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Biol Psychiatry. 2017 Apr 1;81(7):564-572. doi: 10.1016/j.biopsych.2016.10.024. Epub 2016 Oct 28.

A Role for Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α in Nucleus Accumbens Neuron Subtypes in Cocaine Action.

Author information

1
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland.
2
Division of Renal Diseases and Hypertension, The George Washington University, Washington, District of Columbia.
3
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland. Electronic address: mklobo@som.umaryland.edu.

Abstract

BACKGROUND:

Molecules critically involved in cocaine behavioral plasticity are known to regulate and interact with peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). In addition, the PGC-1α promoter has binding sites for early growth response 3 (Egr3), which plays a dynamic role in cocaine action in nucleus accumbens (NAc) medium spiny neuron (MSN) subtypes, those enriched in dopamine receptor D1 (D1-MSN) versus D2 (D2-MSN). However, the role of PGC-1α in NAc in cocaine action is unknown.

METHODS:

PGC-1α messenger RNA and protein were examined in NAc after repeated cocaine exposure. Binding of Egr3 to and histone methylation at the PGC-1α promoter was examined in NAc using chromatin immunoprecipitation after repeated cocaine. PGC-1α ribosome-associated messenger RNA in MSN subtypes was assessed after repeated cocaine using D1-Cre-RiboTag and D2-Cre-RiboTag lines. Finally, PGC-1α was expressed in NAc D1-MSNs versus D2-MSNs using a Cre-inducible adeno-associated virus and Cre lines during cocaine conditioned place preference and cocaine-induced locomotion.

RESULTS:

Repeated cocaine increased PGC-1α levels and increased Egr3 binding and H3K4me3 at the PGC-1α promoter in NAc. Increased PGC-1α occurred in D1-MSNs, while D2-MSNs showed reduced levels. Viral-mediated expression of PGC-1α in D1-MSNs enhanced behavioral responses to cocaine, while expression in D2-MSNs blunted these behaviors.

CONCLUSIONS:

We demonstrate a novel role for PGC-1α in NAc in cocaine action. PGC-1α is enhanced in NAc D1-MSNs, specifically after cocaine exposure. These data are consistent with increased active methylation and Egr3 binding at the PGC-1α promoter. Finally, we demonstrate a bidirectional role for PGC-1α in mediating behavioral plasticity to cocaine through D1-MSNs versus D2-MSNs.

KEYWORDS:

Cocaine; Epigenetics; MSN subtype; Nucleus accumbens; PGC-1α; RiboTag

PMID:
27939396
PMCID:
PMC5346327
DOI:
10.1016/j.biopsych.2016.10.024
[Indexed for MEDLINE]
Free PMC Article

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