Effects of acute THC challenge on behavior and neuroinflammation in HIV-1 Tg26 mice vary based on HIV status, chronic THC history, and sex

Δ⁹-tetrahydrocannabinol (THC) has been studied for its neuroprotective benefits in disease and its ability to improve HIV-1-related symptoms in clinical and preclinical models. Chronic THC administration may cause reduced sensitivity to antinociceptive, hypothermic, and anxiolytic effects following acute THC administration, and HIV status may further influence these effects. Thus, the present study investigated the effects of an acute THC challenge after chronic THC exposure on behavioral and neuroinflammatory measures using the HIV-1 Tg26 neuroHIV mouse model. HIV-1 Tg26 transgenic [Tg26(+/-), n = 32(16f)] mice and their control littermates [Tg26(-/-), n = 31(16f)] received subcutaneous injections of vehicle solution or THC (3 mg/kg), once a day, 5 days per week, for 90 days. After a 7-day drug-free period, all mice were given a high dose of THC (10 mg/kg; intraperitoneally), and their body temperature, antinociception, locomotor activity, and elevated plus maze data were collected. To assess inflammation, cytokine/chemokine levels were assessed via Bio-Plex, and microglial quantification and microglial CCL3/MIP-1α were assessed via immunohistochemistry in various brain regions. THC metabolite levels in the plasma were also collected. A chronic THC history resulted in minor behavioral/physiological changes (e.g., increase in body temperature but no effects on antinociception or locomotor activity) but overall decreases in proinflammatory and anti-inflammatory cytokines/chemokines in various brain regions of female mice. Importantly, across behavioral measures, a chronic THC history attenuated the efficacy of the acute high THC challenge dose, resulting in reduced THC-induced hypothermia, antinociception, and hypolocomotion, especially in females, and occasionally in a genotype-dependent manner. In the elevated plus maze, the acute THC challenge increased anxiety-like behavior in female mice with a chronic THC history compared to chronic vehicle history females, whereas no effects were noted in males. Further, regardless of microglial quantity, Tg26(+/-) mice showed high microglial-CCL3/MIP-1α co-occurrence in a sex- and brain-region dependent manner (e.g., basolateral nucleus of the amygdala in females & dorsal striatum in males). The data suggest that female mice may develop reduced sensitivity to THC's hypothermic, antinociceptive, and anxiolytic effects, and that this insensitivity development may depend on HIV genotype. The sex and genotype effects seen in the behavioral assays may be elucidated by differential effects in the inflammatory measures.