FOSB

FBJ murine osteosarcoma viral oncogene homolog B
Identifiers
Symbols FOSB ; AP-1; G0S3; GOS3; GOSB
External IDs OMIM: 164772 MGI: 95575 HomoloGene: 31403 GeneCards: FOSB Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 2354 14282
Ensembl ENSG00000125740 ENSMUSG00000003545
UniProt P53539 P13346
RefSeq (mRNA) NM_001114171 NM_008036
RefSeq (protein) NP_001107643 NP_032062
Location (UCSC) Chr 19:
45.47 – 45.48 Mb		 Chr 7:
19.3 – 19.31 Mb
PubMed search

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

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 (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, even though Δ2ΔFosB lacks a known transactivation domain, preventing it from affecting gene 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 neural plasticity involved in both behavioral addictions (associated with natural rewards) and drug addictions.[5][7][8] For example, ΔFosB overexpression triggers the development of addiction-related structural 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]

ΔFosB

ΔFosB or Delta FosB 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

Addiction and dependence glossary[8][19][20]
• addiction – a state 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 or as something to be approached
• sensitization – an amplified response to a stimulus resulting from repeated exposure to it
• tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
Signaling cascade in the nucleus accumbens that results in psychostimulant addiction
The signaling cascade involved in psychostimulant addiction
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,[21][22] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP pathway and calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[23][24][25] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-fos gene with the help of corepressors;[24] c-fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[26] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for one or two 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]

Addiction from chronic addictive drug use involves 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 since its viral or genetic overexpression (through chronic addictive drug use) in 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 self-administration and reward sensitization) seen in drug addiction;[5][6][8] it 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 directly oppose the induction of ΔFosB (i.e., increases in its expression).[6][8][32] Increases in nucleus accumbens ΔJunD expression using viral vectors can reduce or, with a large increase, even block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[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, like drugs of abuse, induce gene expression of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB 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 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 (HDACi)[note 2] – that indirectly inhibits the function and further increases in the expression of accumbal ΔFosB by promoting accumbal G9a expression.[9][32][35][36] These reviews and subsequent preliminary evidence which used oral administration or intraperitoneal administration of the sodium salt of butyric acid for an extended period indicate that class I HDACis, and butyrate salts in particular, 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] however, as of August 2015 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 levels have been found to increase upon the use of cocaine.[38] 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.[39] They self-administer cocaine at lower doses than control,[40] but have a greater likelihood of relapse when the drug is withheld.[18][40] ΔFosB increases the expression of AMPA receptor subunit GluR2[39] and also decreases expression of dynorphin, thereby enhancing sensitivity to reward.[18]

ΔFosB accumulation graph

The image above contains clickable links
Top: this depicts the acute expression of various Fos family proteins following an initial exposure to an addictive drug.
Bottom: this illustrates increasing ΔFosB expression from repeated twice daily drug binges, where these phosphorylated (35–37 kD) ΔFosB isoforms persist in mesolimbic dopamine neurons for up to 2 months.[18][27]
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 neural 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 ↑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 ↑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

ΔFosB overexpression in the dorsal striatum (nigrostriatal dopamine pathway) via viral vectors induces levodopa-induced dyskinesias in animal models of Parkinson's disease.[41][42] Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias;[42] postmordem studies of individuals with Parkinson's disease that were treated with levodopa have also observed similar dorsal striatal ΔFosB overexpression.[42] 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;[42] the signal transduction involved in this effect is unknown.[42]

ΔFosB expression in the nucleus accumbens shell increases resilience to stress and is induced in this region by acute exposure to social defeat stress.[43][44][45]

See also

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), valproic acid, trichostatin A, and SAHA;[35][36] butyric acid is a naturally occurring short-chain fatty acid in humans, while the latter three compounds are FDA-approved drugs with medical indications unrelated to addiction.
  3. ↑ Specifically, prolonged administration of butyrate salts appears to reduce an animal's motivation to acquire and use the associated addictive drug without affecting an animals motivation to attain other rewards (i.e., it does not appear to cause motivational anhedonia) as well as reduce the amount of the drug that is self-administered when it is readily available.[32][36][37]
  4. ↑ In other words, c-Fos repression allows ΔFosB to accumulate within nucleus accumbens dopamine neurons more rapidly because it is selectively induced in this state.[8]
  5. ↑ 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. ↑

References

  1. 1 2 "Entrez Gene: FOSB FBJ murine osteosarcoma viral oncogene homolog B".
  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.
  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.
  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.
  5. 1 2 3 4 5 6 7 8 9 10 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.
  6. 1 2 3 4 5 6 7 8 9 10 11 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.
  7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 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.Table 1"
  8. 1 2 3 4 5 6 Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin. Neurosci. 15 (4): 431–443. PMC 3898681. PMID 24459410.
  9. 1 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.
  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. PMID 25313003.
  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.
  12. 1 2 3 4 5 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. 1 2 3 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.
    Table 3
  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.
  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.
  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.
  17. 1 2 3 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.
  18. 1 2 3 4 5 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.
  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.
  20. ↑ "Glossary of Terms". Mount Sinai School of Medicine. Department of Neuroscience. Retrieved 9 February 2015.
  21. ↑ 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.
  22. ↑ Descarries L, Berube-Carriere N, Riad M, Bo GD, Mendez JA, Trudeau LE (August 2008). "Glutamate in dopamine neurons: synaptic versus diffuse transmission". Brain Res. Rev. 58 (2): 290–302. doi:10.1016/j.brainresrev.2007.10.005. PMID 18042492.
  23. ↑ Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.
  24. 1 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. Retrieved 21 July 2014.
  25. ↑ 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. ↑ 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.
  27. 1 2 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
  28. 1 2 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.
  29. ↑ 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.
  30. ↑ Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.
  31. ↑ 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. 1 2 3 4 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.
  33. ↑ 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.
  34. ↑ 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. 1 2 McCowan TJ, Dhasarathy A, Carvelli L (February 2015). "The Epigenetic Mechanisms of Amphetamine" (PDF). J. Addict. Prev. (Avens Publishing Group) (S1): 1–7. ISSN 2330-2178. Retrieved 30 April 2015.
  36. 1 2 3 4 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. 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. 1 2 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.

     • 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.
  38. ↑ 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.
  39. 1 2 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.
  40. 1 2 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.
  41. ↑ 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.
  42. 1 2 3 4 5 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.
  43. ↑ "ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS". Mount Sinai School of Medicine. NESTLER LAB: LABORATORY OF MOLECULAR PSYCHIATRY. Retrieved 6 September 2014.
  44. ↑ 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.
  45. ↑ 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. PMID 25446562. .

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