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: 10609878
• 负责人: JACK BERGMAN
• 金额: $ 55.63万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609878
• 关键词: Abate; Address; Adolescence; Adolescent; Adult; Amygdaloid structure; Anatomy; Anisotropy; Anterior; Behavior assessment; Behavioral; Biological Assay; Brain; Cannabinoids; Cannabis; Chronic; Cognition; Cognitive; Cognitive deficits; Competence; Data; Development; Diffusion Magnetic Resonance Imaging; Discrimination; Dorsal; Dose; Exposure to; Female; Functional Magnetic Resonance Imaging; Health; Hippocampus; Human; Impaired cognition; Knowledge; Laboratory Animals; Learning; Life; Longitudinal Studies; Male Adolescents; Measures; Memory; Milk; Monkeys; Motivation; Neuropsychology; Outcome; Pharmaceutical Preparations; Pharmacotherapy; Positioning Attribute; Predisposition; Process; Protocols documentation; Psychological reinforcement; Regimen; Regional Anatomy; 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; awake; 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; neural; neuroimaging; nonhuman primate; programs; putamen; reinforcer; 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精神活性物质，及其 使用没有减少的迹象。对人类的研究表明，在这一关键时期大量使用大麻 在发育过程中，大脑的结构和功能会发生改变，认知和行为过程也会受到损害。 然而，大麻使用造成的神经变化和神经心理缺陷的程度 在青少年时期持续到成年的疾病仍然知之甚少，阻碍了对长期疾病的评估。 健康风险。因此，仍然迫切需要对这一问题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 成瘾本研究通过对非人灵长类动物的纵向研究来满足这一需求， 研究青春期长期接触大麻素Δ9-THC的长期影响。在这 在一项研究中，一组青春期的雄性和雌性松鼠猴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。每日治疗将持续整个青春期6 月，在此期间，将收集观察和活动数据，以评估行为状态和 对药物治疗效果的任何耐受性。将在术前、术中和术后收集神经影像学数据 每日治疗，以评估可能与慢性疾病相关的神经结构或功能变化 接触Δ9-THC。在慢性治疗方案停止后，受试者将保持6周无药物治疗 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 研究以确定先前暴露于Δ9-THC是否可能对动机产生持续影响， 认知功能的类型。首先，使用行为经济学需求分析，将评估动机 通过比较甜炼乳的增强强度，一种非常可口的增甜剂， 不同的治疗组。随后，两个任务（刺激辨别/反转和延迟匹配到 位置）将用于比较学习，反应抑制和空间短期记忆。 治疗组。将在上述测试之前和之后收集神经影像学信息。最后， 将研究Δ9-THC自我给药的获得，以确定青少年是否暴露于Δ9-THC。 THC可能增强了其强化作用。最后，研究将以最终的神经影像学扫描结束。 总的来说，这些纵向研究将提供有关神经异常持续性的信息 可能是由青春期Δ9-THC暴露产生的，它们与认知障碍的关系 或对Δ9-THC滥用相关效应的敏感性变化，以及此类后遗症和关联是否可 与慢性剂量Δ9-THC有关或在男性和女性中存在差异。

项目成果

Resting state networks of awake adolescent and adult squirrel monkeys using ultra-high field (9.4T) functional magnetic resonance imaging.

使用超高场 (9.4T) 功能磁共振成像显示清醒的青少年和成年松鼠猴的静息状态网络。

• DOI: 10.1101/2023.01.08.523000
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Yassin,Walid;deMoura,FernandoB;Withey,SarahL;Cao,Lei;Kangas,BrianD;Bergman,Jack;Kohut,StephenJ
• 通讯作者: Kohut,StephenJ

Probabilistic Reinforcement Schedules in Neuropsychiatric Medications Development.

神经精神药物开发中的概率强化计划。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Kangas,BrianD