Abstract
Induction of histone acetylation in the nucleus accumbens (NAc), a key brain reward region, promotes cocaine-induced alterations in gene expression. Histone deacetylases (HDACs) tightly regulate the acetylation of histone tails, but little is known about the functional specificity of different HDAC isoforms in the development and maintenance of cocaine-induced plasticity, and previous studies of HDAC inhibitors report conflicting effects on cocaine-elicited behavioral adaptations. Here we demonstrate that specific and prolonged blockade of HDAC1 in NAc of mice increased global levels of histone acetylation, but also induced repressive histone methylation and antagonized cocaine-induced changes in behavior, an effect mediated in part through a chromatin-mediated suppression of GABAA receptor subunit expression and inhibitory tone on NAc neurons. Our findings suggest a new mechanism by which prolonged and selective HDAC inhibition can alter behavioral and molecular adaptations to cocaine and inform the development of therapeutics for cocaine addiction.
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Acknowledgements
The authors would like to thank R. Neve (Massachusetts Institute of Technology) for viral vectors and M. Baxter for statistical expertise. This work was supported by grants from the US National Institute on Drug Abuse and National Institute of Mental Health (E.J.N.) and the Canadian Institutes for Health Research (P.J.K.; MFE 90086).
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P.J.K., I.M. and E.J.N. designed research; P.J.K., J.F., A.J.R., A.B., D.C. and D.M.D.-W. performed research; P.J.K., A.J.R., D.C. and A.B. analyzed data; R.B.-D. and E.N.O. contributed mutant mice; S.J.H. provided reagents; E.M. generated viral vectors; M.-H.H. contributed to data interpretation; P.J.K. and E.J.N. wrote the paper.
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Kennedy, P., Feng, J., Robison, A. et al. Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation. Nat Neurosci 16, 434–440 (2013). https://doi.org/10.1038/nn.3354
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DOI: https://doi.org/10.1038/nn.3354
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