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Project 1's objective is to characterize the important role of repressive histone methylation in nucleus accumbens (NAc) and prefrontal cortex (PFC) in mediating stimulant and opiate addiction. We have demonstrated downregulation of dimethylation of Lys 9 of histone H3 (H3K9me2) in NAc and PFC after stimulant or opiate exposure, effects mediated via the repression of G9a, a histone methyltransferase which catalyzes this epigenetic mark. We have also demonstrated that such adaptations, which occur with investigator- or self-administered drug, increase behavioral responses to both drugs of abuse. We are now focusing on a small number of target genes–which encode synaptic proteins–for H3K9me2 and related chromatin modifications and characterizing their involvement in addiction-related phenomena. Working with Project 4, we are validating key findings from animal models in NAc and PFC of addicted humans, thus establishing relevance to human addiction.

(Right) Summary of chromatin modifications reported in drug abuse models, as revised by Walker and Nestler, Handb Clin Neurol, 2018.