Starkman Bela G, Sakharkar Amul J, Pandey Subhash C
Department of Psychiatry and Department of Anatomy and Cell Biology, University of Illinois, Chicago, Illinois.
Alcohol Res. 2012;34(3):293-305.
Genetic and environmental factors play a role in the development of alcoholism. Whole-genome expression profiling has highlighted the importance of several genes that may contribute to alcohol abuse disorders. In addition, more recent findings have added yet another layer of complexity to the overall molecular mechanisms involved in a predisposition to alcoholism and addiction by demonstrating that processes related to genetic factors that do not manifest as DNA sequence changes (i.e., epigenetic processes) play a role. Both acute and chronic ethanol exposure can alter gene expression levels in specific neuronal circuits that govern the behavioral consequences related to tolerance and dependence. The unremitting cycle of alcohol consumption often includes satiation and self-medication with alcohol, followed by excruciating withdrawal symptoms and the resultant relapse, which reflects both the positive and negative affective states of alcohol addiction. Recent studies have indicated that behavioral changes induced by acute and chronic ethanol exposure may involve chromatin remodeling resulting from covalent histone modifications and DNA methylation in the neuronal circuits involving a brain region called the amygdala. These findings have helped identify enzymes involved in epigenetic mechanisms, such as the histone deacetylase, histone acetyltransferase, and DNA methyltransferase enzymes, as novel therapeutic targets for the development of future pharmacotherapies for the treatment of alcoholism.
遗传和环境因素在酒精中毒的发展过程中发挥作用。全基因组表达谱分析突出了几个可能导致酒精滥用障碍的基因的重要性。此外，最近的研究结果通过证明与未表现为DNA序列变化的遗传因素相关的过程（即表观遗传过程）发挥作用，为酒精中毒和成瘾易感性所涉及的整体分子机制增添了另一层复杂性。急性和慢性乙醇暴露均可改变特定神经回路中的基因表达水平，这些神经回路控制着与耐受性和依赖性相关的行为后果。饮酒的不间断循环通常包括饮酒带来的饱腹感和自我治疗，随后是极其痛苦的戒断症状以及由此导致的复发，这反映了酒精成瘾的正负情感状态。最近的研究表明，急性和慢性乙醇暴露引起的行为变化可能涉及染色质重塑，这是由涉及一个名为杏仁核的脑区的神经回路中的组蛋白共价修饰和DNA甲基化所导致的。这些发现有助于确定参与表观遗传机制的酶，如组蛋白脱乙酰酶、组蛋白乙酰转移酶和DNA甲基转移酶，作为未来开发治疗酒精中毒药物疗法的新型治疗靶点。
