A Role for Repressive Histone Methylation in Cocaine-Induced Vulnerability to Stress
Open accessAbstract
Substance abuse increases an individual's vulnerability to stress-related illnesses, which is presumably mediated by drug-induced neural adaptations that alter subsequent responses to stress. Here, we identify repressive histone methylation in nucleus accumbens (NAc), an important brain reward region, as a key mechanism linking cocaine exposure to increased stress vulnerability. Repeated cocaine administration prior to subchronic social defeat stress potentiated depressive-like behaviors in mice through decreased levels of histone H3 lysine 9 dimethylation in NAc. Cre-mediated reduction of the histone methyltransferase, G9a, in NAc promoted increased susceptibility to social stress, similar to that observed with repeated cocaine. Conversely, G9a overexpression in NAc after repeated cocaine protected mice from the consequences of subsequent stress. This resilience was mediated, in part, through repression of BDNF-TrkB-CREB signaling, which was induced after repeated cocaine or stress. Identifying such common regulatory mechanisms may aid in the development of new therapies for addiction and depression.
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The HDAC2-inhibitor structures revealed an overall HDAC2 protein conformation similar to a previously solved HDAC2 structure, albeit at significantly higher resolution.
“The structures revealed an overall HDAC2 protein conformation similar to a previously solved HDAC2 structure, albeit at significantly higher resolution (Table 1 and Fig. 2) (17-19, 31, 33).”
From Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants Correlate with Cellular Histone Acetylation but Not Transcription and Cell Viability (2013) · cites this paper as [19]
The Discussion mentions HDAC inhibitors in relation to behavioral effects, while the Results address histone methylation after cocaine and stress; neither section reports an HDAC2 protein structure. Searches for HDAC2-inhibitor structures, protein conformation, and higher-resolution crystal structures found no passage addressing the claim. Page numbers were unavailable in our copy. (LLM, conf=0.77)
Experimental — accuracy not yet measuredRepressive histone modifications are both up- and downregulated after social defeat stress, and these changes are linked to genes with known roles in CSDS-susceptibility.
“Repressive histone modifications are both up-and downregulated after social defeat stress, and these changes are linked to genes with known roles in CSDS-susceptibility.”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [140]
G9a expression is decreased in the NAc of CSDS-susceptible mice.
“The repressive histone lysine methyl-transferase G9a decreases TrkB-CREB signaling and G9a expression is decreased in the NAc of CSDS-susceptible mice [140].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [140]
G9a decreases TrkB-CREB signaling.
“The repressive histone lysine methyl-transferase G9a decreases TrkB-CREB signaling and G9a expression is decreased in the NAc of CSDS-susceptible mice [140].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [140]
G9a overexpression promotes resilience, thought to occur by normalization of TrkB-CREB signaling.
“G9a overexpression promotes resilience, thought to occur by normalization of TrkB-CREB signaling [140].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [140]
Locus-specific modifications change histone acetylation at a particular gene, thereby altering its expression.
“In contrast, locus-specific modifications change histone acetylation at a particular gene, thereby altering its expression.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [69]
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- Authors
- Covington, H. E., Maze, I., Sun, H., Bomze, H. M., DeMaio, K. D., Wu, E. Y., Dietz, D. M., Lobo, M. K., Ghose, S., Mouzon, E., Neve, R. L., Tamminga, C. A., & Nestler, E. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Duke University (US)
- The University of Texas Southwestern Medical Center (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Nestler, Eric J.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 71
- Issue
- 4
- Pages
- 656-670
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3163060
- OpenAlex
- W2067821921
- Cited by
- 289
- References
- 70
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 15 · 2023: 9 · 2022: 16 · 2021: 16 · 2020: 18 · 2019: 20 · 2018: 23 · 2017: 25 · 2016: 26 · 2015: 23 · 2014: 32 · 2013: 26 · 2012: 18
- FWCI
- 10.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Elsevier eBooks
- Funders
- National Institute of Mental Health (R01MH051399, P50MH066172)
- National Institute on Drug Abuse (P01DA008227, R01DA014133)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- cocaine, social defeat stress, stress vulnerability, H3K9 dimethylation, G9a, nucleus accumbens, depression, addiction, epigenetic regulation
- MeSH terms
- Animals, Behavior, Animal, Cocaine, Depression, Histones, Humans, Male, Methylation, Mice, Inbred C57BL, Motor Activity, Nucleus Accumbens, Social Behavior, Stress, Psychological, Signal Transduction, Cyclic AMP Response Element-Binding Protein, Dopamine Uptake Inhibitors, Brain-Derived Neurotrophic Factor, Cocaine-Related Disorders, Receptor, trkB, Mice
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