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

项目摘要 酒精使用障碍（AUD）仍然是一个昂贵的公共卫生问题，缺乏广泛有效的药物， 预防战略。这个项目的首要前提，就像WF-TARC中的其他项目一样，是神经系统 导致对澳元的脆弱性和弹性的基质尚未完全了解。研究使用 非人灵长类动物（NHP）具有优势，使它们成为全面的，翻译的关键部分。 解决这个问题的方法。该项目继续并扩展了正在进行的资助中完成的工作。 周期目的1将扩展我们对12只分组饲养的雄性食蟹猴的表征， 饮用乙醇（EtOH）超过2年。我们将使用MRI评估大脑结构，功能和连通性。在 此外，在当前的资金周期中，我们使用触摸屏硬件实施了家庭笼式认知测试 和我们开发的软件。我们将评估两个临床相关特征：行为灵活性（ 刺激辨别和反转任务）和冲动选择（延迟折扣任务）。我们还将 通过评估苦味剂奎宁降低EtOH的能力来表征对惩罚的抵抗力 消费我们假设，这些措施将在重度和轻度饮酒者之间有所不同。接下来，EtOH 访问将被中断，模拟禁欲，目标2将评估这些相同的措施， 次年我们希望观察到认知功能的增强，对惩罚的抵抗力， 体积，白色物质的完整性和功能连接，但这种“恢复”将是缓慢的 而在停药前乙醇摄入量较高的猴子中则不太完整。在此无EtOH期间 我们还将评估复发模型中对EtOH配对线索的反应性。最后，将恢复对乙醇的使用 和目标3将检查推定的药物治疗的疗效，其潜力是由其他WF- TARC项目。当猴每天6小时接触EtOH时，将长期给予药物（建模 中度饮酒）和之后的22小时/天（模拟重度饮酒）。我们假设假定的药物 对轻度饮酒者比重度饮酒者更有效当这些数据与其他WF的发现相结合时， 在TARC项目中，特定候选物将以强有力的临床前特征出现，以表明其在治疗 澳元。这些NHP研究在WF-TARC的翻译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。综合起来看， 本项目的研究结果，特别是与其他组成部分产生的数据相结合， WF-TARC将提供一个全面的说明， 相对于澳元的弱势。这一知识最终将帮助从业人员将预防工作导向群体 他们将从中受益最多，并将为更有效的药物确定新的目标， 最脆弱的人群。

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.