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

项目摘要 了解艾滋病毒感染者（PWH）的合并症（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播的影响是重要的 风险威尔斯亲王医院使用大麻的高流行率，无论是医疗还是娱乐，都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，大麻被推荐给艾滋病毒感染者， 缓解恶心、增进食欲、减轻疼痛、改善情绪。到目前为止，大麻使用的后果， PWH与HIV治疗的潜在相互作用仍不清楚。在健康的参与者中， 使用与认知缺陷有关，风险决策，反应去抑制和注意力不集中，但 由于其抗炎和抗兴奋毒性，在轻度使用水平下，PWH可能存在促认知作用 特性.此外，几乎没有做什么来确定大麻使用对内源性大麻素的影响。 (EC)系统或威尔斯亲王医院。这一研究领域与认知密切相关，因为病毒影响 富含内皮细胞的大脑区域CNS相关性特别重要，因为EC系统实施监管， 影响多巴胺能系统，对这些认知过程至关重要。该应用程序将使用交叉- 物种的方法来描绘EC系统激活对HIV相关的认知和动机的影响 域.动物研究使机制的见解慢性和戒断影响在这个系统中。两 在人类和动物研究之间将出现行为和机制重叠。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]）与安慰剂对风险决策、反应抑制、奖励学习、时间感知和 动机，加上EC和高香草酸（HVA;多巴胺活性的替代品）水平在HIV+和HIV- 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）使用定量。他们将被随机分配到THC，CBD或 安慰剂和返回进行后续测试和EC和HVA水平的再测定。具体目标2将进行 在啮齿动物HIV模型中进行的2种剂量THC与2种剂量THC的急性、慢性和戒断作用的平行实验 剂量的CBD，加上联合THC/CBD/ART（dolutegravir）在相同的认知和动机测试，加上 EC和HVA水平提供药物作用的方向性和潜在相互作用。每次实验都会训练 并测试HIV-1转基因和野生型同窝出生的大鼠在目标1中使用的任务的跨物种版本。大鼠将 在基线、急性治疗后立即、慢性治疗后、停药期间进行检测。老鼠的大脑 收集并评估EC和多巴胺受体水平，以确定 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的生物学效应及其与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.