Chronic CBD treatment differentially modulates neurobehavioral outcomes and endocannabinoid signaling in an aged HIV-1 Tat transgenic mouse model

Abstract

As the population of older individuals living with HIV continues to expand, identifying non-euphoric therapeutic interventions for HIV-associated complications is essential. While cannabidiol (CBD) has demonstrated neuroprotective potential, its effects following prolonged exposure in the context of an aging biological environment remain poorly understood. This study utilized aged (15–18 months) male and female HIV-1 Tat transgenic mice to evaluate the impact of chronic CBD (3 mg/kg, s.c., for 12 weeks). A behavioral battery was employed to assess object recognition memory, anxiety-like behavior, spontaneous nociception, and locomotor activity. Subsequently, liquid chromatography-tandem mass spectrometry and Western blotting were used to map endocannabinoid ligands (AEA, 2-AG, AA), metabolic enzymes (FAAH, MAGL), and receptors (CB1R, CB2R, GPR55) across the prefrontal cortex, amygdala, brainstem, and spinal cord. Results indicated that chronic CBD improved recognition memory specifically in female Tat(+) mice. While CBD treatment did not affect spinal cord-related tail flick sensitivity it universally increased supraspinal hot plate sensitivity. Chronic CBD treatment also elevated baseline body temperature and modulated body mass without impairing general locomotion. Furthermore, chronic CBD restructured the eCB signaling landscape across all examined CNS regions in a highly sex- and genotype-dependent manner. Notably, cannabinoid receptor and GPR55 expression exhibited distinct regulatory shifts governed by significant three-way interactions. These findings demonstrate that chronic CBD intervention interacts with the eCB system of aged mice in a region-specific manner. These results underscore the critical importance of considering age, sex, and treatment duration when evaluating cannabinoid-based therapies for the management of neuroHIV.