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 - PubMed (original) (raw)

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

Heath D Schmidt et al. J Neurochem. 2012 Jan.

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.

© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1

Figure 1. BDNF protein levels are increased in the VTA following 7 days of forced cocaine abstinence

(A) Coronal section at the level of the VTA. The black triangle represents the region of the midbrain dissected for these studies. (B) VTA BDNF protein was significantly increased in cocaine-experienced animals when compared to yoked saline controls (unpaired t-test, p<0.05). n=4 rats/treatment

Figure 2

Figure 2. BDNF exon I-containing transcripts are increased specifically in the VTA following 7 days of forced cocaine abstinence

BDNF exon I, II, IV and VI transcripts were assessed in the VTA of cocaine self-administration rats and yoked saline controls. The asterisk represents a significant increase in BDNF exon I-containing transcript in cocaine-experienced rats as compared to yoked saline control animals (p<0.01, Bonferroni post hoc test). n=3–6 rats/treatment

Figure 3

Figure 3. Cocaine self-administration results in increased CBP binding and H3 acetylation at BDNF exon I promoters in the VTA

(A) 7 days of forced cocaine abstinence was associated with a significant increase in CBP association with BDNF exon I, but not exon IV, -containing or GAPDH promoters in the VTA (p<0.05, Bonferroni post hoc test). (B) Cocaine self-administration also results in a significant increase in AcH3 association with BDNF exon I-containing promoters in the VTA (p<0.05, Bonferroni post hoc test). n=3–4 rats/treatment.

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