The Effects of CNR1 on Brain Function in Cannabis Users

描述(申请人提供)：摘要。弗朗西斯卡·菲尔贝在精神病学和神经学人群的研究中，在神经心理学和神经成像方法方面拥有丰富的研究经验。尽管她研究了大脑疾病的遗传风险人群，但她并没有直接参与遗传方面的研究。她目前的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，即开发一项独立的、由外部资助的翻译研究，该研究涵盖遗传学、认知和神经成像方法，用于研究人类的药物滥用。一项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，最终领导一项独立的、高效的药物滥用研究计划。提出了三个具体的目标来检验总体的全球假设，即CNR1型会增加一个人在发育中的大脑中长期和不可逆转的药物滥用影响的风险。我们建议(1)确定CNR1型对脑功能的功能意义；(2)识别和表征吸食大麻对脑功能的影响；以及(3)确定这些危险因素对发育中的大脑的综合影响。我们将通过比较成年同胞对(18岁)的大脑功能来检验我们的全球假设，这些成年同胞对(1)多态性一致但对青少年大麻使用不一致，(2)多态性不一致但对青少年大麻使用不一致，以及(3)CNR1基因和大麻使用都不一致。大脑功能将通过功能磁共振成像(FMRI)进行测量，而个体面临的任务将引发多巴胺能奖赏通路的活动。这项研究将提供对增加一个人对物质滥用影响的易感性的遗传决定因素的洞察，以及导致与物质滥用相关的神经功能障碍的潜在神经机制。关联性。这些研究的结果将证明，CNR1基因对药物滥用影响的调节作用会导致持久和有害的影响。这些发现将对药物滥用人群的预防和干预策略产生影响。这些发现还将有助于了解药物滥用所涉及的神经递质途径，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.