| First Author | Chandra R | Year | 2017 |
| Journal | Biol Psychiatry | Volume | 81 |
| Issue | 7 | Pages | 564-572 |
| PubMed ID | 27939396 | Mgi Jnum | J:249905 |
| Mgi Id | MGI:6099929 | Doi | 10.1016/j.biopsych.2016.10.024 |
| Citation | Chandra R, et al. (2017) A Role for Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1alpha in Nucleus Accumbens Neuron Subtypes in Cocaine Action. Biol Psychiatry 81(7):564-572 |
| abstractText | BACKGROUND: Molecules critically involved in cocaine behavioral plasticity are known to regulate and interact with peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). In addition, the PGC-1alpha 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-1alpha in NAc in cocaine action is unknown. METHODS: PGC-1alpha messenger RNA and protein were examined in NAc after repeated cocaine exposure. Binding of Egr3 to and histone methylation at the PGC-1alpha promoter was examined in NAc using chromatin immunoprecipitation after repeated cocaine. PGC-1alpha ribosome-associated messenger RNA in MSN subtypes was assessed after repeated cocaine using D1-Cre-RiboTag and D2-Cre-RiboTag lines. Finally, PGC-1alpha 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-1alpha levels and increased Egr3 binding and H3K4me3 at the PGC-1alpha promoter in NAc. Increased PGC-1alpha occurred in D1-MSNs, while D2-MSNs showed reduced levels. Viral-mediated expression of PGC-1alpha in D1-MSNs enhanced behavioral responses to cocaine, while expression in D2-MSNs blunted these behaviors. CONCLUSIONS: We demonstrate a novel role for PGC-1alpha in NAc in cocaine action. PGC-1alpha is enhanced in NAc D1-MSNs, specifically after cocaine exposure. These data are consistent with increased active methylation and Egr3 binding at the PGC-1alpha promoter. Finally, we demonstrate a bidirectional role for PGC-1alpha in mediating behavioral plasticity to cocaine through D1-MSNs versus D2-MSNs. |
