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

Nature Neuroscience volume 16, pages 434–440 (2013)Cite this article

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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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Figure 1: HDAC1 in NAc regulates locomotor responses to cocaine.
Figure 2: Chronic MS-275 infusion into NAc blocks locomotor responses to cocaine and alters repressive histone methylation.
Figure 3: HDAC binding to KMT gene promoters after repeated cocaine.
Figure 4: Chronic MS-275 infusion prevents cocaine-induced changes in GABAA receptor subunit expression and GABAergic tone in NAc.

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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).

Author information

Author notes

  1. A J Robison

    Present address: Present address: Department of Physiology, Michigan State University, East Lansing, Michigan, USA.,

  2. Jian Feng and A J Robison: These authors contributed equally to this work.

Authors and Affiliations

  1. Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Pamela J Kennedy, Jian Feng, A J Robison, Ana Badimon, Ezekiell Mouzon, Diane M Damez-Werno & Eric J Nestler

  2. Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York, USA

    Ian Maze

  3. Department of Pharmacology and Systems Therapeutics, Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, USA

    Dipesh Chaudhury & Ming-Hu Han

  4. Department of Neurology, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Stephen J Haggarty

  5. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Rhonda Bassel-Duby & Eric N Olson

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Contributions

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.

Corresponding author

Correspondence to Eric J Nestler.

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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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