Chronic THC exposure modulates behavioral outcomes and endocannabinoid signaling in HIV-1 Tg26 mice in a sex-dependent manner.
Barkha J. Yadav-Samudrala, Laith E. Sawaqed, Caitlin J. Huguely Wilkinson, William W. Y. Lee, Havilah P. Ravula, Isabella C. Orsucci, Gabriella Boyer, Justin L. Poklis, Wei Jiang, Sylvia Fitting
Brain Research Bulletin August 1, 2026 DOI: 10.1016/j.brainresbull.2026.112099 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | HIV-1 Tg26 transgenic mice and wild-type controls of both sexes |
| Dose | 3 mg/kg |
| Topics | Cannabis |
| Key points | HIV-1 viral protein expression was associated with impaired cerebellum-dependent motor learning, primarily in female mice, and with altered endocannabinoid signaling (elevated MAGL, depleted 2-AG in females; increased cerebellar CB1R/CB2R in males). Spinal cords showed thermal hyposensitivity and reduced 2-AG and cannabinoid receptors. Chronic THC did not produce detectable antinociception but attenuated the decline in motor coordination while upregulating cerebellar CB1R, suggesting sex-specific endocannabinoid signaling shapes the response to HIV-1 proteins. |
Abstract
While combined antiretroviral therapy (cART) has transitioned HIV-1 into a manageable chronic condition, it fails to eradicate latent viral reservoirs in the central nervous system (CNS) that drive persistent neuroinflammation and synaptodendritic injury. Consequently, people living with human immunodeficiency virus type-1 (HIV-1) often utilize cannabis to manage neurological symptoms, yet the long-term impact of exogenous cannabinoids on the HIV-1-burdened brain remains poorly understood. In this study, we utilized the HIV-1 Tg26 mouse model to evaluate how chronic Δ9-tetrahydrocannabinol (THC, 3mg/kg) exposure influences motor coordination, thermal nociception, and endocannabinoid (eCB) signaling in the context of constitutive viral protein expression. Our results demonstrate that HIV-1 viral protein expression was associated with impaired acquisition of cerebellum-dependent motor learning in a sex-dependent manner. This deficit was primarily driven by females and coincided with altered markers of eCB plasticity, characterized by elevated monoacylglycerol lipase (MAGL) expression and a depletion of 2-arachidonoylglycerol (2-AG). Conversely, males exhibit increased cerebellar CB1R and CB2R expression, which paralleled preserved rotarod performance. In the spinal cord, viral protein expression was associated with thermal hyposensitivity and a reduction in 2-AG and cannabinoid receptor levels, a pattern consistent with HIV-1-associated alterations in sensory processing circuits. While chronic THC failed to produce detectable antinociceptive effects, consistent with spinal CB1R downregulation, it successfully attenuated the temporal decline of motor coordination with upregulating cerebellar CB1R. Data from a separate acute THC cohort demonstrated detectable THC and metabolite concentrations in plasma and cortex, while also revealing sex- and genotype-dependent differences in these measures. Together, these findings identify sex-specific eCB signaling as a critical factor associated with the neurobiological response to HIV-1 proteins and provide a biological framework for understanding sex-dependent variability in cannabinoid efficacy.
Comparable studies
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Citations in the library
Cites 9
- Metabolomic profiling of cannabis use and cannabis intoxication in humans. Neuropsychopharmacology May 1, 2025
- Effects of acute THC challenge on behavior and neuroinflammation in HIV-1 Tg26 mice vary based on HIV status, chronic THC history, and sex. Brain, Behavior, and Immunity May 1, 2026
- Beneficial and adverse effects of THC on cognition in the HIV-1 transgenic rat model: Importance of exploring task- and sex-dependent outcomes. Brain, Behavior, and Immunity April 1, 2025
- Chronic Δ9-tetrahydrocannabinol treatment has dose-dependent effects on open field exploratory behavior and [3H] SR141716A receptor binding in the rat brain. Life Sciences August 15, 2023
- Hippocampal differential expression underlying the neuroprotective effect of delta-9-tetrahydrocannabinol microdose on old mice. Frontiers in Neuroscience July 18, 2023
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