Cognitive Consequences of EtOH Consumption in Group-Housed Nonhuman Primates

项目总结 在美国，大约有1440万成年人被诊断为酒精使用障碍(AUD)。的确有 对影响AUD发展的因素及其特定的长期影响的认识不全面 酒精对大脑的影响以及使有问题的使用永久化的行为。此外，只有7.9%的AUD患者 在接受药物辅助治疗的同时，仍然需要新的药物疗法。 有证据表明，社会压力会增加人们对澳元的脆弱性。证据还表明，认知能力 长期饮酒造成的缺陷导致前额叶皮质的结构和功能缺陷 (PFC)，导致PFC介导的行为缺陷，可在戒断期间或通过 脑乙酰胆碱受体的调节。这项多学科研究使用了成熟的、高度 翻译非人灵长类动物(NHP)模型，将研究(1)社会与 压力/成瘾、长期饮酒和执行功能，(2)靶向药物的能力 脑乙酰胆碱受体逆转酒精诱导的认知障碍和(3)酒精的修复- 在禁欲期间诱发的认知缺陷。群居卫生保健计划形成了社会等级制度，创造了 社会经历的连续体，从环境的丰富(在高排名的“优势”猴子中)到慢性的 社会压力(在地位较低的“下属”猴子中)。在拟议的实验中，群居卫生保健计划将 每天喝几个小时以上的乙醇。这项研究采用了纵向设计，既考虑了内部-也考虑了- 在无酒精、无酒精消费和无酒精状态下临床相关终点的受试者间评估。这个 所采用的认知任务是一种刺激-辨别和反转任务，将以行为灵活性为特征。 已经临床评估或FDA批准用于其他适应症的胆碱能药物的能力 将确定补救慢性乙醇引起的缺陷的方法，这有望为 药物开发的努力。完成后，这项研究将提供对AUD漏洞的重要洞察 对个人饮酒轨迹的影响，长期饮酒对行为的影响以及如何 胆碱能药物可能成为AUD患者的新型药物治疗药物。

PROJECT SUMMARY In the United States, approximately 14.4 million adults are diagnosed with alcohol use disorder (AUD). There is an incomplete understanding of factors influencing the development of AUD, and of the specific long-term effects of alcohol on the brain and behavior that perpetuate problematic use. Moreover, with only 7.9% of AUD patients receiving medication-assisted treatment, there remains a substantial need for novel pharmacotherapies. Evidence suggests that social stress can confer vulnerability to AUD. Evidence also suggests that cognitive deficits caused by long-term alcohol consumption causes structural and functional deficits to the prefrontal cortex (PFC), resulting in deficits in PFC-mediated behavior which may be remediated during abstinence or through modulation of brain acetylcholine receptors. This multi-disciplinary study using well-established, highly translational nonhuman primate (NHP) models, will investigate (1) the relationship between social stress/enrichment, long-term alcohol consumption and executive function, (2) the capability of drugs that target brain acetylcholine receptors to reverse alcohol-induced cognitive deficits and (3) the remediation of alcohol- induced cognitive deficits during abstinence. Group-housed NHPs form social hierarchies that create a continuum of social experiences from environmental enrichment (in high-ranked, “dominant” monkeys) to chronic social stress (in low-ranked, “subordinate” monkeys). In the proposed experiments, group-housed NHPs will drink ethanol over several hours per day. This study uses a longitudinal design that allows for both within- and between-subject assessment of clinically relevant endpoints in ethanol-naïve, -consuming and –free states. The cognitive task to be employed, a stimulus-discrimination-and-reversal task, will characterize behavioral flexibility. The ability of cholinergic drugs that have already been assessed clinically or FDA-approved for other indications to remediate chronic ethanol-induced deficits will be determined, which is expected to provide guidance to medication development efforts. When finished, this study will provide significant insight into AUD vulnerabilities impacting individual drinking trajectories, the effects long-term alcohol consumption on behavior and how cholinergic drugs may be utilized as novel pharmacotherapeutic medications for AUD patients.