Title | HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Taniguchi M, Carreira MB, Cooper YA, Bobadilla A-C, Heinsbroek JA, Koike N, Larson EB, Balmuth EA, Hughes BW, Penrod RD, Kumar J, Smith LN, Guzman D, Takahashi JS, Kim T-K, Kalivas PW, Self DW, Lin Y, Cowan CW |
Journal | Neuron |
Volume | 96 |
Issue | 1 |
Pagination | 130-144.e6 |
Date Published | 2017 Sep 27 |
ISSN | 1097-4199 |
Keywords | Animals, Basic Helix-Loop-Helix Transcription Factors, Cocaine, Conditioning, Operant, Conditioning, Psychological, Dose-Response Relationship, Drug, Drug-Seeking Behavior, Extinction, Psychological, Fear, Gene Expression Regulation, Histone Deacetylases, Male, Mice, Mice, Knockout, Mice, Transgenic, Nucleus Accumbens, Primary Cell Culture, Rats, Reinforcement, Psychology, Self Administration |
Abstract | Individuals suffering from substance-use disorders develop strong associations between the drug's rewarding effects and environmental cues, creating powerful, enduring triggers for relapse. We found that dephosphorylated, nuclear histone deacetylase 5 (HDAC5) in the nucleus accumbens (NAc) reduced cocaine reward-context associations and relapse-like behaviors in a cocaine self-administration model. We also discovered that HDAC5 associates with an activity-sensitive enhancer of the Npas4 gene and negatively regulates NPAS4 expression. Exposure to cocaine and the test chamber induced rapid and transient NPAS4 expression in a small subpopulation of FOS-positive neurons in the NAc. Conditional deletion of Npas4 in the NAc significantly reduced cocaine conditioned place preference and delayed learning of the drug-reinforced action during cocaine self-administration, without affecting cue-induced reinstatement of drug seeking. These data suggest that HDAC5 and NPAS4 in the NAc are critically involved in reward-relevant learning and memory processes and that nuclear HDAC5 limits reinstatement of drug seeking independent of NPAS4. |
DOI | 10.1016/j.neuron.2017.09.015 |
Alternate Journal | Neuron |
PubMed ID | 28957664 |
PubMed Central ID | PMC5761688 |
Grant List | T32 DA007288 / DA / NIDA NIH HHS / United States F31 DA035073 / DA / NIDA NIH HHS / United States R01 NS085418 / NS / NINDS NIH HHS / United States R01 DA032708 / DA / NIDA NIH HHS / United States P01 DA008227 / DA / NIDA NIH HHS / United States R01 DA003906 / DA / NIDA NIH HHS / United States R01 MH091220 / MH / NIMH NIH HHS / United States F32 DA036319 / DA / NIDA NIH HHS / United States R01 DA010460 / DA / NIDA NIH HHS / United States R29 DA010460 / DA / NIDA NIH HHS / United States R01 DA027664 / DA / NIDA NIH HHS / United States R37 DA003906 / DA / NIDA NIH HHS / United States |
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