How HIV disrupts brain cannabinoid receptors in distinct regions

Cannabinoid type 1 receptor (CB1R) regulates glutamate release and plays a key role in neuroprotection and neuroinflammation. Since CB1R is implicated in HIV-associated neurocognitive disorders (HAND), it is important to determine how its expression changes with the neurotoxic human immunodeficiency virus type-1 (HIV-1) transactivator of transcription (Tat) protein. This study examined CB1R dynamics in an inducible HIV-1 Tat transgenic mouse model. Tat expression was induced in Tat(+) mice using doxycycline (DOX). Longitudinal positron emission tomography (PET) with the CB1R-selective radiotracer [11C]-OMAR was performed at baseline, 2 weeks, and 3 months post-induction in Tat(-) and Tat(+) groups to track CB1R alterations across brain regions. Western blot analyses were conducted postmortem in the prefrontal cortex, striatum, hippocampus, cortex, cerebellum, and brainstem. In a longitudinal PET imaging study, we observed a significant upregulation of CB1R expression in the cortex and cerebellum after 2 weeks of DOX treatment in both Tat(-) and Tat(+) mice; however, this increase was not maintained at the 3-month timepoint. Western blot analysis revealed region-specific changes in CB1R levels for both genotypes with upregulation observed at 2 weeks post DOX treatment. Notably, a significant interaction between genotype × DOX in the hippocampus, cerebellum, and brainstem exhibited significant CB1R alteration by Tat expression, suggesting region-dependent regulatory mechanisms. DOX treatment and Tat expression appear to affect CB1R levels in a region-specific manner, underscoring the complexity of HAND. The differences between PET imaging and Western blot results suggest that [11C]-OMAR may lack the affinity and sensitivity to detect subtle CB1R changes at the 3-month timepoint. The low resolution of PET imaging may be another factor contributing to the detection limit. Lastly, these findings emphasize the importance of using multiple methodologies to capture nuanced molecular alterations in neuroinflammatory conditions.