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进行影响兴奋剂滥用风险的情感和药物遗传因素的临床研究的技能发展。培训将建立在候选人在研究情感和成瘾之间关系方面的临床心理学背景上。职业发展计划包括兴奋剂精神药理学、兴奋剂滥用遗传学和成瘾的情感机制方面的指导培训。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和优秀的资源，以确保候选人成功实现他的培训计划。Christopher Kahler博士（主要导师）和dr。Harriet de Wit和Henry Kranzler（共同导师）分别是成瘾的情感机制、兴奋剂精神药理学和成瘾遗传学方面的专家。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，该研究将检验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，并基于药物奖励效果的个体差异导致滥用责任的概念。该模型提出，多巴胺转运基因（一种调节兴奋剂作用关键部位的基因）对安非他明急性强化效应的影响是由享乐能力（一种与体验快乐能力相关的人格特质）的个体差异介导的。从该模型中得出的假设将通过两期双盲受试者设计实验室实验进行检验，比较108名健康的未用药参与者对安慰剂和20mg口服d-安非他明的反应。基因型和享乐能力将在测试前作为药物反应的预测因子进行评估。这项调查的结果有望支持R01申请的提交，该申请将把该模型扩展到兴奋剂滥用脆弱性的其他遗传和情感来源。总而言之，该奖项将为候选人提供必要的专业知识，以开发一个独立的创新研究项目，该项目将产生阐明兴奋剂滥用风险潜在机制的发现，并为更有效的预防干预提供信息。

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.