title: HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner.
abstract: Nonspecific histone deacetylase (HDAC) inhibition has been shown to facilitate the extinction of drug-seeking behavior in a manner resistant to reinstatement. A key open question is which specific HDAC is involved in the extinction of drug-seeking behavior. Using the selective HDAC3 inhibitor RGFP966, we investigated the role of HDAC3 in extinction and found that systemic treatment with RGFP966 facilitates extinction in mice in a manner resistant to reinstatement. We also investigated whether the facilitated extinction is related to the enhancement of extinction consolidation during extinction learning or to negative effects on performance or reconsolidation. These are key distinctions with regard to any compound being used to modulate extinction, because a more rapid decrease in a defined behavior is interpreted as facilitated extinction. Using an innovative combination of behavioral paradigms, we found that a single treatment of RGFP966 enhances extinction of a previously established cocaine-conditioned place preference, while simultaneously enhancing long-term object-location memory within subjects. During extinction consolidation, HDAC3 inhibition promotes a distinct pattern of histone acetylation linked to gene expression within the infralimbic cortex, hippocampus, and nucleus accumbens. Thus, the facilitated extinction of drug-seeking cannot be explained by adverse effects on performance. These results demonstrate that HDAC3 inhibition enhances the memory processes involved in extinction of drug-seeking behavior.
authors.affiliation: Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California, Irvine, CA 92697, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Malvaez
authors.forename: Susan C
authors.initials: SC
authors.lastname: McQuown
authors.forename: George A
authors.initials: GA
authors.lastname: Rogge
authors.forename: Mariam
authors.initials: M
authors.lastname: Astarabadi
authors.forename: Vincent
authors.initials: V
authors.lastname: Jacques
authors.forename: Samantha
authors.initials: S
authors.lastname: Carreiro
authors.forename: James R
authors.initials: JR
authors.lastname: Rusche
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Wood
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000178:Acrylamides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D047369:Chromatin Immunoprecipitation; D003042:Cocaine; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005108:Extinction, Psychological / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D056572:Histone Deacetylase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010655:Phenylenediamines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D013997:Time Factors; D000099186:Histone Deacetylase 3
chemical_list: D000178:Acrylamides; D003042:Cocaine; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D010655:Phenylenediamines; D000099186:Histone Deacetylase 3; C000603861:RGFP966