HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 7; pp. 2647 - 2652
• Main Authors: Malvaez, Melissa, McQuown, Susan C., Rogge, George A., Astarabadi, Mariam, Jacques, Vincent, Carreiro, Samantha, Rusche, James R., Wood, Marcelo A.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences 12.02.2013; National Acad Sciences
• Series: From the Cover
• Subjects: Acetylation; Acetylation - drug effects; Acrylamides - blood; Acrylamides - pharmacokinetics; Acrylamides - pharmacology; adverse effects; Analysis of Variance; Animal behavior; Animal memory; Animals; Behavioral neuroscience; Biological and medical sciences; Biological Sciences; Chromatin Immunoprecipitation; Cocaine; cortex; Drug seeking behavior; Drug-Seeking Behavior - drug effects; Extinction; Extinction, Psychological - drug effects; Fluorescent Antibody Technique; Fundamental and applied biological sciences. Psychology; Gene expression; hippocampus; histone deacetylase; Histone Deacetylase Inhibitors - blood; Histone Deacetylase Inhibitors - pharmacokinetics; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Histones; Histones - metabolism; Learning; Male; Medical sciences; Memory; Memory interference; Mice; Mice, Inbred C57BL; Neuropharmacology; Pharmacology. Drug treatments; Phenylenediamines - blood; Phenylenediamines - pharmacokinetics; Phenylenediamines - pharmacology; Protease inhibitors; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Real-Time Polymerase Chain Reaction; Rodents; T tests; Time Factors; Vehicles; Vertebrates: nervous system and sense organs; Chromatin; CNS stimulant; Psychotropic; Memory; Drug of abuse; Cocaine; Behavior; Long term; long-term memory; epigenetics
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1213364110

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.