The Effects of CNR1 on Brain Function in Cannabis Users

描述（由申请人提供）：概述。Francesca Filbey在神经心理学和神经成像方法方面有丰富的研究经验，研究精神病学和神经学人群。尽管她研究的是那些在基因上有患脑部疾病风险的人群，但她并没有直接参与基因方面的研究。她的近期职业目标是获得必要的研究和专业技能，以实现她的长期目标，即发展一个独立的，外部资助的转化研究，涵盖遗传学，认知和神经影像学方法，以研究人类药物滥用。一个为期五年的职业发展计划将为候选人提供所需的多学科技能，最终领导一个独立和高效的药物滥用研究项目。研究人员提出了三个具体目标，以验证CNR1基因型会增加大脑发育过程中药物滥用的长期和不可逆影响的风险。我们提出(1)确定CNR1基因型对脑功能的功能意义；(2)识别和表征大麻使用对脑功能的影响；(3)确定这些危险因素对发育中的大脑的复合效应。我们将通过比较(1)多态性一致但青少年大麻使用不一致的成年兄弟姐妹（bb - 0 - 18岁）的脑功能来验证我们的全球假设，(2)多态性不一致但青少年大麻使用一致，(3)CNR1基因型和大麻使用都不一致。脑功能将通过功能性磁共振成像（fMRI）来测量，同时向个体展示引发多巴胺能-奖励通路活动的任务。这项研究将提供深入了解基因决定因素，增加一个人对药物滥用影响的脆弱性，以及导致与药物滥用相关的神经功能障碍的潜在神经机制。的相关性。这些研究结果将证明CNR1基因型对药物滥用影响的调节作用导致持久和有害的影响。这些发现将影响药物滥用人群的预防和干预策略。这些发现也将有助于理解与药物滥用有关的神经递质途径，从而有助于开发更有效的药物治疗方法。

DESCRIPTION (provided by applicant): SUMMARY. Francesca Filbey has extensive research experience in neuropsychology and neuroimaging methods in the study of psychiatric and neurologic populations. Although she studied populations who are genetically at-risk for brain disorders, she has not been directly involved in the genetic aspects. Her immediate career goal is to acquire the research and professional skills necessary for achieving her long-term goal of developing an independent, extramurally funded translational research that spans genetics, cognitive and neuroimaging approaches to the study of substance abuse in humans. A five-year Career Development Plan will provide the candidate with the multi-disciplinary skills required to ultimately lead an independent and highly productive research program in substance abuse. Three specific aims are proposed to test the overall global hypothesis that CNR1 genotype increase one's risk to long-term and irreversible effects of substance abuse in the developing brain. We propose (1) to determine the functional significance of CNR1 genotype on brain function; (2) to identify and characterize the effects of marijuana use on brain function; and (3) to determine the compounding effects of these risk factors on the developing brain. We will test our global hypothesis by comparing brain function in adult sib-pairs (> 18 years old) who are (1) concordant for the polymorphism but discordant for adolescent cannabis use, (2) discordant for the polymorphism but concordant for adolescent cannabis use and (3) discordant for both CNR1 genotype and marijuana use. Brain function will be measured by functional magnetic resonance imaging (fMRI) while individuals are presented with tasks that elicit activity in the dopaminergic-reward pathway. This study will offer insight into the genetic determinants that increase one's vulnerability to the effects of substance abuse, in addition to the underlying neural mechanisms that lead to neural dysfunction related to substance abuse. RELEVANCE. The findings from these studies will demonstrate that the modulating effects of CNR1 genotype on the effects of substance abuse leads to enduring and deleterious effects. These findings will impact prevention and intervention strategies in the substance abusing population. These findings will also contribute to the understanding of the neurotransmitter pathways involved in substance abuse, thereby aiding in the development of more effective pharmacotherapies.