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

J. Neurochem. (2012) 120, 202–209. 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. Cocaine‐induced effects at specific BDNF promoters are mediated by distinct epigenetic mechanisms. The molecular mechanisms that regulate time‐dependent changes in VTA BDNF protein expression during drug abstinence are not clear. Here, we show for the first time that VTA BDNF mRNA, specifically exon I‐containing transcript, is increased following 7 days of drug abstinence and that distinct epigenetic mechanisms regulate BDNF gene transcription. These results indicate that targeting specific epigenetic mechanisms that regulate VTA BDNF expression during drug abstinence may prevent cocaine craving and relapse.