A role for repressive histone methylation in cocaine-induced vulnerability to stress.

Published

Journal Article

Substance abuse increases an individual's vulnerability to stress-related illnesses, which is presumably mediated by drug-induced neural adaptations that alter subsequent responses to stress. Here, we identify repressive histone methylation in nucleus accumbens (NAc), an important brain reward region, as a key mechanism linking cocaine exposure to increased stress vulnerability. Repeated cocaine administration prior to subchronic social defeat stress potentiated depressive-like behaviors in mice through decreased levels of histone H3 lysine 9 dimethylation in NAc. Cre-mediated reduction of the histone methyltransferase, G9a, in NAc promoted increased susceptibility to social stress, similar to that observed with repeated cocaine. Conversely, G9a overexpression in NAc after repeated cocaine protected mice from the consequences of subsequent stress. This resilience was mediated, in part, through repression of BDNF-TrkB-CREB signaling, which was induced after repeated cocaine or stress. Identifying such common regulatory mechanisms may aid in the development of new therapies for addiction and depression.

Full Text

Cited Authors

  • Covington, HE; Maze, I; Sun, H; Bomze, HM; DeMaio, KD; Wu, EY; Dietz, DM; Lobo, MK; Ghose, S; Mouzon, E; Neve, RL; Tamminga, CA; Nestler, EJ

Published Date

  • August 2011

Published In

Volume / Issue

  • 71 / 4

Start / End Page

  • 656 - 670

PubMed ID

  • 21867882

Pubmed Central ID

  • 21867882

Electronic International Standard Serial Number (EISSN)

  • 1097-4199

International Standard Serial Number (ISSN)

  • 0896-6273

Digital Object Identifier (DOI)

  • 10.1016/j.neuron.2011.06.007

Language

  • eng