Castino M R, Baker-Andresen D, Ratnu V S, Shevchenko G, Morris K V, Bredy T W, Youngson N A, Clemens K J
School of Psychology, University of New South Wales, Sydney, Australia.
Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
Genes Brain Behav. 2018 Feb;17(2):98-106. doi: 10.1111/gbb.12421. Epub 2017 Sep 28.
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 6 days of extinction training, with each extinction session followed immediately by treatment with NaB or vehicle. On the last day of extinction, rats were killed and the medial ventral prefrontal cortex retained for chromatin immunoprecipitation and quantitative polymerase chain reaction (qPCR). A history of nicotine exposure significantly decreased H3K14 acetylation at the brain-derived neurotrophic factor (BDNF) exon IV promoter, and this effect was abolished with NaB treatment. In contrast, 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 cyclin-dependent kinase 5 (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 both the BDNF and Cdk-5 promoters, and that these changes may contribute to the enhanced extinction of nicotine-seeking by NaB.
成瘾药物会在直接参与学习和记忆过程的基因启动子区域引发广泛的表观遗传变化。我们之前已经表明，组蛋白脱乙酰酶抑制剂丁酸钠（NaB）能加速尼古丁寻求行为的消退，并提供抗复吸能力。在此，我们探究这种效应背后潜在的分子机制。大鼠接受静脉注射尼古丁或生理盐水自我给药，随后进行6天的消退训练，每次消退训练后立即用NaB或赋形剂进行处理。在消退训练的最后一天，处死大鼠并保留内侧腹侧前额叶皮质用于染色质免疫沉淀和定量聚合酶链反应（qPCR）。尼古丁暴露史显著降低了脑源性神经营养因子（BDNF）外显子IV启动子处的H3K14乙酰化，而NaB处理消除了这种效应。相比之下，仅尼古丁自我给药导致BDNF外显子IV和细胞周期蛋白依赖性激酶5（Cdk - 5）启动子区域H3K27me3和H3K9me2标记处的组蛋白甲基化显著降低。定量PCR确定了与NaB处理相关的几个基因的变化，这些变化与尼古丁暴露无关；然而，仅在BDNF IV和BDNF IX的表达中检测到尼古丁暴露史与NaB处理之间的相互作用。这些结果共同表明尼古丁自我给药会导致BDNF和Cdk - 5启动子处发生多种表观遗传变化，并且这些变化可能有助于NaB增强尼古丁寻求行为的消退。
