Neuron
Volume 71, Issue 4, 25 August 2011, Pages 656-670
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Article
A Role for Repressive Histone Methylation in Cocaine-Induced Vulnerability to Stress

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Summary

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.

Highlights

► Cocaine exposure enhances vulnerability to chronic social stress ► Histone H3 dimethylation in nucleus accumbens links cocaine to stress vulnerability ► G9a overexpression in NAc after repeated cocaine protects mice from social stress ► Resilience to stress via repression of BDNF-TrkB-CREB signaling

Cited by (0)

5

These authors contributed equally to this work

6

Present address: Department of Psychology and Neuroscience, Duke University, Box 90086, 417 Chapel Drive, Durham, NC 27708-0086, USA

7

Present address: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA