Molecular and cellular mechanisms of novel targets in alcohol reward

概述 基因表达的持续变化可能介导酒精的许多效应，包括奖赏学习、耐受和依赖，这表明有效改变酒精诱导的基因表达的药物可以被认为是治疗药物。通过抑制调节染色质结构的酶靶向基因表达的药物（表观遗传药物）已广泛用于癌症研究，最近成为神经退行性疾病和药物成瘾的潜在治疗药物。本研究的主要目的是：1）通过检测表观遗传药物对酒精消耗和条件性位置偏爱（CPP）的影响来确定影响酒精奖赏的表观遗传药物; 2）研究所选表观遗传药物对奖赏通路中包括腹侧被盖区（VTA）和延髓核（NA）的基因表达和细胞生理的影响。总的假设是，一些表观遗传药物将通过改变奖励途径中的基因表达和细胞生理学来降低酒精的奖励特性。电生理学和基因表达数据的整合将阐明药物的作用机制，并确定药物开发的新靶点。这项研究将为表观遗传药物治疗酒精成瘾的治疗潜力提供初步的机制证据。

OVERVIEW Persistent changes in gene expression may mediate many effects of alcohol including reward learning, tolerance and dependence, suggesting that agents effective in changing alcohol-induced gene expression could be considered as therapeutic agents. Drugs targeting gene expression through inhibition of enzymes that regulate chromatin structure (epigenetic drugs) have been widely used in cancer research and recently emerged as potential therapeutics for neurodegenerative disorders and drug addiction. The main goals of this project are: 1) to identify epigenetic drugs that affect alcohol reward through testing their effects on alcohol consumption and conditioned place preference (CPP) and 2) to investigate the effects of selected epigenetic drugs on gene expression and cellular physiology in the reward pathway including the ventral tegmental area (VTA) and the nucleus accumbens (NA). The overall hypothesis is that some epigenetic drugs will reduce the rewarding properties of alcohol through changes in gene expression and cellular physiology in the reward pathway. Integration of electrophysiological and gene expression data will elucidate the drug's mechanisms of action and identify novel targets for drug development. This research will provide initial mechanistic evidence for the therapeutic potential of epigenetic drugs in treating alcohol addiction.