A common variation in a human gene that affects the brain's reward processing circuit increases vulnerability to the rewarding effects of the main psychoactive ingredient of cannabis in adolescent females, but not males, according to preclinical research by Weill Cornell Medicine investigators. As adolescence represents a highly sensitive period of brain development with the highest risk for initiating cannabis use, these findings in mice have important implications for understanding the influence of genetics on cannabis dependence in humans.
The brain's endocannabinoid system regulates activity of cannabinoids that are normally produced by the body to influence brain development and regulate mood, as well as those from external sources, such as the psychoactive ingredient THC, also known as Δ9-tetrahydrocannabinol, which is found in cannabis. An enzyme called fatty acid amide hydrolase (FAAH) breaks down a cannabinoid called anandamide that is naturally found in the brain and is most closely related to THC, helping to remove it from circulation.
In the study, published Feb. 12 in Science Advances , the investigators examined mice harboring a human gene variant that causes FAAH to degrade more easily, increasing overall anandamide levels in the brain. They discovered that the variant resulted in an overactive reward circuit in female--but not male adolescent mice--that resulted in higher preference for THC in females. Previous clinical studies linked this FAAH variant with increased risk for problem drug use, but no studies had specifically looked at the mechanistic effect on cannabis dependence.
Our study shows that a variant in the FAAH gene, which is found in about one-third of people, increases vulnerability to THC in females and has large-scale impact on brain regions and pathways responsible for processing reward. Our findings suggest that genetics can be a contributing factor for increased susceptibility to cannabis dependence in select populations." Dr. Caitlin Burgdorf, lead author, recent doctoral graduate from the Weill Cornell Graduate School of Medical Sciences
The team found that female mice with the FAAH variant showed an increased preference for the environment in which they'd been exposed to THC over a neutral environment when they were exposed to the substance during adolescence, and the effect persisted into adulthood. However, if female mice with this variant were exposed to THC for the first time in adulthood, there was no increased preference for THC. These findings in mice parallel observations in humans that a select population of females are more sensitive to the effects of cannabis and demonstrate a quicker progression to cannabis dependence. "Our findings suggest that we have discovered a genetic factor to potentially identify subjects at risk for cannabis dependence," said Dr. Burgdorf. Related Stories
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