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

Makoto Taniguchi, Maria B. Carreira, Yonatan A. Cooper, Ana Clara Bobadilla, Jasper A. Heinsbroek, Nobuya Koike, Erin B. Larson, Evan A. Balmuth, Brandon W. Hughes, Rachel D. Penrod, Jaswinder Kumar, Laura N. Smith, Daniel Guzman, Joseph S. Takahashi, Tae Kyung Kim, Peter W. Kalivas, David W. Self, Yingxi Lin, Christopher W. Cowan

Research output: Contribution to journalArticlepeer-review

74 Scopus citations


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. Taniguchi and colleagues find that the epigenetic enzyme, histone deacetylase 5 (HDAC5), reduces relapse-like behaviors in a model of cocaine addiction and that HDAC5 and its target gene, Npas4, are important in the nucleus accumbens for reward-related learning processes.

Original languageEnglish (US)
Pages (from-to)130-144.e6
Issue number1
StatePublished - Sep 27 2017

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.


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


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