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

描述（由申请人提供）：尽管大麻是美国最常滥用的非法药物，增加对大麻奖励作用敏感性的已知危险因素的作用机制仍然未知。基于我们对大麻依赖中线索引发渴望的神经机制的研究，这些研究的目标是描述遗传和环境因素调节大脑对大麻线索的反应的机制。具体来说，我们将测试大麻素受体1（CNR1）和脂肪酸酰胺水解酶（FAAH）基因，这些基因与对大麻的渴望有关，并且是一种与药物滥用发展有关的环境因素，我们的早期研究结果表明，这与对线索的反应呈正相关，即早期生活压力。为此，我们将在大麻线索暴露任务期间记录当前重度大麻使用者的fMRI BOLD反应，并确定遗传（即，CNR1，FAAH）和环境（即，早期生活压力）变量。基于我们的初步研究结果，我们预测遗传和环境变量将缓和大脑奖励区域对线索的神经反应。拟议的工作将证实遗传学的贡献（即，CNR1和FAAH基因）和环境（即，早期生活压力）对大麻依赖的风险因素，更重要的是，揭示这些已知的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识别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.