Neuron
Volume 96, Issue 1, 27 September 2017, Pages 130-144.e6
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Article
HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors

https://doi.org/10.1016/j.neuron.2017.09.015Get rights and content
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Highlights

  • Nuclear HDAC5 in the NAc attenuates relapse-like drug-seeking behaviors

  • ChIP-seq revealed numerous HDAC5-associated target genes including Npas4

  • NPAS4 in NAc is induced in subset of FOS+ neurons during cocaine-context learning

  • HDAC5 and NPAS4 in NAc are involved in cocaine-conditioned behaviors

Summary

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.

Keywords

cocaine addiction
histone deacetylase
NPAS4
reinstatement
drug self-administration
conditioned place preference
nucleus accumbens
chromatin immunoprecipitation
ChIP-seq
HDAC5

Cited by (0)

8

Present address: Center of Neuroscience, Institute for Scientific Research and High Technology Services of Panama (INDICASAT AIP), Panamá, Republic of Panamá

9

Present address: Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan

10

Present address: Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA

11

Present address: Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, TX 77807, USA

12

These authors contributed equally

13

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