Biology:FOSB

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Short description: Protein


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Protein fosB, also known as FosB and G0/G1 switch regulatory protein 3 (G0S3), is a protein that in humans is encoded by the FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene.[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[5][6] role in the development and maintenance of addiction.[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 and produces a behavioral phenotype that is characteristic of an addiction.[5][8][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]

DeltaFosB

DeltaFosB – more commonly written as ΔFosB – is a truncated splice variant of the FOSB gene.[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]

Chronic administration of anandamide, or N-arachidonylethanolamide (AEA), an endogenous cannabinoid, and additives such as sucralose, a noncaloric sweetener used in many food products of daily intake, are found to induce an overexpression of ΔFosB in the infralimbic cortex (Cx), nucleus accumbens (NAc) core, shell, and central nucleus of amygdala (Amy), that induce long-term changes in the reward system.[19]

Role in addiction

Addiction and dependence glossary[8][20][21][22]
  • 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 · d · e
Signaling cascade in the nucleus accumbens that results in psychostimulant addiction
v · d · e
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,[23][24] 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.[23][25][26] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[23][17][27] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[28] 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][27] 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][27]

Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.[6][29][30] 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][29][31][32] ΔJunD, a transcription factor, and G9a, a histone methyltransferase, both oppose the function of ΔFosB and inhibit increases in its expression.[6][8][33] 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] Repression of c-Fos by ΔFosB, which consequently further induces expression of ΔFosB, forms a positive feedback loop that serves to indefinitely perpetuate the addictive state.

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][34] 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.[35] 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][33][36][37] 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;[33][37][38][39] however, (As of August 2015), few clinical trials involving humans with addiction and any HDAC class I inhibitors have been conducted to test for treatment efficacy in humans or identify an optimal dosing regimen.[note 4]

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][27]

ΔFosB levels have been found to increase upon the use of cocaine.[41] Each subsequent dose of cocaine continues to increase ΔFosB levels with no apparent ceiling of tolerance.[citation needed] 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.[42] They self-administer cocaine at lower doses than control,[43] but have a greater likelihood of relapse when the drug is withheld.[18][43] ΔFosB increases the expression of AMPA receptor subunit GluR2[42] 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 5]		 –
dynorphin ↓
[note 6]		  • Downregulation of κ-opioid feedback loop  • Diminished self-extinguishing response to drug
NF-κB ↑  • Expansion of Nacc dendritic processes
 • NF-κB inflammatory response in the NAcc
 • NF-κB inflammatory response in the CP
  • 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
Opiates Psychostimulants High fat or sugar food Sexual intercourse Physical exercise
(aerobic) 		Environmental
enrichment
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.[44][45] Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias;[45] postmortem studies of individuals with Parkinson's disease that were treated with levodopa have also observed similar dorsal striatal ΔFosB overexpression.[45] Levetiracetam, an antiepileptic drug, has been shown to dose-dependently decrease the induction of dorsal striatal ΔFosB expression in rats when co-administered with levodopa;[45] the signal transduction involved in this effect is unknown.[45]

ΔFosB expression in the nucleus accumbens shell increases resilience to stress and is induced in this region by acute exposure to social defeat stress.[46][47][48]

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.[49]

See also

  • AP-1 (transcription factor)

Notes

  1. ↑ In simplest terms, this means that when either amphetamine or sex is perceived as "more alluring or desirable" through reward sensitization, this effect occurs with the other as well.
  2. ↑ Inhibitors of class I histone deacetylase (HDAC) enzymes are drugs that inhibit four specific histone-modifying enzymes: HDAC1, HDAC2, HDAC3, and HDAC8. Most of the animal research with HDAC inhibitors has been conducted with four drugs: butyrate salts (mainly sodium butyrate), trichostatin A, valproic acid, and SAHA;[36][37] butyric acid is a naturally occurring short-chain fatty acid in humans, while the latter two compounds are FDA-approved drugs with medical indications unrelated to addiction.
  3. ↑ Specifically, prolonged administration of a class I HDAC inhibitor appears to reduce an animal's motivation to acquire and use an addictive drug without affecting an animals motivation to attain other rewards (i.e., it does not appear to cause motivational anhedonia) and reduce the amount of the drug that is self-administered when it is readily available.[33][37][38]
  4. ↑ Among the few clinical trials that employed a class I HDAC inhibitor, one utilized valproate for methamphetamine addiction.[40]
  5. ↑ In other words, c-Fos repression allows ΔFosB to accumulate within nucleus accumbens medium spiny neurons more rapidly because it is selectively induced in this state.[8]
  6. ↑ 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
  1. ↑
      Ion channel
      G proteins & linked receptors
      (Text color) Transcription factors

References

  1. ↑ 1.0 1.1 "Entrez Gene: FOSB FBJ murine osteosarcoma viral oncogene homolog B". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2354. 
  2. ↑ "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. Oct 1990. doi:10.1089/dna.1990.9.579. PMID 1702972. 
  3. ↑ "Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3". Nature Genetics 1 (1): 34–9. Apr 1992. doi:10.1038/ng0492-34. PMID 1301997. 
  4. ↑ "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. May 2008. doi:10.1359/jbmr.080110. PMID 18433296. 
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". The American Journal of Drug and Alcohol Abuse 40 (6): 428–37. Nov 2014. 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. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews. Neuroscience 12 (11): 623–37. Nov 2011. doi:10.1038/nrn3111. 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 exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.". 
  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 "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology 61 (7): 1109–22. Dec 2011. doi:10.1016/j.neuropharm.2011.03.010. 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. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience 15 (4): 431–443. 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. ↑ 9.0 9.1 9.2 "Epigenetic regulation in drug addiction". Annals of Agricultural and Environmental Medicine 19 (3): 491–6. 2012. 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". 
  10. ↑ "Functional role of the N-terminal domain of ΔFosB in response to stress and drugs of abuse". Neuroscience 284: 165–70. Jan 2015. doi:10.1016/j.neuroscience.2014.10.002. PMID 25313003. 
  11. ↑ "A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity". Cell 64 (4): 751–9. Feb 1991. doi:10.1016/0092-8674(91)90504-R. PMID 1900040. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 "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. 2012. doi:10.1080/02791072.2012.662112. PMID 22641964. 
  13. ↑ 13.0 13.1 13.2 "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 363 (1507): 3245–55. Oct 2008. doi:10.1098/rstb.2008.0067. 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
  14. ↑ "Epigenetic mechanisms in drug addiction". Trends in Molecular Medicine 14 (8): 341–50. Aug 2008. doi:10.1016/j.molmed.2008.06.004. PMID 18635399. 
  15. ↑ "Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins". Neuron 62 (3): 335–48. May 2009. doi:10.1016/j.neuron.2009.03.026. PMID 19447090. 
  16. ↑ "Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis". Nature Medicine 6 (9): 985–90. Sep 2000. doi:10.1038/79683. PMID 10973317. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience 12 (11): 623–637. doi:10.1038/nrn3111. 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. ↑ 18.0 18.1 18.2 18.3 18.4 "DeltaFosB: a sustained molecular switch for addiction". Proceedings of the National Academy of Sciences of the United States of America 98 (20): 11042–6. Sep 2001. doi:10.1073/pnas.191352698. PMID 11572966. Bibcode: 2001PNAS...9811042N. 
  19. ↑ "Anandamide and sucralose change ΔFosB expression in the reward system". NeuroReport 31 (3): 240–244. February 2020. doi:10.1097/WNR.0000000000001400. PMID 31923023. 
  20. ↑ "Chapter 15: Reinforcement and Addictive Disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. 2009. pp. 364–375. ISBN 9780071481274. 
  21. ↑ "Glossary of Terms". Department of Neuroscience. http://neuroscience.mssm.edu/nestler/glossary.html. Retrieved 9 February 2015. 
  22. ↑ "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine 374 (4): 363–371. January 2016. 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.".     
  23. ↑ 23.0 23.1 23.2 Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience 11 (3): 257–268. 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
  24. ↑ "Co-transmission of dopamine and glutamate". The Journal of General Physiology 139 (1): 93–96. January 2012. doi:10.1085/jgp.201110659. 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.". 
  25. ↑ Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. http://www.genome.jp/kegg-bin/show_pathway?hsa05031+2354. 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." 
  26. ↑ "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Molecular Neurobiology 51 (2): 696–717. 2015. doi:10.1007/s12035-014-8776-8. PMID 24939695. "Figure 1". 
  27. ↑ 27.0 27.1 27.2 27.3 Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. 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". 
  28. ↑ Nestler EJ (October 2008). "Transcriptional mechanisms of addiction: Role of ΔFosB". Philosophical Transactions of the Royal Society B: Biological Sciences 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. 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". 
  29. ↑ 29.0 29.1 "Neural mechanisms of addiction: the role of reward-related learning and memory". Annual Review of Neuroscience 29: 565–98. 2006. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597. 
  30. ↑ "Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants". Progress in Neurobiology 100: 60–80. Jan 2013. doi:10.1016/j.pneurobio.2012.10.001. PMID 23085425. 
  31. ↑ Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354. 
  32. ↑ "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. Feb 2009. doi:10.1073/pnas.0813179106. PMID 19202072. Bibcode: 2009PNAS..106.2915K. 
  33. ↑ 33.0 33.1 33.2 33.3 "Epigenetic mechanisms of drug addiction". Neuropharmacology 76 Pt B: 259–268. January 2014. doi:10.1016/j.neuropharm.2013.04.004. 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.".     
  34. ↑ "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". The Journal of Neuroscience 33 (8): 3434–42. Feb 2013. doi:10.1523/JNEUROSCI.4881-12.2013. PMID 23426671. 
  35. ↑ "Chapter 15: Reinforcement and addictive disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. 2009. pp. 384–385. ISBN 9780071481274. 
  36. ↑ 36.0 36.1 "The Epigenetic Mechanisms of Amphetamine". J. Addict. Prev. 2015 (Suppl 1). February 2015. 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.". 
  37. ↑ 37.0 37.1 37.2 37.3 "Regulation of chromatin states by drugs of abuse". Curr. Opin. Neurobiol. 30: 112–121. February 2015. doi:10.1016/j.conb.2014.11.002. 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". 
  38. ↑ 38.0 38.1 Primary references involving sodium butyrate:

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

     • "The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals". Addict Biol 20 (4): 676–689. July 2015. 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.". 

     • "Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats". PLOS ONE 10 (4): e0124796. April 2015. doi:10.1371/journal.pone.0124796. PMID 25880762. Bibcode: 2015PLoSO..1024796C. "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.". 
  39. ↑ "Molecular mechanisms of synaptic remodeling in alcoholism". Neurosci. Lett. 601: 11–9. August 2015. doi:10.1016/j.neulet.2015.01.051. PMID 25623036. "Increased HDAC2 expression decreases the expression of genes important for the maintenance of dendritic spine density such as BDNF, Arc, and NPY, leading to increased anxiety and alcohol-seeking behavior. Decreasing HDAC2 reverses both the molecular and behavioral consequences of alcohol addiction, thus implicating this enzyme as a potential treatment target (Fig. 3). HDAC2 is also crucial for the induction and maintenance of structural synaptic plasticity in other neurological domains such as memory formation [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.". 
  40. ↑ "Effect of add-on valproate on craving in methamphetamine depended patients: A randomized trial". Advanced Biomedical Research 5: 149. 2016. doi:10.4103/2277-9175.187404. PMID 27656618. 
  41. ↑ "Cocaine and the AP-1 transcription factor complex". Annals of the New York Academy of Sciences 844 (1): 1–6. May 1998. doi:10.1111/j.1749-6632.1998.tb08216.x. PMID 9668659. Bibcode: 1998NYASA.844....1H. https://zenodo.org/record/1230756. 
  42. ↑ 42.0 42.1 "Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine". Nature 401 (6750): 272–6. Sep 1999. doi:10.1038/45790. PMID 10499584. Bibcode: 1999Natur.401..272K. 
  43. ↑ 43.0 43.1 "Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine". The Journal of Neuroscience 23 (6): 2488–93. Mar 2003. doi:10.1523/JNEUROSCI.23-06-02488.2003. PMID 12657709. 
  44. ↑ "Striatal overexpression of DeltaFosB reproduces chronic levodopa-induced involuntary movements". The Journal of Neuroscience 30 (21): 7335–43. May 2010. doi:10.1523/JNEUROSCI.0252-10.2010. PMID 20505100. 
  45. ↑ 45.0 45.1 45.2 45.3 45.4 "Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats Inducing Critical Molecular Changes in the Striatum". Parkinson's Disease 2015: 253878. 2015. doi:10.1155/2015/253878. 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.". 
  46. ↑ "ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS". NESTLER LAB: LABORATORY OF MOLECULAR PSYCHIATRY. http://neuroscience.mssm.edu/nestler/deltaFosB.html. 
  47. ↑ "[Roles of altered striatal function in major depression]" (in ja). Brain and Nerve = Shinkei Kenkyū No Shinpo 64 (8): 919–26. Aug 2012. PMID 22868883. 
  48. ↑ "∆FosB: a transcriptional regulator of stress and antidepressant responses". European Journal of Pharmacology 753: 66–72. Apr 2015. doi:10.1016/j.ejphar.2014.10.034. 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.". 
  49. ↑ "ΔFosB induction in prefrontal cortex by antipsychotic drugs is associated with negative behavioral outcomes". Neuropsychopharmacology 39 (3): 538–44. February 2014. doi:10.1038/npp.2013.255. PMID 24067299. 

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