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

BackgroundFatty 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.MethodsUsing imaging genetics in 82 healthy adult volunteers, we examined the effects of FAAH C385A on threat- and reward-related human brain function.ResultsCarriers 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.ConclusionsOur results parallel pharmacologic and genetic dissection of eCB signaling, are consistent with the psychotropic effects of Δ9-tetrahydrocannabinol, and highlight specific neural mechanisms through which variability in eCB signaling impacts complex behavioral processes related to risk for addiction and obesity.