Genetic and Environmental Modulators of the Brain's Response to Marijuana Cues

描述(申请人提供)：尽管大麻是美国最常被滥用的非法药物，但增加对大麻有益效果易感性的已知风险因素的作用机制仍不清楚。在我们对大麻依赖中线索引发的渴望的神经机制的研究基础上，这些研究的目标是表征遗传和环境因素调节大脑对大麻线索的反应的机制。具体地说，我们将测试大麻素受体1(CNR1)和脂肪酸酰胺水解酶(FAAH)基因，这两个基因与对大麻的渴望有关，也是一个与药物滥用发展有关的环境因素，我们的早期发现表明，它们与对暗示的反应呈正相关，即早期生活压力。为此，我们将记录当前大量吸食大麻的人在大麻线索暴露任务中的fMRI大胆反应，并确定遗传变量(即CNR1、FAAH)和环境变量(即早期生活应激)之间的主要影响和相互作用。根据我们的初步发现，我们预测遗传和环境变量将缓和大脑奖赏区域对线索的神经反应。这项拟议的工作将证实遗传(即CNR1和FAAH基因)和环境(即早期生活应激)风险因素对大麻依赖的贡献，更重要的是，揭示这些已知风险因素增加大麻依赖发病率的机制。这些研究的成功完成将有助于确定有大麻依赖风险的个人，并为更有针对性的治疗提供信息。

DESCRIPTION (provided by applicant): Despite marijuana being the most commonly abused illicit drug in the U.S., the mechanisms of action for known risk factors that increase susceptibility to marijuana's rewarding effects remain unknown. Building upon our studies on the neural mechanisms of cue-elicited craving in marijuana dependence, the goal of these studies is to characterize the mechanisms by which genetic and environmental factors moderate the brain's response to marijuana cues. Specifically, we will test the cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes, which are associated with craving for marijuana, and, an environmental factor with links to the development of substance abuse, and which our early findings suggest is positively associated with response to cues, namely early life stress. To that end, we will record fMRI BOLD response in current heavy marijuana users during a marijuana cue exposure task, and determine the main effects and interactions between the genetic (i.e., CNR1, FAAH) and environmental (i.e., early life stress) variables. Based on our preliminary findings, we predict that the genetic and environmental variables will moderate the neural response to cues in reward areas of the brain. The proposed work will corroborate the contributions of genetic (i.e., CNR1 and FAAH genes) and environmental (i.e., early life stress) risk factors towards marijuana dependence and, more importantly, uncover the mechanisms by which these known risk factors increase morbidity for marijuana dependence. The successful completion of these studies will help identify individuals who are at risk for marijuana dependence and inform on more targeted treatment.