FOSB explained

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 role in the development and maintenance of addiction.[5] 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.[6] 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.[7]

DeltaFosB

DeltaFosB – more commonly written as ΔFosB – is a truncated splice variant of the FOSB gene.[8] ΔFosB has been implicated as a critical factor in the development of virtually all forms of behavioral and drug addictions. In the brain's reward system, it is linked to changes in a number of other gene products, such as CREB and sirtuins.[9] [10] In the body, ΔFosB regulates the commitment of mesenchymal precursor cells to the adipocyte or osteoblast lineage.[11]

In the nucleus accumbens, ΔFosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction. In other words, once "turned on" (sufficiently 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. ΔFosB expression in D1-type nucleus accumbens medium spiny neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement while decreasing sensitivity to aversion. Based upon the accumulated evidence, a medical review from late 2014 argued that accumbal ΔFosB expression can be used as an addiction biomarker and that the degree of accumbal ΔFosB induction by a drug is a metric for how addictive it is relative to others.

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.[12]

Role in addiction

Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.[13] [14] The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NF-κB). ΔFosB is the most significant biomolecular mechanism in addiction because the 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. ΔFosB overexpression has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[15] [16] ΔJunD, a transcription factor, and G9a, a histone methyltransferase, both oppose the function of ΔFosB and inhibit increases in its expression. Increases in nucleus accumbens ΔJunD expression (via viral vector-mediated gene transfer) or 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). 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.[17] 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.[18] Consequently, ΔFosB is the key mechanism involved in addictions to natural rewards (i.e., behavioral addictions) as well;[19] [17] in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward. Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess bidirectional reward cross-sensitization effects that are mediated through ΔFosB.[20] This phenomenon is notable since, in humans, a dopamine dysregulation syndrome, characterized by drug-induced compulsive engagement in natural rewards (specifically, sexual activity, shopping, and gambling), has also been observed in some individuals taking dopaminergic medications.

ΔFosB inhibitors (drugs or treatments that oppose its action or reduce its expression) may be an effective treatment for addiction and addictive disorders.[21] Current medical reviews of research involving lab animals have identified a drug class – class I histone deacetylase inhibitors – 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.[22] [23] [24] 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 that have developed addictions to ethanol, psychostimulants (i.e., amphetamine and cocaine), nicotine, and opiates;[25] [26] however,, 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.

Plasticity in cocaine addiction

See also: Epigenetics of cocaine addiction. ΔFosB levels have been found to increase upon the use of cocaine.[27] Each subsequent dose of cocaine continues to increase ΔFosB levels with no apparent 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.[28] They self-administer cocaine at lower doses than control,[29] but have a greater likelihood of relapse when the drug is withheld.[30] [29] ΔFosB increases the expression of AMPA receptor subunit GluR2[28] and also decreases expression of dynorphin, thereby enhancing sensitivity to reward.[30]

Target
gene! scope="col"
Target
expression		Neural effectsBehavioral effects
↓ Molecular switch enabling the chronic
induction of ΔFosB 		–
↓
Downregulation of κ-opioid feedback loop Diminished self-extinguishing response to drug
↑ Expansion of Nacc dendritic processes
NF-κB inflammatory response in the
NF-κB inflammatory response in the
Increased drug reward
Locomotor sensitization
↑ Increased drug reward
↑ GluR1 synaptic protein phosphorylation
Expansion of dendritic processes 		Decreased drug reward
(net effect)

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.[31] [32] Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias; postmortem studies of individuals with Parkinson's disease that were treated with levodopa have also observed similar dorsal striatal ΔFosB overexpression. Levetiracetam, an antiepileptic drug, has been shown to dose-dependently decrease the induction of dorsal striatal ΔFosB expression in rats when co-administered with levodopa; the signal transduction involved in this effect is unknown.

ΔFosB expression in the nucleus accumbens shell increases resilience to stress and is induced in this region by acute exposure to social defeat stress.[33] [34] [35]

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.[36]

See also

Notes

Image legend

Further reading

External links

Notes and References

  1. Web site: Entrez Gene: FOSB FBJ murine osteosarcoma viral oncogene homolog B.
  2. Siderovski DP, Blum S, Forsdyke RE, Forsdyke DR . 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 . 1702972 . 10.1089/dna.1990.9.579 .
  3. Martin-Gallardo A, McCombie WR, Gocayne JD, FitzGerald MG, Wallace S, Lee BM, Lamerdin J, Trapp S, Kelley JM, Liu LI . Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3 . Nature Genetics . 1 . 1 . 34–9 . Apr 1992 . 1301997 . 10.1038/ng0492-34 . 1986255 .
  4. Sabatakos G, Rowe GC, Kveiborg M, Wu M, Neff L, Chiusaroli R, Philbrick WM, Baron R . 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 . 18433296 . 2674536 . 10.1359/jbmr.080110 .
  5. Ruffle JK . 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 . 25083822 . 10.3109/00952990.2014.933840 . 19157711 .
    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. Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T . Epigenetic regulation in drug addiction . Annals of Agricultural and Environmental Medicine . 19 . 3 . 491–6 . 2012 . 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 .
  7. Ohnishi YN, Ohnishi YH, Vialou V, Mouzon E, LaPlant Q, Nishi A, Nestler EJ . Functional role of the N-terminal domain of ΔFosB in response to stress and drugs of abuse . Neuroscience . 284 . 165–70 . Jan 2015 . 25313003 . 10.1016/j.neuroscience.2014.10.002 . 4268105.
  8. Nakabeppu Y, Nathans D . A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity . Cell . 64 . 4 . 751–9 . Feb 1991 . 1900040 . 10.1016/0092-8674(91)90504-R . 23904956 .
  9. Renthal W, Nestler EJ . Epigenetic mechanisms in drug addiction . Trends in Molecular Medicine . 14 . 8 . 341–50 . Aug 2008 . 18635399 . 2753378 . 10.1016/j.molmed.2008.06.004 .
  10. 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 . Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins . Neuron . 62 . 3 . 335–48 . May 2009 . 19447090 . 2779727 . 10.1016/j.neuron.2009.03.026 .
  11. Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, Bouali Y, Mukhopadhyay K, Ford K, Nestler EJ, Baron R . Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis . Nature Medicine . 6 . 9 . 985–90 . Sep 2000 . 10973317 . 10.1038/79683 . 20302360 .
  12. Salaya-Velazquez NF, López-Muciño LA, Mejía-Chávez S, Sánchez-Aparicio P, Domínguez-Guadarrama AA, Venebra-Muñoz A . Anandamide and sucralose change ΔFosB expression in the reward system . NeuroReport . 31 . 3 . 240–244 . February 2020 . 31923023 . 10.1097/WNR.0000000000001400 . 210149592 .
  13. Hyman SE, Malenka RC, Nestler EJ . Neural mechanisms of addiction: the role of reward-related learning and memory . Annual Review of Neuroscience . 29 . 565–98 . 2006 . 16776597 . 10.1146/annurev.neuro.29.051605.113009 .
  14. Steiner H, Van Waes V . Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants . Progress in Neurobiology . 100 . 60–80 . Jan 2013 . 23085425 . 3525776 . 10.1016/j.pneurobio.2012.10.001 .
  15. Web site: Alcoholism – Homo sapiens (human) . KEGG Pathway . 31 October 2014 . Kanehisa Laboratories . 29 October 2014.
  16. Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P . 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 . 19202072 . 2650365 . 10.1073/pnas.0813179106 . 2009PNAS..106.2915K . . free .
  17. Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M . 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 . 22641964 . 4040958 . 10.1080/02791072.2012.662112 . .
  18. Olsen CM . Natural rewards, neuroplasticity, and non-drug addictions . Neuropharmacology . 61 . 7 . 1109–22 . Dec 2011 . 21459101 . 3139704 . 10.1016/j.neuropharm.2011.03.010 . 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
  19. Robison AJ, Nestler EJ . Transcriptional and epigenetic mechanisms of addiction . Nature Reviews. Neuroscience . 12 . 11 . 623–37 . Nov 2011 . 21989194 . 3272277 . 10.1038/nrn3111 . 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. .
  20. Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM . 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 . 23426671 . 3865508 . 10.1523/JNEUROSCI.4881-12.2013 . .
  21. Book: Malenka RC, Nestler EJ, Hyman SE . Sydor A, Brown RY . Molecular Neuropharmacology: A Foundation for Clinical Neuroscience . 2009 . McGraw-Hill Medical . New York . 9780071481274 . 384–385 . 2nd . Chapter 15: Reinforcement and addictive disorders .
  22. Nestler EJ . Epigenetic mechanisms of drug addiction . Neuropharmacology . 76 Pt B . 259–268 . January 2014 . 23643695 . 3766384 . 10.1016/j.neuropharm.2013.04.004 . 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. .
  23. McCowan TJ, Dhasarathy A, Carvelli L . The Epigenetic Mechanisms of Amphetamine . J. Addict. Prev. . 2015 . Suppl 1 . February 2015 . 27453897 . 4955852 . 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..
  24. Walker DM, Cates HM, Heller EA, Nestler EJ . Regulation of chromatin states by drugs of abuse . Curr. Opin. Neurobiol. . 30 . 112–121 . February 2015 . 25486626 . 10.1016/j.conb.2014.11.002 . 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 . 4293340.
  25. Primary references involving sodium butyrate:

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

    Simon-O'Brien E, Alaux-Cantin S, Warnault V, Buttolo R, Naassila M, Vilpoux C . The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals . Addict Biol . 20 . 4 . 676–689 . July 2015 . 25041570 . 10.1111/adb.12161 . 28667144 . Altogether, our results clearly demonstrated the efficacy of in preventing excessive ethanol intake and relapse and support the hypothesis that may have a potential use in alcohol addiction treatment..

    Castino MR, Cornish JL, Clemens KJ . Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats . PLOS ONE. 10 . 4 . e0124796 . April 2015 . 25880762 . 4399837 . 10.1371/journal.pone.0124796 . 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.. free .
  26. Kyzar EJ, Pandey SC . Molecular mechanisms of synaptic remodeling in alcoholism . Neurosci. Lett. . 601 . 11–9 . August 2015 . 25623036 . 10.1016/j.neulet.2015.01.051 . 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.. 4506731 .
  27. Hope BT . Cocaine and the AP-1 transcription factor complex . Annals of the New York Academy of Sciences . 844 . 1. 1–6 . May 1998 . 9668659 . 10.1111/j.1749-6632.1998.tb08216.x . 1998NYASA.844....1H . 11683570 .
  28. D. James Surmeier . 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 . Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine . Nature . 401 . 6750 . 272–6 . Sep 1999 . 10499584 . 10.1038/45790 . 1999Natur.401..272K . 4390717 .
  29. Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW . Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine . The Journal of Neuroscience . 23 . 6 . 2488–93 . Mar 2003 . 12657709 . 10.1523/JNEUROSCI.23-06-02488.2003. 6742034 .
  30. Nestler EJ, Barrot M, Self DW . 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 . 11572966 . 58680 . 10.1073/pnas.191352698 . 2001PNAS...9811042N . . free .
  31. Cao X, Yasuda T, Uthayathas S, Watts RL, Mouradian MM, Mochizuki H, Papa SM . Striatal overexpression of DeltaFosB reproduces chronic levodopa-induced involuntary movements . The Journal of Neuroscience . 30 . 21 . 7335–43 . May 2010 . 20505100 . 2888489 . 10.1523/JNEUROSCI.0252-10.2010 .
  32. Du H, Nie S, Chen G, Ma K, Xu Y, Zhang Z, Papa SM, Cao X . Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats Inducing Critical Molecular Changes in the Striatum . Parkinson's Disease . 2015 . 253878 . 2015 . 25692070 . 4322303 . 10.1155/2015/253878 . 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. . free .
  33. Web site: ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS. Mount Sinai School of Medicine. NESTLER LAB: LABORATORY OF MOLECULAR PSYCHIATRY. 6 September 2014. . 28 June 2017. https://web.archive.org/web/20170628021156/http://neuroscience.mssm.edu/nestler/deltaFosB.html. dead.
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  35. Nestler EJ . ∆FosB: a transcriptional regulator of stress and antidepressant responses . European Journal of Pharmacology . 753 . 66–72 . Apr 2015 . 25446562 . 10.1016/j.ejphar.2014.10.034 . 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. . 4380559.
  36. Dietz DM, Kennedy PJ, Sun H, Maze I, Gancarz AM, Vialou V, Koo JW, Mouzon E, Ghose S, Tamminga CA, Nestler EJ . ΔFosB induction in prefrontal cortex by antipsychotic drugs is associated with negative behavioral outcomes . Neuropsychopharmacology . 39 . 3 . 538–44 . February 2014 . 24067299 . 3895248 . 10.1038/npp.2013.255 .

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