title: Increased brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area during cocaine abstinence is associated with increased histone acetylation at BDNF exon I-containing promoters.
abstract: Recent evidence suggests that the persistence of cocaine seeking during periods of protracted drug abstinence following chronic cocaine exposure is mediated, in part, by neuroadaptations in the mesolimbic dopamine system. Specifically, incubation of cocaine-seeking behavior coincides with increased brain-derived neurotrophic factor (BDNF) protein expression in the ventral tegmental area (VTA). However, the molecular mechanisms that regulate time-dependent changes in VTA BDNF protein expression during cocaine abstinence are unclear. The goal of these experiments was to determine whether VTA BDNF transcript levels are altered following cocaine abstinence and identify the molecular mechanisms regulating cocaine-induced changes in VTA BDNF transcription. Rats were allowed to self-administer cocaine (0.25 mg/infusion, i.v.) for 14 days on a fixed-ratio schedule of reinforcement followed by 7 days of forced drug abstinence. BDNF protein and exon I-containing transcripts were significantly increased in the VTA of cocaine-experienced rats following 7 days of forced drug abstinence compared to yoked saline controls. Cocaine-induced changes in BDNF mRNA were associated with increased acetylation of histone 3 and binding of CREB-binding protein to exon I-containing promoters in the VTA. Taken together, these results suggest that drug abstinence following cocaine self-administration remodels chromatin in the VTA resulting in increased expression of BDNF, which may contribute to neuroadaptations underlying cocaine craving and relapse.
authors: Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania School, Philadelphia, Pennsylvania, USA.
authors: Heath D
authors: HD
authors: Schmidt
authors: Gavin R
authors: GR
authors: Sangrey
authors: Shayna B
authors: SB
authors: Darnell
authors: Rachel L
authors: RL
authors: Schassburger
authors: Jang-Ho J
authors: JH
authors: Cha
authors: R Christopher
authors: RC
authors: Pierce
authors: Ghazaleh
authors: G
authors: Sadri-Vakili
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000779:Anesthetics, Local / Q000008:administration & dosage*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders; D003216:Conditioning, Operant / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D006657:Histones / Q000378:metabolism*; D008297:Male; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule; D012646:Self Administration; D018709:Statistics, Nonparametric; D013375:Substance Withdrawal Syndrome / Q000378:metabolism; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000779:Anesthetics, Local; D019208:Brain-Derived Neurotrophic Factor; D006657:Histones; D012333:RNA, Messenger; D050882:CREB-Binding Protein; D003042:Cocaine