Translational Studies of Cannabis Administration, Cognition, and the Endocannabinoid System in HIV

HIV 中大麻施用、认知和内源性大麻素系统的转化研究

• 批准号: 10399609
• 负责人: ARPI MINASSIAN
• 金额: $ 81.22万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10399609
• 关键词: 2-arachidonylglycerol; Acute; Adult; Affect; Animal Experimentation; Animal Model; Animals; Anti-Inflammatory Agents; Anti-Retroviral Agents; Area; Attenuated; Behavior; Behavioral; Biological; Biological Assay; Biological Markers; Brain; Brain region; Cannabidiol; Cannabinoids; Cannabis; Chronic; Clinical Research; Cognition; Cognitive; Cognitive deficits; Complex; Corpus striatum structure; Decision Making; Desire for food; Disease; Disease Progression; Disinhibition; Dopamine; Dopamine Receptor; Dose; Endocannabinoids; Exhibits; Feedback; Formulation; General Population; HIV; HIV risk; HIV-1; Harvest; High Prevalence; Homovanillic Acid; Human; Human immunodeficiency virus test; Individual; Knowledge; Laws; Learning; Lifting; Limbic System; Link; Mediating; Modeling; Moods; Motivation; Nausea; Neurobiology; Neurocognitive Deficit; Neurotransmitters; Oral; Participant; Perception; Persons; Pharmaceutical Preparations; Pharmacology; Placebos; Policies; Population; Prefrontal Cortex; Prevalence; Property; Randomized; Rattus; Rewards; Risk; Risk Behaviors; Risk-Taking; Rodent Model; Role; Severity of illness; Statistical Data Interpretation; Symptoms; System; Testing; Tetrahydrocannabinol; Therapeutic; Time; Time Perception; Training; Transgenic Organisms; Viral Load result; Virus; Withdrawal; adverse outcome; anandamide; antiretroviral therapy; behavior test; cannabinoid treatment; cannabis withdrawal; cognitive control; cognitive function; cognitive process; cognitive testing; comorbidity; dopamine system; endogenous cannabinoid system; excitotoxicity; exogenous cannabinoid; experimental study; follow-up; improved; inattention; insight; marijuana use; marijuana user; neurobiological mechanism; neurochemistry; nonhuman primate; pain relief; receptor expression; response; substance use; therapeutic development; translational study; transmission process

PROJECT SUMMARY Understanding how co-morbidities in persons with HIV (PWH) such as substance use affect risk-taking, decision- making, and other cognitive behaviors is important given implications for everyday functioning and transmission risk. The high prevalence of cannabis use in PWH, medicinally and recreationally, may indicate disease severity, impart therapeutic benefits, or adverse consequences. In fact, cannabis is recommended to those with HIV to alleviate nausea, improve appetite, relieve pain, and lift mood. To-date, the consequences of cannabis use in PWH remain unclear as do potential interactions with HIV treatments. In healthy participants, heavy cannabis use is associated with cognitive deficits e.g., risky decision-making, response disinhibition and inattention, but pro-cognitive effects in PWH may exist at mild use levels due to its anti-inflammatory and anti-excitotoxic properties. Furthermore, little has been done to determine the effects of cannabis use on the endocannabinoid (EC) system in general or in PWH. This area of study is especially germane to cognition since the virus affects brain regions rich in ECs. CNS relevance is of particular importance given that the EC system exerts regulatory effects over the dopaminergic system, critical for these cognitive processes. This application will utilize a cross- species approach to delineate the effects EC system activation has on HIV-relevant cognitive and motivational domains. Animal studies enable mechanistic insights on chronic and withdrawal effects in this system. Both behavioral and mechanistic overlap will occur between the human and animal studies. Specific Aim 1 will determine the effects of the two primary cannabis constituents (Δ9-tetrahydrocannabinol [THC], cannabidiol [CBD]) vs. placebo on risky decision-making, response inhibition, reward learning, temporal perception, and motivation, plus EC and homovanillic acid (HVA; a surrogate for dopamine activity) levels in HIV+ and HIV- subjects. Participants with infrequent cannabis use will undergo baseline cognitive testing and biomarker assays with antiretrovirals (ART) use quantified. They will be randomized to a 5-day course of either THC, CBD, or placebo and return for follow-up testing and re-assaying of ECs and HVA levels. Specific Aim 2 will conduct parallel experiments in a rodent model of HIV on acute, chronic, and withdrawal effects of 2 doses of THC vs. 2 doses of CBD, plus combined THC/CBD/ART (dolutegravir) on the same cognitive and motivational tests, plus EC and HVA levels to provide directionality and potential interaction of drug effects. Each experiment will train and test HIV-1 transgenic and wildtype littermate rats on cross-species versions of tasks used in Aim 1. Rats will be tested at baseline, immediately after acute, then chronic treatment, then during withdrawal. The brains of rats will be harvested and assessed for EC and dopamine receptor levels to determine potential mechanisms of the beneficial/negative effects of cannabinoid treatments on symptoms related to HIV. Disentangling the cognitive and biological effects of THC and CBD and their relation with ART is a much-needed advance in the HIV field and will inform development of therapeutics and policy advice for co-morbid substance use.

项目摘要 了解艾滋病毒（PWH）（例如使用物质使用）的合并症如何影响冒险，决策 - 制作和其他认知行为对每天的运作和传播都具有重要意义 风险。在药物和娱乐活动中，PWH中大麻使用的高流行率可能表明疾病的严重程度， 带来治疗益处或不利后果。实际上，向患有艾滋病毒的人推荐大麻 减轻恶心，改善食欲，营救疼痛和举起情绪。迄今为止，大麻使用的后果 PWH仍然不清楚与HIV治疗的潜在相互作用。在健康的参与者中，大麻 使用与认知的使用相关，例如，有风险的决策，反应抑制和注意力不集中，但 由于其抗炎和抗脱毒性，PWH中的亲认知效应可能在轻度使用水平上存在 特性。此外，几乎没有做任何事情来确定使用大麻对内源性大麻素的影响 （EC）通常或PWH中的系统。该研究领域尤其是认知，因为病毒会影响 大脑区域富含EC。考虑到EC系统发挥监管，CNS相关性尤其重要 对多巴胺能系统的影响，对这些认知过程至关重要。此应用程序将利用一个交叉 物种方法来描述EC系统激活对HIV相关的认知和动机的影响 域。动物研究可以对该系统中的慢性和戒断效应进行机理见解。两个都 人类和动物研究之间将发生行为和机械重叠。具体目标1将 确定两种主要大麻构成的影响（Δ9-四氢大麻酚[THC]，大麻二酚 [CBD]）与安慰剂有关风险的决策，反应抑制，奖励学习，临时看法和 HIV+和HIV-的动机，加上EC和同性恋酸（HVA；多巴胺活性的替代物）水平 主题。不经常使用大麻的参与者将接受基线认知测试和生物标志物测定 使用抗逆转录病毒（ART）使用量化。他们将被随机分为THC，CBD或 安慰剂和返回以进行后续测试和重新评估ECS和HVA水平。具体目标2将进行 在急性，慢性和戒断作用的啮齿动物模型中的平行实验2剂量的THC与2剂量 CBD的剂量，以及在相同的认知和动机测试中的THC/CBD/ART（DoluteGravir）的组合 EC和HVA水平提供了药物影响的方向性和潜在相互作用。每个实验将训练 以及在AIM 1中使用的跨物种版本上测试HIV-1转基因和野生型窝窝大鼠。大鼠将 在基线，急性后，然后在戒断期间立即进行测试。老鼠的大脑 将收集并评估EC和多巴胺受体水平，以确定 大麻素治疗对与HIV有关的症状的有益/负面影响。解开认知 THC和CBD的生物学效应及其与艺术的关系在HIV领域非常需要 并将为合并物质使用的理论和政策建议的发展提供信息。