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FBJ murine osteosarcoma viral oncogene homolog B
Symbols  ; AP-1; G0S3; GOS3; GOSB
External IDs GeneCards:
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
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, 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]

Its truncated splice variant, ΔFosB, has been identified as playing a central, crucial (necessary and sufficient)[4] role in the development of many forms of behavioral plasticity and neuroplasticity involved in both behavioral addictions (associated with natural rewards) and drug addictions.[5]


ΔFosB or Delta FosB is a truncated splice variant of FosB.[6] ΔFosB has been implicated as a critical factor in the development of virtually all forms of behavioral and drug addictions.[4][7][8] 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][11] In the body, ΔFosB regulates the commitment of mesenchymal precursor cells to the adipocyte or osteoblast lineage.[12]

In the nucleus accumbens, ΔFosB functions as a "molecular switch" and "master control protein" in the development of an addiction;[13][14] in other words, once "turned on" (sufficiently overexpressed) ΔFosB triggers a series of transcription events that ultimately result in addictive behavior.

Role in addiction

Addiction glossary[15][16]
addiction – a state characterized by compulsive engagement in rewarding behavior or compulsive drug use, despite adverse consequences
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
addictive drug – a drug that is both rewarding and reinforcing
addictive behavior – a behavior that is both rewarding and reinforcing
sensitization – an amplified response to a stimulus resulting from repeated exposure to it
drug tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
drug dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated drug intake
physical dependence – dependence that involves physical–somatic withdrawal symptoms (e.g., fatigue)
psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)

Signaling cascade in the nucleus accumbens that results in psychostimulant addiction

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, methylphenidate, phenethylamine, and cocaine. Following presynaptic dopamine and glutamate co-release by such psychostimulants, postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP pathway and calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[17][18] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-fos gene with the help of corepressors.[18] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for one or two months, slowly accumulates following repeated exposure to stimulants through this process.[13][19] 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.[13][19]

Current models of addiction from chronic addictive drug use involve alterations in gene expression in the mesocorticolimbic projection.[4][20][21] 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 (NFκB).[4] ΔFosB is the most significant gene transcription factor in addiction since its viral or genetic overexpression in the nucleus accumbens is necessary and sufficient for many of the neural adaptations seen in drug addiction;[4] it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, phenylcyclidine, opiates, and substituted amphetamines.[4][20][22] ΔJunD is the transcription factor which directly opposes ΔFosB.[4] Increases in nucleus accumbens ΔJunD expression using viral vectors (a genetically engineered virus) 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).[4]

ΔFosB also plays an important role in regulating behavioral responses to natural (non-drug) rewards, such as palatable food, sex, and exercise.[4][7] 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.[4][7][8] Consequently, ΔFosB is the key transcription factor involved in addictions to natural rewards (i.e., behavioral addictions) as well;[4][7][8] in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward.[7] 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 that are mediated through ΔFosB.[5][8] 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.[8]

ΔFosB inhibitors (drugs that oppose its action) may be an effective treatment for addiction and addictive disorders.[23]

Cocaine use

ΔFosB levels have been found to increase upon the use of cocaine.[24] 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. This consequence of cocaine use may contribute to sensitization to the drug.

Transgenic mice exhibiting inducible expression of ΔFosB primarily in the nucleus accumbens and dorsal striatum exhibit sensitized behavioural responses to cocaine.[25] They self-administer cocaine at lower doses than control,[26] but have a greater likelihood of relapse when the drug is withheld.[14][26] ΔFosB increases the expression of AMPA receptor subunit GluR2[25] and also decreases expression of dynorphin, thereby enhancing sensitivity to reward.[14]

Other functions

ΔFosB expression in the nucleus accumbens shell increases resilience to stress and is induced in this region by acute exposure to social defeat stress.[27][28]

ΔFosB overexpression in the striatum (via viral vectors) produces involuntary movements akin to those seen in chronic levodopa treatment of Parkinson's disease.[29]

Summary of addiction-related plasticity

Form of neural or behavioral plasticity Type of reinforcer Sources
Opiates Psychostimulants High fat or sugar food Sexual reward Exercise Environmental enrichment
ΔFosB expression
in the nucleus accumbens
Behavioral Plasticity
Escalation of intake Yes Yes Yes [8]
Yes Not applicable Yes Yes Attenuated Attenuated [8]
conditioned place preference
Reinstatement of drug-seeking behavior [8]
Neurochemical Plasticity
CREB phosphorylation
in the nucleus accumbens
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [8]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [8]
Altered striatal opioid signaling μ-opioid receptors μ-opioid receptors
κ-opioid receptors
μ-opioid receptors μ-opioid receptors No change No change [8]
Changes in striatal opioid peptides dynorphin dynorphin enkephalin dynorphin dynorphin [8]
Mesocorticolimbic Synaptic Plasticity
Number of dendrites in the nucleus accumbens [8]
Dendritic spine density in
the nucleus accumbens
No change [8]

See also


  1. ^ a b "Entrez Gene: FOSB FBJ murine osteosarcoma viral oncogene homolog B". 
  2. ^ Siderovski DP, Blum S, Forsdyke RE, Forsdyke DR (October 1990). "A set of human putative lymphocyte G0/G1 switch genes includes genes homologous to rodent cytokine and zinc finger protein-encoding genes". DNA Cell Biol. 9 (8): 579–587.  
  3. ^ Martin-Gallardo A, McCombie WR, Gocayne JD, FitzGerald MG, Wallace S, Lee BM, Lamerdin J, Trapp S, Kelley JM, Liu LI (April 1992). "Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3". Nat. Genet. 1 (1): 34–39.  
  4. ^ a b c d e f g h i j k Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637.  
  5. ^ a b Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". J. Neurosci. 33 (8): 3434–3442.  
  6. ^ Nakabeppu Y, Nathans D (February 1991). "A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity". Cell 64 (4): 751–759.  
  7. ^ a b c d e Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". J. Psychoactive Drugs 44 (1): 38–55.  
  8. ^ a b c d e f g h i j k l m n o p q r Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology 61 (7): 1109–1122. PMC 3139704. PMID 21459101. doi: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"
  9. ^ Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 363 (1507): 3245–3255.  
  10. ^ Renthal W, Nestler EJ (August 2008). "Epigenetic mechanisms in drug addiction". Trends in Molecular Medicine 14 (8): 341–350.  
  11. ^ 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): 335–348.  
  12. ^ Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, Bouali Y, Mukhopadhyay K, Ford K, Nestler EJ, Baron R (September 2000). "Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis.". Nature Medicine 6 (9): 985–990.  
  13. ^ a b c Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637.  
  14. ^ a b c Nestler EJ, Barrot M, Self DW (September 2001). "DeltaFosB: a sustained molecular switch for addiction". Proc. Natl. Acad. Sci. U.S.A. 98 (20): 11042–11046.  
  15. ^ 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.  
  16. ^ Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin Neurosci 15 (4): 431–443.  
  17. ^ Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. 
  18. ^ a b Renthal W, Nestler EJ (2009). "Chromatin regulation in drug addiction and depression". Dialogues Clin. Neurosci. 11 (3): 257–268.  
  19. ^ a b Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clin. Psychopharmacol. Neurosci. 10 (3): 136–143.  
  20. ^ a b Hyman SE, Malenka RC, Nestler EJ (2006). "Neural mechanisms of addiction: the role of reward-related learning and memory". Annu. Rev. Neurosci. 29: 565–598.  
  21. ^ Steiner H, Van Waes V (January 2013). "Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants". Prog. Neurobiol. 100: 60–80.  
  22. ^ Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. 
  23. ^ 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.  
  24. ^ Hope BT (May 1998). "Cocaine and the AP-1 transcription factor complex". Ann. N. Y. Acad. Sci. 844: 1–6.  
  25. ^ a b Kelz MB, Chen J, Carlezon WA, Whisler K, Gilden L, Beckmann AM, Steffen C, Zhang YJ, Marotti L, Self DW, Tkatch T, Baranauskas G, Surmeier DJ, Neve RL, Duman RS, Picciotto MR, Nestler EJ (September 1999). "Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine". Nature 401 (6750): 272–276.  
  26. ^ a b Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW (March 2003). "Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine". J. Neurosci. 23 (6): 2488–2493.  
  27. ^ "ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS". Mount Sinai School of Medicine. NESTLER LAB: LABORATORY OF MOLECULAR PSYCHIATRY. Retrieved 6 September 2014. Role of ΔFosB in Depression
    More recently, we have shown that induction of ΔFosB in nucleus accumbens in response to chronic stress represents a positive, adaptive mechanism to help the animal cope with the stress. In the social defeat paradigm, for example, animalsthat are resilient to the deleterious effects of defeat stress show greater induction of ΔFosB than vulnerable animals. Moreover, chronic administration of antidepressant medications induces ΔFosB in nucleus accumbens and the behavioral effects of these treatments can be blocked by blockade of ΔFosB activity in this brain region. Together, these data demonstrate that ΔFosB is a novel mechanism of resilience and a potentially important mediator of antidepressant action. ...
    Interesting comparisons and contrasts with CREB are evident. Both ΔFosB and CREB are induced by stress and by drugs of abuse, yet they exert opposite effects on behavior. CREB reduces behavioral responses to emotional stimuli and induces a depression-like state in the extreme, whereas ΔFosB sensitizes reward and induces antidepressant-like responses. Also, the CREB signal is relatively short-lived, while the ΔFosB signal is long-lived.
  28. ^ Furuyashiki T, Deguchi Y (August 2012). "[Roles of altered striatal function in major depression]". Brain Nerve (in Japanese) 64 (8): 919–26.  
  29. ^ 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". J. Neurosci. 30 (21): 7335–7343.  
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