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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.

SUBMITTER: Filbey FM

PROVIDER: S-EPMC2820137 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Impulsivity, variation in the cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) genes, and marijuana-related problems.

Project description:OBJECTIVE:Impulsivity is associated with increased marijuana use and subsequent marijuana-related problems among marijuana users. In addition, single nucleotide polymorphisms (SNPs) in the cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes have been associated with cannabis-related phenotypes. This exploratory study tested whether the association between different aspects of impulsivity and the number of marijuana-related problems among users is explicated by variation in these putative cannabinoid-related genes. METHOD:A total of 151 young adult regular marijuana users (used on M= 41.4% of the prior 60 days, SD = 24.3%) provided DNA and completed measures of trait (Barratt Impulsiveness Scale) and behavioral impulsivity (Stop Signal Task and Delay Discounting Questionnaire), as well as a self-report of marijuana-related problems. Three CNR1 and five FAAH SNPs were genotyped, tested for haplotype blocks, and subsequently examined for association with phenotypes described above. RESULTS:CNR1 variation significantly moderated the association between trait-level, but not behavioral, impulsivity and marijuana-related problems, such that the combination of higher trait impulsivity and CNR1 variation was associated with a greater number of marijuana-related problems. In contrast, there were no significant FAAH by impulsivity interactions; however, there was a main effect of FAAH on marijuana-related problems. CONCLUSIONS:These findings support an association with CNR1 and FAAH genes and marijuana-related problems among regular marijuana users. CNR1 variation emerged as a moderator of the relationship between trait impulsivity and marijuana problems, thus suggesting that marijuana users with CNR1 risk variants and a higher trait impulsivity are at greater risk for developing marijuana-related problems and supporting a role for CNR1 in a broader impulsivity phenotype.

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Marijuana withdrawal and craving: influence of the cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes.

Project description:AimTo examine whether withdrawal after abstinence and cue-elicited craving were associated with polymorphisms within two genes involved in regulating the endocannabinoid system, cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH). Two single nucleotide polymorphisms (SNPs) in the CNR1 (rs2023239) and FAAH (rs324420) genes, associated previously with substance abuse and functional changes in cannabinoid regulation, were examined in a sample of daily marijuana smokers.ParticipantsParticipants were 105 students at the University of Colorado, Boulder between the ages of 18 and 25 years who reported smoking marijuana daily.MeasurementsParticipants were assessed once at baseline and again after 5 days of abstinence, during which they were exposed to a cue-elicited craving paradigm. Outcome measures were withdrawal and craving collected using self-reported questionnaires. In addition, urine samples were collected at baseline and on day 5 for the purposes of 11-nor-9-carboxy-Delta9-tetrahydrocannabinol (THC-COOH) metabolite analysis.FindingsBetween the two sessions, THC-COOH metabolite levels decreased significantly, while measures of withdrawal and craving increased significantly. The CNR1 SNP displayed a significant abstinence x genotype interaction on withdrawal, as well as a main effect on overall levels of craving, while the FAAH SNP displayed a significant abstinence x genotype interaction on craving.ConclusionsThese genetic findings may have both etiological and treatment implications. However, longitudinal studies will be needed to clarify whether these genetic variations influence the trajectory of marijuana use/dependence. The identification of underlying genetic differences in phenotypes such as craving and withdrawal may aid genetically targeted approaches to the treatment of cannabis dependence.

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CNR1 and FAAH variation and affective states induced by marijuana smoking.

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