Cognitive Consequences of EtOH Consumption in Group-Housed Nonhuman Primates

群居非人类灵长类动物消耗乙醇的认知后果

• 批准号: 10560503
• 负责人: Lindsey Galbo Thomma
• 金额: $ 3.56万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-08-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10560503
• 关键词: Abstinence; Acute; Adult; Affect; Agonist; Alcohol consumption; Alcohols; Behavior; Behavioral; Brain; Brain region; Cholinergic Agents; Cholinergic Receptors; Chronic; Clinical; Cognition; Cognitive; Cognitive deficits; Consumption; Decision Making; Development; Diagnosis; Discrimination; Drug Targeting; Ethanol; FDA approved; Goals; Home; Hour; Human; Impaired cognition; Individual; Individual Differences; Laboratory Animals; Long-Term Effects; Macaca fascicularis; Mediating; Modeling; Monkeys; Muscarinic Acetylcholine Receptor; Nicotinic Receptors; Patients; Pharmaceutical Preparations; Pharmacotherapy; Prefrontal Cortex; Recovery; Research; Role; Schedule; Social Dominance; Social Hierarchy; Social Interaction; Stimulus; Stress; Structure; Substance Use Disorder; System; Technology; Time; Training; Treatment outcome; United States; alcohol abstinence; alcohol abuse therapy; alcohol effect; alcohol use disorder; antagonist; chronic alcohol ingestion; clinically relevant; cognitive performance; cognitive task; cognitive testing; cohort; drinking; economic impact; effective therapy; environmental enrichment for laboratory animals; executive function; experience; experimental study; flexibility; insight; longitudinal design; male; medication-assisted treatment; multidisciplinary; neurobiological mechanism; nonhuman primate; novel; novel therapeutics; pharmacologic; receptor; remediation; social; social group; social stress; touchscreen

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.

项目摘要 在美国，大约有1440万成年人被诊断出患有酒精使用障碍（AUD）。有 对因素的不完全理解会影响AUD的发展和特定的长期影响 大脑上的酒精和行为，使有问题的使用。而且，只有7.9％的AUD患者 接受药物辅助治疗，对新型药物疗法的需求仍然很大。 有证据表明，社会压力可以赋予AUD脆弱性。证据也表明认知 长期饮酒引起的缺陷导致前额叶皮层的结构和功能不足 （PFC），导致PFC介导的行为定义，该行为可能在禁欲期间或通过 调节脑乙酰胆碱受体。这项使用良好的，高度的多学科研究 翻译的非人类灵长类动物（NHP）模型将调查（1）社会之间的关系 压力/富集，长期饮酒和执行功能，（2）针对目标的药物的能力 脑乙酰胆碱受体可逆转酒精诱导的认知缺陷，（3）对酒精的补救 戒酒期间诱发认知防御。组成的NHP构成了创建一个社会等级制度 社会经验的连续体从环境丰富（以高级，“占主导地位”猴子）到慢性 社会压力（在低级，“下属”猴子中）。在拟议的实验中，组为组的NHP将 每天喝几个小时的乙醇。这项研究使用纵向设计，可用于内部和 对乙醇， - 耗尽和不含状态的临床相关终点的受试者之间的评估。这 要使用的认知任务，刺激性歧视和反向任务将表征行为灵活性。 胆碱能药物已经在临床上进行了评估或FDA批准的其他适应症的能力 要确定慢性乙醇引起的缺陷，预计将为指导提供指导 用药开发工作。完成后，这项研究将为AUD漏洞提供重大的见解 影响单个饮酒轨迹，长期饮酒对行为的影响以及如何 胆碱能药物可以用作AUD患者的新型药物治疗药物。