title: Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation.
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.
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Kennedy
authors.forename: Jian
authors.initials: J
authors.lastname: Feng
authors.forename: A J
authors.initials: AJ
authors.lastname: Robison
authors.forename: Ian
authors.initials: I
authors.lastname: Maze
authors.forename: Ana
authors.initials: A
authors.lastname: Badimon
authors.forename: Ezekiell
authors.initials: E
authors.lastname: Mouzon
authors.forename: Dipesh
authors.initials: D
authors.lastname: Chaudhury
authors.forename: Diane M
authors.initials: DM
authors.lastname: Damez-Werno
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.forename: Ming-Hu
authors.initials: MH
authors.lastname: Han
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D003042:Cocaine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D011897:Random Allocation
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011725:Pyridines; C118739:entinostat; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D003042:Cocaine