title: A Role for Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α in Nucleus Accumbens Neuron Subtypes in Cocaine Action.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Chandra
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Michel
authors.initials: M
authors.lastname: Engeln
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: T Chase
authors.initials: TC
authors.lastname: Francis
authors.affiliation: Division of Renal Diseases and Hypertension, The George Washington University, Washington, District of Columbia.
authors.forename: Prasad
authors.initials: P
authors.lastname: Konkalmatt
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Dipal
authors.initials: D
authors.lastname: Patel
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland. Electronic address: mklobo@som.umaryland.edu.
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Lobo
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D051776:Early Growth Response Protein 3 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism
chemical_list: C497369:Egr3 protein, mouse; D006657:Histones; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D051776:Early Growth Response Protein 3; D003042:Cocaine
keywords: Cocaine; Epigenetics; MSN subtype; Nucleus accumbens; PGC-1α; RiboTag