2. Academic Validation
  3. Epigenetic regulation of cocaine intake through dopaminergic control of cholinergic interneurons in male mice

Epigenetic regulation of cocaine intake through dopaminergic control of cholinergic interneurons in male mice

  • Nat Commun. 2025 Dec 9;16(1):10964. doi: 10.1038/s41467-025-65958-8.
Robert G Lewis # 1 2,  Lauren Otsuka # 1 2,  Daniela Punzo 1 2,  Yasmine Sherafat 3 4,  Ermanno Florio 1 2,  Mingqi Zhou 5,  Valeria Lallai 3,  Thu Dinh Nha Pham 1 2,  Marcus Seldin 5,  Christie D Fowler 3,  Emiliana Borrelli 6 7 8
Affiliations

Affiliations

  • 1 INSERM U1233, Center for Epigenetics and Metabolism, University of California, Irvine, CA, USA.
  • 2 Department of Microbiology and Molecular Genetics, University of California, Irvine, CA, USA.
  • 3 Department of Neurobiology and Behavior, University of California, Irvine, CA, USA.
  • 4 Department of Psychology, California State University, San Marcos, CA, USA.
  • 5 Department of Biological Chemistry, University of California, Irvine, CA, USA.
  • 6 INSERM U1233, Center for Epigenetics and Metabolism, University of California, Irvine, CA, USA. [email protected].
  • 7 Department of Microbiology and Molecular Genetics, University of California, Irvine, CA, USA. [email protected].
  • 8 Department of Pharmacological Sciences, University of California, Irvine, CA, USA. [email protected].
  • # Contributed equally.
PMID: 41365875 DOI: 10.1038/s41467-025-65958-8
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.

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