Histone Methylation: a role in excessive ethanol intake and self-administration

组蛋白甲基化：在过量乙醇摄入和自我给药中的作用

• 批准号: 8391913
• 负责人: Jennifer Anne Rinker
• 金额: $ 4.92万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391913
• 关键词: Acetylation; Acute; Address; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Alleles; Amino Acids; Animals; Area; Attention; Behavior; Blood; Brain; Brain region; Chromatin; Chromatin Structure; Chronic; Cocaine; Consumption; Data; Dependence; Development; Disease; Drug Addiction; Enzymes; Epigenetic Process; Ethanol; Event; Excision; Expenditure; Exposure to; G9a histone methyltransferase; Gene Expression; Genes; Health; Healthcare; Heavy Drinking; Herpes Simplex Infections; Histone Acetylation; Histone H3; Histones; Hypermethylation; Infusion procedures; Intraperitoneal Injections; Lead; Link; Literature; Lysine; Maintenance; Mediating; Methylation; Modification; Molecular; Motivation; Mus; Mutant Strains Mice; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Nucleus Accumbens; Phosphorylation; Prevention strategy; Procedures; Property; Proteins; Psychological reinforcement; Publishing; Recording of previous events; Regulation; Reinforcement Schedule; Relative (related person); Reporting; Research; Rewards; Role; Self Administration; Self-Administered; Simplexvirus; Site; Testing; Time; Training; Viral Vector; Western Blotting; Withdrawal; Work; adeno-associated viral vector; alcohol effect; alcohol exposure; alcohol response; alcohol use initiation; binge drinking; chromatin modification; chromatin remodeling; cost; design; drinking; drinking behavior; drug maintenance; drug of abuse; histone modification; insight; interest; mRNA Expression; overexpression; protein expression; recombinase; reinforcer; research study; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): A growing body of literature has implicated aberrant changes in gene expression induced by drugs of abuse as possible mechanisms for long-term neuroplastic changes that likely contribute to the transition to dependence. Specifically, these changes in gene expression have been linked to the ability of drugs of abuse to induce posttranslation modifications to core histone proteins, thereby relaxing or compacting chromatin structure and increasing or decreasing gene expression, respectively. These posttranslational changes include: acetylation, phosphorylation, and methylation of histone amino acid residues. Examination of the epigenetic mechanisms of drug addiction has predominantly focused on the role of histone acetylation and phosphorylation, while histone methylation has received far less attention. Histone acetylation has been implicated in the regulation of acute responses to ethanol, development of tolerance, and withdrawal. A recent examination of the impact of cocaine on histone modifications demonstrated a role for ¿FosB, a transcription factor induced by a number of drugs of abuse, in suppressing the activity of histone methyltransferases, G9a and G9a-like protein (GLP), and consequently reducing methylation of histone H3 on lysine 9 (H3K9) in the nucleus accumbens (NAc). This effect resulted in reductions of dimethylated H3K9 (H3K9me2) and the activation of numerous genes involved in dendritic plasticity. Until recently, the impact of ethanol on histone methylation has received little attention, and no published reports have examined the impact of voluntary ethanol consumption on H3K9me2 in regions of the brain associated with the maintenance of drug taking behavior. Because ethanol, like cocaine, induces ¿FosB in discrete reward-related regions of the brain, it is reasonable to conceive that neuroplastic changes induced by excessive ethanol consumption might be mediated by changes in histone methylation. Therefore, the experiments outlined in this proposal are designed to test the hypothesis that ethanol consumption and the reinforcing effects of ethanol are mediated, in part, by the suppression of H3K9me2 in the NAc, and that the reinforcing effects and consumption of ethanol can be modulated by manipulating H3K9me2. We predict that ethanol consumption, in both binge-drinking and operant self- administration paradigms, will increase deltaFosB and decrease H3K9me2, G9a and GLP (Specific Aim 1). As well, we predict that regional overexpression of G9a and conditional suppression of G9a in the NAc will decrease and increase binge-like ethanol consumption, respectively (Specific Aim 2). Similarly, we predict that regional overexpression or suppression of G9a in the NAc will correspondingly alter the motivation to respond for ethanol reinforcers in an operant self-administration paradigm (Specific Aim 3). The predicted results would provide the first evidence that histone dimethylation is an epigenetic mechanism involved in binge-like ethanol consumption and operant self-administration of ethanol. Understanding these mechanisms may provide insight into more targeted treatments and prevention strategies for alcohol abuse and dependence disorders. PUBLIC HEALTH RELEVANCE: Binge-like and excessive alcohol consumption are major health concerns, as these types of behaviors can lead to a host of adverse health consequences, including the development of alcoholism, which costs billions of dollars in annual healthcare expenditures and other related costs. Repeated exposure to alcohol can cause neuroadaptive changes, i.e., epigenetic changes, in key circuitry in the brain, altering the neurobiological response to alcohol and possibly contributing to the transition to alcohol dependence. Results from the proposed research will help elucidate the mechanisms underlying alcohol-induced neuroplastic changes and provide insight into the development of more targeted treatment and prevention strategies.

描述（由申请人提供）：越来越多的文献表明，滥用药物引起的基因表达异常变化是可能导致向依赖性转变的长期神经塑性变化的可能机制。与滥用药物诱导核心组蛋白翻译后修饰的能力有关，从而分别松弛或压缩染色质结构以及增加或减少基因表达，这些翻译后变化包括：乙酰化，组蛋白氨基酸残基的磷酸化和甲基化对药物成瘾的表观遗传机制的研究主要集中在组蛋白乙酰化和磷酸化的作用上，而组蛋白乙酰化在急性反应的调节中受到的关注要少得多。最近一项关于可卡因对组蛋白修饰影响的研究证明了 ¿ FosB 是一种由多种滥用药物诱导的转录因子，可抑制组蛋白甲基转移酶、G9a 和 G9a 样蛋白 (GLP) 的活性，从而减少伏隔核中组蛋白 H3 赖氨酸 9 (H3K9) 的甲基化。 NAc) 导致二甲基化 H3K9 (H3K9me2) 减少并激活许多参与树突的基因。直到最近，乙醇对组蛋白甲基化的影响还很少受到关注，并且没有发表的报告研究了自愿摄入乙醇对与维持吸毒行为相关的大脑区域中的 H3K9me2 的影响。 , 诱发 ¿ FosB 在大脑中与奖赏相关的离散区域中，可以合理地认为过量乙醇消耗引起的神经塑性变化可能是由组蛋白甲基化的变化介导的。因此，本提案中概述的实验旨在检验乙醇消耗的假设。乙醇的增强作用部分是通过抑制 NAc 中的 H3K9me2 介导的，并且乙醇的增强作用和消耗可以通过操纵来调节我们预测，在酗酒和操作性自我给药模式中，乙醇消耗都会增加 deltaFosB 并减少 H3K9me2、G9a 和 GLP（具体目标 1）。此外，我们预测 G9a 的区域过度表达和条件性抑制。 NAc 中的 G9a 将分别减少和增加暴饮暴食型乙醇消耗（具体目标 2）。类似地，我们预测区域过度表达或。 NAc 中 G9a 的抑制将相应地改变操作性自我给药范式中对乙醇增强剂的反应动机（具体目标 3）。预测结果将提供第一个证据，证明组蛋白二甲基化是参与暴食样乙醇的表观遗传机制。了解这些机制可以帮助我们深入了解酒精滥用和依赖性障碍的更有针对性的治疗和预防策略。 公共卫生相关性：暴饮暴食和过量饮酒是主要的健康问题，因为这些类型的行为可能导致一系列不良健康后果，包括酗酒，每年造成数十亿美元的医疗支出和其他相关费用反复接触酒精会导致大脑关键回路的神经适应性变化，即表观遗传变化，改变对酒精的神经生物学反应，并可能导致向酒精依赖的转变。将有助于阐明酒精引起的神经塑性变化的机制，并为制定更有针对性的治疗和预防策略提供见解。