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

项目总结 了解艾滋病毒携带者(PWH)的共病，如药物使用，如何影响风险承担，决策 制造和其他认知行为对日常功能和传递具有重要意义 风险。威尔斯亲王医院在医疗和娱乐方面大麻使用率很高，这可能表明疾病的严重性， 给予治疗益处或不良后果。事实上，大麻被推荐给艾滋病毒携带者 缓解恶心，改善食欲，缓解疼痛，提振情绪。到目前为止，大麻使用的后果是 PWH仍然不清楚，与HIV治疗的潜在相互作用也是如此。在健康参与者中，大量大麻 使用与认知缺陷有关，例如危险的决策、反应去抑制和注意力不集中，但是 PWH的前认知作用可能是由于其抗炎和抗兴奋毒性而在温和的使用水平上存在的 属性。此外，几乎没有采取行动来确定大麻使用对内源性大麻素的影响。 (EC)一般系统或威尔斯亲王医院的系统。这一研究领域与认知尤其密切相关，因为病毒会影响 富含内皮细胞的大脑区域。CNS的相关性特别重要，因为欧共体系统对 对多巴胺能系统的影响，对这些认知过程至关重要。这个应用程序将利用一个交叉- 用物种方法描述EC系统激活对HIV相关认知和动机的影响 域名。通过动物研究，可以对该系统中的慢性和戒断效应进行机械性的洞察。两者都有 人类和动物的研究将会出现行为学和机械学的重叠。具体目标1将 确定两种主要大麻成分(Δ、9-四氢大麻酚、大麻二酚)的效果 [CBD])与安慰剂相比，风险决策、反应抑制、奖励学习、时间知觉以及 动机，加上艾滋病毒和艾滋病毒中EC和高香草酸(HVA；多巴胺活性的替代物)水平- 研究对象。不经常使用大麻的参与者将接受基线认知测试和生物标记物分析 抗逆转录病毒药物(ART)的使用是量化的。他们将随机接受为期5天的THC、CBD或 安慰剂，并返回进行后续测试和重新检测ECs和HVA水平。《特定目标2》将进行 两种剂量的THC对HIV啮齿动物模型的急性、慢性和戒断效应的平行实验 剂量的CBD，加上THC/CBD/ART(多洛替格列韦)的组合，进行相同的认知和动机测试，加上 EC和HVA水平，以提供药物效应的方向性和潜在的相互作用。每个实验都会训练 并在AIM 1中使用的跨物种版本的任务中测试HIV-1转基因和野生型产仔鼠。 在基线时、急性治疗后立即进行测试，然后在慢性治疗后，然后在戒断期间进行测试。大鼠的大脑 将收集并评估EC和多巴胺受体水平，以确定潜在的机制 大麻素治疗对艾滋病毒相关症状的有利/消极影响。解开认知的纠缠 THC和CBD的生物学效应及其与抗逆转录病毒治疗的关系是艾滋病毒领域亟需的进展 并将为共病药物使用的治疗方法和政策建议的发展提供信息。

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.