Epigenetic Mechanisms of Positive Affective State of Alcoholism

多巴胺对滥用药物的奖赏和增强特性很重要，腹侧 被盖区(VTA)是延伸的杏仁核结构的多巴胺来源，包括 伏隔核、前额叶皮质、杏仁核和海马体。酒精引起的脑组织结构改变 延伸杏仁核神经元的生理学可能是酒精渴求和酒精寻求的基础 与酗酒有关。慢性酒精暴露可降低多巴胺神经元的敏感性 在酒精戒断时，VTA对γ-氨基丁酸(GABA)的抑制作用。我们的初步数据 组蛋白脱乙酰酶(HDAC)可以逆转这种对GABA反应的减少。 抑制剂；这一发现表明酒精诱导的VTA神经元的变化是由表观遗传学维持的 可以通过药物操控的机制。护理计划的研究组成部分项目1 乙醇戒断对大鼠VTA神经元GABA-A功能的影响 电生理和分子生物学方法研究组蛋白乙酰化在脑缺血中的作用 酒精戒断时的GABA-A功能减退。该项目的目标是：1)确定是否 在戒断过程中观察到的GABA低敏感性是由于HDAC活性增加和 GABA-A受体亚单位表达，2)鉴定GABA-A亚单位表达，HDAC活性， 和组蛋白乙酰化在戒酒过程中发生改变，以及3)识别新的基因 用RNA测序和染色质调节酒精戒断过程中GABA的敏感性 免疫沉淀和DNA测序(ChlP-seq)与表观遗传核心合作。最终， 这些研究是理解酒精诱导的中枢神经系统神经元适应所必需的 与上瘾有关，并与本中心的其他组成部分一起，将提供大量信息 关于维持酒精诱导的脑变化的表观遗传学机制。

Dopamine is important for the rewarding and reinforcing properties of drugs of abuse, and the ventral tegmental area (VTA) is the source of dopamine to structures in the extended amygdala, including the nucleus accumbens, prefrontal cortex, amygdala and hippocampus. Alcohol-induced alterations of the physiology of neurons of the extended amygdala may underlie the alcohol craving and alcohol seeking associated with alcoholism. Chronic ethanol exposure induces a decrease in sensitivity of dopamine neurons of the VTA to inhibition by gamma aminobutyric acid (GABA) during alcohol withdrawal. Our preliminary data show that this reduction in response to GABA is reversed by treatment with histone deacetylase (HDAC) Inhibitors; this finding indicates that the alcohol-induced change in VTA neurons is maintained by epigenetic mechanisms that can be pharmacologically manipulated. Research Component Project 1 of the CARE plans to examine reduction in GABA-A function in VTA neurons from rats during ethanol withdrawal using electrophysio-^logical and molecular biological methods and to characterize the role of histone acetylation in GABA-A hypofunction during alcohol withdrawal. The goals of this project are: 1) To determine whether GABA hyposensitivity observed during withdrawal is due to increased HDAC activity and reductions in GABA-A receptor subunit expression, 2) To identify whether GABA-A subunit expression, HDAC activity, and histone acetylation are altered during withdrawal from chronic alcohol, and 3) To identify new genes that regulate GABA sensitivity during ethanol withdrawal using RNA sequencing (RNA-seq) and chromatin immunoprecipitation and DNA sequencing (ChlP-seq) in collaboration with the Epigenetic Core. Ultimately, these studies are needed to understand ethanol-induced adaptation of central nervous system neurons involved in addiction, and, with the other components of this Center, will provide a great deal of information on epigenetic mechanisms involved in maintaining alcohol-induced brain changes.