HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors

Neuron. 2017 Sep 27;96(1):130-144.e6. doi: 10.1016/j.neuron.2017.09.015.

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.

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Cocaine / pharmacology*
  • Conditioning, Operant / drug effects*
  • Conditioning, Operant / physiology*
  • Conditioning, Psychological / physiology
  • Dose-Response Relationship, Drug
  • Drug-Seeking Behavior / physiology
  • Extinction, Psychological
  • Fear / physiology
  • Fear / psychology
  • Gene Expression Regulation / physiology
  • Histone Deacetylases / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / physiology*
  • Primary Cell Culture
  • Rats
  • Reinforcement, Psychology
  • Self Administration

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Npas4 protein, rat
  • Hdac5 protein, rat
  • Histone Deacetylases
  • Cocaine