The Mind Research Network, Albuquerque, NM 87106, USA.
Neuropsychopharmacology. 2010 Mar;35(4):967-75. doi: 10.1038/npp.2009.200. Epub 2009 Dec 9.
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.
先前的研究强调了大麻依赖（CD）与大麻素受体 1（CNR1）和脂肪酸酰胺水解酶（FAAH）基因的相关性，本研究旨在探讨这些遗传效应的神经机制。为此，我们在 37 名 3 天戒断的大麻使用者中采集了 DNA 样本和 fMRI 数据，采用线索诱发渴求范式。根据先前与 CD 表型相关的两个单核苷酸多态性（SNP），即 CNR1 上的 rs2023239 和 FAAH 上的 rs324420，对参与者进行了分组。组间比较显示，与该 SNP 的 A/A 基因型相比，CNR1 rs2023239 G 等位基因携带者在暴露于大麻线索时，大脑中与奖励相关的区域（如眶额皮质（OFC）、下额回（IFG）和前扣带皮层（ACG））的活动明显更高。FAAH 组对比显示，FAAH rs324420 C 纯合子在奖励回路中广泛区域的激活也更高，特别是在 OFC、ACG 和伏隔核（NAc），而 FAAH A 等位基因携带者则不然。此外，OFC 和 NAc 的神经反应与风险等位基因总数之间存在正相关（经聚类校正后 p<0.05）。这些发现与先前报道的 CNR1 和 FAAH 与 CD 中间表型之间的关联一致，表明这些遗传效应的潜在机制可能是 CNR1 G 等位基因和 FAAH C/C 基因型携带者对大麻线索的大脑奖励区域的神经反应增强。
