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.
Hariri
Ahmad R
AR
Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. haririar@upmc.edu
Gorka
Adam
A
Hyde
Luke W
LW
Kimak
Mark
M
Halder
Indrani
I
Ducci
Francesca
F
Ferrell
Robert E
RE
Goldman
David
D
Manuck
Stephen B
SB
D000328:Adult; D000581:Amidohydrolases / Q000235:genetics*; D000704:Analysis of Variance; D001007:Anxiety / Q000235:genetics*; D001921:Brain / Q000033:anatomy & histology / Q000098:blood supply / Q000502:physiology*; D001931:Brain Mapping; D063385:Cannabinoid Receptor Modulators / Q000235:genetics; D063388:Endocannabinoids; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000097:blood; D011569:Psychiatric Status Rating Scales; D012044:Regression Analysis; D012201:Reward; D015398:Signal Transduction / Q000235:genetics; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D010100:Oxygen; D000099252:Fatty Acid Amide Hydrolases