Drug-Induced Activation of Dopamine D1 Receptor Signaling and Inhibition of Class I/II Histone Deacetylase Induce Chromatin Remodeling in Reward Circuitry and Modulate Cocaine-Related Behaviors
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Chromatin remodeling, including histone modification, is involved in stimulant-induced gene expression and addiction behavior. To further explore the role of dopamine D(1) receptor signaling, we measured cocaine-related locomotor activity and place preference in mice pretreated for up to 10 days with the D(1) agonist SKF82958 and/or the histone deacetylase inhibitor (HDACi), sodium butyrate. Cotreatment with D(1) agonist and HDACi significantly enhanced cocaine-induced locomotor activity and place preference, in comparison to single-drug regimens. However, butyrate-mediated reward effects were transient and only apparent within 2 days after the last HDACi treatment. These behavioral changes were associated with histone modification changes in striatum and ventral midbrain: (1) a generalized increase in H3 phosphoacetylation in striatal neurons was dependent on activation of D(1) receptors; (2) H3 deacetylation at promoter sequences of tyrosine hydroxylase (Th) and brain-derived neurotrophic factor (Bdnf) in ventral midbrain, together with upregulation of the corresponding gene transcripts after cotreatment with D(1) agonist and HDACi. Collectively, these findings imply that D(1) receptor-regulated histone (phospho)acetylation and gene expression in reward circuitry is differentially regulated in a region-specific manner. Given that the combination of D(1) agonist and HDACi enhances cocaine-related sensitization and reward, the therapeutic benefits of D(1) receptor antagonists and histone acetyl-transferase inhibitors (HATi) warrant further investigation in experimental models of stimulant abuse.
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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 [107]
The Results section, “Activation of D1 Signaling is Linked to a Nucleosomal Response in Striatum” (page unavailable), reports increased striatal H3 phosphoacetylation after acute and repeated D1-agonist treatment. It does not establish increased total cellular acetylation of both H3 and H4 across stimulants, opioids, alcohol, and nicotine, or attribute such an increase to an imbalance of HAT and HDAC function; it also reports unchanged global H3 acetylation in agonist-treated cultures. (LLM, conf=0.88)
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- Authors
- Schroeder, F. A., Penta, K. L., Matevossian, A., Jones, S. R., Konradi, C., Tapper, A. R., & Akbarian, S.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Wake Forest University Health Sciences (US)
- Vanderbilt University (US)
- Corresponding author
- Akbarian, Schahram
- Venue
- Neuropsychopharmacology
- Published
- 2008-02-20
- Volume
- 33
- Issue
- 12
- Pages
- 2981-2992
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC2746694
- OpenAlex
- W2037717401
- Cited by
- 139
- References
- 60
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 14 · 2020: 1 · 2019: 6 · 2018: 5 · 2017: 4 · 2016: 14 · 2015: 7 · 2014: 16 · 2013: 16 · 2012: 10
- FWCI
- 4.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship@UMassChan (submittedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (U01AA014091)
- National Institute on Drug Abuse (R01DA017660, R01DA021325, R01DA030161)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- dopamine D1 receptor, histone deacetylase inhibition, sodium butyrate, cocaine reward, place preference, histone acetylation, histone deacetylation, striatum, ventral midbrain, tyrosine hydroxylase, brain-derived neurotrophic factor, gene expression regulation, stimulant use disorder, histone modifications
- MeSH terms
- Acetylation, Animals, Brain, Brain Chemistry, Cocaine, Disease Models, Animal, Dopamine, Enzyme Inhibitors, Histone Deacetylases, Histones, Male, Mice, Inbred C57BL, Synaptic Transmission, Reward, Tyrosine 3-Monooxygenase, Signal Transduction, Receptors, Dopamine D1, Dopamine Agonists, Dopamine Uptake Inhibitors, Brain-Derived Neurotrophic Factor, Cocaine-Related Disorders, Chromatin Assembly and Disassembly, Mice, Histone Deacetylase 1, Histone Deacetylase Inhibitors
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