Genetic Variation and Sex Mediate Differential Responses to ∆-9-tetrahydrocannabinol among Inbred Mice
Authors:   ,   University of Tennessee Health Science Center, Parks Cory 
Published: April 2021

The plant Cannabis sativa has been used by people for both recreational and medicinal use for thousands of years, but scientific investigation of the plant and its components didn’t begin until the early nineteen hundreds when Cannabis components known as phytocannabinoids were characterized and later isolated. In the 1970’s, ∆9-tetrahydrocannabinol (THC) was isolated and recognized as the major constituent responsible for the psychoactive and intoxicating effects associated with consumption of cannabis. This opened the door for intensive research in the field that lead to the discovery of the endogenous cannabinoid system and its associated receptors, effectors of signaling, and biosynthetic enzymes. The primary cannabinoid receptor, cannabinoid receptor 1, is a G-protein coupled receptor (GPCR) that primarily associates with Gi/o proteins, giving it the properties of having mainly inhibitory actions by decreasing release of neurotransmitters and hormones. Upon receptor activation, the Gi/o protein disassociates with and inhibits adenylyl cyclase, decreasing cAMP production, a major second messenger of the cell. After stimulation by cannabinoids, cannabinoid receptors undergo a desensitization process where they are internalized by β-arrestins. This internalization subjects the receptors to intracellular trafficking during which the majority are degraded. This causes a decrease in surface levels of cannabinoid receptors and makes the cells less sensitive to agonists. Cannabis is among the most widely used psychoactive drugs in the world. In the United States, use and legalization of cannabis continues to grow. The spreading use and legalization of cannabis has the social consequence of a diminished sense of risk to the individual. This can be harmful in and of itself, but cannabis THC concentrations in the U.S. have tripled over the last 20 years, giving rise to a more potent drug, potentially increasing risk of adverse effects associated with use. Effects of acute, short term use include faulty judgment and perception, memory impairment, motor skill dysfunction, alteration of mood, and low levels of attention and alertness. Effects associated with more chronic, long term use include risk of dependence, an increased risk of developing psychotic disorders such as schizophrenia, and long-term cognitive impairment. For cannabis, and other drugs of abuse, initial response and/or tolerance to drug effects can predict later dependence and problematic use. In the work presented here, we identify sex and genetic (strain) differences in initial response and rapid tolerance to THC, the main psychoactive ingredient in cannabis, between highly genetically divergent inbred mouse strains—C57BL/6J (B6) and DBA/2J (D2). To identify variation in THC response we use the cannabinoid-induced tetrad test which quantifies the strength of agonist mediated cannabinoid receptor signaling by measuring the level of motor activity, nociception, and hypothermia elicited by receptor activation. We then extend our study of THC response variation to the BXD genetic reference population derived from B6 and D2 strains. Increasing the number of strains tested by tenfold (N=20) we detect significant strain and sex variation in THC response and use online tools to perform QTL mapping and correlation searches to begin to uncover potential genetic drivers of variation in response to THC.