Amphetamine Sensitization: Role of Dopamine Transporters

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DESCRIPTION (provided by applicant): Repeated exposure to psychostimulant drugs typically leads to behavioral sensitization, which refers to enhanced motor responsiveness after administration of the same or lower doses of the drug. This phenomenon, which persists well after drug taking ceases, has been suggested to contribute to various aspects of human drug addiction, including "craving" and relapse. In the research proposed here, I will investigate the role of dopamine transporter (DAT) function in the expression of behavioral sensitization. The DAT is responsible for clearing DA from the extracellular space. Using inbred Lewis and Fischer 344 rats, which have been described as addiction-prone and addiction-resistant, respectively, I will measure DAT number and function in the striatum and nucleus accumbens using quantitative autoradiography to measure in vitro radioligand binding and in vivo high-speed chronoamperometry to measure clearance of exogenous DA. Measurements will be made in untreated rats and those withdrawn from daily intravenous injections of saline or amphetamine (AMPH). These inbred rat strains exhibit basal differences in the number of DATs expressed in striatum and nucleus accumbens, but it is not clear if this leads to differences in DAT function. I will pay particular attention to correlation between individual differences in the susceptibility to express sensitization and all of the following: DAT number in dSTR, NAc and their respective subregions, basal DAT activity in these areas, and the ability of either frequent DA application and/or systemic AMPH to regulate DAT function. These experiments will help elucidate the role of the DAT in behavioral sensitization and further our understanding of the neuroadaptations associated with repeated drug intake.