Identifying new targets for the treatment of alcohol dependence and relapse: epigenetic analysis of the abstinent brain

确定治疗酒精依赖和复发的新靶点：戒酒大脑的表观遗传学分析

• 批准号: 10052955
• 负责人: Rita P Cervera Juanes
• 金额: $ 69.19万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10052955
• 关键词: Abstinence; Advanced Development; Affect; Alcohol abuse; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholic beverage heavy drinker; Alcohols; Attention; Behavioral; Brain; Cause of Death; Chronic; DNA Methylation; Data; Development; Disease remission; Drug Metabolic Detoxication; Electrophysiology (science); Epigenetic Process; Ethanol; Exposure to; FDA approved; Female; Gene Expression; Gene Proteins; Gene Targeting; Genes; Glutamates; Goals; Heavy Drinking; Intoxication; Lead; Link; Macaca; Maps; Measures; Mediating; Modeling; Molecular; Mus; Nature; Nucleus Accumbens; Outpatients; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Population; Primates; Progressive Disease; Proteins; Publishing; Relapse; Reporting; Rodent; Rodent Model; Sampling; Self Administration; Sequence Analysis; Signal Transduction; Support Groups; Synaptic plasticity; Testing; Time; Tissues; Transcript; Translations; United States; Up-Regulation; Variant; alcohol abuse therapy; alcohol exposure; alcohol relapse; alcohol use disorder; bisulfite; brain tissue; chronic alcohol ingestion; dependence relapse; design; differential expression; drinking; drinking behavior; effective therapy; gamma-Aminobutyric Acid; genetic manipulation; genome-wide; male; negative emotional state; neural circuit; neuroadaptation; neurotransmission; new therapeutic target; novel; patch clamp; preference; prevent; preventable death; relapse risk; sex; success; synaptic function; tool; transcriptome sequencing; transcriptomics; transmission process

SUMMARY Alcohol use disorder (AUD) affects more than 12% of the US population and is the fourth leading preventable cause of death in the US. AUD is associated with compulsive drinking and emergence of a negative emotional state during abstinence, resulting in two-thirds of afflicted people relapsing within months of completing alcohol cessation treatment. Repeated cycles of intoxication and abstinence are linked to persistent alterations in the brain that remain long after detoxification, which drive relapse of drinking, often at levels higher than before abstinence. Identifying the molecular mechanisms that lead to hazardous alcohol use and contribute to the high rates of relapse is imperative for the effective design of better treatments to curb alcohol abuse. Our previous studies illustrate the power of integrating epigenetic, transcriptomic, circuitry, pharmacology and behavioral tools to elucidate the molecular underpinnings contributing to hazardous alcohol use. Those studies, using genome- wide DNA methylation (DNAm) analysis of the nucleus accumbens (NAc) to compare macaque alcohol-naive and alcohol-drinkers, identified differential DNAm (D-DNAm) signals, mapping to genes not previously linked to alcohol use, but with high relevance to synaptic plasticity modulation. Experimental manipulation of two of these DNAm-linked genes resulted in altered glutamate and GABA neurotransmission and changes in ethanol intake. The the next critical step is to understand how repeated abstinence/relapse cycles alters DNAm signals and how these changes contribute to adaptations in neurocircuitry. We hypothesize that some D-DNAm signals associated with chronic alcohol use may persist during abstinence, contributing to risk of relapse. In addition, de novo D-DNAm signals generated during repeated cycles of abstinence/relapse, may further heighten relapse risk. To identify abstinence-associated DNAm, we will use the highly translational macaque alcohol self- administration model and our proven genome-wide approach to identify D-DNAm in the NAc of macaques following > 12 months of chronic alcohol self-administration and then 3 cycles of forced abstinence (each cycle: 1 month abstinence and 3 months of open-access). After integrating gene and transcript variant expression and D-DNAm data generated from the same subjects and tissues, a subset of compelling, novel targets will be selected for functional study using pharmacological and genetic manipulation approaches in a mouse chronic intermittent ethanol (CIE) model. This rodent CIE model has been extensively used to model cycles of alcohol exposure and withdrawal leading to an escalation of drinking during relapse. In addition to recording ethanol intake, the effects of target manipulation on neurotransmission will be evaluated using patch-clamp electrophysiological analysis. Overall, these studies will aid in our understanding of the molecular mechanism(s) establishing risk for relapse. This information will be critical to advancing the development of effective therapies for alcohol abuse and to prevent relapse.

概括 酒精使用障碍（AUD）影响了美国人口的12％以上，是可以预防的第四次领先 美国死亡原因。 AUD与强迫性饮酒和负面情绪的出现有关 戒酒期间的状态，导致三分之二的患者在完成酒精后几个月内复发 停止处理。反复的中毒和禁欲的循环与持续的改变有关 排毒后很长时间保持饮酒复发的大脑通常比以前高 节制。识别导致危险饮酒的分子机制，并有助于高 有效设计更好的治疗方法来遏制酒精滥用是必须的。我们的先前 研究说明了整合表观遗传学，转录组，电路，药理学和行为工具的力量 阐明有助于危害酒精的分子基础。这些研究，使用基因组 伏隔核（NAC）的宽DNA甲基化（DNAM）分析比较了猕猴的酒精。 和酒精饮用器，鉴定出差异DNAM（DNAM）信号，映射到以前与之相关的基因 饮酒，但与突触可塑性调制相关。其中两个的实验操作 DNAM关联的基因导致谷氨酸和GABA神经传递的改变以及乙醇摄入的变化。 下一个关键步骤是了解重复的禁欲/复发周期如何改变DNAM信号以及如何改变 这些变化有助于神经循环的适应。我们假设一些D-DNAM信号 与慢性饮酒有关的戒酒可能会持续存在，导致复发风险。此外，de 在禁欲/复发的重复循环中产生的Novo D-DNAM信号，可能会进一步增强复发 风险。为了识别禁欲相关的DNAM，我们将使用高度翻译的猕猴自我 管理模型和我们久经考验的全基因组方法，以识别猕猴NAC中的D-DNAM 遵循> 12个月的慢性酒精自我给药，然后是3个强迫戒酒的循环（每个周期： 1个月的禁欲和3个月的开放式访问）。在整合基因和转录物变体表达和 D-DNAM数据是从同一受试者和组织产生的，一个引人注目的新目标将是 在小鼠慢性中使用药理学和遗传操纵方法选择进行功能研究 间歇性乙醇（CIE）模型。该啮齿动物CIE模型已广泛用于建模酒精周期 暴露和退出导致复发期间饮酒的升级。除了记录乙醇 摄入量，将使用贴片钳评估目标操纵对神经传递的影响 电生理分析。总体而言，这些研究将有助于我们理解分子机制 建立复发的风险。这些信息对于推进有效疗法的发展至关重要 酗酒并防止复发。