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

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.