FOSB: Difference between revisions

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 reinforcing; 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 drug use; physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens); psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia); 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 distress; tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose;
	v; t; e;

VALUE_ERROR (nil)
Identifiers
Aliases
External IDs	GeneCards: [1]
Orthologs
	n/a
	n/a
	n/a
	n/a
	n/a
	n/a
	n/a
	n/a
	n/a
	n/a
	Wikidata
View/Edit Human

VisualWikitext

Latest revision as of 15:22, 4 January 2019

FBJ murine osteosarcoma viral oncogene homolog B, also known as Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog B, FOSB or FosB, is a protein that, in humans, is encoded by the FOSB gene.^[1]^[2]^[3]

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.^[1] 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.^[4]

The ΔFosB splice variant has been identified as playing a central, crucial (necessary and sufficient)^[5]^[6] role in the development and maintenance of pathological behavior and neuroplasticity involved in both behavioral addictions (associated with natural rewards) and drug addictions.^[5]^[7]^[8] 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.^[9] ΔFosB differs from the full length FosB and further truncated Δ2ΔFosB in its capacity to produce these effects, as only accumbal ΔFosB overexpression is associated with pathological responses to drugs.^[10]

Delta FosB

Delta FosB or ΔFosB is a truncated splice variant of FosB.^[11] ΔFosB has been implicated as a critical factor in the development of virtually all forms of behavioral and drug addictions.^[6]^[7]^[12] In the brain's reward system, it is linked to changes in a number of other gene products, such as CREB and sirtuins.^[13]^[14]^[15] In the body, ΔFosB regulates the commitment of mesenchymal precursor cells to the adipocyte or osteoblast lineage.^[16]

In the nucleus accumbens, ΔFosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction.^[5]^[17]^[18] 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.^[5]^[17]^[18] 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.^[5]^[8] 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.^[5]

Role in addiction

Signaling cascade in the nucleus accumbens that results in psychostimulant addiction

The signaling cascade involved in psychostimulant addiction

Note: colored text contains article links.

G_s

cAMP

ΔFosB

JunD

c-Fos

SIRT1

HDAC1

^{[Color legend 1]}

The image above contains clickable links

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,^[22]^[23] 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.^[22]^[24]^[25] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;^[22]^[17]^[26] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.^[27] 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.^[17]^[26] 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.^[17]^[26]

Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.^[6]^[28]^[29] 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).^[6] ΔFosB is the most significant biomolecular mechanism in addiction because the overexpression of 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.^[5]^[6]^[8] ΔFosB overexpression has been implicated in addictions to alcohol (ethanol), cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.^[5]^[6]^[28]^[30]^[31] ΔJunD, a transcription factor, and G9a, a histone methyltransferase, both oppose the function of ΔFosB and inhibit increases in its expression.^[6]^[8]^[32] Increases in nucleus accumbens ΔJunD expression (via viral vector-mediated gene transfer) or G9a expression (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).^[9]^[6]

ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.^[6]^[12] Natural rewards, similar to 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 overexpression.^[6]^[7]^[12] Consequently, ΔFosB is the key mechanism involved in addictions to natural rewards (i.e., behavioral addictions) as well;^[6]^[7]^[12] in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward.^[12] 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.^[7]^[33] 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.^[7]

ΔFosB inhibitors (drugs or treatments that oppose its action or reduce its expression) may be an effective treatment for addiction and addictive disorders.^[34] 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 ΔFosB by inducing G9a expression in the nucleus accumbens after prolonged use.^[9]^[32]^[35]^[36] 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;^[32]^[36]^[37]^[38] 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

ΔFosB accumulation from excessive drug use

ΔFosB accumulation graph

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.^[18]^[26]

ΔFosB levels have been found to increase upon the use of cocaine.^[39] Each subsequent dose of cocaine continues to increase ΔFosB levels 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.^[40] They self-administer cocaine at lower doses than control,^[41] but have a greater likelihood of relapse when the drug is withheld.^[18]^[41] ΔFosB increases the expression of AMPA receptor subunit GluR2^[40] and also decreases expression of dynorphin, thereby enhancing sensitivity to reward.^[18]

Neural and behavioral effects of validated ΔFosB transcriptional targets^[5]^[13]
Target gene	Target expression	Neural effects	Behavioral effects
c-Fos	↓	Molecular switch enabling the chronic induction of ΔFosB^{[note 4]}	–
dynorphin	↓ ^{[note 5]}	• Downregulation of κ-opioid feedback loop	• Increased drug reward
NF-κB	↑	• 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
GluR2	↑	• Decreased sensitivity to glutamate	• Increased drug reward
Cdk5	↑	• GluR1 synaptic protein phosphorylation • Expansion of NAcc dendritic processes	• Decreased drug reward (net effect)

Summary of addiction-related plasticity


Form of neuroplasticity or behavioral plasticity	Type of reinforcer						Sources
Form of neuroplasticity or behavioral plasticity	Opiates	Psychostimulants	High fat or sugar food	Sexual intercourse	Physical exercise (aerobic)	Environmental enrichment	Sources
ΔFosB expression in nucleus accumbens D1-type MSNs	↑	↑	↑	↑	↑	↑	^[7]
Behavioral plasticity
Escalation of intake	Yes	Yes	Yes				^[7]
Psychostimulant cross-sensitization	Yes	Not applicable	Yes	Yes	Attenuated	Attenuated	^[7]
Psychostimulant self-administration	↑	↑	↓		↓	↓	^[7]
Psychostimulant conditioned place preference	↑	↑	↓	↑	↓	↑	^[7]
Reinstatement of drug-seeking behavior	↑	↑			↓	↓	^[7]
Neurochemical plasticity
CREB phosphorylation in the nucleus accumbens	↓	↓	↓		↓	↓	^[7]
Sensitized dopamine response in the nucleus accumbens	No	Yes	No	Yes			^[7]
Altered striatal dopamine signaling	↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3		↑DRD2	↑DRD2	^[7]
Altered striatal opioid signaling	No change or ↑μ-opioid receptors	↑μ-opioid receptors ↑κ-opioid receptors	↑μ-opioid receptors	↑μ-opioid receptors	No change	No change	^[7]
Changes in striatal opioid peptides	↑dynorphin No change: enkephalin	↑dynorphin	↓enkephalin		↑dynorphin	↑dynorphin	^[7]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens	↓	↑		↑			^[7]
Dendritic spine density in the nucleus accumbens	↓	↑		↑			^[7]

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.^[42]^[43] Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias;^[43] postmortem studies of individuals with Parkinson's disease that were treated with levodopa have also observed similar dorsal striatal ΔFosB overexpression.^[43] 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;^[43] the signal transduction involved in this effect is unknown.^[43]

ΔFosB expression in the nucleus accumbens shell increases resilience to stress and is induced in this region by acute exposure to social defeat stress.^[44]^[45]^[46]

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.^[47]

Notes

↑ 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;^[35]^[36] 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 readily available.^[32]^[36]^[37]
↑ 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.^[8]
↑ ΔFosB has been implicated in causing both increases and decreases in dynorphin expression in different studies;^[5]^[13] this table entry reflects only a decrease.

Image legend

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

References

↑ ^1.0 ^1.1 "Entrez Gene: FOSB FBJ murine osteosarcoma viral oncogene homolog B".
↑ 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. PMID 1702972.
↑ 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 FosB isoform (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.
↑ ^5.0 ^5.1 ^5.2 ^5.3 ^5.4 ^5.5 ^5.6 ^5.7 ^5.8 ^5.9 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 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.
↑ ^6.00 ^6.01 ^6.02 ^6.03 ^6.04 ^6.05 ^6.06 ^6.07 ^6.08 ^6.09 ^6.10 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 of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure^14,22–24. 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 consumption^14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
↑ ^7.00 ^7.01 ^7.02 ^7.03 ^7.04 ^7.05 ^7.06 ^7.07 ^7.08 ^7.09 ^7.10 ^7.11 ^7.12 ^7.13 ^7.14 ^7.15 ^7.16 ^7.17 ^7.18 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 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
↑ ^8.0 ^8.1 ^8.2 ^8.3 ^8.4 ^8.5 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 ... 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.
↑ ^9.0 ^9.1 ^9.2 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 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
↑ 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. PMID 25313003.
↑ Nakabeppu Y, Nathans D (Feb 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. PMID 1900040.
↑ ^12.0 ^12.1 ^12.2 ^12.3 ^12.4 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. PMID 22641964.
↑ ^13.0 ^13.1 ^13.2 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 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
↑ 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. PMID 18635399.
↑ 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. PMID 19447090.
↑ 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 DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis". Nature Medicine. 6 (9): 985–90. doi:10.1038/79683. PMID 10973317.
↑ ^17.0 ^17.1 ^17.2 ^17.3 ^17.4 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. PMID 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
↑ ^18.0 ^18.1 ^18.2 ^18.3 ^18.4 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. PMID 11572966.
↑ 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. ISBN 9780071481274.
↑ "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 disorder.
↑ ^22.0 ^22.1 ^22.2 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 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
↑ 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
↑ ^26.0 ^26.1 ^26.2 ^26.3 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 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
↑ 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 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
↑ ^28.0 ^28.1 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. PMID 23085425.
↑ 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 DeltaFosB 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. PMID 19202072.
↑ ^32.0 ^32.1 ^32.2 ^32.3 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 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.
↑ 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. ISBN 9780071481274.
↑ ^35.0 ^35.1 McCowan TJ, Dhasarathy A, Carvelli L (February 2015). "The Epigenetic Mechanisms of Amphetamine". J. Addict. Prev. 2015 (Suppl 1). PMC 4955852. PMID 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.
↑ ^36.0 ^36.1 ^36.2 ^36.3 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
↑ ^37.0 ^37.1 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 amphetamine^1,3,4,13,14, studies suggest that more chronic regimens block psychostimulant-induced plasticity^3,5,11,12. ... 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 drug^1,3,4,13,14. 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 drug^5,11,12. 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 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". 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 addiction.
↑ 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. PMC 4506731. 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 [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.
↑ 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.
↑ ^40.0 ^40.1 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 deltaFosB in the brain controls sensitivity to cocaine". Nature. 401 (6750): 272–6. doi:10.1038/45790. PMID 10499584.
↑ ^41.0 ^41.1 Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW (Mar 2003). "Striatal cell type-specific overexpression of DeltaFosB enhances 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 DeltaFosB reproduces chronic levodopa-induced involuntary movements". The Journal of Neuroscience. 30 (21): 7335–43. doi:10.1523/JNEUROSCI.0252-10.2010. PMC 2888489. PMID 20505100.
↑ ^43.0 ^43.1 ^43.2 ^43.3 ^43.4 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". Parkinson's Disease. 2015: 253878. doi:10.1155/2015/253878. PMC 4322303. PMID 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.
↑ "ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS". Mount Sinai School of Medicine. NESTLER LAB: LABORATORY OF MOLECULAR PSYCHIATRY. Retrieved 6 September 2014.
↑ Furuyashiki T, Deguchi Y (Aug 2012). "[Roles of altered striatal 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, 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.
↑ 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". Neuropsychopharmacology. 39 (3): 538–44. doi:10.1038/npp.2013.255. PMC 3895248. PMID 24067299.

External links

ROLE OF ΔFOSB 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.

[34] 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.

[39] 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;^[35]^[36] 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.

[41] 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.^[32]^[36]^[37]

[46] 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.^[8]

[47] ΔFosB has been implicated in causing both increases and decreases in dynorphin expression in different studies;^[5]^[13] this table entry reflects only a decrease.

[22] 
Ion channel
G proteins & linked receptors
(Text color) Transcription factors

[entrez-1] 1.0 ^1.1 "Entrez Gene: FOSB FBJ murine osteosarcoma viral oncogene homolog B".

[pmid1702972-2] 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. PMID 1702972.

[pmid1301997-3] 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.

[Δ2ΔFosB_transactivation_osteoclast-4] 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". Journal of Bone and Mineral Research. 23 (5): 584–95. doi:10.1359/jbmr.080110. PMC 2674536. PMID 18433296.

[What_the_ΔFosB?-5] 5.0 ^5.1 ^5.2 ^5.3 ^5.4 ^5.5 ^5.6 ^5.7 ^5.8 ^5.9 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 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.

[Nestler-6] 6.00 ^6.01 ^6.02 ^6.03 ^6.04 ^6.05 ^6.06 ^6.07 ^6.08 ^6.09 ^6.10 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 of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure^14,22–24. 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 consumption^14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.

[Natural_and_drug_addictions-7] 7.00 ^7.01 ^7.02 ^7.03 ^7.04 ^7.05 ^7.06 ^7.07 ^7.08 ^7.09 ^7.10 ^7.11 ^7.12 ^7.13 ^7.14 ^7.15 ^7.16 ^7.17 ^7.18 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 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

[Cellular_basis-8] 8.0 ^8.1 ^8.2 ^8.3 ^8.4 ^8.5 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 ... 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.

[G9a_reverses_ΔFosB_plasticity-9] 9.0 ^9.1 ^9.2 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 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

[FosB_ΔFosB_Δ2ΔFosB_drugs-10] 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. PMID 25313003.

[pmid1900040-11] Nakabeppu Y, Nathans D (Feb 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. PMID 1900040.

[ΔFosB_reward-12] 12.0 ^12.1 ^12.2 ^12.3 ^12.4 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. PMID 22641964.

[pmid18640924-13] 13.0 ^13.1 ^13.2 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 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

[pmid18635399-14] 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. PMID 18635399.

[pmid19447090-15] 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. PMID 19447090.

[pmid10973317-16] 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 DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis". Nature Medicine. 6 (9): 985–90. doi:10.1038/79683. PMID 10973317.

[Nestler1-17] 17.0 ^17.1 ^17.2 ^17.3 ^17.4 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. PMID 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

[pmid11572966-18] 18.0 ^18.1 ^18.2 ^18.3 ^18.4 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. PMID 11572966.

[Addiction_glossary-19] 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. ISBN 9780071481274.

[Nestler_Labs_Glossary-20] "Glossary of Terms". Mount Sinai School of Medicine. Department of Neuroscience. Retrieved 9 February 2015.

[Brain_disease-21] 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 disorder.

[Nestler-Renthal_Figure_2-23] 22.0 ^22.1 ^22.2 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 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

[Glutamate-dopamine_cotransmission_review-24] 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.

[Amphetamine_KEGG_ΔFosB-25] 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.

[Meth_cAMP/calcium-dependent_cascade-26] 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

[Nestler2-27] 26.0 ^26.1 ^26.2 ^26.3 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 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

[{{nowrap|c-Fos}}_repression-28] 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 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

[Nestler,_Hyman,_and_Malenka_2-29] 28.0 ^28.1 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.

[Addiction_genetics-30] 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. PMID 23085425.

[Alcoholism_ΔFosB-31] Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.

[MPH_ΔFosB-32] Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (Feb 2009). "Methylphenidate-induced dendritic spine formation and DeltaFosB 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. PMID 19202072.

[Nestler_2014_epigenetics-33] 32.0 ^32.1 ^32.2 ^32.3 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 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.

[Amph_and_sex_addiction-35] 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_2009_04-36] 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. ISBN 9780071481274.

[Amphetamine_epigenetics-37] 35.0 ^35.1 McCowan TJ, Dhasarathy A, Carvelli L (February 2015). "The Epigenetic Mechanisms of Amphetamine". J. Addict. Prev. 2015 (Suppl 1). PMC 4955852. PMID 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.

[Chromatin_states-38] 36.0 ^36.1 ^36.2 ^36.3 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

[HDACi_primaries-40] 37.0 ^37.1 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 amphetamine^1,3,4,13,14, studies suggest that more chronic regimens block psychostimulant-induced plasticity^3,5,11,12. ... 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 drug^1,3,4,13,14. 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 drug^5,11,12. 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 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". 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 addiction.

[HDAC_alcoholism_review-42] 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. PMC 4506731. 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 [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.

[pmid9668659-43] 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.

[pmid10499584-44] 40.0 ^40.1 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 deltaFosB in the brain controls sensitivity to cocaine". Nature. 401 (6750): 272–6. doi:10.1038/45790. PMID 10499584.

[pmid12657709-45] 41.0 ^41.1 Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW (Mar 2003). "Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine". The Journal of Neuroscience. 23 (6): 2488–93. PMID 12657709.

[pmid20505100-48] 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". The Journal of Neuroscience. 30 (21): 7335–43. doi:10.1523/JNEUROSCI.0252-10.2010. PMC 2888489. PMID 20505100.

[Levetiracetam-49] 43.0 ^43.1 ^43.2 ^43.3 ^43.4 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". Parkinson's Disease. 2015: 253878. doi:10.1155/2015/253878. PMC 4322303. PMID 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.

[Nestler's_lab-50] "ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS". Mount Sinai School of Medicine. NESTLER LAB: LABORATORY OF MOLECULAR PSYCHIATRY. Retrieved 6 September 2014.

[Stress_and_NAcc_shell-51] Furuyashiki T, Deguchi Y (Aug 2012). "[Roles of altered striatal function in major depression]". Brain and Nerve = Shinkei Kenkyū No Shinpo (in Japanese). 64 (8): 919–26. PMID 22868883.

[NAcc_∆FosB_depression-52] 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, 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.

[pmid24067299-53] 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". Neuropsychopharmacology. 39 (3): 538–44. doi:10.1038/npp.2013.255. PMC 3895248. PMID 24067299.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[Color legend 1]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[note 1]

[33]

[34]

[note 2]

[35]

[36]

[note 3]

[37]

[38]

[39]

[40]

[41]

[note 4]

[note 5]

[42]

[43]

[44]

[45]

[46]

[47]

@@ Line 1: / Line 1: @@
-<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
+{{For|the silicon wafer box|FOUP}}
-{{PBB_Controls
+{{Use dmy dates|date=July 2014}}
-| update_page = yes
+{{Infobox_gene}}
-| require_manual_inspection = no
+'''FBJ murine osteosarcoma viral oncogene homolog B''', also known as '''Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog B''', '''FOSB''' or '''FosB''', is a [[protein]] that, in humans, is encoded by the ''FOSB'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: FOSB FBJ murine osteosarcoma viral oncogene homolog B| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2354| accessdate = }}</ref><ref name="pmid1702972">{{cite journal | vauthors = Siderovski DP, Blum S, Forsdyke RE, Forsdyke DR | title = A set of human putative lymphocyte G0/G1 switch genes includes genes homologous to rodent cytokine and zinc finger protein-encoding genes | journal = DNA and Cell Biology | volume = 9 | issue = 8 | pages = 579–87 | date = Oct 1990 | pmid = 1702972 | doi = 10.1089/dna.1990.9.579 }}</ref><ref name="pmid1301997">{{cite journal | vauthors = Martin-Gallardo A, McCombie WR, Gocayne JD, FitzGerald MG, Wallace S, Lee BM, Lamerdin J, Trapp S, Kelley JM, Liu LI | title = Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3 | journal = Nature Genetics | volume = 1 | issue = 1 | pages = 34–9 | date = Apr 1992 | pmid = 1301997 | doi = 10.1038/ng0492-34 }}</ref>
-| update_protein_box = yes
-| update_summary = yes
+The FOS gene family consists of four members: [[C-Fos|FOS]], FOSB, [[FOSL1]], and [[FOSL2]]. These genes encode [[leucine zipper]] proteins that can [[dimerize]] with proteins of the [[C-jun|JUN]] family (e.g., [[c-Jun]], [[JunD]]), thereby forming the [[transcription factor]] complex [[AP-1 (transcription factor)|AP-1]]. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation.<ref name="entrez"/> FosB and its truncated [[splice variant]]s, '''ΔFosB''' and further truncated '''Δ2ΔFosB''', are all involved in [[osteosclerosis]], although Δ2ΔFosB lacks a known [[transactivation domain]], in turn preventing it from affecting [[Transcription (biology)|transcription]] through the AP-1 complex.<ref name="Δ2ΔFosB transactivation osteoclast">{{cite journal | vauthors = Sabatakos G, Rowe GC, Kveiborg M, Wu M, Neff L, Chiusaroli R, Philbrick WM, Baron R | title = 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 | journal = Journal of Bone and Mineral Research | volume = 23 | issue = 5 | pages = 584–95 | date = May 2008 | pmid = 18433296 | pmc = 2674536 | doi = 10.1359/jbmr.080110 }}</ref>
-| update_citations = yes
+The ΔFosB [[Protein splicing|splice]] [[variant of uncertain significance|variant]] has been identified as playing a central, ''crucial'' ([[necessary and sufficient]])<ref name="What the ΔFosB?" /><ref name="Nestler" /> role in the development and maintenance of [[pathology|pathological behavior]] and [[neuroplasticity]] involved in both [[behavioral addiction]]s (associated with [[natural reward]]s) and [[drug addictions]].<ref name="What the ΔFosB?">{{cite journal | vauthors = Ruffle JK | title = Molecular neurobiology of addiction: what's all the (Δ)FosB about? | journal = The American Journal of Drug and Alcohol Abuse | volume = 40 | issue = 6 | pages = 428–37 | date = Nov 2014 | pmid = 25083822 | doi = 10.3109/00952990.2014.933840 | quote =  <br />ΔFosB as a therapeutic biomarker<br />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.&nbsp;...<br /><br />Conclusions<br />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. }}</ref><ref name="Natural and drug addictions" /><ref name="Cellular basis" /> ΔFosB [[overexpression]] (i.e., an abnormally and excessively high level of ΔFosB [[gene expression|expression]] which produces a pronounced gene-related [[phenotype]]) triggers the development of addiction-related [[neuroplasticity]] throughout the [[reward system]].<ref name="G9a reverses ΔFosB plasticity">{{cite journal | vauthors = Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T | title = Epigenetic regulation in drug addiction | journal = Annals of Agricultural and Environmental Medicine | volume = 19 | issue = 3 | pages = 491–6 | year = 2012 | pmid = 23020045 | doi =  | quote = 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&nbsp;... 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 }}</ref> ΔFosB differs from the full length FosB and further truncated Δ2ΔFosB in its capacity to produce these effects, as only [[accumbal]] ΔFosB overexpression is associated with pathological responses to drugs.<ref name="FosB ΔFosB Δ2ΔFosB drugs">{{cite journal | vauthors = Ohnishi YN, Ohnishi YH, Vialou V, Mouzon E, LaPlant Q, Nishi A, Nestler EJ | title = Functional role of the N-terminal domain of ΔFosB in response to stress and drugs of abuse | journal = Neuroscience | volume = 284 | issue =  | pages = 165–70 | date = Jan 2015 | pmid = 25313003 | doi = 10.1016/j.neuroscience.2014.10.002 | pmc=4268105}}</ref>
+=={{anchor|Delta FosB}}Delta FosB==
+'''Delta FosB''' or '''ΔFosB''' is a truncated [[splice variant]] of FosB.<ref name="pmid1900040">{{cite journal | vauthors = Nakabeppu Y, Nathans D | title = A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity | journal = Cell | volume = 64 | issue = 4 | pages = 751–9 | date = Feb 1991 | pmid = 1900040 | doi = 10.1016/0092-8674(91)90504-R }}</ref> ΔFosB has been implicated as a critical factor in the development of virtually all forms of [[behavioral addiction|behavioral]] and [[drug addiction]]s.<ref name="Nestler" /><ref name="Natural and drug addictions" /><ref name="ΔFosB reward"/> In the brain's [[reward system]], it is linked to changes in a number of other gene products, such as [[CREB]] and [[sirtuin]]s.<ref name="pmid18640924" /><ref name="pmid18635399">{{cite journal | vauthors = Renthal W, Nestler EJ | title = Epigenetic mechanisms in drug addiction | journal = Trends in Molecular Medicine | volume = 14 | issue = 8 | pages = 341–50 | date = Aug 2008 | pmid = 18635399 | pmc = 2753378 | doi = 10.1016/j.molmed.2008.06.004 }}</ref><ref name="pmid19447090">{{cite journal | vauthors = 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 | title = Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins | journal = Neuron | volume = 62 | issue = 3 | pages = 335–48 | date = May 2009 | pmid = 19447090 | pmc = 2779727 | doi = 10.1016/j.neuron.2009.03.026 }}</ref> In the body, ΔFosB regulates the commitment of mesenchymal [[precursor cell]]s to the [[adipocyte]] or [[osteoblast]] lineage.<ref name="pmid10973317">{{cite journal | vauthors = Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, Bouali Y, Mukhopadhyay K, Ford K, Nestler EJ, Baron R | title = Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis | journal = Nature Medicine | volume = 6 | issue = 9 | pages = 985–90 | date = Sep 2000 | pmid = 10973317 | doi = 10.1038/79683 }}</ref>
+In the [[nucleus accumbens]], ΔFosB functions as a "sustained molecular switch" and "master control protein" in the development of an [[addiction]].<ref name="What the ΔFosB?" /><ref name="Nestler1" /><ref name="pmid11572966" /> In other words, once "turned on" (sufficiently overexpressed) ΔFosB triggers a series of [[gene transcription|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.<ref name="What the ΔFosB?" /><ref name="Nestler1" /><ref name="pmid11572966" /> ΔFosB expression in [[D1-type]] nucleus accumbens [[medium spiny neuron]]s directly and positively regulates drug [[self-administration]] and [[reward sensitization]] through [[positive reinforcement]] while decreasing sensitivity to [[wikt:aversion|aversion]].<ref name="What the ΔFosB?" /><ref name="Cellular basis" /> Based upon the accumulated evidence, a medical review from late 2014 argued that [[accumbal]] ΔFosB expression can be used as an addiction [[biomarker (medicine)|biomarker]] and that the degree of accumbal ΔFosB induction by a drug is a metric for how addictive it is relative to others.<ref name="What the ΔFosB?" /><!--
+-->{{clear right}}
+===Role in addiction===
+{{addiction glossary|collapse=yes|width=610px|reverse citation order=yes}}
+{{Psychostimulant addiction|align=right}}
+Chronic [[addictive drug]] use causes alterations in [[gene expression]] in the [[mesocorticolimbic projection]], which arise through [[transcriptional]] and [[epigenetic]] mechanisms.<ref name="Nestler" /><ref name="Nestler, Hyman, and Malenka 2">{{cite journal | vauthors = Hyman SE, Malenka RC, Nestler EJ | title = Neural mechanisms of addiction: the role of reward-related learning and memory | journal = Annual Review of Neuroscience | volume = 29 | issue =  | pages = 565–98 | year = 2006 | pmid = 16776597 | doi = 10.1146/annurev.neuro.29.051605.113009 }}</ref><ref name="Addiction genetics">{{cite journal | vauthors = Steiner H, Van Waes V | title = Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants | journal = Progress in Neurobiology | volume = 100 | issue =  | pages = 60–80 | date = Jan 2013 | pmid = 23085425 | pmc = 3525776 | doi = 10.1016/j.pneurobio.2012.10.001 }}</ref>  The most important [[transcription factor]]s that produce these alterations are ΔFosB, cyclic adenosine monophosphate ([[cyclic adenosine monophosphate|cAMP]]) response element binding protein ([[cAMP response element binding protein|CREB]]), and nuclear factor kappa B ([[nuclear factor kappa B|NF-κB]]).<ref name="Nestler" /> ΔFosB is the most significant biomolecular mechanism in addiction because the [[overexpression]] of ΔFosB in the [[D1-type]] [[medium spiny neuron]]s 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.<ref name="What the ΔFosB?" /><ref name="Nestler" /><ref name="Cellular basis" /> ΔFosB overexpression has been implicated in addictions to [[ethanol|alcohol (ethanol)]], [[cannabinoid]]s, [[cocaine]], [[methylphenidate]], [[nicotine]], [[opioid]]s, [[phencyclidine]], [[propofol]], and [[substituted amphetamines]], among others.<ref name="What the ΔFosB?" /><!--Preceding review covers ΔFosB in propofol addiction--><ref name="Nestler" /><ref name="Nestler, Hyman, and Malenka 2" /><ref name="Alcoholism ΔFosB">{{cite web | title=Alcoholism – Homo sapiens (human) | url=http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354 | work=KEGG Pathway | accessdate=31 October 2014 | author=Kanehisa Laboratories | date=29 October 2014}}</ref><ref name="MPH ΔFosB">{{cite journal | vauthors = Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P | title = Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 8 | pages = 2915–20 | date = Feb 2009 | pmid = 19202072 | pmc = 2650365 | doi = 10.1073/pnas.0813179106 | quote = <!--Despite decades of clinical use of methylphenidate for ADHD, concerns have been raised that long-term treatment of children with this medication may result in subsequent drug abuse and addiction.&nbsp;... Thus, although oral administration of clinical doses of methylphenidate is not associated with euphoria or with abuse problems, nontherapeutic use of high doses or i.v. administration may lead to addiction (39, 40).--> }}</ref>  [[ΔJunD]], a transcription factor, and [[EHMT2|G9a]], a [[histone methyltransferase]], both oppose the function of ΔFosB and inhibit increases in its expression.<ref name="Nestler" /><ref name="Cellular basis" /><ref name="Nestler 2014 epigenetics" /> Increases in nucleus accumbens ΔJunD expression (via [[viral vector]]-mediated gene transfer) or G9a expression (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).<ref name="G9a reverses ΔFosB plasticity" /><ref name="Nestler" />
+ΔFosB also plays an important role in regulating behavioral responses to [[natural reward]]s, such as palatable food, sex, and exercise.<ref name="Nestler" /><ref name="ΔFosB reward">{{cite journal | vauthors = Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M | title = Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms | journal = Journal of Psychoactive Drugs | volume = 44 | issue = 1 | pages = 38–55 | year = 2012 | pmid = 22641964 | pmc = 4040958 | doi = 10.1080/02791072.2012.662112 | quote = <!-- It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. Next, the induction of c-Fos, a downstream (repressed) target of DeltaFosB, was measured in sexually experienced and naive animals. The number of mating-induced c-Fos-IR cells was significantly decreased in sexually experienced animals compared to sexually naive controls. Finally, DeltaFosB levels and its activity in the NAc were manipulated using viral-mediated gene transfer to study its potential role in mediating sexual experience and experience-induced facilitation of sexual performance. Animals with DeltaFosB overexpression displayed enhanced facilitation of sexual performance with sexual experience relative to controls. In contrast, the expression of DeltaJunD, a dominant-negative binding partner of DeltaFosB, attenuated sexual experience-induced facilitation of sexual performance, and stunted long-term maintenance of facilitation compared to DeltaFosB overexpressing group. Together, these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance.&nbsp;... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry. --> }}</ref> Natural rewards, similar to drugs of abuse, [[inducible gene|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 overexpression.<ref name="Nestler" /><ref name="Natural and drug addictions">{{cite journal | vauthors = Olsen CM | title = Natural rewards, neuroplasticity, and non-drug addictions | journal = Neuropharmacology | volume = 61 | issue = 7 | pages = 1109–22 | date = Dec 2011 | pmid = 21459101 | pmc = 3139704 | doi = 10.1016/j.neuropharm.2011.03.010 | quote = Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA&nbsp;... 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).&nbsp;... 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).&nbsp;... 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).}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704/table/T1/?report=objectonly Table 1]</ref><ref name="ΔFosB reward" /> Consequently, ΔFosB is the key mechanism involved in addictions to natural rewards (i.e., behavioral addictions) as well;<ref name="Nestler">{{cite journal | vauthors = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nature Reviews. Neuroscience | volume = 12 | issue = 11 | pages = 623–37 | date = Nov 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 | quote =  ΔFosB has been linked directly to several addiction-related behaviors&nbsp;...  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 exposure<sup>14,22–24</sup>. 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 consumption<sup>14,26–30</sup>. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. }}</ref><ref name="Natural and drug addictions" /><ref name="ΔFosB reward"/> in particular, ΔFosB in the nucleus accumbens is critical for the [[reinforcing]] effects of sexual reward.<ref name="ΔFosB 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{{#tag:ref|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.|group="note"}} that are mediated through ΔFosB.<ref name="Natural and drug addictions" /><ref name="Amph and sex addiction"><!--Supplemental primary source-->{{cite journal | vauthors = Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM | title = Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator | journal = The Journal of Neuroscience | volume = 33 | issue = 8 | pages = 3434–42 | date = Feb 2013 | pmid = 23426671 | pmc = 3865508 | doi = 10.1523/JNEUROSCI.4881-12.2013 | quote = <!-- Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior.&nbsp;... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets.&nbsp;... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity --> }}</ref>  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.<ref name="Natural and drug addictions" />
+ΔFosB inhibitors (drugs or treatments that oppose its action or reduce its expression) may be an effective treatment for addiction and addictive disorders.<ref name="Malenka_2009_04">{{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 384–385 | edition = 2nd | chapter = Chapter 15: Reinforcement and addictive disorders }}</ref> Current medical reviews of research involving lab animals have identified a drug class – class I [[histone deacetylase inhibitor]]s{{#tag:ref|Inhibitors of class I [[histone deacetylase]] (HDAC) enzymes are drugs that inhibit four specific [[histone-modifying enzyme]]s: [[HDAC1]], [[HDAC2]], [[HDAC3]], and [[HDAC8]]. Most of the animal research with HDAC inhibitors has been conducted with four drugs: [[butyric acid|butyrate salts]] (mainly [[sodium butyrate]]),  [[trichostatin A]], [[valproic acid]], and [[vorinostat|SAHA]];<ref name="Amphetamine epigenetics" /><ref name="Chromatin states" /> butyric acid is a naturally occurring [[short-chain fatty acid]] in humans, while the latter two compounds are FDA-approved drugs with [[medical indication]]s unrelated to addiction.|group="note"}} – that indirectly inhibits the function and further increases in the expression of accumbal ΔFosB by inducing [[G9a]] expression in the nucleus accumbens after prolonged use.<ref name="G9a reverses ΔFosB plasticity" /><ref name="Nestler 2014 epigenetics">{{vcite2 journal | vauthors = Nestler EJ | title = Epigenetic mechanisms of drug addiction | journal = Neuropharmacology | volume = 76 Pt B | issue = | pages = 259–268 | date = January 2014 | pmid = 23643695 | pmc = 3766384 | doi = 10.1016/j.neuropharm.2013.04.004 | quote = 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.&nbsp;...  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).<br />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).&nbsp;... 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. }}</ref><ref name="Amphetamine epigenetics">{{cite journal | vauthors = McCowan TJ, Dhasarathy A, Carvelli L | title = The Epigenetic Mechanisms of Amphetamine | journal = J. Addict. Prev. | volume = 2015 | issue = Suppl 1 | pages = | date = February 2015 | pmid = 27453897 | pmc = 4955852 | doi = | quote = 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.}}</ref><ref name="Chromatin states">{{vcite2 journal | vauthors = Walker DM, Cates HM, Heller EA, Nestler EJ | title = Regulation of chromatin states by drugs of abuse | journal = Curr. Opin. Neurobiol. | volume = 30 | issue = | pages = 112–121 | date = February 2015 | pmid = 25486626 | doi = 10.1016/j.conb.2014.11.002 | quote = 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 | pmc=4293340}}</ref>  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{{#tag:ref|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-administration|self-administered]] when it is readily available.<ref name="Nestler 2014 epigenetics" /><ref name="Chromatin states" /><ref name="HDACi primaries" />|group="note"}} that have developed addictions to ethanol, psychostimulants (i.e., amphetamine and cocaine), nicotine, and opiates;<ref name="Nestler 2014 epigenetics" /><ref name="Chromatin states" /><ref name="HDACi primaries">Primary references involving sodium butyrate:<br /><br />{{bull}}{{vcite2 journal | vauthors = 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 | title = Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation | journal = Nat. Neurosci. | volume = 16 | issue = 4 | pages = 434–440 | date = April 2013 | pmid = 23475113 | pmc = 3609040 | doi = 10.1038/nn.3354 | quote = While acute HDAC inhibition enhances the behavioral effects of cocaine or amphetamine<sup>1,3,4,13,14</sup>, studies suggest that more chronic regimens block psychostimulant-induced plasticity<sup>3,5,11,12</sup>.&nbsp;... 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 drug<sup>1,3,4,13,14</sup>. 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 expression<sup>3</sup> or decreased acquisition of behavioral adaptations to drug<sup>5,11,12</sup>. 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.}}<br /><br />{{bull}}{{vcite2 journal | vauthors = Simon-O'Brien E, Alaux-Cantin S, Warnault V, Buttolo R, Naassila M, Vilpoux C | title = The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals | journal = Addict Biol | volume = 20 | issue = 4 | pages = 676–689 | date = July 2015 | pmid = 25041570 | doi = 10.1111/adb.12161 | quote = Altogether, our results clearly demonstrated the efficacy of {{abbr|NaB|sodium butyrate}} in preventing excessive ethanol intake and relapse and support the hypothesis that {{abbr|HDACi|HDAC inhibitors}} may have a potential use in alcohol addiction treatment.}}<br /><br />{{bull}}{{vcite2 journal | vauthors = Castino MR, Cornish JL, Clemens KJ | title = Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats | journal = PLoS ONE | volume = 10 | issue = 4 | pages = e0124796 | date = April 2015 | pmid = 25880762 | pmc = 4399837 | doi = 10.1371/journal.pone.0124796 | quote = treatment with NaB significantly attenuated nicotine and nicotine + cue reinstatement when administered immediately&nbsp;... 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.}}</ref><ref name="HDAC alcoholism review">{{cite journal | vauthors = Kyzar EJ, Pandey SC | title = Molecular mechanisms of synaptic remodeling in alcoholism | journal = Neurosci. Lett. | volume = 601 | issue = | pages = 11–9 | date = August 2015 | pmid = 25623036 | doi = 10.1016/j.neulet.2015.01.051 | quote = 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&nbsp;... 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.&nbsp;... 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&nbsp;... 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.| pmc = 4506731 }}</ref> however, {{as of|August 2015|lc=y}} 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}}
+{{Annotated image 4
+| caption = 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]]).<br />Bottom: this illustrates the progressive increase in ΔFosB expression in the nucleus accumbens following repeated twice daily drug binges, where these [[phosphorylated]] (35–37&nbsp;[[kilodalton]]) ΔFosB [[isoform]]s persist in the [[D1-type]] [[medium spiny neurons]] of the nucleus accumbens for up to 2&nbsp;months.<ref name="pmid11572966" /><ref name="Nestler2" />
+| header = ΔFosB accumulation from excessive drug use
+| header_background = aliceblue
+| alt = ΔFosB accumulation graph
+| image = ΔFosB accumulation.svg
+| align = right
+| icon = none
+| image-width = 400
+| image-left = 0
+| image-top = 0
+| width = 400
+| height = 440
+| annotations =
 }}
+ΔFosB levels have been found to increase upon the use of cocaine.<ref name="pmid9668659">{{cite journal | vauthors = Hope BT | title = Cocaine and the AP-1 transcription factor complex | journal = Annals of the New York Academy of Sciences | volume = 844 | issue =  | pages = 1–6 | date = May 1998 | pmid = 9668659 | doi = 10.1111/j.1749-6632.1998.tb08216.x }}</ref> Each subsequent dose of cocaine continues to increase ΔFosB levels 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 [[dendrite|dendritic]] branches and [[dendritic spine|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 [[drug sensitization|sensitized]] behavioural responses to cocaine.<ref name="pmid10499584">{{cite journal |authorlink13=D. James Surmeier | vauthors = 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 | title = Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine | journal = Nature | volume = 401 | issue = 6750 | pages = 272–6 | date = Sep 1999 | pmid = 10499584 | doi = 10.1038/45790 }}</ref> They self-administer cocaine at lower doses than control,<ref name="pmid12657709">{{cite journal | vauthors = Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW | title = Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine | journal = The Journal of Neuroscience | volume = 23 | issue = 6 | pages = 2488–93 | date = Mar 2003 | pmid = 12657709 | doi =  }}</ref> but have a greater likelihood of [[relapse]] when the drug is withheld.<ref name="pmid11572966">{{cite journal | vauthors = Nestler EJ, Barrot M, Self DW | title = DeltaFosB: a sustained molecular switch for addiction | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 20 | pages = 11042–6 | date = Sep 2001 | pmid = 11572966 | pmc = 58680 | doi = 10.1073/pnas.191352698 | quote = <!-- Although the ΔFosB signal is relatively long-lived, it is not permanent. ΔFosB degrades gradually and can no longer be detected in brain after 1–2 months of drug withdrawal&nbsp;... Indeed, ΔFosB is the longest-lived adaptation known to occur in adult brain, not only in response to drugs of abuse, but to any other perturbation (that doesn't involve lesions) as well. --> }}</ref><ref name="pmid12657709"/> ΔFosB increases the expression of [[AMPA receptor]] subunit GluR2<ref name="pmid10499584"/> and also decreases expression of [[dynorphin]], thereby enhancing sensitivity to reward.<ref name="pmid11572966"/>
+<!-- Left-aligned Wikitable -->
+{| class="wikitable" style="float:left; text-align:center"
+|+ Neural and behavioral effects of validated ΔFosB transcriptional targets<ref name="What the ΔFosB?" /><ref name="pmid18640924">{{cite journal | vauthors = Nestler EJ | title = Review. Transcriptional mechanisms of addiction: role of DeltaFosB | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 363 | issue = 1507 | pages = 3245–55 | date = Oct 2008 | pmid = 18640924 | pmc = 2607320 | doi = 10.1098/rstb.2008.0067 | quote = 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.&nbsp;... <br />Examples of validated targets for ΔFosB in nucleus accumbens&nbsp;... GluR2&nbsp;... dynorphin&nbsp;... Cdk5&nbsp;... NFκB&nbsp;... c-Fos }}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607320/table/tbl3/ Table 3]</ref>
+! scope="col" | Target<br />gene
+! scope="col" | Target<br />[[gene expression|expression]]
+! scope="col" | Neural effects
+! scope="col" | Behavioral effects
+|-
+| scope="row" style="height: 40px"| [[c-Fos]]     || ↓ || Molecular switch enabling the chronic<br /> induction of ΔFosB{{#tag:ref|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.<ref name="Cellular basis" />|group="note"}} || –
+|-
+| scope="row" style="height: 40px"| [[dynorphin]] || ↓<br />{{#tag:ref|ΔFosB has been implicated in causing both increases and decreases in dynorphin expression in different studies;<ref name="What the ΔFosB?" /><ref name="pmid18640924" /> this table entry reflects only a decrease. |group="note"}} || style="text-align:left" | {{bull}}Downregulation of [[κ-opioid receptor|κ-opioid]] feedback loop || style="text-align:left" | {{bull}}Increased drug reward
+|-
+| scope="row" style="height: 40px"| [[NF-κB]]     || ↑ || style="text-align:left" | {{bull}}Expansion of [[Nucleus accumbens|Nacc]] dendritic processes<br />{{bull}}NF-κB inflammatory response in the {{abbr|NAcc|nucleus accumbens}}<br />{{bull}}NF-κB inflammatory response in the {{abbrlink|CP|caudate putamen}}<br />|| style="text-align:left" | {{bull}}Increased drug reward<br />{{bull}}Increased drug reward<br />{{bull}}[[Stereotypy|Locomotor sensitization]]
+|-
+| scope="row" style="height: 40px"| [[GluR2]]     || ↑ || style="text-align:left" | {{bull}}Decreased [[sensitization|sensitivity]] to [[glutamate]] || style="text-align:left" | {{bull}}Increased drug reward
+|-
+| scope="row" style="height: 40px"| [[Cdk5]]      || ↑ || style="text-align:left" | {{bull}}[[GluR1]] synaptic protein phosphorylation <br />{{bull}}Expansion of {{abbr|NAcc|nucleus accumbens}} dendritic processes || {{bull}}Decreased drug reward<br /><small>(net effect)</small>
+|}
+{{clear}}
-<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
+===Summary of addiction-related plasticity===
-{{GNF_Protein_box
+{{FOSB addiction table}}
- | image =
- | image_source =
- | PDB =
- | Name = FBJ murine osteosarcoma viral oncogene homolog B
- | HGNCid = 3797
- | Symbol = FOSB
- | AltSymbols =; DKFZp686C0818; G0S3; GOS3; GOSB; MGC42291
- | OMIM = 164772
- | ECnumber =
- | Homologene = 31403
- | MGIid = 95575
- | GeneAtlas_image1 = PBB_GE_FOSB_202768_at_tn.png
- | Function = {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0008134 |text = transcription factor binding}} {{GNF_GO|id=GO:0043565 |text = sequence-specific DNA binding}} {{GNF_GO|id=GO:0046983 |text = protein dimerization activity}}
- | Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
- | Process = {{GNF_GO|id=GO:0000074 |text = regulation of progression through cell cycle}} {{GNF_GO|id=GO:0000122 |text = negative regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0007275 |text = multicellular organismal development}} {{GNF_GO|id=GO:0007610 |text = behavior}}
- | Orthologs = {{GNF_Ortholog_box
-    | Hs_EntrezGene = 2354
-    | Hs_Ensembl = ENSG00000125740
-    | Hs_RefseqProtein = NP_006723
-    | Hs_RefseqmRNA = NM_006732
-    | Hs_GenLoc_db =
-    | Hs_GenLoc_chr = 19
-    | Hs_GenLoc_start = 50663093
-    | Hs_GenLoc_end = 50670254
-    | Hs_Uniprot = P53539
-    | Mm_EntrezGene = 14282
-    | Mm_Ensembl = ENSMUSG00000003545
-    | Mm_RefseqmRNA = NM_008036
-    | Mm_RefseqProtein = NP_032062
-    | Mm_GenLoc_db =
-    | Mm_GenLoc_chr = 7
-    | Mm_GenLoc_start = 18463363
-    | Mm_GenLoc_end = 18467953
-    | Mm_Uniprot = P13346
-  }}
-}}
+===Other functions in the brain===
-==Overview==
+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]].<ref name="pmid20505100">{{cite journal | vauthors = Cao X, Yasuda T, Uthayathas S, Watts RL, Mouradian MM, Mochizuki H, Papa SM | title = Striatal overexpression of DeltaFosB reproduces chronic levodopa-induced involuntary movements | journal = The Journal of Neuroscience | volume = 30 | issue = 21 | pages = 7335–43 | date = May 2010 | pmid = 20505100 | pmc = 2888489 | doi = 10.1523/JNEUROSCI.0252-10.2010 }}</ref><ref name="Levetiracetam">{{cite journal | vauthors = Du H, Nie S, Chen G, Ma K, Xu Y, Zhang Z, Papa SM, Cao X | title = Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats Inducing Critical Molecular Changes in the Striatum | journal = Parkinson's Disease | volume = 2015 | issue =  | pages = 253878 | year = 2015 | pmid = 25692070 | pmc = 4322303 | doi = 10.1155/2015/253878 | quote =  Furthermore, the transgenic overexpression of ΔFosB reproduces AIMs in hemiparkinsonian rats without chronic exposure to L-DOPA [13].&nbsp;... 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.&nbsp;... 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].&nbsp;... Furthermore, ΔFosB overexpression has been observed in postmortem striatal studies of Parkinsonian patients chronically treated with L-DOPA [26].&nbsp;... 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. }}</ref> Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias;<ref name="Levetiracetam" /> postmortem studies of individuals with Parkinson's disease that were treated with [[levodopa]] have also observed similar dorsal striatal ΔFosB overexpression.<ref name="Levetiracetam" /> [[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;<ref name="Levetiracetam" /> the [[signal transduction]] involved in this effect is unknown.<ref name="Levetiracetam" />
-'''FBJ murine osteosarcoma viral oncogene homolog B''' (also known as '''FOSB''' or '''FosB''') is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: FOSB FBJ murine osteosarcoma viral oncogene homolog B| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2354| accessdate = }}</ref>
-<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
+ΔFosB expression in the [[nucleus accumbens shell]] increases resilience to stress and is induced in this region by acute exposure to [[social defeat]] stress.<ref name="Nestler's lab">{{cite web|title=ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS|url=http://neuroscience.mssm.edu/nestler/deltaFosB.html|website=Mount Sinai School of Medicine|publisher=NESTLER LAB: LABORATORY OF MOLECULAR PSYCHIATRY|accessdate=6 September 2014|quote=<!-- Role of ΔFosB in Depression<br />  More recently, we have shown that induction of ΔFosB in nucleus accumbens in response to chronic stress represents a positive, adaptive mechanism to help the animal cope with the stress. In the social defeat paradigm, for example, animalsthat are resilient to the deleterious effects of defeat stress show greater induction of ΔFosB than vulnerable animals. Moreover, chronic administration of antidepressant medications induces ΔFosB in nucleus accumbens and the behavioral effects of these treatments can be blocked by blockade of ΔFosB activity in this brain region. Together, these data demonstrate that ΔFosB is a novel mechanism of resilience and a potentially important mediator of antidepressant action.&nbsp;...<br />Interesting comparisons and contrasts with CREB are evident. Both ΔFosB and CREB are induced by stress and by drugs of abuse, yet they exert opposite effects on behavior. CREB reduces behavioral responses to emotional stimuli and induces a depression-like state in the extreme, whereas ΔFosB sensitizes reward and induces antidepressant-like responses. Also, the CREB signal is relatively short-lived, while the ΔFosB signal is long-lived. -->}}</ref><ref name="Stress and NAcc shell">{{cite journal | vauthors = Furuyashiki T, Deguchi Y | title = [Roles of altered striatal function in major depression] | language = Japanese | journal = Brain and Nerve = Shinkei Kenkyū No Shinpo | volume = 64 | issue = 8 | pages = 919–26 | date = Aug 2012 | pmid = 22868883 | doi =  }}</ref><ref name="NAcc ∆FosB depression">{{cite journal | vauthors = Nestler EJ | title = ∆FosB: a transcriptional regulator of stress and antidepressant responses | journal = European Journal of Pharmacology | volume = 753 | issue =  | pages = 66–72 | date = Apr 2015 | pmid = 25446562 | doi = 10.1016/j.ejphar.2014.10.034 | quote = 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. | pmc=4380559}}</ref><!--Expand upon this with the last refs quote-->
-{{PBB_Summary
-| section_title =
-| summary_text = The Fos gene family consists of 4 members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation.<ref name="entrez">{{cite web | title = Entrez Gene: FOSB FBJ murine osteosarcoma viral oncogene homolog B| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2354| accessdate = }}</ref>
-}}
-==Delta FosB==
+[[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.<ref name="pmid24067299">{{cite journal |vauthors = Dietz DM, Kennedy PJ, Sun H, Maze I, Gancarz AM, Vialou V, Koo JW, Mouzon E, Ghose S, Tamminga CA, Nestler EJ |title = ΔFosB induction in prefrontal cortex by antipsychotic drugs is associated with negative behavioral outcomes |journal = Neuropsychopharmacology |volume = 39 |issue = 3 |pages = 538–44 |date = February 2014 |pmid = 24067299 |pmc = 3895248 |doi = 10.1038/npp.2013.255 }}</ref>
-'''Delta FosB''' is a truncated [[splice variant]] of FosB. Delta FosB has been implicated in the development of [[drug addiction]] and control of the [[reward system]] in the [[brain]].<ref name="Werme">{{cite journal |author=Werme M, Messer C, Olson L, ''et al'' |title=Delta FosB regulates wheel running |journal=J. Neurosci. |volume=22 |issue=18 |pages=8133–8 |year=2002 |pmid=12223567 |doi=}}</ref>
-==See also==
+== See also ==
 * [[AP-1 (transcription factor)]]
-==References==
+==Notes==
-{{reflist}}
+{{reflist|group=note}}
+;Image legend
+{{reflist|group=Color legend}}
-==Further reading==
+== References ==
-{{refbegin | 2}}
+{{reflist|33em}}
-{{PBB_Further_reading
-| citations =
+== Further reading ==
-*{{cite journal  | author=Martin-Gallardo A, McCombie WR, Gocayne JD, ''et al.'' |title=Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3. |journal=Nat. Genet. |volume=1 |issue= 1 |pages= 34-9 |year= 1993 |pmid= 1301997 |doi= 10.1038/ng0492-34 }}
+{{refbegin|33em}}
-*{{cite journal  | author=Siderovski DP, Blum S, Forsdyke RE, Forsdyke DR |title=A set of human putative lymphocyte G0/G1 switch genes includes genes homologous to rodent cytokine and zinc finger protein-encoding genes. |journal=DNA Cell Biol. |volume=9 |issue= 8 |pages= 579-87 |year= 1991 |pmid= 1702972 |doi=  }}
+* {{cite journal | vauthors = Schuermann M, Jooss K, Müller R | title = fosB is a transforming gene encoding a transcriptional activator | journal = Oncogene | volume = 6 | issue = 4 | pages = 567–76 | date = Apr 1991 | pmid = 1903195 | doi =  }}
-*{{cite journal  | author=Nakabeppu Y, Nathans D |title=A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity. |journal=Cell |volume=64 |issue= 4 |pages= 751-9 |year= 1991 |pmid= 1900040 |doi=  }}
+* {{cite journal | vauthors = Brown JR, Ye H, Bronson RT, Dikkes P, Greenberg ME | title = A defect in nurturing in mice lacking the immediate early gene fosB | journal = Cell | volume = 86 | issue = 2 | pages = 297–309 | date = Jul 1996 | pmid = 8706134 | doi = 10.1016/S0092-8674(00)80101-4 }}
-*{{cite journal  | author=Schuermann M, Jooss K, Müller R |title=fosB is a transforming gene encoding a transcriptional activator. |journal=Oncogene |volume=6 |issue= 4 |pages= 567-76 |year= 1991 |pmid= 1903195 |doi=  }}
+* {{cite journal | vauthors = Heximer SP, Cristillo AD, Russell L, Forsdyke DR | title = Sequence analysis and expression in cultured lymphocytes of the human FOSB gene (G0S3) | journal = DNA and Cell Biology | volume = 15 | issue = 12 | pages = 1025–38 | date = Dec 1996 | pmid = 8985116 | doi = 10.1089/dna.1996.15.1025 }}
-*{{cite journal  | author=Brown JR, Ye H, Bronson RT, ''et al.'' |title=A defect in nurturing in mice lacking the immediate early gene fosB. |journal=Cell |volume=86 |issue= 2 |pages= 297-309 |year= 1996 |pmid= 8706134 |doi=  }}
+* {{cite journal | vauthors = Liberati NT, Datto MB, Frederick JP, Shen X, Wong C, Rougier-Chapman EM, Wang XF | title = Smads bind directly to the Jun family of AP-1 transcription factors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 9 | pages = 4844–9 | date = Apr 1999 | pmid = 10220381 | pmc = 21779 | doi = 10.1073/pnas.96.9.4844 }}
-*{{cite journal  | author=Heximer SP, Cristillo AD, Russell L, Forsdyke DR |title=Sequence analysis and expression in cultured lymphocytes of the human FOSB gene (G0S3). |journal=DNA Cell Biol. |volume=15 |issue= 12 |pages= 1025-38 |year= 1997 |pmid= 8985116 |doi=  }}
+* {{cite journal | vauthors = Yamamura Y, Hua X, Bergelson S, Lodish HF | title = Critical role of Smads and AP-1 complex in transforming growth factor-beta -dependent apoptosis | journal = The Journal of Biological Chemistry | volume = 275 | issue = 46 | pages = 36295–302 | date = Nov 2000 | pmid = 10942775 | doi = 10.1074/jbc.M006023200 }}
-*{{cite journal  | author=Liberati NT, Datto MB, Frederick JP, ''et al.'' |title=Smads bind directly to the Jun family of AP-1 transcription factors. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue= 9 |pages= 4844-9 |year= 1999 |pmid= 10220381 |doi=  }}
+* {{cite journal | vauthors = Bergman MR, Cheng S, Honbo N, Piacentini L, Karliner JS, Lovett DH | title = 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 |journal=[[Biochemical Journal]] |volume=369 | issue = Pt 3 | pages = 485–96 | date = Feb 2003 | pmid = 12371906 | pmc = 1223099 | doi = 10.1042/BJ20020707 }}
-*{{cite journal  | author=Yamamura Y, Hua X, Bergelson S, Lodish HF |title=Critical role of Smads and AP-1 complex in transforming growth factor-beta -dependent apoptosis. |journal=J. Biol. Chem. |volume=275 |issue= 46 |pages= 36295-302 |year= 2000 |pmid= 10942775 |doi= 10.1074/jbc.M006023200 }}
+* {{cite journal | vauthors = Milde-Langosch K, Kappes H, Riethdorf S, Löning T, Bamberger AM | title = FosB is highly expressed in normal mammary epithelia, but down-regulated in poorly differentiated breast carcinomas | journal = Breast Cancer Research and Treatment | volume = 77 | issue = 3 | pages = 265–75 | date = Feb 2003 | pmid = 12602926 | doi = 10.1023/A:1021887100216 }}
-*{{cite journal  | author=Bergman MR, Cheng S, Honbo N, ''et al.'' |title=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. |journal=Biochem. J. |volume=369 |issue= Pt 3 |pages= 485-96 |year= 2003 |pmid= 12371906 |doi= 10.1042/BJ20020707 }}
+* {{cite journal | vauthors = Baumann S, Hess J, Eichhorst ST, Krueger A, Angel P, Krammer PH, Kirchhoff S | title = An unexpected role for FosB in activation-induced cell death of T cells | journal = Oncogene | volume = 22 | issue = 9 | pages = 1333–9 | date = Mar 2003 | pmid = 12618758 | doi = 10.1038/sj.onc.1206126 }}
-*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
+* {{cite journal | vauthors = Holmes DI, Zachary I | title = Placental growth factor induces FosB and c-Fos gene expression via Flt-1 receptors | journal = FEBS Letters | volume = 557 | issue = 1–3 | pages = 93–8 | date = Jan 2004 | pmid = 14741347 | doi = 10.1016/S0014-5793(03)01452-2 }}
-*{{cite journal  | author=Milde-Langosch K, Kappes H, Riethdorf S, ''et al.'' |title=FosB is highly expressed in normal mammary epithelia, but down-regulated in poorly differentiated breast carcinomas. |journal=Breast Cancer Res. Treat. |volume=77 |issue= 3 |pages= 265-75 |year= 2003 |pmid= 12602926 |doi=  }}
+* {{cite journal | vauthors = Konsman JP, Blomqvist A | title = Forebrain patterns of c-Fos and FosB induction during cancer-associated anorexia-cachexia in rat | journal = The European Journal of Neuroscience | volume = 21 | issue = 10 | pages = 2752–66 | date = May 2005 | pmid = 15926923 | doi = 10.1111/j.1460-9568.2005.04102.x }}
-*{{cite journal  | author=Baumann S, Hess J, Eichhorst ST, ''et al.'' |title=An unexpected role for FosB in activation-induced cell death of T cells. |journal=Oncogene |volume=22 |issue= 9 |pages= 1333-9 |year= 2003 |pmid= 12618758 |doi= 10.1038/sj.onc.1206126 }}
-*{{cite journal  | author=Holmes DI, Zachary I |title=Placental growth factor induces FosB and c-Fos gene expression via Flt-1 receptors. |journal=FEBS Lett. |volume=557 |issue= 1-3 |pages= 93-8 |year= 2004 |pmid= 14741347 |doi=  }}
-*{{cite journal  | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
-*{{cite journal  | author=Konsman JP, Blomqvist A |title=Forebrain patterns of c-Fos and FosB induction during cancer-associated anorexia-cachexia in rat. |journal=Eur. J. Neurosci. |volume=21 |issue= 10 |pages= 2752-66 |year= 2005 |pmid= 15926923 |doi= 10.1111/j.1460-9568.2005.04102.x }}
-}}
 {{refend}}
 == External links ==
+* [http://neuroscience.mssm.edu/nestler/deltaFosB.html ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS]
+* [http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354 KEGG Pathway – human alcohol addiction]
+* [http://www.genome.jp/kegg-bin/show_pathway?hsa05031+2354 KEGG Pathway – human amphetamine addiction]
+* [http://www.genome.jp/kegg-bin/show_pathway?hsa05030+2354 KEGG Pathway – human cocaine addiction]
 * {{MeshName|FOSB+protein,+human}}
 {{NLM content}}
-{{Transcription factors}}
+{{Addiction|state=expanded}}
+{{Amphetamine}}
+{{Transcription factors|g1}}
+[[Category:Addiction|Δ0]]
+[[Category:Oncogenes]]
 [[Category:Transcription factors]]
-{{WH}}
-{{WikiDoc Sources}}