Cited by 640Neurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology ResearchSubstance Abuse Treatment and Outcomes

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ΔFosB: A sustained molecular switch for addiction

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Nestler, Eric J., Barrot, Michel, Self, David W.·2001·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.191352698PMC PMC58680

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Abstract

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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Background
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Background
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Background
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Background
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Background
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“Intriguingly, repeated drug exposure causes accumulation of its splicing variant ΔFosB in D1 MSNs due to its increased stability (Nestler et al., 2001).”
Background
Cell type–specific epigenetic priming of gene expression in nucleus accumbens by cocaine
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Self-citation
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“One may speculate that the upregulation of delta-FOSB, a constituent of AP-1 that was proposed as a general mechanism of addiction (Nestler et al., 2001) may contribute to PDYN regulation if this transcription factor activates PDYN expression by binding to the T allele of PDYN promoter SNP…”
Background
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“In mice, inducible overexpression of DFosB in this neuronal population facilitates the acquisition of cocaine self-administration at a low-threshold dose of cocaine (Kelz et al. 1999; Colby et al. 2003).”
BackgroundInfluential
Nicotine increases FosB expression within a subset of reward- and memory-related brain regions during both peri- and post-adolescence
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“FosB and its splice variant isoforms (e.g., deltaFosB) are known to accumulate in nucleus accumbens, a striatal region implicated in reward, after exposure to virtually all classes of abused drugs (reviewed by Nestler et al. 2001).”
Background
Lmo4 in the nucleus accumbens regulates cocaine sensitivity
Lasek, A. W., Kapfhamer, D., Kharazia, V., Gesch, J., Giorgetti, F., & Heberlein, U. (2010) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2010.00620.x · Cited by 27
“For example, the transcription factors CREB and FosB have been implicated in the rewarding and psychostimulant properties of cocaine (Carlezon et al. 2005; Kelz et al. 1999; Nestler et al. 2001).”
Background
Cytoplasmic Versus Nuclear Localization of Fos-Related Proteins in the Frog, Rana esculenta, Testis: In Vivo and Direct In Vitro Effect of a Gonadotropin-Releasing Hormone Agonist1
Cobellis, G., Meccariello, R., Minucci, S., Palmiero, C., Pierantoni, R., & Fasano, S. (2003) · Biology of Reproduction · doi:10.1095/biolreprod.102.008938 · Cited by 26
“Similar data pertaining to the molecular weights of Fos family proteins have already been reported [39].”
Result
4-MeO-PCP and 3-MeO-PCMo, new dissociative drugs, produce rewarding and reinforcing effects through activation of mesolimbic dopamine pathway and alteration of accumbal CREB, deltaFosB, and BDNF levels
Abiero, A., Botanas, C. J., Custodio, R. J. P., Sayson, L. V., Kim, M., Lee, H. J., Kim, H. J., Lee, K. W., Jeong, Y., Seo, J., et al. (2019) · Psychopharmacology · doi:10.1007/s00213-019-05412-y · Cited by 25
“DeltaFosB is a member of the Fos family of transcription factors that accumulate in the NAc and dorsal striatum after chronic exposure to abused drugs (Nestler et al. 2001; McClung et al. 2004).”
Neuroadaptations of Cdk5 in Cholinergic Interneurons of the Nucleus Accumbens and Prefrontal Cortex of Inbred Alcohol‐preferring Rats Following Voluntary Alcohol Drinking
Camp, M., Mayfield, R. D., McCracken, M. L., McCracken, L. M., & Alcantara, A. A. (2006) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2006.00160.x · Cited by 26
Effects of repeated morphine on locomotion, place preference and dopamine in heterozygous glial cell line‐derived neurotrophic factor knockout mice
Airavaara, M., Tuomainen, H., Piepponen, P. T., Saarma, M., & Ahtee, L. (2006) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2006.00260.x · Cited by 26
“One possible explanation could be a difference in the expression of transcription factor DFosB that has been linked to psychomotor sensitization and drug addiction (Nestler et al. 2001).”
Background
Tumor-infiltrating nerves functionally alter brain circuits and modulate behavior in a mouse model of head-and-neck cancer
Barr, J. L., Walz, A., Restaino, A. C., Amit, M., Barclay, S. M., Vichaya, E. G., Spanos, W. C., Dantzer, R., Talbot, S., & Vermeer, P. D. (2024) · eLife · doi:10.7554/elife.97916 · Cited by 36
“To assess this, brain sections from MOC2-7 tumor-bearing and non- tumor-bearing animals were immunofluorescently stained for cFos and ΔFosB, two markers of neuronal activity with different courses of expression ( Chung, 2015 ; Hudson, 2018 ; Nestler et al., 2001 ).”
Pharmacology of drugs of abuse
Reynolds, E. W., & Bada, H. S. (2003) · Obstetrics and Gynecology Clinics of North America · doi:10.1016/s0889-8545(03)00078-0 · Cited by 25
“Not only does DFosB provide a mechanism through which drug-induced changes in gene transcription can persist for long periods, but it may also contribute to relapse after prolonged abstinence [17].”
Background
Negative rebound in hippocampal neurogenesis following exercise cessation
Nishijima, T., Kamidozono, Y., Ishiizumi, A., Amemiya, S., & Kita, I. (2017) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00397.2016 · Cited by 25
N-acetylcysteine treatment blocks the development of ethanol-induced behavioural sensitization and related ΔFosB alterations
Morais‐Silva, G., Alves, G. C., & Marin, M. T. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.07.009 · Cited by 26
“Its accumulation increases the motivational properties and psychomotor effects of abuse drugs (Nestler et al., 2001).”
Transcriptional Regulation of NMDA Receptor Expression
Bai, G., & Hoffman, P. W. (2008) · Frontiers in neuroscience · doi:10.1201/9781420044157.ch5 · Cited by 26
Cortical–striatal gene expression in neonatal hippocampal lesion (NVHL)‐amplified cocaine sensitization
Chambers, R. A., McClintick, J. N., Sentir, A. M., Berg, S. A., Runyan, M., Choi, K. H., & Edenberg, H. J. (2013) · Genes Brain & Behavior · doi:10.1111/gbb.12051 · Cited by 24
“This is explainable by the fact that we assessed mRNA and not protein; long lasting FosB protein elevations appear to linger after cocaine due to slow degradation rather than due to sustained elevations in RNA (Damez-Werno et al. 2012; Nestler et al. 2001).”
BackgroundResult
Imidazoline receptor antisera‐selected/Nischarin regulates the effect of agmatine on the development of morphine dependence
Li, F. R., Wu, N., Su, R., Chen, Y., Lu, X., Liu, Y., & Li, J. (2011) · Addiction Biology · doi:10.1111/j.1369-1600.2011.00373.x · Cited by 24
Exercise reward induces appetitive 50-kHz calls in rats
Heyse, N. C., Brenes, J. C., & Schwarting, R. K. W. (2015) · Physiology & Behavior · doi:10.1016/j.physbeh.2015.04.021 · Cited by 24
Ionotropic glutamatergic neurotransmission in the ventral tegmental area modulates ΔFosB expression in the nucleus accumbens and abstinence syndrome in morphine withdrawal rats
Wang, H., Xiang, X., Guo, Y., Wu, W.-R., Cao, D., Wang, H., & Zhao, Y. (2005) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2005.10.017 · Cited by 25
Dysregulation of BET proteins in levodopa-induced dyskinesia
Figge, D. A., & Standaert, D. G. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.03.003 · Cited by 23
“Following LID development, dysregulated transcription factor activity leads to the sustained over expression of several activity regulated immediate-early genes (IEG) essential to the formation of long-term neuronal memory (Nestler et al., 2001; West et al., 2002; Figge et al., 2013).”
Influential
3,4,5-Trimethoxycinnamin acid ameliorates restraint stress-induced anxiety and depression
Leem, Y., & Oh, S. (2014) · Neuroscience Letters · doi:10.1016/j.neulet.2014.11.016 · Cited by 23
CREB-B acts as a key mediator of NPF/NO pathway involved in phase-related locomotor plasticity in locusts
Hou, L., Li, B., Ding, D., Kang, L., & Wang, X. (2019) · PLoS Genetics · doi:10.1371/journal.pgen.1008176 · Cited by 23
Behavioral profile of mice with impaired cognition in the elevated plus-maze due to a deficiency in neural cell adhesion molecule
Jürgenson, M., Aonurm‐Helm, A., & Zharkovsky, A. (2010) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2010.07.006 · Cited by 23
“The inducible transcription factor FosB and its truncated form ΔFosB (35–37 kDa) have been found to have prolonged induction characteristics and might be the markers of chronic activation of neuronal populations (Chen et al., 1997; Nestler et al., 2001).”
Deciphering the Actions of Antiparkinsonian and Antipsychotic Drugs on cAMP/DARPP-32 Signaling
Bonito-Oliva, A., Feyder, M. T., & Fisone, G. (2011) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2011.00038 · Cited by 24
“Chronic administration of cocaine, a drug which promotes dopaminergic transmission, leads to the accumulation of stable, alternatively spliced isoforms of the transcription factor FosB, generally denominated as FosB (Hope et al., 1994; Nestler et al., 2001).”
Background
Perinatal protein malnutrition enhances rewarding cocaine properties in adult rats
Valdomero, A., Bussolino, D. F., Orsingher, O. A., & Cuadra, G. R. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.08.055 · Cited by 23
Clinical benefits and risks of N-methyl-d-aspartate receptor antagonists to treat severe opioid use disorder: A systematic review
Fluyau, D., Revadigar, N., & Pierre, C. G. (2020) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2020.107845 · Cited by 22
Multidimensional Intersection of Nicotine, Gene Expression, and Behavior
Sherafat, Y., Bautista, M. R., & Fowler, C. D. (2021) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2021.649129 · Cited by 25
“Adolescent nicotine exposure also induces an upregulation in DeltaFosB in the NAcc [167], a transcription factor associated with neural changes underlying substance abuse [168].”
Background
The Relationship between Duration of Initial Alcohol Exposure and Persistence of Molecular Tolerance Is Markedly Nonlinear
Velázquez‐Marrero, C., Wynne, P. M., Bernardo, A., Palacio, S., Martin, G. E., & Treistman, S. N. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.5429-10.2011 · Cited by 21
“Examples of potential drug-activated molecular switches include transcription factors such as fosB and CREB (Kelz et al., 1999; Nestler et al., 2001; Hyman et al., 2006; Renthal et al., 2008) and secondary signaling molecules such as PKA (Coe et al., 1996; Pandey et al., 2001; Lin et al., 2006).”
BackgroundInfluential
Current Perspectives on the Neurobiology of Drug Addiction: A Focus on Genetics and Factors Regulating Gene Expression
Duncan, J. R. (2012) · ISRN Neurology · doi:10.5402/2012/972607 · Cited by 22
Studying the neurobiology of stimulant and alcohol abuse and dependence in genetically manipulated mice
Stephens, D. N., Mead, A. N., & Ripley, T. L. (2002) · Behavioural Pharmacology · doi:10.1097/00008877-200209000-00004 · Cited by 22
“…Substance P. Animals inducibly expressing DFosB were more sensitive to both acute and repeated cocaine administration, showed facilitated place conditioning to both cocaine and morphine, increased self-administration of cocaine, and increased anxiolytic effects of alcohol (Nestler et al., 2001).”
Background
The role of catecholamines in modulating responses to stress: Sex‐specific patterns, implications, and therapeutic potential for post‐traumatic stress disorder and opiate withdrawal
Ross, J. A., & Bockstaele, E. J. V. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14714 · Cited by 20
Increased alcohol consumption in sleep-restricted rats is mediated by delta FosB induction
García‐García, F., Priego-Fernández, S., López-Muciño, L. A., Acosta-Hernández, M. E., & Peña-Escudero, C. (2021) · Alcohol · doi:10.1016/j.alcohol.2021.02.004 · Cited by 21
Sensitization of sodium appetite: evidence for sustained molecular changes in the lamina terminalis
Hurley, S. W., Zhang, Z., Beltz, T. G., Xue, B., & Johnson, A. K. (2014) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00210.2014 · Cited by 21
Cognitive Behavioral Therapy for Chronic Pain—One Therapeutic Approach for the Opioid Epidemic
Majeed, M. H., & Sudak, D. M. (2017) · Journal of Psychiatric Practice · doi:10.1097/pra.0000000000000262 · Cited by 21
Assessing effects of oxytocin on alcohol consumption in socially housed prairie voles using radio frequency tracking
Walcott, A. T., & Ryabinin, A. E. (2020) · Addiction Biology · doi:10.1111/adb.12893 · Cited by 21
An unexpected increase in restraint duration alters the expression of stress response habituation
Kearns, R., & Spencer, R. L. (2013) · Physiology & Behavior · doi:10.1016/j.physbeh.2013.03.029 · Cited by 23
Early psychosocial stressors: relationship to suicidality and course of bipolar illness
Leverich, G. S., Perez, S., Luckenbaugh, D. A., & Post, R. M. (2002) · Clinical Neuroscience Research · doi:10.1016/s1566-2772(02)00041-5 · Cited by 22
Why are Antidepressant Drugs Effective Smoking Cessation Aids?
Shoaib, M. C., & Buhidma, Y. (2017) · Current Neuropharmacology · doi:10.2174/1570159x15666170915142122 · Cited by 22
Social Housing Leads to Increased Ethanol Intake in Male Mice Housed in Environmentally Enriched Cages
Fulenwider, H. D., Robins, M. T., Caruso, M. A., & Ryabinin, A. E. (2021) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2021.695409 · Cited by 20
“To test whether ethanol consumption in HM2 cages resulted in pharmacologically-relevant levels of ethanol across all animals, we also assessed levels of FosB, a marker of longterm, repeated neuronal activation (Nestler et al., 2001) in brain regions known to respond to ethanol exposure: NAcc, NAcs, CeA, and EW.”
Background
d ‐Cycloserine enhanced extinction of cocaine‐induced conditioned place preference is attenuated in serotonin transporter knockout rats
Karel, P., Calabrese, F., Riva, M. A., Brivio, P., van der Veen, B., Reneman, L., Verheij, M. M. M., & Homberg, J. R. (2016) · Addiction Biology · doi:10.1111/adb.12483 · Cited by 19
Alcohol’s Effects on Pair-Bond Maintenance in Male Prairie Voles
Walcott, A. T., & Ryabinin, A. E. (2017) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2017.00226 · Cited by 20
Cytisine modulates chronic voluntary ethanol consumption and ethanol-induced striatal up-regulation of ΔFosB in mice
Sajja, R. K., & Rahman, S. (2013) · Alcohol · doi:10.1016/j.alcohol.2013.02.003 · Cited by 20
Repeated acetyl‐ l ‐carnitine administration increases phospho‐Thr34 DARPP‐32 levels and antagonizes cocaine‐induced increase in Cdk5 and phospho‐Thr75 DARPP‐32 levels in rat striatum
Scheggi, S., Rauggi, R., Nanni, G., Tagliamonte, A., & Gambarana, C. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03230.x · Cited by 20
Chronic stress causes striatal disinhibition mediated by SOM-interneurons in male mice
Rodrigues, D., Jacinto, L., Falcão, M., Castro, A. C., Cruz, A., Santa, C., Manadas, B. J., Marques, F., Sousa, N., & Monteiro, P. (2022) · Nature Communications · doi:10.1038/s41467-022-35028-4 · Cited by 22
Cocainomics: New Insights into the Molecular Basis of Cocaine Addiction
Hemby, S. E. (2010) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-009-9189-8 · Cited by 19
“…repeated cocaine administration leads to sustained elevation of ΔFosB levels in brain regions associated with the behavioral effects of cocaine (Brenhouse and Stellar 2006; Hope et al. 1994; McClung and Nestler 2003; Moratalla et al. 1996; Nestler 2001; Nestler et al. 2001; Perrotti et al. 2005).”
Background
Increased rewarding properties of morphine in perinatally protein-malnourished rats
Valdomero, A., Velazquez, E. E., de Olmos, S., de Olmos, J. S., Orsingher, O. A., & Cuadra, G. R. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.09.006 · Cited by 19
Differential effects of water deprivation and rehydration on Fos and FosB/ΔFosB staining in the rat brainstem
Ji, L. L., Gottlieb, H. B., Penny, M. L., Fleming, T., Toney, G. M., & Cunningham, J. T. (2006) · Experimental Neurology · doi:10.1016/j.expneurol.2006.08.020 · Cited by 19

Authors: Nestler, E. J., Barrot, M., & Self, D. W.
Affiliations: The University of Texas Southwestern Medical Center (US)
ORCID: Nestler, Eric J.
Barrot, Michel
Self, David W.
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
DOI: 10.1073/pnas.191352698
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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ΔFosB: A sustained molecular switch for addiction

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