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的自我管理的精神活性物质，它 使用没有显示减排的迹象。在人类中的研究表明，在这一关键时期使用大麻 发育时期可以改变大脑结构和功能，并损害认知和行为过程。 但是，神经元的变化和神经心理学的定义程度 在青少年期间，持续到成年期仍然很少了解，从而阻碍了长期评估 健康风险。因此，继续迫切需要对 青少年大麻暴露对大脑发育，认知能力和 瘾。本研究通过非人类隐私的纵向研究解决了这一需求 检查青少年期间长期暴露于大麻素δ-THC的长期影响。在这个 研究，一群青春期的男性和女性松鼠猴每天都会以低活性剂量进行治疗 或高活性剂量的δ9-THC或使用媒介物。每日治疗将在整个青少年中继续持续6个 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 对药物治疗影响的任何耐受性。神经影像学数据将在之前，期间和之后收集 每日治疗以评估可能与慢性有关的神经元结构或功能的变化 暴露于Δ9-THC。慢性方案停产后，受试者将保持无药物6周 为了消除亲脂性大麻素。接下来，使用基于触摸屏的任务，受试者将是 研究案以确定事先暴露于Δ9-THC是否可能对动机或不同 认知功能的类型。首先，使用行为经济需求分析，将评估动机 通过比较加浓缩牛奶的增强强度（一种非常可口的增强剂） 不同的治疗组。随后，两个任务（刺激歧视/逆转和延迟匹配到 位置）将用于比较学习，响应抑制和空间短期记忆 治疗组。在上述测试之前和之后，将收集神经影像学信息。最后， 将研究Δ9-THC自我给药的获取，以确定青少年是否暴露于Δ9- THC可能增强了其增强作用。最后，该研究将包括最终的神经影像学扫描。 总体而言，这些纵向研究将提供有关神经异常持续性的信息 这可能是由于青少年期间Δ9-THC暴露而产生的，它们与认知障碍的关联 或对δ9-THC滥用相关影响的敏感性的变化，以及这种后遗症和关联是否可以 与男性和女性的慢性剂量Δ9-THC有关。