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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BackgroundResultSelf-citation
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Weiner, J. M., Sun, W. L., Zhou, L., Kreiter, C. M., Jenab, S., & Quiñones-Jenab, V. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.03.071 · Cited by 13
Cocaine
Trifilieff, P., & Martínez, D. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-418679-8.00005-8 · Cited by 14
Fat rather than sugar diet leads to binge-type eating, anticipation, effort behavior and activation of the corticolimbic system
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“[45] suggested that ΔFosB is a transcription factor”
Background
The Antidepressant-Like and Analgesic Effects of Kratom Alkaloids are accompanied by Changes in Low Frequency Oscillations but not ΔFosB Accumulation
Buckhalter, S., Soubeyrand, E., Ferrone, S. A. E., Rasmussen, D. J., Manduca, J. D., Al-Abdul-Wahid, S., Frie, J. A., Khokhar, J. Y., Akhtar, T. A., & Perreault, M. L. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.696461 · Cited by 13
The anatomy of co-morbid neuropsychiatric disorders based on cortico-limbic synaptic interactions
Totterdell, S. (2006) · Neurotoxicity Research · doi:10.1007/bf03033236 · Cited by 13
“…in spine density in the shell region of the nucleus accumbens, prefrontal cortex and the CA1 region of the hippocampus (Robinson and Kolb, 1999; Nestler et al., 2001; Crombag et al., 2005) There is good evidence for a role for glutamatedopamine interactions in the ventral tegmental area and…”
Glucocorticoid Dependency of Surgical Stress‐Induced FosB/ΔFosB Expression in the Paraventricular and Supraoptic Nuclei of the Rat Hypothalamus
Das, G., Uchida, K., Kageyama, K., Iwasaki, Y., Suda, T., & Itoi, K. (2009) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2009.01902.x · Cited by 13
Differences in basal and morphine-induced FosB/ΔFosB and pCREB immunoreactivities in dopaminergic brain regions of alcohol-preferring AA and alcohol-avoiding ANA rats
Kaste, K., Kivinummi, T., Piepponen, P. T., Kiianmaa, K., & Ahtee, L. (2009) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2009.03.004 · Cited by 12
“Repeated stimuli, such as repeated exposure to drugs of abuse, lead to a gradual increase in ΔFosB levels, an effect that persists for a relatively long time after the cessation of drug treatment (Hope et al., 1994; Nestler et al., 2001).”
Background
Prenatal exposure to cocaine decreases adenylyl cyclase activity in embryonic mouse striatum
Unterwald, E. M., Ivković, S., Cuntapay, M., Stroppolo, A., Guinea, B., & Ehrlich, M. E. (2003) · Developmental Brain Research · doi:10.1016/s0165-3806(03)00058-0 · Cited by 13
From Transcriptional Regulation to Aggressive Behavior
D'Souza, U. M., Kel, A., & Sluyter, F. (2003) · Behavior Genetics · doi:10.1023/a:1025778817885 · Cited by 12
5-Hydroxytryptophan Reduces Levodopa-Induced Dyskinesia via Regulating AKT/mTOR/S6K and CREB/ΔFosB Signals in a Mouse Model of Parkinson’s Disease
Choi, Y., Huh, E., Lee, S.-M., Kim, J. H., Park, M. G., Seo, S., Kim, S. Y., & Oh, M. S. (2023) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2022.141 · Cited by 12
Cell-type- and region-specific modulation of cocaine seeking by micro-RNA-1 in striatal projection neurons
Forget, B., Martín‐García, E., Godino, A., Rodriguez, L. D., Kappès, V., Poirier, P., Andrianarivelo, A., Senabre, E., Allichon, M., Marias, M., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01328-2 · Cited by 14
Behavioral and Gene Regulatory Responses to Developmental Drug Exposures in Zebrafish
Mech, A. M., Merteroglu, M., Sealy, I. M., Teh, M., White, R. J., Havelange, W., Brennan, C. H., & Busch‐Nentwich, E. M. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.795175 · Cited by 14
Reduction of Cocaine-Induced Locomotor Effects by Enriched Environment Is Associated with Cell-Specific Accumulation of ΔFosB in Striatal and Cortical Subregions
Lafragette, A., Bardo, M. T., Lardeux, V., Solinas, M., & Thiriet, N. (2016) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyw097 · Cited by 13
“…1997) and, because of its stability, Δ FosB accumulates in several brain regions, including the prefrontal cortex and striatum, thought to be involved in habit formation after chronic administration of cocaine (Hope et al., 1994; Nestler et al., 2001; McClung et al., 2004; Perrotti et al., 2008).”
FGF2 Antiproliferative Stimulation Induces Proteomic Dynamic Changes and High Expression of FOSB and JUNB in K‐Ras‐Driven Mouse Tumor Cells
Vitorino, F. N. D. L., Montoni, F., Moreno, J. N., de Souza, B. F., Lopes, M. D. C., Cordeiro, B., Fonseca, C. S., Gilmore, J., Sardiu, M., Reis, M. S., et al. (2018) · Proteomics · doi:10.1002/pmic.201800203 · Cited by 7
Effects of Alcohol Consumption on Pair Bond Maintenance and Potential Neural Substrates in Female Prairie Voles
Walcott, A. T., & Ryabinin, A. E. (2019) · Alcohol and Alcoholism · doi:10.1093/alcalc/agz041 · Cited by 12
“While acute neural activation leads to temporary expression of the full-length FosB protein, repeated neural activation results in accumulation of the delta-FosB protein (Kelz and Nestler, 2000; Nestler et al., 2001).”
Background
Molecular hydrogen attenuates methamphetamine-induced behavioral sensitization and activation of ERK-ΔFosB signaling in the mouse nucleus accumbens
Wen, D., Hui, R., Liu, Y., Luo, Y., Wang, J., Shen, X., Xie, B., Feng, Y., Cong, B., & Ma, C. (2019) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2019.109781 · Cited by 12
Adaptation of Respiratory-Related Brain Regions to Long-Term Hypercapnia: Focus on Neuropeptides in the RTN
Dereli, A. S., Yaseen, Z., Carrive, P., & Kumar, N. N. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01343 · Cited by 11
Carnosic Acid Alleviates Levodopa-Induced Dyskinesia and Cell Death in 6-Hydroxydopamine-lesioned Rats and in SH-SY5Y Cells
Lai, C.-Y., Lin, C., Wu, C., Tsai, C., & Tsai, C.-W. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.703894 · Cited by 12
“Study also indicated that ΔFosB is accumulated after abusing some drugs and increased the sensitivity to the behavioral effects (Nestler et al., 2001).”
Background
Overexpression of ΔFosB is associated with attenuated cocaine-induced suppression of saccharin intake in mice.
Freet, C. S., Steffen, C., Nestler, E. J., & Grigson, P. S. (2009) · Behavioral Neuroscience · doi:10.1037/a0015033 · Cited by 12
“, 1998; Perez-Otano, Mandelzys, & Morgan, 1998) to form activator protein-1 complexes (Chen et al., 1995; Curran & Franza, 1988; Nestler et al., 2001).”
Self-citation
Region-specific changes in markers of neuroplasticity revealed in HIV-1 transgenic rats by low-dose methamphetamine
Ohene‐Nyako, M., Persons, A. L., & Napier, T. C. (2018) · Brain Structure and Function · doi:10.1007/s00429-018-1701-6 · Cited by 11
Increased accumbens Cdk5 expression in rats after short-access to self-administered cocaine, but not after long-access sessions
Seiwell, A. P., Reveron, M. E., & Duvauchelle, C. L. (2007) · Neuroscience Letters · doi:10.1016/j.neulet.2007.02.043 · Cited by 12
A new genetic model of activity-induced Ras signaling dependent pre-synaptic plasticity in Drosophila
Freeman, A. A. H., Bowers, M. E., Vrailas‐Mortimer, A. D., Timmerman, C., Roux, S., Ramaswami, M., & Sanyal, S. (2010) · Brain Research · doi:10.1016/j.brainres.2010.02.061 · Cited by 11
The Molecular Mechanisms of Reward
Winstanley, C. A., & Nestler, E. J. (2008) · Elsevier eBooks · doi:10.1016/b978-012370509-9.00004-8 · Cited by 11
Self-citation
Assessing contributions of nucleus accumbens shell subregions to reward-seeking behavior
Reed, M. D., Hildebrand, D. G. C., Santangelo, G., Moffa, A., Pira, A. S., Rycyna, L., Radic, M., Price, K. E., Archbold, J., McConnell, K., et al. (2015) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2015.05.001 · Cited by 15
“his persisting switch may be involved in the long-term changes hat enable reinstatement of drug-seeking behavior even after long eriods of extinction (Hope et al., 1994; Nestler et al., 2001).”
Background
Region-specific increases in FosB/ΔFosB immunoreactivity in the rat brain in response to chronic sleep restriction
Hall, S., Deurveilher, S., Ko, K. R., Burns, J., & Semba, K. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.01.024 · Cited by 11
Differential Expression of DeltaFosB in Reward Processing Regions Between Binge Eating Prone and Resistant Female Rats
Amissah, R. Q., Chometton, S., Calvez, J., Guèvremont, G., Timofeeva, E., & Timofeev, I. (2020) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2020.562154 · Cited by 11
Differential regulation of CDK5 and c-Fos expression by morphine in the brain of Lewis and Fischer 344 rat strains
Salas, E., Alonso, E., Polanco, M. J., Cano, V., Ruiz‐Gayo, M., & Alguacil, L. F. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.11.001 · Cited by 11
Transcription MRI: A New View of the Living Brain
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Stimulation of corticotropin-releasing factor gene expression by FosB in rat hypothalamic 4B cells
Kageyama, K., Itoi, K., Iwasaki, Y., Niioka, K., Watanuki, Y., Yamagata, S., Nakada, Y., Das, G., Suda, T., & Daimon, M. (2013) · Peptides · doi:10.1016/j.peptides.2013.11.004 · Cited by 11
The effect of electroacupuncture on extinction responding of heroin-seeking behavior and FosB expression in the nucleus accumbens core
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Lower ΔFosB expression in the dopaminergic system after stevia consumption in rats housed under environmental enrichment conditions
Salinas-Velarde, I. D., Bernal‐Morales, B., Pacheco, P., Sánchez-Aparicio, P., Pascual-Mathey, L. I., & Venebra-Muñoz, A. (2021) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2021.10.001 · Cited by 10
Moderate and severe perinatal asphyxia induces differential effects on cocaine sensitization in adult rats
Galeano, P., Romero, J. I., Rojas, M. J. L., Suárez, J., Holubiec, M. I., Bisagno, V., Santín, L. J., de Fonseca, F. R., Capani, F., & Blanco, E. (2013) · Synapse · doi:10.1002/syn.21660 · Cited by 10
“On the other hand, isoforms of DFosB are highly stable and accumulate after repeated cocaine exposure in NAcc and dorsal striatum for weeks (Nestler et al., 2001).”
Background
Accumbal FosB/ΔFosB immunoreactivity and conditioned place preference in alcohol-preferring AA rats and alcohol-avoiding ANA rats treated repeatedly with cocaine
Marttila, K., Piepponen, P. T., Kiianmaa, K., & Ahtee, L. (2007) · Brain Research · doi:10.1016/j.brainres.2007.05.036 · Cited by 10
Exploring time-dependent changes in conditioned place preference for food reward and associated changes in the nucleus accumbens
Tuplin, E. W. N., & Holahan, M. R. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2018.12.031 · Cited by 10
Cytoplasmic Polyadenylation Element Binding Proteins CPEB1 and CPEB3 Regulate the Translation of FosB and Are Required for Maintaining Addiction-Like Behaviors Induced by Cocaine
Drisaldi, B., Colnaghi, L., Levine, A. A., Huang, Y.-Y., Snyder, A. M., Metzger, D. J., Theis, M., Kandel, D. B., Kandel, E. R., & Fioriti, L. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00207 · Cited by 10
“…in both initiating and maintaining changes in gene expression after drug exposure by affecting not only known target mRNAs of CPEBs but also two newly identified CPEB target mRNAs: FosB and its spliced form∆FosB, whose expression increases following chronic cocaine treatment (Nestler et al., 2001).”
BackgroundInfluential
Nerve injury alters restraint-induced activation of the basolateral amygdala in male rats
Kang, J. W. M., Mor, D., & Keay, K. A. (2021) · Brain Structure and Function · doi:10.1007/s00429-021-02235-6 · Cited by 10
Neurobiological Theories of Addiction
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Role of GIRK Channels in Addictive Substance Effects
Sugaya, N., Kobayashi, T., & Ikeda, K. (2013) · Journal of Drug and Alcohol Research · doi:10.4303/jdar/235823 · Cited by 10
“Indeed, a considerable evidence indicates that several addictive substances commonly induce cAMP, CREB, and ΔFosB in neurons in the NAc, reflecting adaptations characterized by upregulation of the cAMP pathway [6] [65] [73] [74] [94].”
Background
Gamma-delta T cells suppress microbial metabolites that activate striatal neurons and induce repetitive/compulsive behavior in mice
Cox, L. M., Tatematsu, B. K., Guo, L., LeServe, D. S., Mayrink, J., Oliveira, M. G., Donnelly, D. J., Fonseca, R. C., Lemos, L., Lanser, T. B., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.01.214 · Cited by 10
Sex differences in contextual fear conditioning and extinction after acute and chronic nicotine treatment
Keady, J. V., Hessing, M. C., Songrady, J. C., McLaurin, K. A., & Turner, J. R. (2024) · Biology of Sex Differences · doi:10.1186/s13293-024-00656-6 · Cited by 9
Alternative splicing in addiction
Bhatnagar, A., & Heller, E. A. (2025) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2025.102340 · Cited by 11
Novel neurotherapeutic targets for substance use disorders: Neuroplasticity, neuroinflammation, gasotransmitters and non-canonical organ systems
Sharma, P., Sawaya, M. F., Dumitrescu, A. M., Kolluru, G. K., Schmoutz, C. D., Salinas, A. G., Cannon, C. E., Kumbhare, D., Korneeva, N. L., Vest, M. F., et al. (2025) · Neurotherapeutics · doi:10.1016/j.neurot.2025.e00770 · Cited by 13
“Long-term substance use can lead to an expression switch from c-fos to FosB, which has a longer half-life and results in more stable changes in gene transcription which is critical for the development of addiction [90].”
Circadian disruption favors alcohol consumption and differential ΔFosB accumulation in Corticolimbic structures
Reséndiz‐Flores, M., & Escobar, C. (2018) · Addiction Biology · doi:10.1111/adb.12674 · Cited by 9
“Also, this ΔFosB accumulation seems to favor motivational responses and the development of compulsive behaviors (Nestler et al. 2001; Ozburn et al. 2012).”
Background

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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