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Divergent effects of genetic variation in endocannabinoid signaling on human threat- and reward-related brain function.

ABSTRACT: 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.Using imaging genetics in 82 healthy adult volunteers, we examined the effects of FAAH C385A on threat- and reward-related human brain function.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.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.

SUBMITTER: Hariri AR

PROVIDER: S-EPMC3215587 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Divergent effects of genetic variation in endocannabinoid signaling on human threat- and reward-related brain function.

Hariri Ahmad R AR 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

Biological psychiatry 20081221 1

<h4>Background</h4>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.<h4>Methods</h4>Using imaging genetics in 82 healthy adult volunteers, we examined the effects of FAAH C385A on threat- and reward-related human brain function.<h4>Results</h4>Carriers of FAAH 385A, associated with reduced enzyme and possibly incr ...[more]

PMID: 19103437

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Project description:CONTEXT:The CACNA1C gene (alpha-1C subunit of the L-type voltage-gated calcium channel) has been identified as a risk gene for bipolar disorder and schizophrenia, but the mechanism of association has not been explored. OBJECTIVE:To identify the neural system mechanism that explains the genetic association between the CACNA1C gene and psychiatric illness using neuroimaging and human brain expression. DESIGN:We used blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to measure brain activation in circuitries related to bipolar disorder and schizophrenia by comparing CACNA1C genotype groups among healthy subjects. We tested the effect of genotype on messenger RNA (mRNA) levels of CACNA1C in postmortem human brain. A case-control analysis was used to determine the association of CACNA1C genotype with schizophrenia. SETTING:National Institutes of Health Clinical Center. PATIENTS:Healthy men and women of white race/ethnicity participated in the fMRI study. Postmortem samples from normal human brains were used for the brain expression study. Patients with schizophrenia and healthy subjects were used in the case-control analysis. MAIN OUTCOME MEASURES:BOLD fMRI, mRNA levels in postmortem brain samples, and genetic association with schizophrenia. RESULTS:The risk-associated single-nucleotide polymorphism (SNP rs1006737) in CACNA1C predicted increased hippocampal activity during emotional processing (P = .001 uncorrected, P((false recovery rate [FDR])) = .05, z = 3.20) and increased prefrontal activity during executive cognition (P = 2.8e-05 uncorrected, P(FDR) = .01, z = 4.03). The risk-associated SNP also predicted increased expression of CACNA1C mRNA in human brain (P = .002). CACNA1C was associated with schizophrenia in our case-control sample (odds ratio, 1.77; P = .03). CONCLUSIONS:The risk-associated SNP in CACNA1C maps to circuitries implicated in genetic risk for bipolar disorder and schizophrenia. Its effects in human brain expression implicate a molecular and neural system mechanism for the clinical genetic association.

Dataset Information

Divergent effects of genetic variation in endocannabinoid signaling on human threat- and reward-related brain function.

Publications

Divergent effects of genetic variation in endocannabinoid signaling on human threat- and reward-related brain function.

Similar Datasets

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