Chromatin Remodeling Is a Key Mechanism Underlying Cocaine-Induced Plasticity in Striatum
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Given that cocaine induces neuroadaptations through regulation of gene expression, we investigated whether chromatin remodeling at specific gene promoters may be a key mechanism. We show that cocaine induces specific histone modifications at different gene promoters in striatum, a major neural substrate for cocaine's behavioral effects. At the cFos promoter, H4 hyperacetylation is seen within 30 min of a single cocaine injection, whereas no histone modifications were seen with chronic cocaine, consistent with cocaine's ability to induce cFos acutely, but not chronically. In contrast, at the BDNF and Cdk5 promoters, genes that are induced by chronic, but not acute, cocaine, H3 hyperacetylation was observed with chronic cocaine only. DeltaFosB, a cocaine-induced transcription factor, appears to mediate this regulation of the Cdk5 gene. Furthermore, modulating histone deacetylase activity alters locomotor and rewarding responses to cocaine. Thus, chromatin remodeling is an important regulatory mechanism underlying cocaine-induced neural and behavioral plasticity.
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Acute and chronic drug exposures (stimulants, opioids, alcohol, nicotine) increase total cellular levels of acetylation of histones H3 and H4, apparently by unbalancing HAT and HDAC function.
“These studies have shown that acute and chronic drug exposures (stimulants, opioids, alcohol, nicotine) increase total cellular levels of acetylation of histones H3 and H4 105- 110 , apparently by unbalancing HAT and HDAC function.”
From Substance use disorders: a comprehensive update of classification, epidemiology, neurobiology, clinical aspects, treatment and prevention (2023) · cites this paper as [105]
The section “Cocaine Induces Acetylation and Phosphoacetylation of Histones at Specific Gene Promoters” (page unavailable) reports increased H4 acetylation at selected promoters after acute cocaine and H3 acetylation after chronic cocaine. The paper does not establish increased total cellular H3 and H4 acetylation across the listed drugs. It also says the basis of the acute-to-chronic switch is unknown and reports no evidence that cocaine changes levels of the HDACs examined, so the proposed HAT–HDAC imbalance is not established here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredChromatin remodeling plays a role in multiple physiological and pathological processes in the brain, including circadian rhythms, learning and memory, drug addiction, and depression.
“Chromatin remodeling plays a role in multiple physiological and pathological processes in the brain, including circadian rhythms, 32 learning and memory, 33 drug addiction, 34 and depression.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [34]
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- Authors
- Kumar, A., Choi, K.-H., Renthal, W., Tsankova, N. M., Theobald, D. E. H., Truong, H.-T., Russo, S. J., LaPlant, Q., Sasaki, T. S., Whistler, K. N., Neve, R. L., Self, D. W., & Nestler, E. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Harvard University (US)
- Corresponding author
- Nestler, Eric J.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2005-10
- Volume
- 48
- Issue
- 2
- Pages
- 303-314
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W1989407684
- Cited by
- 764
- References
- 62
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 18 · 2023: 22 · 2022: 18 · 2021: 23 · 2020: 16 · 2019: 33 · 2018: 29 · 2017: 30 · 2016: 61 · 2015: 32 · 2014: 59 · 2013: 54 · 2012: 65
- FWCI
- 13.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Texas Southwestern Medical Center
- National Institute of Mental Health
- National Institute on Drug Abuse
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- cocaine, chromatin remodeling, histone modifications, histone acetylation, striatum, c-fos, brain-derived neurotrophic factor, cyclin-dependent kinase 5, ΔFosB, histone deacetylase, gene expression regulation, locomotor activity, cocaine reward
- MeSH terms
- Acetylation, Animals, Behavior, Animal, Butyrates, Cocaine, Conditioning, Operant, Corpus Striatum, Drug Administration Schedule, Drug Interactions, Enzyme Inhibitors, Gene Expression Regulation, Histone Deacetylases, Histones, Immunohistochemistry, Male, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neuronal Plasticity, Promoter Regions, Genetic, RNA, Messenger, Time Factors, PC12 Cells, Proto-Oncogene Proteins c-fos, Rats, Sprague-Dawley, Gene Transfer Techniques, Dopamine Uptake Inhibitors, Brain-Derived Neurotrophic Factor, Reverse Transcriptase Polymerase Chain Reaction, Protein Subunits, Chromatin Assembly and Disassembly, Immunoprecipitation, Cyclin-Dependent Kinase 5, Mice, Rats
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