UC San Diego

HIV-associated neurocognitive impairment (NCI) remains prevalent in people with HIV (PWH) despite effective antiretroviral therapy (ART). Cannabis use is common in this population, and its primary constituents—delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)—are thought to exert distinct effects on cognition. This thesis examined the therapeutic potential of THC and CBD on NCI using the HIV-1 transgenic (HIV-1tg) rat model, which expresses seven of nine HIV proteins and recapitulates key features of PWH on ART. Translatable operant tasks—the Iowa Gambling Task (IGT), Probabilistic Reversal Learning Task (PRLT), and Progressive Ratio Breakpoint Task (PRBT)—along with the cannabinoid tetrad, were used to assess effects on risk-based decision-making, cognitive flexibility, motivation, and physiological responses.Study 1 showed THC produced function-dependent cognitive effects in HIV-1tg rats: 3 mg/kg THC enhanced learning but impaired decision-making, with no effect on reversal learning. These effects were specific to HIV-1tg rats and reflected the function-dependent effects of cannabis in PWH. Study 2 confirmed that the cognitive effects of THC were not due to differences in physiological or motivational responses. Study 3 found that CBD (0.3 and 3 mg/kg) had minimal effects, though 0.3 mg/kg CBD modestly reduced motivation in both genotypes.Findings suggest that THC, but not CBD, modulates cognition in HIV-1tg rats in a task-specific manner. These results emphasize the need to consider function specificity, individual variability, and cannabinoid interactions in treatment approaches. Future studies should explore alternate delivery methods, expanded dose ranges, and combinatorial cannabinoid strategies to better assess therapeutic potential for HIV-associated NCI.