Memories associated with drugs of abuse, such as methamphetamine (METH), increase relapse vulnerability to substance use disorder by triggering craving. The nucleus accumbens (NAc) is essential to these drug-associated memories, but underlying mechanisms are poorly understood. Posttranslational chromatin modifications, such as histone methylation, modulate gene transcription; thus, we investigated the role of the associated epigenetic modifiers in METH-associated memory. Conditioned place preference was used to assess the epigenetic landscape in the NAc supporting METH-associated memory (n = 79). The impact of histone methylation (H3K4me2/3) on the formation and expression of METH-associated memory was determined by focal, intra-NAc knockdown (KD) of a writer, the methyltransferase mixed-lineage leukemia 1 (Mll1) (n = 26), and an eraser, the histone lysine (K)-specific demethylase 5C (Kdm5c) (n = 38), of H3K4me2/3. A survey of chromatin modifications in the NAc of animals forming a METH-associated memory revealed the global induction of several modifications associated with active transcription. This correlated with a pattern of gene activation, as revealed by microarray analysis, including upregulation of oxytocin receptor (Oxtr) and FBJ osteosarcoma oncogene (Fos), the promoters of which also had increased H3K4me3. KD of Mll1 reduced H3K4me3, Fos and Oxtr levels and disrupted METH-associated memory. KD of Kdm5c resulted in hypermethylation of H3K4 and prevented the expression of METH-associated memory. The development and expression of METH-associated memory are supported by regulation of H3K4me2/3 levels by MLL1 and KDM5C, respectively, in the NAc. These data indicate that permissive histone methylation, and the associated epigenetic writers and erasers, represent potential targets for the treatment of substance abuse relapse, a psychiatric condition perpetuated by unwanted associative memories.
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