Affective and Genetic Correlates of Amphetamine Response

描述（由申请人提供）：该奖项的目标是支持候选人的技能发展，以进行影响兴奋剂滥用风险的情感和药物遗传学因素的临床研究。培训将建立在候选人的临床心理学背景上，研究情感与成瘾之间的联系。职业发展计划包括兴奋剂精神药理学，兴奋剂滥用的遗传学和成瘾的情感机制的指导培训。布朗大学酒精和成瘾研究中心提供了一个智力刺激的环境与优秀的资源，以确保候选人的成功实现他的培训计划。克里斯托弗·卡勒博士（主要导师）和哈里特·德威特博士和亨利·克兰兹勒博士（共同导师）分别是成瘾、兴奋剂精神药理学和成瘾遗传学的情感机制专家。该研究计划将涉及进行一项实验性药物遗传学实验室研究，测试一种假定的兴奋剂滥用脆弱性模型，该模型综合了情感和遗传风险来源，并以药物奖励效应的个体差异赋予滥用责任的概念为基础。这个模型提出，多巴胺转运蛋白基因（一种调节兴奋剂作用关键位点的基因）对安非他明急性强化效应的影响是由个体享乐能力（一种与体验快乐的能力相关的人格特质）的差异介导的。将使用两个阶段的双盲受试者内设计实验室实验，在108名健康的药物初治受试者中比较安慰剂与20 mg口服d-苯丙胺的反应，对来自该模型的假设进行检验。将在检测前评估基因型和享乐能力，作为药物应答的预测因子。这项调查的结果预计将支持提交R 01申请，这将扩大这一模型的其他遗传和情感来源的兴奋剂滥用的脆弱性。总而言之，该奖项将为候选人提供必要的专业知识，以制定独立的创新研究计划，该计划将产生阐明兴奋剂滥用风险的机制并为更有效的预防干预提供信息的发现。 公共卫生相关性：兴奋剂滥用是一种主要的公共卫生流行病，具有巨大的社会成本。本项目将阐明人格和基因如何伴随着使个体易于滥用兴奋剂，这将具有以下价值：（a）了解哪些个体滥用兴奋剂的风险最大;（B）开发更有效的预防治疗方法。

DESCRIPTION (provided by applicant): The goal of this award is to support the development of the candidate's skills to perform clinical research of affective and pharmacogenetic factors that influence stimulant abuse risk. Training will build upon the candidate's clinical psychology background in research on the association between affect and addiction. The career development plan consists of mentored training in stimulant psychopharmacology, the genetics of stimulant abuse, and affective mechanisms underlying addiction. The Brown University Center for Alcohol and Addiction Studies provides an intellectually stimulating environment with outstanding resources to ensure the candidate's successful achievement of his training plan. Dr. Christopher Kahler (primary mentor) and Drs. Harriet de Wit and Henry Kranzler (co-mentors) are each experts in affective mechanisms underlying addiction, stimulant psychopharmacology, and addiction genetics, respectively. The research plan will involve conducting an experimental pharmacogenetics laboratory study, which tests a putative model of stimulant abuse vulnerability that integrates affective and genetic sources of risk and is based on the notion that individual differences in the rewarding effects of drugs confer abuse liability. This model proposes that the influence of the dopamine transporter gene (a gene that regulates a key site of action for stimulants) on amphetamine's acute reinforcing effects is mediated by individual differences in hedonic capacity (a personality trait related to the ability to experience pleasure). Hypotheses derived from this model will be tested using a two-session double-blind within-subjects design laboratory experiment comparing response to placebo vs. 20mg oral d-amphetamine in 108 healthy drug-naive participants. Genotype and hedonic capacity will be assessed prior to testing as predictors of drug response. Results of this investigation are expected to support the submission of an R01 application that will expand this model to other genetic and affective sources of stimulant abuse vulnerability. In sum, this award will provide the candidate the necessary expertise to develop an independent innovative research program that will generate findings that elucidate mechanisms underlying stimulant abuse risk and inform more effective preventative interventions. PUBLIC HEALTH RELEVANCE: Stimulant abuse is a major public health epidemic with substantial societal costs. This project will elucidate how personality and genes concomitantly predispose individuals to stimulant abuse, which will have value for: (a) understanding which individuals are at greatest risk for stimulant abuse; and (b) developing more effective prevention treatments.