Class i HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation

Pamela J. Kennedy, Jian Feng, A. J. Robison, Ian Maze, Ana Badimon, Ezekiell Mouzon, Dipesh Chaudhury, Diane M. Damez-Werno, Stephen J. Haggarty, Ming Hu Han, Rhonda Bassel-Duby, Eric N. Olson, Eric J. Nestler

Research output: Contribution to journalArticle

103 Scopus citations

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 GABA A 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.

Original languageEnglish (US)
Pages (from-to)434-440
Number of pages7
JournalNature neuroscience
Volume16
Issue number4
DOIs
StatePublished - Apr 1 2013

ASJC Scopus subject areas

  • Neuroscience(all)

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    Kennedy, P. J., Feng, J., Robison, A. J., Maze, I., Badimon, A., Mouzon, E., Chaudhury, D., Damez-Werno, D. M., Haggarty, S. J., Han, M. H., Bassel-Duby, R., Olson, E. N., & Nestler, E. J. (2013). Class i HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation. Nature neuroscience, 16(4), 434-440. https://doi.org/10.1038/nn.3354