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

Herbert E. Covington, Ian Maze, HaoSheng Sun, Howard M. Bomze, Kristine D. DeMaio, Emma Y. Wu, David M. Dietz, Mary Kay Lobo, Subroto Ghose, Ezekiel Mouzon, Rachael L. Neve, Carol A. Tamminga, Eric J. Nestler

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)656-670
Number of pages15
JournalNeuron
Volume71
Issue number4
DOIs
StatePublished - Aug 25 2011

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Cocaine
Histones
Methylation
Nucleus Accumbens
Brain-Derived Neurotrophic Factor
Reward
Lysine
Substance-Related Disorders
Depression
Brain
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Covington, H. E., Maze, I., Sun, H., Bomze, H. M., DeMaio, K. D., Wu, E. Y., ... Nestler, E. J. (2011). A role for repressive histone methylation in cocaine-induced vulnerability to stress. Neuron, 71(4), 656-670. https://doi.org/10.1016/j.neuron.2011.06.007

A role for repressive histone methylation in cocaine-induced vulnerability to stress. / Covington, Herbert E.; Maze, Ian; Sun, HaoSheng; Bomze, Howard M.; DeMaio, Kristine D.; Wu, Emma Y.; Dietz, David M.; Lobo, Mary Kay; Ghose, Subroto; Mouzon, Ezekiel; Neve, Rachael L.; Tamminga, Carol A.; Nestler, Eric J.

In: Neuron, Vol. 71, No. 4, 25.08.2011, p. 656-670.

Research output: Contribution to journalArticle

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 2011, 'A role for repressive histone methylation in cocaine-induced vulnerability to stress', Neuron, vol. 71, no. 4, pp. 656-670. https://doi.org/10.1016/j.neuron.2011.06.007
Covington HE, Maze I, Sun H, Bomze HM, DeMaio KD, Wu EY et al. A role for repressive histone methylation in cocaine-induced vulnerability to stress. Neuron. 2011 Aug 25;71(4):656-670. https://doi.org/10.1016/j.neuron.2011.06.007
Covington, Herbert E. ; Maze, Ian ; Sun, HaoSheng ; Bomze, Howard M. ; DeMaio, Kristine D. ; Wu, Emma Y. ; Dietz, David M. ; Lobo, Mary Kay ; Ghose, Subroto ; Mouzon, Ezekiel ; Neve, Rachael L. ; Tamminga, Carol A. ; Nestler, Eric J. / A role for repressive histone methylation in cocaine-induced vulnerability to stress. In: Neuron. 2011 ; Vol. 71, No. 4. pp. 656-670.
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