title: Divergent effects of genetic variation in endocannabinoid signaling on human threat- and reward-related brain function.
abstract: 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.
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. haririar@upmc.edu
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Hariri
authors.forename: Adam
authors.initials: A
authors.lastname: Gorka
authors.forename: Luke W
authors.initials: LW
authors.lastname: Hyde
authors.forename: Mark
authors.initials: M
authors.lastname: Kimak
authors.forename: Indrani
authors.initials: I
authors.lastname: Halder
authors.forename: Francesca
authors.initials: F
authors.lastname: Ducci
authors.forename: Robert E
authors.initials: RE
authors.lastname: Ferrell
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Manuck
mesh_terms: 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
chemical_list: D000581:Amidohydrolases; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D010100:Oxygen; D000099252:Fatty Acid Amide Hydrolases