PT  - JOURNAL ARTICLE
AU  - Ethan M. Anderson
AU  - Erin B. Larson
AU  - Daniel Guzman
AU  - Anne Marie Wissman
AU  - Rachael L. Neve
AU  - Eric J. Nestler
AU  - David W. Self
TI  - Overexpression of the histone dimethyltransferase G9a in nucleus accumbens shell increases cocaine self-administration, stress-induced reinstatement, and anxiety
AID  - 10.1523/JNEUROSCI.1657-17.2017
DP  - 2017 Dec 07
TA  - The Journal of Neuroscience
PG  - 1657-17
4099  - http://www.jneurosci.org/content/early/2017/12/07/JNEUROSCI.1657-17.2017.short
4100  - http://www.jneurosci.org/content/early/2017/12/07/JNEUROSCI.1657-17.2017.full
AB  - Repeated exposure to cocaine induces lasting epigenetic changes in neurons that promote the development and persistence of addiction. One epigenetic alteration involves reductions in levels of the histone dimethyltransferase, G9a, in nucleus accumbens (NAc) after chronic cocaine administration. This reduction in G9a may enhance cocaine reward since overexpressing G9a in the NAc decreases cocaine-conditioned place preference. Thus, we hypothesized that HSV-mediated G9a overexpression in the NAc shell (NAcSh) would attenuate cocaine self-administration and cocaine-seeking behavior. Instead, we found that G9a overexpression, and the resulting increase in H3K9 histone dimethylation, increases sensitivity to cocaine reinforcement and enhances motivation for cocaine in self-administering male rats. Moreover, when G9a overexpression is limited to the initial 15 days of cocaine self-administration training, it produces an enduring post-expression enhancement in cocaine self-administration, and prolonged (over 5 weeks) increases in reinstatement of cocaine seeking induced by footshock stress, but in the absence of continued global elevations in H3K9 dimethylation. The increase in stress-induced reinstatement is paralleled by heightened anxiety measures, suggesting that countering the cocaine-induced decreases in endogenous G9a with ectopic G9a overexpression leads to lasting anxiogenic effects. Finally, we found an enduring reduction in phosphorylated CREB levels in the NAcSh that could account for the increased anxiety. These data demonstrate a novel role for G9a in promoting co-morbid cocaine addiction and anxiety, and suggest that increased epigenetic repression of transcription through H3K9 during cocaine use can have long-lasting and unexpected negative consequences on behavior.Significance Statement:Cocaine addiction is a neuropsychiatric disorder that is detrimental to society and currently has no effective treatments. The difficulty in treating drug addiction is compounded by the high co-morbidity with other psychiatric illness including anxiety disorders. Here we demonstrate that G9a, an epigenetic repressor of gene expression, acting in the nucleus accumbens---a brain reward region, is capable of increasing both addiction- and anxiety-like behaviors in rats. These findings are intriguing because repeated cocaine exposure decreases G9a in this region and thereby enhances expression of certain addiction-promoting genes. However, our results suggest that countering this cocaine-induced decrease in G9a activity actually exacerbates addiction and sensitivity to relapse under stressful situations.