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普遍的自我管理的精神活性物质，它的 使用量没有减少的迹象。对人体的研究表明，在这一关键时期大量使用大麻 发育阶段会改变大脑的结构和功能，损害认知和行为过程。 然而，大麻使用造成的神经变化和神经心理缺陷的程度 在青春期坚持到成年仍然鲜为人知，阻碍了对长期 健康风险。因此，仍然迫切需要对 青少年大麻暴露对大脑发育、认知能力和 上瘾。目前的研究通过对非人类灵长类动物的纵向研究来解决这一需求 研究青春期长期接触大麻素Δ9-THC的影响。在这 研究发现，成群的青春期雄性和雌性松鼠猴子将每天接受低活性剂量的治疗 或高活性剂量的Δ9-THC或与赋形剂一起使用。每天的治疗将持续到青春期，为期6年。 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 对药物治疗效果的耐受性。将在之前、期间和之后收集神经成像数据 日常治疗以评估神经结构或功能的变化，这些变化可能与慢性 暴露于Δ9-THC。在停止长期服药后，受试者将在6周内保持无药状态 以消除亲脂性大麻素。接下来，使用基于触摸屏的任务，主题将 研究以确定之前接触Δ9-THC是否会对动机产生持久的影响或不同 认知功能的类型。首先，使用行为经济需求分析，将评估动机 通过比较甜炼乳的增强强度，一种非常可口的增强剂，在 不同的治疗组。随后，两项任务(刺激辨别/反转和延迟匹配 位置)将被用来比较学习、反应抑制和空间短期记忆 治疗组。神经影像信息将在上述测试之前和之后收集。最后， 将对收购Δ9-THc自我管理进行研究，以确定青少年是否接触Δ9-THc- THC可能增强了其补益作用。最后，这项研究将以最后的神经成像扫描结束。 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。 这可能是由青春期接触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的变化，以及这些后遗症和关联是否可以 与慢性剂量Δ-9-THC有关或男女不同。