Affective and Genetic Correlates of Amphetamine Response

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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.