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. Author manuscript; available in PMC: 2022 Aug 30.
Published in final edited form as: Curr Psychopharmacol. 2021 Jan 8;11(1):11–17. doi: 10.2174/2211556009666210108112737

Fig. (2). Epigenetic and transcriptional effects of chronic cocaine exposure and psychostimulant abuse.

Fig. (2).

Histone acetylation and methylation on Lys residues result from cocaine and methamphetamine abuse (dull green). After repeated cocaine exposure, Protein-arginine (R)-methyltransferase-6 (PRMT6) and its associated histone decreased in the NAc of mice and rats and the NAc of cocaine-dependent humans due to dimethylation of R2 on histone H3 (H3R2me2a), which was asymmetric. Downregulation of demethylation by PRMT6 selectively occurred in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (DRD2) (D2-MSNs), with opposite regulation manifested in D1-MSNs. These changes appeared to protect against cocaine-seeking and associated behavioral abnormalities (dull orange). Acute cocaine increased DA and histone H3 glutamine 5 dopaminylation (H3Q5dop), with a secondary decreased in D2 expression (bright green). Withdrawal from cocaine led to the accumulation of histone H3 glutamine 5 dopaminylation (H3Q5-dop) and subsequent D2 expression inhibition. Administration of the Src kinase signaling inhibitor 1 (p140CAP) during cocaine withdrawal reduced H3R2me2a binding. Inhibited dopaminylation induced a “homeostatic brake” and decreased NAc Src signaling in NAc D2-MSNs accompanied by decreased cocaine reward and motivation to self-administer cocaine (tan). These results are consistent with the idea that the DRD2 Taq A2 allele serves as a genetic protective mechanism (bright yellow).