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: 10705422
• 负责人: ARPI MINASSIAN
• 金额: $ 13.2万
• 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/10705422
• 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; Cannabis policy; 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; Learning; Lifting; Limbic System; Link; Mediating; Medicine; Modeling; Moods; Motivation; Nausea; Neurobiology; Neurocognitive Deficit; Neurotransmitters; Oral; Participant; Perception; Persons; Pharmaceutical Preparations; Pharmacology; Placebos; Policies; Population; Prefrontal Cortex; Prevalence; Property; Randomized; Rat Transgene; Rattus; Recommendation; Recreation; Rewards; Risk; Risk Behaviors; Risk Taking; Rodent Model; Role; Severity of illness; Statistical Data Interpretation; Symptoms; System; Testing; Tetrahydrocannabinol; Therapeutic; Time Perception; Training; Transgenic Organisms; Viral Load result; Virus; Withdrawal; adverse outcome; anandamide; antiretroviral therapy; behavior test; cannabinoid administration; cannabinoid treatment; cannabis administration; 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; neuroprotection; nonhuman primate; pain relief; receptor expression; remediation; 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. Project Summary/Abstract Page 6

项目总结