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ΔFosB: A sustained molecular switch for addiction
Open accessAbstract
The longevity of some of the behavioral abnormalities that characterize drug addiction has suggested that regulation of neural gene expression may be involved in the process by which drugs of abuse cause a state of addiction. Increasing evidence suggests that the transcription factor ΔFosB represents one mechanism by which drugs of abuse produce relatively stable changes in the brain that contribute to the addiction phenotype. ΔFosB, a member of the Fos family of transcription factors, accumulates within a subset of neurons of the nucleus accumbens and dorsal striatum (brain regions important for addiction) after repeated administration of many kinds of drugs of abuse. Similar accumulation of ΔFosB occurs after compulsive running, which suggests that ΔFosB may accumulate in response to many types of compulsive behaviors. Importantly, ΔFosB persists in neurons for relatively long periods of time because of its extraordinary stability. Therefore, ΔFosB represents a molecular mechanism that could initiate and then sustain changes in gene expression that persist long after drug exposure ceases. Studies in inducible transgenic mice that overexpress either ΔFosB or a dominant negative inhibitor of the protein provide direct evidence that ΔFosB causes increased sensitivity to the behavioral effects of drugs of abuse and, possibly, increased drug seeking behavior. This work supports the view that ΔFosB functions as a type of sustained “molecular switch” that gradually converts acute drug responses into relatively stable adaptations that contribute to the long-term neural and behavioral plasticity that underlies addiction.
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“ΔFOSB is a pivotal transcription factor involved in the regulation of addictive behaviours and the neuropathology of drug dependence49,50.”
From Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system (2025) · cites this paper as [50]
In the citing paper
“One of the most dramatic examples of protein expression induction is in the transcription factor ΔFosB, a Fos family protein, which accumulates in the NAc after chronic exposure to drugs of abuse, including alcohol, amphetamine, cannabinoids, cocaine, nicotine, opiates, and phencyclidine [86,87].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [87]
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BackgroundSelf-citationBarrot, M., Olivier, J. D. A., Perrotti, L. I., DiLeone, R. J., Berton, O., Eisch, A. J., Impey, S., Storm, D. R., Neve, R. L., Yin, J. C., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.172091899 · Cited by 508
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“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript by a long half-life leading to its accumulation during repeated or long lasting stimulation (Nestler et al., 2001).”
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“…to cocaine induces FosB in D1+ MSNs (Berretta et al., 1992), whereas chronic exposure induces FosB, a stable product of the FosB gene generated by alternative splicing (Hope et al., 1994; Nestler et al., 2001; Nestler, 2008), in D1+ MSNs (Nye et al., 1995; Moratalla et al., 1996; Lee et al., 2006).”
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“• Once created, a molecule of ΔFosB lasts for 6 to 8 weeks before breaking apart chemically (Nestler, Barrot, and Self, 2001).”
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“…mice, selectively within this same subset of NAc and dorsal striatal neuron, increases an animal’s sensitivity to the rewarding effects of cocaine and morphine and also increases incentive motivation for the drug (Kelz et al., 1999; Nestler et al., 2001; Colby et al., 2003; Zachariou et al., 2003).”
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“Whereas overexpression of ⌬FosB in dynorphin neurons increases the rewarding effects of cocaine and morphine (Kelz et al., 1999; Nestler et al., 2001), overexpression of ⌬FosB primarily in the enkephalin neurons does not alter the rewarding effects of these drugs.”
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“…and intermediate-lived transcriptional regulators such as c-fos, NAC-1 and Homer 1a (Mackler et al., 2000; Szumlinski et al., 2006) is followed by relatively longlived transcriptional regulators such as -fosB that accumulate with repeated administration (Nestler et al., 2001; Girault et al., 2007).”
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“Enhanced expression of ΔFosB has been implicated in the long-term effects produced by substances of abuse, including dopaminergic drugs such as cocaine (Nestler et al., 2001).”
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“Furthermore, repeated administration of abuse substances favors the accumulation of ΔFosB, a transcription factor that modulates the expression of glutamatergic receptors, tyrosine hydroxylase (TH), DA transporter (DAT), and DA receptor type 2 (D2) (Nestler 2001; Nestler et al. 2001).”
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“…because proteins such as c-Fos and DFosB, but also Arc, a marker of neuritic outgrowth, and BDNF, which is involved in spine formation, are all elevated after AMPH or cocaine exposure (Nestler et al., 2001; Klebaur et al., 2002; Meredith et al., 2002; Grimm et al., 2003; Fumagalli et al., 2006).”
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“…in inducible bitransgenic mice increases an animal's sensitivity and incentive motivation for drugs of abuse, such as cocaine (Kelz et al. 1999; Nestler et al. 2001), whereas overexpression of a dominant negative antagonist of DFosB exerts the opposite behavioral effects (Peakman et al. 2000).”
BackgroundSelf-citationΔFosB Induction in Orbitofrontal Cortex Mediates Tolerance to Cocaine-Induced Cognitive Dysfunction
Winstanley, C. A., LaPlant, Q. C., Theobald, D. E. H., Green, T. A., Bachtell, R. K., Perrotti, L. I., Dileone, R., Russo, S. J., Garth, W. J., Self, D. W., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2566-07.2007 · Cited by 144
“The persistence of addiction indicates that changes in gene transcription are involved, partly mediated by the transcription factor FosB, a truncated product of the fosB gene (Nestler et al., 2001).”
BackgroundSelf-citationAmmon, S., Mayer, P. E., Riechert, U., Tischmeyer, H., & Höllt, V. (2003) · Molecular Brain Research · doi:10.1016/s0169-328x(03)00057-3 · Cited by 139
Does the difference between physically active and couch potato lie in the dopamine system?
Knab, A. M., & Lightfoot, J. T. (2010) · International Journal of Biological Sciences · doi:10.7150/ijbs.6.133 · Cited by 148
“Several immediate early genes that are activated in dopaminergic neurons following stimulation include those of the Fos family [65, 106, 123, 178].”
Lindley, T. E., Doobay, M. F., Sharma, R. V., & Davisson, R. L. (2003) · Circulation Research · doi:10.1161/01.res.0000112964.40701.93 · Cited by 137
ΔFosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer’s Disease
Corbett, B. F., You, J. C., Zhang, X., Pyfer, M. S., Tosi, U., Iascone, D. M., Petrof, I., Hazra, A., Fu, C.-H., Stephens, G. S., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.06.040 · Cited by 130
“However, unlike the products of other immediate early genes, such as c-Fos, DFosB has an unusually long half-life that allows it to accumulate and remain in chronically active cells for weeks (McClung et al., 2004; Nestler et al., 2001).”
BackgroundSelf-citationInduction of ΔFosB in the Periaqueductal Gray by Stress Promotes Active Coping Responses
Berton, O., Covington, H. E., Ebner, K., Tsankova, N. M., Carle, T. L., Ulery, P., Bhonsle, A., Barrot, M., Krishnan, V., Singewald, G. M., et al. (2007) · Neuron · doi:10.1016/j.neuron.2007.06.033 · Cited by 129
Self-citationVilpoux, C., Warnault, V., Pierrefiche, O., Daoust, M., & Naassila, M. (2009) · Alcoholism: Clinical and Experimental Research · doi:10.1111/j.1530-0277.2009.00916.x · Cited by 131
“Specific molecular mechanisms underlie these different stages of transition and are responsible for progression from tolerance to dependence, withdrawal, craving, and relapse (Koob et al., 2004; Nestler et al., 2001; Ron and Jurd, 2005).”
BackgroundAstrocyte–neuron subproteomes and obsessive–compulsive disorder mechanisms
Soto, J. S., Jami‐Alahmadi, Y., Chacon, J., Moye, S. L., Castro, B. D., Wohlschlegel, J. A., & Khakh, B. S. (2023) · Nature · doi:10.1038/s41586-023-05927-7 · Cited by 138
Making a bad thing worse: adverse effects of stress on drug addiction
Cleck, J. N., & Blendy, J. A. (2008) · Journal of Clinical Investigation · doi:10.1172/jci33946 · Cited by 122
The dopamine D1 receptor is a critical mediator for cocaine‐induced gene expression
Zhang, D., Zhang, L., Lou, D. W., Nakabeppu, Y., Zhang, J., & Xu, M. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.01089.x · Cited by 126
“Repeated cocaine injections induce long lasting AP-1 transcription complexes consisting of DFosB (Hope et al. 1994; Nye et al. 1995; Nestler et al. 1999; Nestler et al. 2001).”
BackgroundInfluentialMorphine-induced Changes of Gene Expression in the Brain
Ammon-Treiber, S., & Höllt, V. (2004) · Addiction Biology · doi:10.1080/13556210412331308994 · Cited by 124
“…neuronal growth, it has been hypothesized that repeated opiate administration increases dendritic spines in the NAc, mediated via delta fosB and subsequently Cdk5, resulting in long-lived sensitized responses to drugs of abuse (Nye and Nestler, 1996; Kelz and Nestler, 2000; Nestler et al., 2001).”
BackgroundObesity – A neuropsychological disease? Systematic review and neuropsychological model
Jauch‐Chara, K., & Oltmanns, K. M. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.12.001 · Cited by 136
Taniguchi, M., Carreira, M. B., Cooper, Y. A., Bobadilla, A., Heinsbroek, J. A., Koike, N., Larson, E. B., Balmuth, E. A., Hughes, B. W., Penrod, R. D., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.09.015 · Cited by 124
Self-citationWINSTANLEY, C. A. (2007) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1401.024 · Cited by 119
Teegarden, S. L., Scott, A., & Bale, T. L. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.05.029 · Cited by 123
“ΔFosB is induced in the nucleus accumbens following chronic exposure to drugs of abuse and natural rewards (Nestler et al. 2001; Teegarden and Bale 2007; Wallace et al. 2008).”
BackgroundRhodes, J. S., & Garland, T. (2003) · Psychopharmacology · doi:10.1007/s00213-003-1399-9 · Cited by 116
“Furthermore, dopaminergic function may have been altered in selected mice in association with increased motivation (Koob 1996; Salamone 1996) for running, or possibly addiction to wheel running (Berridge and Robinson 1998; Nestler et al. 2001; Werme et al. 2002).”
ΔFosB in the Nucleus Accumbens Regulates Food-Reinforced Instrumental Behavior and Motivation
Olausson, P., Jentsch, J. D., Tronson, N. C., Neve, R. L., Nestler, E. J., & Taylor, J. R. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.1124-06.2006 · Cited by 117
“Experiment 3: inducible overexpression of FosB in bitransgenic mice; progressive ratio Given that previous drug exposure induces striatal FosB (Nestler et al., 2001) and was found here to increase progressive ratio responding, we next tested whether transgenic striatal overexpression of FosB also…”
BackgroundSelf-citationNatural and Drug Rewards Act on Common Neural Plasticity Mechanisms with ΔFosB as a Key Mediator
Pitchers, K. K., Vialou, V., Nestler, E. J., Laviolette, S. R., Lehman, M. N., & Coolen, L. M. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.4881-12.2013 · Cited by 119
“Thus, natural and drug rewards not only converge on the same neural pathway, they converge on the same molecular mediators (Nestler et al., 2001; Wallace et al., 2008; Hedges et al., 2009; Pitchers et al., 2010b), and likely in the same neurons in the NAc (Frohmader et al., 2010b), to influence the…”
BackgroundSelf-citationReinstatement of cocaine seeking induced by drugs, cues, and stress in adolescent and adult rats
Anker, J. J., & Carroll, M. E. (2009) · Psychopharmacology · doi:10.1007/s00213-009-1721-2 · Cited by 118
“However, unlike dopamine levels that decrease shortly thereafter, delta-FosB proteins are enduring, and a single molecule reportedly lasts several weeks after its formation (Nestler et al. 2001).”
Epigenetic landscape of amphetamine and methamphetamine addiction in rodents
Godino, A., Jayanthi, S., & Cadet, J. L. (2015) · Epigenetics · doi:10.1080/15592294.2015.1055441 · Cited by 113
“Specifically, drug-induced DfosB accumulates in the striatum due to its high stability, leading to the speculation that this accumulation might be responsible, in part, for the transcriptional differences observed after acute and chronic drug use.(33) Indeed, acute METH was found to increase FosB/DfosB, c-Fos, c-Jun a…”
BackgroundFrom neurobiology to treatment: progress against addiction
Nestler, E. J. (2002) · Nature Neuroscience · doi:10.1038/nn945 · Cited by 111
Self-citationCarlezon, W. A., & Konradi, C. L. (2004) · Neuropharmacology · doi:10.1016/j.neuropharm.2004.06.021 · Cited by 108
Phosphorylation of DARPP-32 at Threonine-34 is Required for Cocaine Action
Zachariou, V., Sgambato, V., Sasaki, T. S., Svenningsson, P., Berton, O., Fienberg, A. A., Nairn, A. C., Greengard, P., & Nestler, E. J. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300832 · Cited by 113
“Sustained induction of DFosB in the nucleus accumbens following repeated exposure to cocaine or other drugs of abuse leads to numerous neuronal adaptations via regulation of the expression of a wide range of gene targets (Nestler et al, 2001; McClung and Nestler, 2003).”
BackgroundInfluentialSelf-citationPérez-Cadahía, B., Drobic, B., & Davie, J. R. (2011) · Biochemistry and Cell Biology · doi:10.1139/o10-138 · Cited by 137
“DFosB was originally established as a transcriptional repressor, but later studies in cell culture showed that it can either induce or repress AP-1mediated transcription, depending on the AP-1 site used (Nestler et al. 2001).”
BackgroundKnight, W. D., Little, J. T., Carreno, F. R., Toney, G. M., Mifflin, S. W., & Cunningham, J. T. (2011) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00830.2010 · Cited by 109
Psychological and neural mechanisms of relapse
Stewart, J. (2008) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2008.0084 · Cited by 113
“…in fact, studies have shown selective and persistent changes in transcription factors known to be involved in neuroplasticity (Chen et al. 1995; Nestler et al. 1999, 2001), drug-induced changes in synaptic facilitation and long-term potentiation of DA neurons in the VTA (Bonci & Williams 1996;…”
Levandis, G., Bazzini, E., Armentero, M., Nappi, G., & Blandini, F. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2007.08.011 · Cited by 106
Peakman, M., Colby, C. R., Perrotti, L. I., Tekumalla, P. K., Carle, T. L., Ulery, P. G., Chao, J. R., Duman, C. H., Steffen, C., Monteggia, L. M., et al. (2003) · Brain Research · doi:10.1016/s0006-8993(03)02230-3 · Cited by 101
Self-citationTranscriptional Induction of FosB/ΔFosB Gene by Mechanical Stress in Osteoblasts
Inoue, D., Kido, S., & Matsumoto, T. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m404096200 · Cited by 104
Ozek, C., Krolewski, R. C., Buchanan, S. M., & Rubin, L. L. (2018) · Scientific Reports · doi:10.1038/s41598-018-35716-6 · Cited by 99
Periadolescent Mice Show Enhanced ΔFosB Upregulation in Response to Cocaine and Amphetamine
Ehrlich, M. E., Sommer, J., Canas, E., & Unterwald, E. M. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-21-09155.2002 · Cited by 98
D1 dopamine receptor: A putative neurochemical and behavioral link to cocaine action
Hummel, M., & Unterwald, E. M. (2002) · Journal of Cellular Physiology · doi:10.1002/jcp.10078 · Cited by 99
Carle, T. L., Ohnishi, Y. N., Ohnishi, Y. H., Alibhai, I. N., Wilkinson, M. B., Kumar, A., & Nestler, E. J. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05575.x · Cited by 102
“…is still unclear; however, the long-lasting accumulation of DFosB in the brain is one crucial element for causing the long-lasting neural and behavioral plasticity associated with addiction (Hiroi et al., 1997; Kelz et al., 1999; Nestler et al., 2001; Colby et al., 2003; Zachariou et al., 2006).”
BackgroundSelf-citationRegulation of ΔFosB Stability by Phosphorylation
Ulery, P. G., Rudenko, G., & Nestler, E. J. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.4970-05.2006 · Cited by 99
“…induction of its mRNA (Chen et al., 1995), we speculated that, unlike full-length FosB and all other Fos family proteins, which are intrinsically unstable, FosB may be an unusually stable transcription factor (Hope et al., 1994b; Chen et al., 1997; Nestler et al., 2001; McClung et al., 2004).”
Self-citationCytoskeletal Genes Regulation by Chronic Morphine Treatment in Rat Striatum
Cynthia Marie-claire, A., Courtin, C., Roques, B. P., & Noble, F. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300513 · Cited by 101
“Several heat-shock proteins (hsp70, hsp40, hsp27 and hsp105) are upregulated in the frontal cortex of rats chronically treated with morphine (Ammon et al, 2003; Fan et al, 2002, 2003; Loguinov et al, 2001; Nestler et al, 2001).”
BackgroundNeurobiological Processes in Adolescent Addictive Disorders
Schepis, T. S., Adinoff, B. H., & Rao, U. (2008) · American Journal on Addictions · doi:10.1080/10550490701756146 · Cited by 100
Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice
Holder, J. L., Zhang, L., Kublaoui, B. M., Dileone, R., Öz, O. K., Bair, C.-H., Lee, Y.-H., & Zinn, A. R. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00446.2003 · Cited by 95
“Transcription is especially attractive as a mechanism for long-term regulation of food intake and energy expenditure, as has been demonstrated for other complex behaviors such as addiction (24).”
Metadata
- Authors
- Nestler, E. J., Barrot, M., & Self, D. W.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-09-25
- Volume
- 98
- Issue
- 20
- Pages
- 11042-11046
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC58680
- OpenAlex
- W2000696407
- Cited by
- 640
- References
- 45
- Citations by year
- 2026: 24 · 2025: 32 · 2024: 41 · 2023: 31 · 2022: 27 · 2021: 30 · 2020: 17 · 2019: 25 · 2018: 23 · 2017: 23 · 2016: 24 · 2015: 22 · 2014: 17 · 2013: 29 · 2012: 27
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- ΔFosB, drug addiction, transcription factors, Fos family, nucleus accumbens, dorsal striatum, drug-seeking behavior, neuronal gene expression, behavioral plasticity, transgenic mice, protein stability
- MeSH terms
- Animals, Brain, Humans, Models, Neurological, Neurons, Proto-Oncogene Proteins c-fos, Genes, fos, Substance-Related Disorders
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