Project 2: Mechanisms underlying vulnerability to ethanol self-administration: behavioral and brain imaging studies in group-housed monkeys

项目 2：乙醇自我管理脆弱性的潜在机制：群养猴子的行为和大脑成像研究

• 批准号: 10526644
• 负责人: Paul W. Czoty
• 金额: $ 30.69万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-10 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10526644
• 关键词: Abstinence; Address; Alcohol consumption; Alcoholic beverage heavy drinker; Behavioral; Brain; Brain imaging; Brain region; Characteristics; Chronic; Cognitive; Consultations; Cues; Data; Discrimination; Environmental Risk Factor; Ethanol; Functional Magnetic Resonance Imaging; Funding; Future; Heavy Drinking; Home; Human; Image; Impulsivity; Intake; Knowledge; Light; Long-Term Effects; Macaca fascicularis; Magnetic Resonance Imaging; Measures; Mediating; Modeling; Monkeys; Neurobiology; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Population; Positioning Attribute; Prevention strategy; Preventive; Public Health; Punishment; Quinine; Recovery; Relapse; Research Design; Resistance; Rest; Rodent; Self Administration; Social Behavior; Social Dominance; Stimulus; Structure; Technology; Time; Translations; Vulnerable Populations; Work; alcohol research; alcohol use disorder; behavior test; clinically relevant; cognitive ability; cognitive function; cognitive testing; cost; discounting; drinking; effective intervention; efficacy evaluation; flexibility; forest; gray matter; human subject; imaging study; improved; male; neural; nonhuman primate; novel; pre-clinical; resilience; social; software development; touchscreen; translational approach; treatment strategy; white matter

PROJECT SUMMARY Alcohol use disorder (AUD) persists as a costly public health problem that lacks widely effective medications and preventive strategies. The overarching premise of this Project, like others in the WF-TARC, is that the neural substrates that contribute to vulnerability and resilience to AUD are not fully understood. Studies using nonhuman primates (NHP) have advantages that make them a critical part of a comprehensive, translational approach to addressing this topic. This project continues and extends work accomplished in the ongoing funding cycle. Aim 1 will extend our characterization of 12 group-housed male cynomolgus monkeys who have been drinking ethanol (EtOH) for >2 years. We will assess brain structure, function and connectivity using MRI. In addition, in the current funding cycle we implemented home cage cognitive testing using touchscreen hardware and software that we developed. We will assess two clinically relevant characteristics: behavioral flexibility (with a stimulus discrimination and reversal task) and impulsive choice (with a delay discounting task). We will also characterize resistance to punishment by assessing the ability of the bitter tastant quinine to decrease EtOH consumption. We hypothesize that these measures will differ between heavy and light drinkers. Next, EtOH access will be discontinued, modeling abstinence, and Aim 2 will assess these same measures over the following year. We expect to observe increases in cognitive function, resistance to punishment, grey matter volumes, white matter integrity and functional connectivity in all monkeys but that this “recovery” will be slower and less complete in monkeys that had higher EtOH intakes prior to discontinuation. During this EtOH-free period we will also assess reactivity to EtOH-paired cues in a model of relapse. Finally, access to EtOH will be reinstated and Aim 3 will examine the efficacy of putative pharmacotherapies whose potential is suggested by other WF- TARC projects. Drugs will be administered chronically when monkeys have access to EtOH 6 hrs/day (modeling moderate drinking) and, later, 22 hrs/day (modeling heavy drinking). We hypothesize that putative medications will be more efficacious in light vs. heavy drinkers. When these data are combined with findings from other WF- TARC projects, specific candidates will emerge with a strong preclinical profile to suggest their utility in treating AUD. These NHP studies occupy a critical position in the translational structure of the WF-TARC, supporting forward and backward translation to inform and extend findings in rodent and human projects. Taken together, the results of the studies in this Project, particularly in combination with data generated in other components of the WF-TARC, will provide a comprehensive account of brain differences between populations that are resistant versus vulnerable to AUD. This knowledge will ultimately help practitioners direct preventive efforts to groups who will most benefit from them and will identify new targets for more effective medications that can be targeted to the most vulnerable populations.

项目概要 酒精使用障碍（AUD）仍然是一个代价高昂的公共卫生问题，缺乏广泛有效的药物和 与 WF-TARC 中的其他项目一样，该项目的首要前提是神经系统。 使用的研究尚未完全了解导致 AUD 脆弱性和恢复力的因素。 非人类灵长类动物（NHP）的优势使它们成为全面、转化的关键部分 该项目将继续并扩展现有资金中已完成的工作。 目标 1 将扩展我们对 12 只群养雄性食蟹猴的特征描述。 饮用乙醇 (EtOH) 超过 2 年我们将使用 MRI 评估大脑结构、功能和连接性。 此外，在当前的融资周期中，我们使用触摸屏硬件实施了家庭笼认知测试 我们将评估两个临床相关特征：行为灵活性（与 刺激歧视和逆转任务）和冲动选择（带有延迟贴现任务）。 通过评估苦味奎宁减少乙醇的能力来表征对惩罚的抵抗力 我们认为这些措施在重度饮酒者和轻度饮酒者之间会有所不同。 将停止访问，模拟禁欲，目标 2 将评估这些相同的措施 我们预计明年会观察到认知功能、对惩罚的抵抗力、灰质的增加。 所有猴子的体积、白质完整性和功能连接性，但这种“恢复”会更慢 在停药前摄入较高乙醇的猴子中，该结果不太完整。 我们还将评估复发模型中对乙醇配对线索的反应性，最后，将恢复对乙醇的使用。 目标 3 将检验假定的药物疗法的功效，其潜力已被其他 WF- TARC 项目。当猴子每天 6 小时接触乙醇时，将长期给药（建模） 适度饮酒），后来是每天 22 小时（模拟大量饮酒）。 当这些数据与其他 WF- 的研究结果相结合时，对轻度饮酒者和重度饮酒者会更有效。 TARC 项目中，特定候选药物将具有强大的临床前特征，以表明其在治疗方面的效用 AUD。这些 NHP 研究在 WF-TARC 的转化结构中占据关键地位，支持 向前和向后翻译以告知和扩展啮齿动物和人类项目的发现， 该项目的研究结果，特别是与其他组成部分生成的数据相结合 WF-TARC，将提供耐药人群之间大脑差异的全面说明 这些知识最终将帮助临床医生针对群体开展预防工作。 谁将从中受益最多，并将确定可针对的更有效药物的新目标 最弱势群体。