Chr 19: 45.47 – 45.48 Mb
Chr 7: 19.3 – 19.31 Mb
FBJ murine osteosarcoma viral oncogene homolog B, also known as FOSB
or FosB, is a protein that, in humans, is encoded by the FOSB
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,
FosB and its truncated splice variants, ΔFosB
and further truncated Δ2ΔFosB, are all involved in osteosclerosis,
ΔFosB lacks a known transactivation domain, in turn
preventing it from affecting transcription through the AP-1
ΔFosB splice variant has been identified as playing a central,
crucial (necessary and sufficient) role in the development and
maintenance of pathological behavior and neural plasticity involved in
both behavioral addictions (associated with natural rewards) and drug
ΔFosB overexpression (i.e., an abnormally and
excessively high level of
ΔFosB expression which produces a
pronounced gene-related phenotype) triggers the development of
addiction-related neuroplasticity throughout the reward system.
ΔFosB differs from the full length
FosB and further truncated
ΔFosB in its capacity to produce these effects, as only accumbal
ΔFosB overexpression is associated with pathological responses to
1 Delta FosB
1.1 Role in addiction
1.1.1 Plasticity in cocaine addiction
1.2 Summary of addiction-related plasticity
1.3 Other functions in the brain
2 See also
5 Further reading
6 External links
ΔFosB is a truncated splice variant of FosB. ΔFosB
has been implicated as a critical factor in the development of
virtually all forms of behavioral and drug addictions. In
the brain's reward system, it is linked to changes in a number of
other gene products, such as
CREB and sirtuins. In the
ΔFosB regulates the commitment of mesenchymal precursor cells
to the adipocyte or osteoblast lineage.
In the nucleus accumbens,
ΔFosB functions as a "sustained molecular
switch" and "master control protein" in the development of an
addiction. In other words, once "turned on" (sufficiently
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
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. 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
Role in addiction
Addiction and dependence glossary
addiction – a brain disorder characterized by compulsive engagement
in rewarding stimuli despite adverse consequences
addictive behavior – a behavior that is both rewarding and
addictive drug – a drug that is both rewarding and reinforcing
dependence – an adaptive state associated with a withdrawal syndrome
upon cessation of repeated exposure to a stimulus (e.g., drug intake)
drug sensitization or reverse tolerance – the escalating effect of a
drug resulting from repeated administration at a given dose
drug withdrawal – symptoms that occur upon cessation of repeated
physical dependence – dependence that involves persistent
physical–somatic withdrawal symptoms (e.g., fatigue and delirium
psychological dependence – dependence that involves
emotional–motivational withdrawal symptoms (e.g., dysphoria and
reinforcing stimuli – stimuli that increase the probability of
repeating behaviors paired with them
rewarding stimuli – stimuli that the brain interprets as
intrinsically positive and desirable or as something to approach
sensitization – an amplified response to a stimulus resulting from
repeated exposure to it
substance use disorder – a condition in which the use of substances
leads to clinically and functionally significant impairment or
tolerance – the diminishing effect of a drug resulting from repeated
administration at a given dose
Signaling cascade in the nucleus accumbens that results in
Note: colored text contains article links.
[Color legend 1]
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, 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. Phosphorylated
CREB increases levels of ΔFosB, which in turn represses the c-Fos
gene with the help of corepressors; c-Fos repression acts
as a molecular switch that enables the accumulation of
ΔFosB in the
neuron. 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
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
Chronic addictive drug use causes alterations in gene expression in
the mesocorticolimbic projection, which arise through transcriptional
and epigenetic mechanisms. The most important
transcription factors that produce these alterations are ΔFosB,
cyclic adenosine monophosphate (cAMP) response element binding protein
(CREB), and nuclear factor kappa B (NF-κB).
ΔFosB is the most
significant biomolecular mechanism in addiction because the
ΔFosB in the
D1-type medium spiny neurons in the
nucleus accumbens is necessary and sufficient for many of the neural
adaptations and behavioral effects (e.g., expression-dependent
increases in drug self-administration and reward sensitization) seen
in drug addiction.
ΔFosB overexpression has been
implicated in addictions to alcohol (ethanol), cannabinoids, cocaine,
methylphenidate, nicotine, opioids, phencyclidine, propofol, and
substituted amphetamines, among others. ΔJunD, a
transcription factor, and G9a, a histone methyltransferase, both
oppose the function of
ΔFosB and inhibit increases in its
expression. Increases in nucleus accumbens ΔJunD
expression (via viral vector-mediated gene transfer) or
(via pharmacological means) reduces, or with a large increase can even
block, many of the neural and behavioral alterations seen in chronic
drug abuse (i.e., the alterations mediated by ΔFosB).
ΔFosB also plays an important role in regulating behavioral responses
to natural rewards, such as palatable food, sex, and exercise.
Natural rewards, like drugs of abuse, induce gene expression of ΔFosB
in the nucleus accumbens, and chronic acquisition of these rewards can
result in a similar pathological addictive state through ΔFosB
ΔFosB is the key mechanism
involved in addictions to natural rewards (i.e., behavioral
addictions) as well; in particular,
ΔFosB in the nucleus
accumbens is critical for the reinforcing effects of sexual
reward. Research on the interaction between natural and drug
rewards suggests that dopaminergic psychostimulants (e.g.,
amphetamine) and 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 through ΔFosB. This phenomenon is notable since, in
humans, a dopamine dysregulation syndrome, characterized by
drug-induced compulsive engagement in natural rewards (specifically,
sexual activity, shopping, and gambling), has also been observed in
some individuals taking dopaminergic medications.
ΔFosB inhibitors (drugs or treatments that oppose its action or
reduce its expression) may be an effective treatment for addiction and
addictive disorders. Current medical reviews of research involving
lab animals have identified a drug class – class I histone
deacetylase inhibitors[note 2] – that indirectly inhibits the
function and further increases in the expression of accumbal
G9a expression in the nucleus accumbens after prolonged
use. These reviews and subsequent preliminary evidence
which used oral administration or intraperitoneal administration of
the sodium salt of butyric acid or other class I HDAC inhibitors for
an extended period indicate that these drugs have efficacy in reducing
addictive behavior in lab animals[note 3] that have developed
addictions to ethanol, psychostimulants (i.e., amphetamine and
cocaine), nicotine, and opiates; however, as of August
2015[update] no clinical trials involving human addicts and any HDAC
class I inhibitors have been conducted to test for treatment efficacy
in humans or identify an optimal dosing regimen.
Plasticity in cocaine addiction
See also: Epigenetics of cocaine addiction
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
in the nucleus accumbens following repeated twice daily drug binges,
where these phosphorylated (35–37 kilodalton)
persist in the
D1-type medium spiny neurons of the nucleus accumbens
for up to 2 months.
ΔFosB levels have been found to increase upon the use of cocaine.
Each subsequent dose of cocaine continues to increase
with no ceiling of tolerance. Elevated levels of
ΔFosB leads to
increases in brain-derived neurotrophic factor (BDNF) levels, which in
turn increases the number of dendritic branches and spines present on
neurons involved with the nucleus accumbens and prefrontal cortex
areas of the brain. This change can be identified rather quickly, and
may be sustained weeks after the last dose of the drug.
Transgenic mice exhibiting inducible expression of
ΔFosB primarily in
the nucleus accumbens and dorsal striatum exhibit sensitized
behavioural responses to cocaine. They self-administer cocaine at
lower doses than control, but have a greater likelihood of relapse
when the drug is withheld.
ΔFosB increases the expression of
AMPA receptor subunit GluR2 and also decreases expression of
dynorphin, thereby enhancing sensitivity to reward.
Neural and behavioral effects of validated
Molecular switch enabling the chronic
induction of ΔFosB[note 4]
• Downregulation of κ-opioid feedback loop
• Increased drug reward
• Expansion of Nacc dendritic processes
NF-κB inflammatory response in the NAcc
NF-κB inflammatory response in the CP
• Increased drug reward
• Increased drug reward
• Locomotor sensitization
• Decreased sensitivity to glutamate
• Increased drug reward
GluR1 synaptic protein phosphorylation
• Expansion of NAcc dendritic processes
• Decreased drug reward
Summary of addiction-related plasticity
Form of neuroplasticity
or behavioral plasticity
Type of reinforcer
High fat or sugar food
ΔFosB expression in
Escalation of intake
conditioned place preference
Reinstatement of drug-seeking behavior
in the nucleus accumbens
Sensitized dopamine response
in the nucleus accumbens
Altered striatal dopamine signaling
↑DRD1, ↓DRD2, ↑DRD3
↑DRD1, ↓DRD2, ↑DRD3
Altered striatal opioid signaling
No change or
Changes in striatal opioid peptides
No change: enkephalin
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens
Dendritic spine density in
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. Dorsal striatal
overexpressed in rodents and primates with dyskinesias; postmortem
studies of individuals with
Parkinson's disease that were treated with
levodopa have also observed similar dorsal striatal ΔFosB
overexpression. 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; the signal transduction involved in this effect is
ΔFosB expression in the nucleus accumbens shell increases resilience
to stress and is induced in this region by acute exposure to social
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
AP-1 (transcription factor)
^ 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.
^ 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; 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.
^ 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
^ 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.
ΔFosB has been implicated in causing both increases and decreases
in dynorphin expression in different studies; this table entry
reflects only a decrease.
G proteins & linked receptors
(Text color) Transcription factors
^ a b c GRCh38:
Ensembl release 89: ENSG00000125740 - Ensembl, May
^ a b c GRCm38:
Ensembl release 89: ENSMUSG00000003545 - Ensembl, May
^ a b "
FOSB FBJ murine osteosarcoma viral oncogene
^ Siderovski DP, Blum S, Forsdyke RE, Forsdyke DR (Oct 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.
^ Martin-Gallardo A, McCombie WR, Gocayne JD, FitzGerald MG, Wallace
S, Lee BM, Lamerdin J, Trapp S, Kelley JM, Liu LI (Apr 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. PMID 1301997.
^ Sabatakos G, Rowe GC, Kveiborg M, Wu M, Neff L, Chiusaroli R,
Philbrick WM, Baron R (May 2008). "Doubly truncated
(Delta2DeltaFosB) induces osteosclerosis in transgenic mice and
modulates expression and phosphorylation of Smads in osteoblasts
independent of intrinsic AP-1 activity". Journal of Bone and Mineral
Research. 23 (5): 584–95. doi:10.1359/jbmr.080110.
PMC 2674536 . PMID 18433296.
^ a b c d e f g h i j Ruffle JK (Nov 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. PMID 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
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. ...
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
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
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.
^ a b c d e f g h i j k Robison AJ, Nestler EJ (Nov 2011).
Transcriptional and epigenetic mechanisms of addiction". Nature
Reviews. Neuroscience. 12 (11): 623–37. doi:10.1038/nrn3111.
PMC 3272277 . PMID 21989194.
ΔFosB has been linked
directly to several addiction-related behaviors ... Importantly,
genetic or viral overexpression of ΔJunD, a dominant negative mutant
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.
^ a b c d e f g h i j k l m n o p q r s Olsen CM (Dec 2011). "Natural
rewards, neuroplasticity, and non-drug addictions". Neuropharmacology.
61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010.
PMC 3139704 . PMID 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
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).
^ a b c d e f Nestler EJ (December 2013). "Cellular basis of memory
for addiction". Dialogues Clin. Neurosci. 15 (4): 431–443.
PMC 3898681 . PMID 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 ...
ΔFosB target is cFos: as
ΔFosB accumulates with repeated
drug exposure it represses c-Fos and contributes to the molecular
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.
^ a b c 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. 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
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
^ Ohnishi YN, Ohnishi YH, Vialou V, Mouzon E, LaPlant Q, Nishi A,
Nestler EJ (Jan 2015). "Functional role of the N-terminal domain of
ΔFosB in response to stress and drugs of abuse". Neuroscience. 284:
165–70. doi:10.1016/j.neuroscience.2014.10.002. PMC 4268105 .
^ Nakabeppu Y, Nathans D (Feb 1991). "A naturally occurring truncated
FosB that inhibits Fos/Jun transcriptional activity". Cell. 64
(4): 751–9. doi:10.1016/0092-8674(91)90504-R.
^ a b c d e 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". Journal of Psychoactive Drugs. 44 (1): 38–55.
doi:10.1080/02791072.2012.662112. PMC 4040958 .
^ a b c Nestler EJ (Oct 2008). "Review.
Transcriptional mechanisms of
addiction: role of DeltaFosB". Philosophical Transactions of the Royal
Society of London. Series B, Biological Sciences. 363 (1507):
3245–55. doi:10.1098/rstb.2008.0067. PMC 2607320 .
PMID 18640924. Recent evidence has shown that
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
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 ...
^ Renthal W, Nestler EJ (Aug 2008). "
Epigenetic mechanisms in drug
addiction". Trends in Molecular Medicine. 14 (8): 341–50.
doi:10.1016/j.molmed.2008.06.004. PMC 2753378 .
^ 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". Neuron. 62 (3): 335–48.
doi:10.1016/j.neuron.2009.03.026. PMC 2779727 .
^ Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, Bouali Y,
Mukhopadhyay K, Ford K, Nestler EJ, Baron R (Sep 2000).
Overexpression of Delta
FosB transcription factor(s) increases bone
formation and inhibits adipogenesis". Nature Medicine. 6 (9):
985–90. doi:10.1038/79683. PMID 10973317.
^ a b c d e Robison AJ, Nestler EJ (November 2011). "Transcriptional
and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11):
623–637. doi:10.1038/nrn3111. PMC 3272277 .
ΔFosB serves as one of the master control
proteins governing this structural plasticity. ...
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.
Epigenetic basis of drug regulation of gene expression
^ a b c d e Nestler EJ, Barrot M, Self DW (Sep 2001). "DeltaFosB: a
sustained molecular switch for addiction". Proceedings of the National
Academy of Sciences of the United States of America. 98 (20):
11042–6. doi:10.1073/pnas.191352698. PMC 58680 .
^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement
and Addictive Disorders". In Sydor A, Brown RY. Molecular
Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.).
New York: McGraw-Hill Medical. pp. 364–375.
^ "Glossary of Terms". Mount Sinai School of Medicine. Department of
Neuroscience. Retrieved 9 February 2015.
^ 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. PMID 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
^ a b c Renthal W, Nestler EJ (September 2009). "Chromatin regulation
in drug addiction and depression". Dialogues Clin. Neurosci. 11 (3):
257–268. PMC 2834246 . PMID 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
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
^ Broussard JI (January 2012). "Co-transmission of dopamine and
glutamate". J. Gen. Physiol. 139 (1): 93–96.
doi:10.1085/jgp.201110659. PMC 3250102 . PMID 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.
^ Kanehisa Laboratories (10 October 2014). "
Amphetamine – Homo
sapiens (human)". 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.
^ 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". Mol. Neurobiol. 51 (2):
696–717. doi:10.1007/s12035-014-8776-8. PMC 4359351 .
PMID 24939695. Figure 1
^ a b c d Nestler EJ (December 2012). "
Transcriptional mechanisms of
drug addiction". Clin. Psychopharmacol. Neurosci. 10 (3): 136–143.
doi:10.9758/cpn.2012.10.3.136. PMC 3569166 .
PMID 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
persists in neurons for at least several weeks after cessation of drug
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
^ Nestler EJ (October 2008). "Review.
Transcriptional mechanisms of
addiction: role of DeltaFosB". Philos. Trans. R. Soc. Lond., B, Biol.
Sci. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067.
PMC 2607320 . PMID 18640924. Recent evidence has shown
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
ΔFosB after chronic drug exposure
^ a b 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. PMID 16776597.
^ Steiner H, Van Waes V (Jan 2013). "Addiction-related gene
regulation: risks of exposure to cognitive enhancers vs. other
psychostimulants". Progress in Neurobiology. 100: 60–80.
doi:10.1016/j.pneurobio.2012.10.001. PMC 3525776 .
^ Kanehisa Laboratories (29 October 2014). "
Alcoholism – Homo
sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.
^ Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (Feb
2009). "Methylphenidate-induced dendritic spine formation and
FosB expression in nucleus accumbens". Proceedings of the
National Academy of Sciences of the United States of America. 106 (8):
2915–20. doi:10.1073/pnas.0813179106. PMC 2650365 .
^ a b c d Nestler EJ (January 2014). "
Epigenetic mechanisms of drug
addiction". Neuropharmacology. 76 Pt B: 259–268.
doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384 .
PMID 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
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.
^ Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen
LM (Feb 2013). "Natural and drug rewards act on common neural
plasticity mechanisms with
ΔFosB as a key mediator". The Journal of
Neuroscience. 33 (8): 3434–42. doi:10.1523/JNEUROSCI.4881-12.2013.
PMC 3865508 . PMID 23426671.
^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement
and addictive disorders". In Sydor A, Brown RY. Molecular
Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.).
New York: McGraw-Hill Medical. pp. 384–385.
^ a b McCowan TJ, Dhasarathy A, Carvelli L (February 2015). "The
Epigenetic Mechanisms of Amphetamine". J. Addict. Prev. 2015 (Suppl
1). PMC 4955852 . PMID 27453897.
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.
^ a b c d Walker DM, Cates HM, Heller EA, Nestler EJ (February 2015).
"Regulation of chromatin states by drugs of abuse". Curr. Opin.
Neurobiol. 30: 112–121. doi:10.1016/j.conb.2014.11.002.
PMC 4293340 . PMID 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
^ a b Primary references involving sodium butyrate:
• Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E,
et al. (April 2013). "Class I HDAC inhibition blocks cocaine-induced
plasticity by targeted changes in histone methylation". Nat. Neurosci.
16 (4): 434–440. doi:10.1038/nn.3354. PMC 3609040 .
PMID 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.
PMID 25041570. 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
• Castino MR, Cornish JL, Clemens KJ (April 2015). "Inhibition
of histone deacetylases facilitates extinction and attenuates
reinstatement of nicotine self-administration in rats". PLoS ONE. 10
(4): e0124796. doi:10.1371/journal.pone.0124796. PMC 4399837 .
PMID 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
^ Kyzar EJ, Pandey SC (August 2015). "Molecular mechanisms of synaptic
remodeling in alcoholism". Neurosci. Lett. 601: 11–9.
doi:10.1016/j.neulet.2015.01.051. PMID 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 . 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
, 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
^ 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. PMID 9668659.
^ a b 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 (Sep 1999).
"Expression of the transcription factor delta
FosB in the brain
controls sensitivity to cocaine". Nature. 401 (6750): 272–6.
doi:10.1038/45790. PMID 10499584.
^ a b Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW (Mar 2003).
"Striatal cell type-specific overexpression of Delta
incentive for cocaine". The Journal of Neuroscience. 23 (6):
2488–93. PMID 12657709.
^ Cao X, Yasuda T, Uthayathas S, Watts RL, Mouradian MM, Mochizuki H,
Papa SM (May 2010). "Striatal overexpression of Delta
chronic levodopa-induced involuntary movements". The Journal of
Neuroscience. 30 (21): 7335–43. doi:10.1523/JNEUROSCI.0252-10.2010.
PMC 2888489 . PMID 20505100.
^ a b c d e Du H, Nie S, Chen G, Ma K, Xu Y, Zhang Z, Papa SM, Cao X
Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia in
Hemiparkinsonian Rats Inducing Critical Molecular Changes in the
Striatum". Parkinson's Disease. 2015: 253878. doi:10.1155/2015/253878.
PMC 4322303 . PMID 25692070. Furthermore, the transgenic
ΔFosB reproduces AIMs in hemiparkinsonian rats
without chronic exposure to L-DOPA . ... 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 . ... 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.
^ "ROLE OF Δ
FOSB IN THE NUCLEUS ACCUMBENS". Mount Sinai School of
Medicine. NESTLER LAB: LABORATORY OF MOLECULAR PSYCHIATRY. Retrieved 6
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function in major depression]". Brain and Nerve = Shinkei Kenkyū No
Shinpo (in Japanese). 64 (8): 919–26. PMID 22868883.
^ Nestler EJ (Apr 2015). "∆FosB: a transcriptional regulator of
stress and antidepressant responses". European Journal of
Pharmacology. 753: 66–72. doi:10.1016/j.ejphar.2014.10.034.
PMC 4380559 . PMID 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,
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.
^ 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
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ROLE OF Δ
FOSB IN THE NUCLEUS ACCUMBENS
KEGG Pathway – human alcohol addiction
KEGG Pathway – human amphetamine addiction
KEGG Pathway – human cocaine addiction
FOSB protein, human 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.
Addiction and Dependence
Cognitive behavioral therapy
Discrimination against drug addicts
Dopamine dysregulation syndrome
Addiction recovery groups
List of twelve-step groups
Mixed amphetamine salts
TAAR1 (full agonist)
CART (mRNA inducer)
5-HT1A receptor (low affinity ligand)
MAO (weak competitive inhibitor)
Doping in sport
History and culture of substituted amphetamines
History of Benzedrine
Neurobiological effects of physical exercise
Neurobiological effects of physical exercise § Attention deficit
Recreational drug use
Transcription factors and intracellular receptors
(1) Basic domains
(1.1) Basic leucine zipper (bZIP)
Activating transcription factor
Basic helix-loop-helix (bHLH)
Myogenic regulatory factors
(1.6) Basic helix-span-helix (bHSH)
Zinc finger DNA-binding domains
Nuclear receptor (Cys4)
(2.2) Other Cys4
General transcription factors
(2.5) Alternating composition
Octamer transcription factor: 1
(3.2) Paired box
(3.3) Fork head / winged helix
(3.4) Heat shock factors
(3.5) Tryptophan clusters
Interferon regulatory factors
(3.6) TEA domain
transcriptional enhancer factor
(4) β-Scaffold factors with minor groove contacts
(4.1) Rel homology region
(4.4) MADS box
(4.6) TATA-binding proteins
(4.7) High-mobility group
(4.10) Cold-shock domain
(0) Other transcription factors
(0.3) Pocket domain
(0.5) AP-2/EREBP-related factors
see also transcription factor/coregu