Morphine Epigenomically Regulates Behavior through Alterations in Histone H3 Lysine 9 Dimethylation in the Nucleus Accumbens

• DOI: 10.1523/jneurosci.1357-12.2012
• Publication Date: 2012-11-28T17:43:04Z
• Authors: HaoSheng Sun; Ian Maze; David M. Dietz; Kimberly N. Scobie; Pamela J. Kennedy; Diane Damez-Werno; Rachael L. Neve; Venetia Zachariou; Li Shen; Eric J. Nestler
• Keywords: Chromatin immunoprecipitation; Epigenomics; Brain stimulation reward

Dysregulation of histone modifying enzymes has been associated with numerous psychiatric disorders. Alterations in G9a (Ehmt2), a methyltransferase that catalyzes the euchromatic dimethylation H3 at lysine 9 (H3K9me2), implicated recently mediating neural and behavioral plasticity response to chronic cocaine administration. Here, we show morphine, like cocaine, decreases expression, global levels H3K9me2, mouse nucleus accumbens (NAc), key brain reward region. In contrast, other methyltransferases or demethylases, methylated marks, were not affected NAc by morphine. Through viral-mediated gene transfer conditional mutagenesis, found overexpression opposes morphine locomotor sensitization concomitantly promotes analgesic tolerance naloxone-precipitated withdrawal, whereas downregulation enhances delays development tolerance. We identified downstream targets providing comprehensive chromatin immunoprecipitation followed massively parallel sequencing analysis H3K9me2 distribution absence presence These data provide novel insight into epigenomic regulation suggest chromatin-based mechanisms through which morphine-induced addictive-like behaviors arise.