Persistent histone modifications at the BDNF and Cdk‐5 promoters following extinction of nicotine‐seeking in rats

Abstract

Drugs of addiction lead to a wide range of epigenetic changes at the promoter regions of genes directly implicated in learning and memory processes. We have previously shown that the histone deactylase inhibitor, sodium butyrate (NaB), accelerates the extinction of nicotine-seeking and provides resistance to relapse. Here we explore the potential molecular mechanisms underlying this effect. Rats received intravenous nicotine or saline self-administration, followed by six days of extinction training, with each extinction session followed immediately by treatment with NaB or vehicle. On the last day of extinction, rats were sacrificed and the medial ventral prefrontal cortex retained for ChIP and qPCR. A history of nicotine exposure signficantly decreased H3K14 acetylation at the BDNF exon IV promoter, and this effect was abolished with NaB treatment. In contrats, nicotine self-administration alone, resulted in a significant decrease in histone methylation at the H3K27me3 and H3K9me2 marks in the promoter regions of BDNF exon IV and Cdk-5. Quantitative PCR identified changes in several genes associated with NaB treatment that were independent of nicotine exposure, however an interaction of nicotine history and NaB treatment was detected only in the expression of BDNF IV and BDNF IX. Together these results suggest that nicotine self-administration leads to a number of epigenetic changes at the BDNF promoter, and that these changes may contribute to the enhanced extinction of nicotine-seeking by NaB.

A natural antisense to brain-derived neurotrophic factor impairs extinction of drug seeking

“…To examine the persistence of elevated asBdnf-IV across extinction we assessed changes in gene expression following six days of extinction training compared to those that occur simply as a consequence of prior nicotine exposure (abstinence). This is the same time point at which we have previously observed decreases in H3K27 trimethylation and H3K9 dimethylation at the BDNF exon IV promoter (12). Rats underwent 12 days of selfadministration followed by 6 days of extinction training (Fig.…”

“…We have previously shown that following 6 days of extinction from nicotine selfadministration, H3K27me 3 is decreased in the promoter region of Bdnf-IV (12), leading to the hypothesis that the Exon IV antisense transcript induces a permissive chromatin state in the rat IL (Fig. 7).…”

“…gene has 9 exons, including exon IX that is common to all splice variants and contains the protein coding region of the gene (purple section). Here we described a novel antisense transcript opposite exon 4 of the Bdnf gene that is associated with a reduction in the repressive H3K27me 3 (12) and increase in Bdnf-IV mRNA transcription. A second antisense transcript opposite exon 9 of the Bdnf gene (asBdnf-IX) has been previously reported (14) and exerts a repressive influence over Bdnf-IX gene expression through increased histone H3K27me 3 .…”

“…Recent work in our laboratory has shown that, within the IL, extinction of nicotine self-administration is associated with epigenetic modifications in the promoter region of Bdnf exon IV, an activity-dependent Bdnf splice variant that is increased following exposure to drugs of abuse (11). These changes include decreases in the repressive epigenetic marks H3K27me 3 and H3K9me 2 , thereby promoting a permissive chromatin state (12). Importantly, despite these changes, Bdnf-IV mRNA expression was unchanged, suggesting that nicotine self-administration epigenetically primes Bdnf-IV expression, and that this priming persists across extinction in the absence of detectable changes in gene expression.…”

Multidimensional Intersection of Nicotine, Gene Expression, and Behavior

“…An elegant study in mice demonstrated that nicotine increases expression of the Ash2l/Mef2c complex during cortical development, which subsequently leads to changes in histone methylation in the promoter region of glutamatergic synaptic genes and representative changes in dendritic spine number and branching (Jung et al, 2016 ). In rats, chronic nicotine exposure has also been associated with a decrease in methylation of several genes in the medial prefrontal cortex, orbitofrontal cortex, and NAcc (Mychasiuk et al, 2013 ; Castino et al, 2018 ). In the prefrontal cortex, nicotine self-administration was correlated with decreased histone methylation at the H3K27me3 and H3K9me2 marks in the BDNF and cyclin-dependent kinase 5 gene, but in contrast, withdrawal from nicotine elicited a decrease in H3K14 acetylation at the BDNF promoter (Castino et al, 2018 ), demonstrating different changes across stages of drug use.…”