Endocannabinoids, Cannabis, and Neurocognitive Deficits in HIV

内源性大麻素（EC）系统在神经炎症和神经退行性疾病的发病机制中起着关键作用，包括调节促炎细胞因子、内皮细胞激活和氧化应激。在过去的十年中，临床前研究表明，EC系统的抗炎和神经保护特性，包括EC CB2受体的激活，可能在减少hiv诱导的中枢神经系统（CNS）损伤和预防hiv相关神经认知障碍（HAND）的发展方面具有治疗效用。相比之下，据报道，外源性大麻使用在慢性暴露后会诱发神经认知和功能障碍。尽管这些影响背后的神经生物学机制仍然是推测性的，但大麻暴露减少了人类和小鼠EC配体和受体的表达，这表明EC系统的破坏可能在这种药物的有害影响中起关键作用。而

DESCRIPTION: The endocannabinoid (EC) system plays a critical role in the pathogenesis of neuroinflammatory and neurodegenerative disorders, including regulating pro-inflammatory cytokines, endothelial activation, and oxidative stress. Over the past decade, preclinical studies have indicated that the anti-inflammatory and neuroprotective properties of the EC system, including activation of the EC CB2 receptor, may have therapeutic utility in reducing HIV-induced damage to the central nervous system (CNS) and preventing the development of HIV-associated neurocognitive disorders (HAND). In contrast, exogenous cannabis use is reported to induce neurocognitive and functional impairment after chronic exposure. Although the neurobiological mechanisms underlying these effects remain speculative, cannabis exposure reduces EC ligand and receptor expression in both humans and mice, suggesting that disruption of the EC system may play a critical role in the detrimental effects of this drug. While recent work indicates that exogenous cannabis can block upregulated EC activity in schizophrenia patients, the individual and combined effects of HIV and cannabis use on the EC system have not been characterized, representing a fundamental gap in our knowledge. Thus, this application will examine the relationship between cannabis use, EC function, and mechanisms of HIV-related pathogenesis implicated in the development of HAND. We will quantify cerebrospinal fluid (CSF) and plasma levels of the two primary endocannabinoid ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), in HIV- and HIV+ participants (n of 50 per group) with no cannabis use (d 5 times over lifetime), light cannabis use (1-4 times per month in past year), and heavy cannabis use (>10 times per month in past year and meeting criteria for lifetime cannabis abuse or dependence). To assess potential mechanisms of HIV-EC interaction, we will also examine expression of the CB2 receptor in monocytes and T- cells, as well as the EC ligand deactivation enzymes fatty acid amide hydrolase (FAAH) and monoacyglycerol lipase (MAGL). We propose that EC ligand and receptor expression will be elevated in cannabis-naive HIV+ participants as a compensatory protective mechanism, but decline in participants with heavy cannabis use. We will also test the hypothesis that higher levels of AEA, 2-AG and CB2 expression will be associated with lower levels of neuroinflammatory markers, endothelial activation, and oxidative stress. Finally, we propose that heavy cannabis use will impair neurocognitive performance compared to no cannabis use in HIV+ participants, but higher EC activity will be associated with better neurocognitive function. In summary, this approach will allow us to elucidate several key issues, including the interaction between cannabis and the EC system, potential mechanisms that underlie these effects (lower CB2 receptor and increased FAAH expression), the assessment of EC effects on multiple biological processes implicated in HIV-mediated CNS deterioration, and the relationship between EC activity and neurocognitive performance.