Histone arginine methylation in cocaine action in the nucleus accumbens.

TitleHistone arginine methylation in cocaine action in the nucleus accumbens.
Publication TypeJournal Article
Year of Publication2016
AuthorsDamez-Werno DM, Sun H, Scobie KN, Shao N, Rabkin J, Dias C, Calipari ES, Maze I, Pena CJ, Walker DM, Cahill ME, Chandra R, Gancarz A, Mouzon E, Landry JA, Cates H, Lobo M-K, Dietz D, C Allis D, Guccione E, Turecki G, Defilippi P, Neve RL, Hurd YL, Shen L, Nestler EJ
JournalProc Natl Acad Sci U S A
Volume113
Issue34
Pagination9623-8
Date Published2016 Aug 23
ISSN1091-6490
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.

DOI10.1073/pnas.1605045113
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID27506785
PubMed Central IDPMC5003250
Grant ListK99 DA042111 / DA / NIDA NIH HHS / United States
P01 DA008227 / DA / NIDA NIH HHS / United States
R01 DA014133 / DA / NIDA NIH HHS / United States