Epigenetic regulation of cocaine intake through dopaminergic control of cholinergic interneurons in male mice
Year: 2025
Type: article
Abstract: Substance use disorders are chronic neuropsychiatric conditions influenced by multiple factors, shaping individuals' vulnerability to addictive drugs like cocaine. Here, we reveal that dopamine D2 receptor mediated inhibition of striatal cholinergic interneurons regulates the motivation for cocaine intake by modulating acetylcholine signaling in striatal circuits. This acetylcholine-dependent mechanism contributes to cocaine self-administration through the muscarinic M4 receptor and the histone acetyltransferase Kat5/Tip60. We discover that Kat5 is upregulated in response to cocaine and further show that this leads to acetylation of histone H4 on lysine 8, an epigenetic modification that increases immediate early gene expression and muscarinic M4 receptor in dopamine D1 receptor-expressing medium spiny neurons. Notably, this chain of events is absent in male mice lacking D2 receptor-mediated inhibition of cholinergic interneurons, resulting in reduced cocaine consumption. These findings expand our understanding of how cocaine manipulates striatal circuits to reinforce drug-seeking behavior.
Source: Nature Communications
Authors: Robert G. Lewis, Lauren Otsuka, Daniela Punzo, Yasmine Sherafat, Ermanno Florio, Mingqi Zhou, Valeria Lallai, Thu Dinh Nha Pham, Marcus Seldin, Christie D. Fowler, Emiliana Borrelli
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Health and Human Services, Institut National de la Santé et de la Recherche Médicale, National Institutes of Health, University of California, Irvine, National Institute on Drug Abuse, National Cancer Institute, National Institute of General Medical Sciences, School of Medicine, University of California, Irvine, Center for Complex Biological Systems, University of California, Irvine
Awards: G1750422835, G2225470952, G2645848829, G3050426486, G3187125929, Role of the Nicotinic Receptor Modulator Lynx1 in Nicotine Dependence, Drugs of abuse, Dopamine and the Circadian Clock: a Metabolomic Study, Training Program in Substance Use and Use Disorders, G4658115531, Systems Biology of Morphogeneisis and Spatial Information Flow, G5025827294, G5924795866, G6525298058, G6934149425, G706942239, G7490797224, G7751614424, Circulating miRNAs and Epigenetic Regulation in Nicotine Addiction, G9000088035, Cancer Center Support Grant
OpenAlex ID: W4417154895