Chronic {triangleup}9-Tetrahydrocannabinol Vapor Self-Administration Modulates Gut Microbiota and the Immune and Endocannabinoid Systems in Female Sprague-Dawley Rats

Vaping of cannabis and its primary components, including {triangleup}9-tetrahydrocannabinol (THC), has increased during the last decade, especially among adolescents and adults. While the behavioral consequences of THC, including anxiety, depression, and associated impacts on reward-related signaling, are well documented, evaluation of additional pathways that have implications for neuronal function remains relatively unexplored. Further, despite evidence of the impact of THC on several physiologic processes, most studies have focused on the brain even though the endocannabinoid system with which THC interacts has widespread expression and functions throughout the body. To address these gaps, we obtained biological samples from adult female Sprague-Dawley rats (N=5-6 per group; all females) that were passively exposed to THC or vehicle vapor and then allowed to self-administer vaporized THC or vehicle intermittently for nine months. Animals were euthanized, and brain and peripheral organs were collected for analyses. We evaluated genes of endocannabinoid system-related receptors, modulators, ion channels, and metabolic enzymes, along with immune and microbiome-related pathways in 9 peripheral organs, 14 brain regions, and plasma. We observed that rats exposed to chronic intermittent THC vapor administration had widespread modulation of several endocannabinoid-system genes only in the brain, with most changes occurring in the dorsal striatum and hippocampus. In contrast, endocannabinoid-system gene expression in all evaluated peripheral organs remained unchanged after THC exposure. Similar findings occurred with immune-relevant genes, where il-1beta, il-6, ccl2, and mx1 were modulated only in the brain while expression in peripheral organs remained unchanged. Immune system modulation following chronic THC exposure significantly elevated plasma concentrations of IL-17A, gut microbiota dysbiosis, and global changes to circulating metabolites, including several amino acids, fatty acids, aminosugar, and nucleic acids. Our findings provide, for the first time, a whole-body evaluation of the molecular effects of chronic THC exposure throughout adulthood on the endocannabinoid and immune systems that have implications for cannabinoid-related behavioral effects.