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

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

Author information

1
Departments of Neuroscience and Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA.
2
Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA; Neuroscience Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3
Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
4
Departments of Neuroscience and Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
5
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
6
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
7
Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA.
8
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
9
Departments of Neuroscience and Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA. Electronic address: cowanc@musc.edu.

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

PMID:
28957664
PMCID:
PMC5761688
DOI:
10.1016/j.neuron.2017.09.015
[Indexed for MEDLINE]
Free PMC Article

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