Histone Arginine Methylation in Cocaine Action in the Nucleus Accumbens

Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9623-8. doi: 10.1073/pnas.1605045113. Epub 2016 Aug 9.

Abstract

Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms-such as histone acetylation and methylation on Lys residues-have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motivation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction.

Keywords: ChIP-seq; Src; drug addiction; histone arginine (R) methylation; medium spiny neurons.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Animals
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cocaine / administration & dosage*
  • Cocaine-Related Disorders / genetics
  • Cocaine-Related Disorders / metabolism*
  • Cocaine-Related Disorders / pathology
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Male
  • Methylation
  • Mice
  • Mice, Inbred C57BL
  • Neurons / metabolism
  • Neurons / pathology
  • Nucleus Accumbens / metabolism*
  • Nucleus Accumbens / pathology
  • Protein Processing, Post-Translational*
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D1 / genetics
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism

Substances

  • Carrier Proteins
  • Histones
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • p140cap protein, mouse
  • PRMT6 protein, mouse
  • Protein-Arginine N-Methyltransferases
  • Cocaine