Glucocorticoid Receptor Dysregulation: a Genetic Risk Factor for Excessive Alcohol Consumption in High Drinking in the Dark (HDID-1) Mice

糖皮质激素受体失调：黑暗中大量饮酒 (HDID-1) 小鼠过量饮酒的遗传风险因素

• 批准号: 9759165
• 负责人: Antonia Savarese
• 金额: $ 6.12万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-16 至 2021-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759165
• 关键词: Agonist; Air; Alcohol abuse; Alcohol consumption; Alcohols; Animals; Area; Automobile Driving; Basic Science; Behavioral Genetics; Bilateral; Biological; Blood; Brain; Breeding; Cannulas; Cannulations; Chronic; Data; Dependence; Development; Dexamethasone; Dose; Ethanol; Exhibits; Exposure to; FK506 binding protein 5; Failure; Fellowship; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Glucocorticoid Receptor; Goals; Health; Heavy Drinking; Hour; Implant; Infusion procedures; Intoxication; Literature; Measures; Messenger RNA; Mifepristone; Modeling; Molecular; Mus; Neurobiology; Nucleus Accumbens; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Prevention; Proteins; Rattus; Relapse; Research Training; Resistance; Rewards; Risk; Risk Factors; Role; Saline; Severities; Signal Transduction; Societies; Stress; Study models; System; Therapeutic Effect; Tissue-Specific Gene Expression; Training; Withdrawal; Work; alcohol abuse therapy; alcohol exposure; alcohol response; alcohol use disorder; base; behavioral pharmacology; binge drinking; drinking; experimental study; genetic risk factor; glucocorticoid receptor alpha; glucocorticoid-induced orphan receptor; high risk; high risk drinking; insight; new therapeutic target; pressure; prevent; receptor expression; receptor sensitivity; response; tacrolimus binding protein 4; transcriptomics; vapor

Project Summary Binge drinking has significant negative consequences for health and society, and is a major predictor for the development of an alcohol use disorder (AUD). The High Drinking in the Dark (HDID-1) line of mice, selectively bred for high blood ethanol concentrations (BECs) in a limited access binge-like drinking task, exhibit differential gene expression of a number of glucocorticoid receptor (GR) regulator proteins relative to their low- drinking founder line, HS/Npt. GR expression has been shown to be altered in response to chronic alcohol exposure and to promote further alcohol intake in dependence-like models, but GR dysregulation has not yet been identified as a genetic risk factor for excessive alcohol consumption in non-dependent animals. Preliminary data show that HDID-1 mice exhibit a dose-dependent reduction in binge drinking when given mifepristone, a GR antagonist, after only being exposed to a single 2-hour ethanol drinking session. These data suggest that selection for high BECs in the HDID-1 line has led to a sensitized GR system that may promote binge drinking. The goal of this fellowship project is to investigate the role of enhanced GR activity as a genetic risk factor for excessive alcohol consumption. Aim 1 will characterize GR expression and transcriptional activity in the brains of the high-drinking HDID-1 mice relative to the low-drinking founder line, HS/Npt. Specifically, GR and GR-related signaling genes in the nucleus accumbens (NAc) will be quantified, as GR expression in the NAc has previously been shown to promote alcohol intake. Aim 2 will determine whether pharmacological manipulation of GR in the NAc can bi-directionally modulate binge drinking. Bilateral cannulation will be performed in the NAc of (1) HDID-1 mice to deliver a GR antagonist and attempt to reduce binge drinking, and of (2) HS/Npt mice to deliver a GR agonist and attempt to increase binge drinking. The results of this aim will determine whether GR manipulation in the NAc is sufficient to alter binge drinking. Aim 3 will investigate whether GR antagonism in HDID-1 mice is sufficient to prevent escalated drinking after chronic intermittent ethanol (CIE) vapor exposure, a model of relapse-like drinking. The results of this aim will determine whether the same mechanisms driving binge drinking in HDID-1 mice also underlie relapse-like drinking. Aim 1 utilizes a basic science approach to examine molecular pathways that may have been altered through selection pressure, while Aims 2 and 3 will provide translational insight into potential pharmacological treatments for patients with AUD. Together, the experiments in this project will provide a better understanding of how GR activity in the brain contributes to excessive alcohol consumption in both non-dependent and dependent-like models of drinking.

项目摘要 酗酒对健康和社会有重大的负面影响，是 出现酒精使用障碍(AUD)。有选择地在黑暗中高饮酒(HDID-1)系小鼠 在有限准入狂欢类饮酒任务中培育出高血液酒精浓度(BEC)，展示 几种糖皮质激素受体(GR)调节蛋白的基因表达差异 饮酒方正系列，HS/NPT。已有研究表明，长期饮酒会改变GR的表达 在类似依赖的模型中，暴露并促进进一步的酒精摄入，但GR失调还没有 被确定为非依赖动物过度饮酒的遗传风险因素。 初步数据显示，HDID-1小鼠在服用HDID-1后表现出剂量依赖性的酗酒减少 米非司酮，一种GR拮抗剂，只接触了一次2小时的酒精饮用期。这些 数据表明，在HDID-1系列中选择高BEC导致了敏化GR系统，这可能 提倡酗酒。该奖学金项目的目标是调查增强的GR活动在以下方面的作用 过量饮酒的遗传风险因素。目标1将描述GR的表达和 高饮酒的HDID-1小鼠大脑中的转录活性相对于低饮酒的创始人系， HS/NPT.具体地说，伏核(NAC)中的GR和GR相关信号基因将被量化， 此前已有研究表明，NAC中GR的表达可促进酒精摄取。目标2将决定 NAC内GR的药理操作是否能双向调节酗酒。双边 将在(1)HDID-1小鼠的NAC中进行插管，以输送GR拮抗剂并尝试减少 狂饮，以及(2)HS/NPT小鼠递送GR激动剂并试图增加酗酒。这个 这一目标的结果将决定NAC中的GR操作是否足以改变酗酒。目标3 将调查HDID-1小鼠体内的GR拮抗作用是否足以防止慢性饮酒升级 间歇性乙醇(CIE)蒸气暴露，一种复发性饮酒模型。这一目标的结果将是 确定驱动HDID-1小鼠酗酒的相同机制是否也是复发的基础 喝酒。目标1利用一种基础科学方法来检查可能已经改变的分子途径 通过选择压力，而目标2和3将提供对潜在药理学的翻译洞察 AUD患者的治疗。总之，这个项目中的实验将提供一个更好的理解 大脑中的GR活动如何导致非依赖型和非依赖型的过度饮酒 依赖式的饮酒模式。