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

BACKGROUND: Molecules critically involved in cocaine behavioral plasticity are known to regulate and interact with peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha). In addition, the PGC-1a 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 D-2 (D2-MSN). However, the role of PGC-1 alpha in NAc in cocaine action is unknown. METHODS: PGC-1 alpha messenger RNA and protein were examined in NAc after repeated cocaine exposure. Binding of Egr3 to and histone methylation at the PGC-1 alpha promoter was examined in NAc using chromatin immunopre-cipitation after repeated cocaine. PGC-1 alpha ribosome-associated messenger RNA in MSN subtypes was assessed after repeated cocaine using D1-Cre-RiboTag and D2-Cre-RiboTag lines. Finally, PGC-1 alpha 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-1 alpha levels and increased Egr3 binding and H3K4me3 at the PGC-1 alpha promoter in NAc. Increased PGC-1 alpha occurred in D1-MSNs, while D2-MSNs showed reduced levels. Viral-mediated expression of PGC-1 alpha in D1-MSNs enhanced behavioral responses to cocaine, while expression in D2-MSNs blunted these behaviors. CONCLUSIONS: We demonstrate a novel role for PGC-1 alpha in NAc in cocaine action. PGC-1 alpha is enhanced in NAc D1-MSNs, specifically after cocaine exposure. These data are consistent with increased active methylation and Egr3 binding at the PGC-1 alpha promoter. Finally, we demonstrate a bidirectional role for PGC-1 alpha in mediating behavioral plasticity to cocaine through D1-MSNs versus D2-MSNs.