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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要在美国，大约有 1440 万成年人被诊断患有酒精使用障碍 (AUD)。对影响澳元发展的因素以及具体的长期影响的了解不完全此外，只有 7.9% 的 AUD 患者存在酒精对大脑的影响以及持续存在问题的行为。在接受药物辅助治疗的情况下，仍然非常需要新的药物疗法。有证据表明，社会压力会导致澳元的脆弱性。也有证据表明，认知能力会影响澳元。长期饮酒造成的缺陷会导致前额皮质的结构和功能缺陷（PFC），导致 PFC 介导的行为缺陷，可以在禁欲期间或通过这项多学科研究使用了完善的、高度成熟的方法来调节大脑乙酰胆碱受体。转化非人类灵长类动物（NHP）模型，将研究（1）社会之间的关系压力/浓缩、长期饮酒和执行功能，(2) 靶向药物的能力大脑乙酰胆碱受体逆转酒精引起的认知缺陷，以及（3）修复酒精- 禁欲期间的认知缺陷从环境丰富（在高级的“统治”猴子中）到慢性的社会经历的连续体社会压力（在低等级的“从属”猴子中）。每天喝几个小时的乙醇这项研究采用纵向设计，允许内部和外部。在未使用乙醇、消耗乙醇和未使用乙醇的状态下对临床相关终点进行受试者间评估。要采用的认知任务，即刺激辨别和逆转任务，将表征行为灵活性。已针对其他适应症进行临床评估或 FDA 批准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，预计将为药物开发工作完成后，这项研究将为 AUD 的漏洞提供重要的见解。影响个人饮酒轨迹、长期饮酒对行为的影响以及如何影响胆碱能药物可用作 AUD 患者的新型药物治疗药物。