Beneficial and adverse effects of THC on cognition in the HIV-1 transgenic rat model: Importance of exploring task-and sex-dependent outcomes

HIV-associated neurocognitive impairment (NCI) is an untreated concern among people living with HIV (PLWH). Cannabis use in PLWH may complicate outcomes on cognition, with evidence to suggest function-dependent effects that are modulated by several factors including use patterns (e.g., frequency of use) and demographic influences (e.g., age). Animal studies can control for these factors. Here, we characterized the impact of the primary psychoactive ingredient in cannabis (delta-9-tetrahydrocannabinol; THC), on function-dependent cognitive outcomes in HIV-1 transgenic (Tg) rats using cross-species translatable assays. Female and male HIV-1Tg rats and their controls were tested in the rat Iowa Gambling Task (IGT; to measure risk-based decision-making), and the Probabilistic Reversal Learning Task (PRLT; to measure learning and cognitive flexibility). Rats were tested at baseline, then retested following acute and chronic exposures to THC (0, 0.3, 3 mg/kg, intraperitoneal injection). At baseline, HIV-1Tg rats took longer to make decisions, but exhibited intact cognition across tasks, suggestive of a speed-accuracy trade-off and early cognitive deficits. Both acute and chronic THC exposures produced selective effects on primary performance measures in HIV-1Tg rats, including enhanced learning performance but worsened risk-based decision-making, not observed in controls. This work confirms function-dependent effects of THC on cognitive function in an animal model of HIV using cross-species translatable tasks used in the clinic. Findings are consistent with evidence for function-dependent cannabis effects observed in HIV, and suggest THC may drive cannabis-induced changes observed on cognitive performance in PLWH. These data may serve as guidance for clinicians prescribing cannabis to patients with HIV, and for further research exploring the interactive effects of HIV and cannabinoid treatment on cognitive function.