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

项目总结 酒精使用障碍(AUD)仍然是一个代价高昂的公共健康问题，缺乏广泛有效的药物和 预防策略。这个项目的首要前提，就像WF-TARC中的其他项目一样，是神经 对澳元的脆弱性和复原力的底物还没有完全了解。研究使用 非人灵长类(NHP)具有优势，使它们成为一个全面的、可翻译的 解决这一主题的方法。该项目继续并延伸了正在进行的资助中完成的工作。 周而复始。目标1将扩展我们对12只群养雄性食蟹猴的特征，这些猴子已经 饮酒(乙醇)2年。我们将使用MRI评估大脑的结构、功能和连接性。在……里面 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式认知测试 以及我们开发的软件。我们将评估两个与临床相关的特征：行为灵活性(与 刺激辨别和反转任务)和冲动选择(带有延迟折扣任务)。我们还将 通过评估苦味奎宁降低乙醇的能力来表征对惩罚的抵抗力 消费。我们假设，这些措施在酗酒和不饮酒的人之间会有所不同。接下来，Etoh 访问将被停止，模拟禁欲，目标2将评估这些相同的措施 第二年。我们希望观察到认知功能、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”将会更慢 而在停药前乙醇摄入量较高的猴子中，则不太完整。在这段没有乙醇的时期 我们还将在复发模型中评估对乙醇配对线索的反应性。最后，将恢复对Etoh的访问 和目标3将检查假定的药物疗法的疗效，其潜力被其他WF- TARC项目。当猴子每天接触乙醇6小时(建模)时，将长期给药 适量饮酒)，然后，每天22小时(模拟重度饮酒)。我们假设推定的药物 对少量饮酒者比重度饮酒者更有效。当这些数据与其他WF的发现结合在一起时- TARC项目，特定的候选者将出现强有力的临床前档案，以表明他们在治疗中的有效性 澳元。这些NHP研究在WF-TARC的翻译结构中占据了关键地位，支持 向前和向后翻译，以通知和扩展啮齿动物和人类项目的研究结果。加在一起， 本项目的研究结果，特别是与本项目其他组成部分产生的数据相结合 WF-TARC将全面解释抗性种群之间的大脑差异 与易受澳元影响的情况相比。这一知识最终将帮助从业者将预防工作引导到群体中 谁将从这些药物中受益最多，并将确定新的靶点，以获得更有效的靶向药物 给最脆弱的人群。

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.