Linking Temporal Differences in d-Amphetamine Subjective Effects to DRD2 and DAT

Vanderbilt University, Nashville TN

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Abstract

? DESCRIPTION (provided by applicant): While the speed of delivery of drugs of abuse to the brain are thought to underlie their addictive potential, no research has focused on individual differences in speed of psychostimulant-induced high and liking and whether such differences are reflected at the level of the brain, personality, or genetics. Yet, preliminary data from our research group indicates there are dramatic differences in the temporal profile of subjective responses to oral d-amphetamine. The research proposed in this fellowship will use Positron Emission Tomography (PET) to assess multiple aspects of dopamine system function (striatal and extrastriatal D2-like binding potential, dopamine transporter levels, and d-amphetamine-induced dopamine release) and relate these PET measures to differences in positive subjective responses (drug high and liking) to d-amphetamine, with a particular emphasis on the timing of peak positive subjective drug effects. Furthermore, the proposed research will assess how individual differences in dopamine system function and the positive subjective effects of d-amphetamine vary with personality traits and genetic polymorphisms in healthy adults. Specifically, we will investigate the role of commonly studied polymorphisms in dopamine-related genes as well as a signal nucleotide polymorphism in the cadherin 13 gene previously found to be associated with the positive subjective effects of d-amphetamine in a genome wide association study. The goal of this research plan is to better understand individual differences that confer potential risk for psychostimulant addiction including a fast rise in dopamine and increased subjective high/liking after drug intake. The applicant's long-term goals are to identify how differences in dopamine system function relate to addiction risk at the level of behavioral endophenotypes including subjective drug high/liking time to peak, novelty seeking, and impulsivity (including steep temporal discounting). This fellowship will help the applicant develop expertise in measuring variation in the dopamine system (through PET and genetic approaches) and prepare him for a productive career as an independent investigator of dopamine's role in addiction risk, externalizing behaviors, and other traits often associated with drug addiction.