Neural, Cognitive and Abuse-Related Consequences of Chronic THC Exposure during Adolescence in Nonhuman Primates

非人类灵长类动物青春期长期接触 THC 的神经、认知和虐待相关后果

• 批准号: 10399441
• 负责人: JACK BERGMAN
• 金额: $ 71.84万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399441
• 关键词: Abate; Address; Adolescence; Adolescent; Adult; Amygdaloid structure; Anatomy; Anisotropy; Anterior; Attention; Behavioral; Biological Assay; Brain; Cannabinoids; Cannabis; Chronic; Cognition; Cognitive; Cognitive deficits; Competence; Data; Development; Diffuse; Diffusion Magnetic Resonance Imaging; Discrimination; Dorsal; Dose; Exposure to; Female; Functional Magnetic Resonance Imaging; Health; Hippocampus (Brain); Human; Impaired cognition; Knowledge; Laboratory Animals; Lead; Learning; Life; Longitudinal Studies; Male Adolescents; Measures; Memory; Milk; Monkeys; Motivation; Neuropsychology; Outcome; Palate; Pharmaceutical Preparations; Pharmacotherapy; Positioning Attribute; Predisposition; Process; Protocols documentation; Psychological reinforcement; Regimen; Research; Rest; Risk; Rodent; Saimiri; Scanning; Self Administration; Sex Differences; Short-Term Memory; Stimulus; Structural defect; Structure; THC exposure; Techniques; Testing; Thalamic structure; Thick; Time; Translational Research; addiction; anatomic imaging; awake; base; behavior test; behavioral economic analysis; behavioral economics; brain abnormalities; cognitive change; cognitive function; cognitive load; cognitive performance; cognitive testing; critical period; dosage; drug abuse vulnerability; emerging adult; endogenous cannabinoid system; flexibility; gray matter; imaging study; interest; lipophilicity; male; marijuana use; men' s group; multimodality; neuroimaging; nonhuman primate; programs; putamen; reinforcer; relating to nervous system; response; touchscreen; treatment group; white matter; young adult

Cannabis is the most widely self-administered psychoactive substance among adolescents in the U.S., and its use shows no signs of abatement. Studies in humans suggest that heavy cannabis use during this critical period of development can alter brain structure and function and impair cognitive and behavioral processes. However, the extent to which neural changes and neuropsychological deficits produced by cannabis use during adolescence persist into adulthood remains poorly understood, hampering the assessment of long-term health risks. Consequently, there continues to be a pressing need for carefully controlled research on the potential long-term impact of adolescent cannabis exposure on brain development, cognitive competency and addiction. The present research addresses this need with longitudinal studies in nonhuman primates to examine the long-term impact of chronic exposure to the cannabinoid Δ9-THC during adolescence. In this research, groups of adolescent male and female squirrel monkeys will be treated daily with a low active dose or a high active dose of Δ9-THC or with vehicle. Daily treatment will continue throughout adolescence for 6 months, during which time observational and activity data will be collected to assess behavioral status and the any tolerance to the effects of drug treatment. Neuroimaging data will be collected before, during, and after daily treatment to evaluate changes in neural structure or function that may be associated with chronic exposure to Δ9-THC. After the chronic regimens are discontinued, subjects will remain drug-free for 6 weeks to allow for the elimination of the lipophilic cannabinoid. Next, using touchscreen-based tasks, subjects will be studied to determine whether prior exposure to Δ9-THC may have persisting effects on motivation or different types of cognitive function. First, using a behavioral economic demand analysis, motivation will be assessed by comparing the reinforcing strength of sweetened condensed milk, a highly palatable reinforcer, in the different treatment groups. Subsequently, two tasks (stimulus discrimination/reversal and delayed matching to position) will be used to compare learning, response inhibition, and spatial short-term memory across treatment groups. Neuroimaging information will be collected prior to and following the above testing. Finally, the acquisition of Δ9-THC self-administration will be studied to determine whether adolescent exposure to Δ9- THC may have enhanced its reinforcing effects. Lastly, the study will conclude with a final neuroimaging scan. Overall, these longitudinal studies will provide information regarding the persistence of neural abnormalities that may be produced by Δ9-THC exposure during adolescence, their association with cognitive impairments or changes in sensitivity to abuse-related effects of Δ9-THC, and whether such sequelae and associations can be related to the chronic dosage Δ9-THC or differ in males and females.

大麻是美国青少年中最广泛自我使用的精神活性物质，其 对人类的研究表明，在这一关键时期，大麻的使用没有减少的迹象。 发育时期会改变大脑结构和功能，并损害认知和行为过程。 然而，使用大麻造成的神经变化和神经心理缺陷的程度 对青春期持续到成年期的认知仍然知之甚少，这阻碍了长期评估 考虑到健康风险，仍然迫切需要对其进行仔细控制的研究。 青少年接触大麻对大脑发育、认知能力和认知能力的潜在长期影响 目前的研究通过对非人类灵长类动物的纵向研究来满足这一需求。 研究青春期期间长期接触大麻素 Δ9-THC 的长期影响。 研究中，青少年雄性和雌性松鼠猴群体将每天接受低活性剂量的治疗 或高活性剂量的 Δ9-THC 或与媒介物一起每日治疗将持续整个青春期 6。 几个月，在此期间将收集观察和活动数据以评估行为状态和 将在药物治疗之前、期间和之后收集对药物治疗效果的任何耐受性。 每日治疗以评估可能与慢性病相关的神经结构或功能的变化 暴露于 Δ9-THC 长期治疗方案停止后，受试者将在 6 周内保持不用药状态。 接下来，受试者将使用基于触摸屏的任务来消除亲脂性大麻素。 研究以确定先前接触 Δ9-THC 是否可能对动机或其他方面产生持续影响 首先，使用行为经济需求分析来评估动机。 通过比较甜炼乳（一种高度适口的强化剂）的强化强度， 随后，进行两项任务（刺激辨别/逆转和延迟匹配） 位置）将用于比较学习、反应抑制和空间短期记忆 最后，将在上述测试之前和之后收集神经影像学信息。 将研究 Δ9-THC 自我给药的获得情况，以确定青少年是否接触 Δ9- THC 可能增强了其强化作用。最后，该研究将以最终的神经影像扫描结束。 总的来说，这些纵向研究将提供有关神经异常持续存在的信息 可能是由青少年时期接触 Δ9-THC 产生的，它们与认知障碍有关 或对 Δ9-THC 滥用相关影响的敏感性变化，以及此类后遗症和关联是否可以 与长期剂量Δ9-THC有关或在男性和女性中存在差异。