title: Individual and additive effects of the CNR1 and FAAH genes on brain response to marijuana cues.
abstract: As previous work has highlighted the significance of the cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes with respect to cannabis dependence (CD), this study sought to characterize the neural mechanisms that underlie these genetic effects. To this end, we collected DNA samples and fMRI data using a cue-elicited craving paradigm in thirty-seven 3-day-abstinent regular marijuana users. The participants were grouped according to their genotype on two single-nucleotide polymorphisms (SNPs) earlier associated with CD phenotypes: rs2023239 in CNR1 and rs324420 in FAAH. Between-group comparisons showed that carriers of the CNR1 rs2023239 G allele had significantly greater activity in reward-related areas of the brain, such as the orbitofrontal cortex (OFC), inferior frontal gyrus (IFG), and anterior cingulate gyrus (ACG), during exposure to marijuana cues, as compared with those with the A/A genotype for this SNP. The FAAH group contrasts showed that FAAH rs324420 C homozygotes also had greater activation in widespread areas within the reward circuit, specifically in the OFC, ACG, and nucleus accumbens (NAc), as compared with the FAAH A-allele carriers. Moreover, there was a positive correlation between neural response in OFC and NAc and the total number of risk alleles (cluster-corrected p<0.05). These findings are in accord with earlier reported associations between CNR1 and FAAH and CD intermediate phenotypes, and suggest that the underlying mechanism of these genetic effects may be enhanced neural response in reward areas of the brain in carriers of the CNR1 G allele and FAAH C/C genotype in response to marijuana cues.
authors.affiliation: The Mind Research Network, Albuquerque, NM 87106, USA. ffilbey@mrn.org
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Filbey
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Schacht
authors.forename: Ursula S
authors.initials: US
authors.lastname: Myers
authors.forename: Robert S
authors.initials: RS
authors.lastname: Chavez
authors.forename: Kent E
authors.initials: KE
authors.lastname: Hutchison
mesh_terms: D000293:Adolescent; D000328:Adult; D000581:Amidohydrolases / Q000235:genetics*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology*; D001931:Brain Mapping; D002186:Cannabinoids / Q000494:pharmacology; D003463:Cues; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D002189:Marijuana Abuse / Q000235:genetics* / Q000473:pathology*; D008875:Middle Aged; D010100:Oxygen / Q000097:blood; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics*; D055815:Young Adult; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D002186:Cannabinoids; D010100:Oxygen; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C543264:Cnr1 protein, rat