title: BRG1 in the Nucleus Accumbens Regulates Cocaine-Seeking Behavior.
abstract: Drug addiction is defined as a chronic disease characterized by compulsive drug seeking and episodes of relapse despite prolonged periods of drug abstinence. Neurobiological adaptations, including transcriptional and epigenetic alterations in the nucleus accumbens, are thought to contribute to this life-long disease state. We previously demonstrated that the transcription factor SMAD3 is increased after 7 days of withdrawal from cocaine self-administration. However, it is still unknown which additional factors participate in the process of chromatin remodeling and facilitate the binding of SMAD3 to promoter regions of target genes. Here, we examined the possible interaction of BRG1-also known as SMARCA4, an adenosine triphosphatase-containing chromatin remodeler-and SMAD3 in response to cocaine exposure.
  
  
  
  The expression of BRG1, as well as its binding to SMAD3 and target gene promoter regions, was evaluated in the nucleus accumbens and dorsal striatum of rats using western blotting, co-immunoprecipitation, and chromatin immunoprecipitation following abstinence from cocaine self-administration. Rats were assessed for cocaine-seeking behaviors after either intra-accumbal injections of the BRG1 inhibitor PFI3 or viral-mediated overexpression of BRG1.
  
  
  
  After withdrawal from cocaine self-administration, BRG1 expression and complex formation with SMAD3 are increased in the nucleus accumbens, resulting in increased binding of BRG1 to the promoter regions of Ctnnb1, Mef2d, and Dbn1. Intra-accumbal infusion of PFI3 attenuated, whereas viral overexpression of Brg1 enhanced, cocaine-reinstatement behavior.
  
  
  
  BRG1 is a key mediator of the SMAD3-dependent regulation of cellular and behavioral plasticity that mediates cocaine seeking after a period of withdrawal.
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York; Research Institute on Addictions, Program in Neuroscience, Department of Psychology, State University of New York at Buffalo, Buffalo, New York.
authors.forename: Zi-Jun
authors.initials: ZJ
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York; Research Institute on Addictions, Program in Neuroscience, Department of Psychology, State University of New York at Buffalo, Buffalo, New York.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Martin
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York; Research Institute on Addictions, Program in Neuroscience, Department of Psychology, State University of New York at Buffalo, Buffalo, New York.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Mueller
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York; Research Institute on Addictions, Program in Neuroscience, Department of Psychology, State University of New York at Buffalo, Buffalo, New York.
authors.forename: Aaron
authors.initials: A
authors.lastname: Caccamise
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York; Research Institute on Addictions, Program in Neuroscience, Department of Psychology, State University of New York at Buffalo, Buffalo, New York.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Werner
authors.affiliation: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York; Research Institute on Addictions, Program in Neuroscience, Department of Psychology, State University of New York at Buffalo, Buffalo, New York.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Gancarz
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York.
authors.forename: Jun-Xu
authors.initials: JX
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York; Research Institute on Addictions, Program in Neuroscience, Department of Psychology, State University of New York at Buffalo, Buffalo, New York; Department of Psychology, California State University Bakersfield, Bakersfield, California. Electronic address: ddietz@buffalo.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Dietz
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000008:administration & dosage; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000235:genetics / Q000503:physiopathology*; D003463:Cues; D004265:DNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D058999:Drug-Seeking Behavior / Q000502:physiology*; D008297:Male; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D051900:Smad3 Protein / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D053961:Azabicyclo Compounds; D009687:Nuclear Proteins; C000603674:PF-06687252; D011725:Pyridines; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D014157:Transcription Factors; C578929:Smarca4 protein, rat; D004265:DNA Helicases; D003042:Cocaine
keywords: BRG1; Chromatin remodeling; Cocaine; Cue-induced reinstatement; SMAD3; Self-administration