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

项目概要 了解艾滋病毒感染者 (PWH) 的共病（例如药物滥用）如何影响风险承担、决策 考虑到对日常功能和传播的影响，制作和其他认知行为很重要 风险。艾滋病毒感染者中大麻的使用率很高，无论是药用还是娱乐用途，可能表明疾病的严重程度， 带来治疗益处或不良后果。事实上，建议艾滋病毒感染者使用大麻 缓解恶心、改善食欲、缓解疼痛、提振情绪。迄今为止，吸食大麻的后果 PWH 以及与 HIV 治疗的潜在相互作用仍不清楚。在健康参与者中，大量大麻 使用与认知缺陷有关，例如冒险决策、反应抑制和注意力不集中，但是 由于其抗炎和抗兴奋性毒性，在轻度使用水平下可能存在对产妇的促认知作用 属性。此外，几乎没有采取任何措施来确定大麻使用对内源性大麻素的影响 (EC) 一般系统或 PWH 系统。该研究领域与认知尤其密切相关，因为该病毒会影响 富含 EC 的大脑区域。鉴于 EC 系统发挥监管作用，CNS 相关性尤为重要 对多巴胺能系统的影响，对这些认知过程至关重要。该应用程序将利用交叉 物种方法来描述 EC 系统激活对 HIV 相关认知和动机的影响 域。动物研究可以从机制上了解该系统的慢性和戒断效应。两者都 人类和动物研究之间会出现行为和机械重叠。具体目标 1 将 确定两种主要大麻成分（Δ9-四氢大麻酚 [THC]、大麻二酚 [CBD]）与安慰剂在风险决策、反应抑制、奖励学习、时间感知和 动机，加上 HIV 和 HIV 中的 EC 和高香草酸（HVA；多巴胺活性的替代物）水平 科目。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 抗逆转录病毒药物（ART）的使用进行了量化。他们将被随机分配到为期 5 天的 THC、CBD 或 安慰剂并返回进行后续测试和重新测定 EC 和 HVA 水平。具体目标 2 将进行 在 HIV 啮齿动物模型中对 2 剂 THC 与 2 剂的急性、慢性和戒断效应进行平行实验 CBD 剂量，加上在相同的认知和动机测试中组合的 THC/CBD/ART（多替拉韦），加上 EC 和 HVA 水平可提供药物作用的方向性和潜在相互作用。每个实验都会训练 并测试 HIV-1 转基因和野生型同窝大鼠执行目标 1 中使用的跨物种任务。大鼠将 在基线时进行测试，在急性治疗后立即进行测试，然后在慢性治疗期间进行测试，然后在停药期间进行测试。老鼠的大脑 将收集并评估 EC 和多巴胺受体水平，以确定潜在的机制 大麻素治疗对艾滋病毒相关症状的有益/负面影响。解开认知 THC 和 CBD 的生物效应及其与 ART 的关系是 HIV 领域急需的进展 并将为共病药物使用的治疗方法和政策建议的开发提供信息。

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.