The Effects of CNR1 on Brain Function in Cannabis Users

描述（由申请人提供）：摘要。Francesca Filbey在神经心理学和神经影像学方法方面拥有丰富的研究经验，用于精神病和神经病学人群的研究。虽然她研究的人群在遗传上有患脑部疾病的风险，但她并没有直接参与遗传方面的研究。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，即开发一个独立的，由校外资助的翻译研究，跨越遗传学，认知和神经影像学方法来研究人类药物滥用。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，最终领导一个独立的和高效的药物滥用研究计划。提出了三个具体的目标，以测试整体的全球假设，CNR 1基因型增加一个人的风险，长期和不可逆的影响，药物滥用在大脑发育。我们建议（1）确定CNR 1基因型对脑功能的功能意义;（2）确定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影响。我们将通过比较成年同胞对（> 18岁）的脑功能来测试我们的整体假设，这些成年同胞对（1）多态性一致，但青少年大麻使用不一致，（2）多态性不一致，但青少年大麻使用一致，（3）CNR 1基因型和大麻使用不一致。大脑功能将通过功能性磁共振成像（fMRI）进行测量，同时向个体提供引发多巴胺能奖励途径活动的任务。这项研究将提供深入了解的遗传决定因素，增加了一个人的脆弱性，药物滥用的影响，除了潜在的神经机制，导致神经功能障碍有关的药物滥用。本案无关这些研究的结果将证明CNR 1基因型对物质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物质滥用中涉及的神经递质通路，从而有助于开发更有效的药物疗法。

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.