment.
77 (3): 265–75. doi:10.1023/A:1021887100216 (https://doi.org/10.1023%2FA%3A1021887100216). PMID 12602926 (https://w
ww.ncbi.nlm.nih.gov/pubmed/12602926).
Baumann S, Hess J, Eichhorst ST, Krueger A, Angel P, Krammer PH, Kirchhoff S (March 2003). "An unexpected role for FosB
in activation-induced cell death of T cells". Oncogene. 22 (9): 1333–9. doi:10.1038/sj.onc.1206126 (https://doi.org/10.1038%2F
sj.onc.1206126). PMID 12618758 (https://www.ncbi.nlm.nih.gov/pubmed/12618758).
Holmes DI, Zachary I (January 2004). "Placental growth factor induces FosB and c-Fos gene expression via Flt-1 receptors".
FEBS Letters. 557 (1–3): 93–8. doi:10.1016/S0014-5793(03)01452-2 (https://doi.org/10.1016%2FS0014-5793%2803%290145
2-2). PMID 14741347 (https://www.ncbi.nlm.nih.gov/pubmed/14741347).
Konsman JP, Blomqvist A (May 2005). "Forebrain patterns of c-Fos and FosB induction during cancer-associated anorexia-
cachexia in rat". The European Journal of Neuroscience. 21 (10): 2752–66. doi:10.1111/j.1460-9568.2005.04102.x (https://doi.
org/10.1111%2Fj.1460-9568.2005.04102.x). PMID 15926923 (https://www.ncbi.nlm.nih.gov/pubmed/15926923).

External links
ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS (http://neuroscience.mssm.edu/nestler/deltaFosB.html)
KEGG Pathway – human alcohol addiction (http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354)
KEGG Pathway – human amphetamine addiction (http://www.genome.jp/kegg-bin/show_pathway?hsa05031+2354)
KEGG Pathway – human cocaine addiction (http://www.genome.jp/kegg-bin/show_pathway?hsa05030+2354)
FOSB+protein,+human (https://meshb.nlm.nih.gov/record/ui?name=FOSB%20protein,%20human) at the US National Library
of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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