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

Nat Neurosci. 2013 Apr;16(4):434-40. doi: 10.1038/nn.3354. Epub 2013 Mar 10.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Cocaine / antagonists & inhibitors
  • Cocaine / pharmacology*
  • Histone Deacetylase 1 / antagonists & inhibitors*
  • Histone Deacetylase 1 / metabolism*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histones / antagonists & inhibitors
  • Histones / metabolism
  • Male
  • Methylation / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Neuronal Plasticity / drug effects*
  • Neuronal Plasticity / physiology*
  • Pyridines / pharmacology
  • Random Allocation

Substances

  • Benzamides
  • Histone Deacetylase Inhibitors
  • Histones
  • Pyridines
  • entinostat
  • Hdac1 protein, mouse
  • Histone Deacetylase 1
  • Cocaine