Significance We demonstrate that protein-R (arginine)-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the nucleus accumbens (NAc) of mice and rats after repeated cocaine exposure, as well as in the NAc of cocaine-addicted humans. We show that cocaine-induced PRMT6 down-regulation occurs selectively in NAc medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) and serves to protect against cocaine-induced behavioral abnormalities. Furthermore, we provide the first, to our knowledge, genome-wide characterization of H3R2me2a within a specific brain region in vivo, and identify Src kinase signaling inhibitor 1 (Srcin1 or p140Cap) as a key target for this chromatin modification. Srcin1 induction in the NAc after cocaine exposure, which is associated with reduced Src signaling, decreases cocaine reward.