Divergent Effects of Genetic Variation in Endocannabinoid Signaling on Human Threat- and Reward-Related Brain Function

Background: Fatty acid amide hydrolase (FAAH) is a key enzyme in regulating endocannabinoid (eCB) signaling. A common single nucleotide polymorphism (C385A) in the human FAAH gene has been associated with increased risk for addiction and obesity. Methods: Using imaging genetics in 82 healthy adult volunteers, we examined the effects of FAAH C385A on threat- and reward-related human brain function. Results: Carriers of FAAH 385A, associated with reduced enzyme and possibly increased eCB signaling, had decreased threat-related amygdala reactivity but increased reward-related ventral striatal reactivity in comparison with C385 homozygotes. Similarly divergent effects of FAAH C385A genotype were manifest at the level of brain-behavior relationships. The 385A carriers showed decreased correlation between amygdala reactivity and trait anxiety but increased correlation between ventral striatal reactivity and delay discounting, an index of impulsivity. Conclusions: Our results parallel pharmacologic and genetic dissection of eCB signaling, are consistent with the psychotropic effects of Delta(9)-tetrahydrocannabinol, and highlight specific neural mechanisms through which variability in eCB signaling impacts complex behavioral processes related to risk for addiction and obesity.