Dopamine Transporter--Structure/function Studies Of Tran

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The dopamine transporter (DAT) has been a principal brain receptor site that has been correlated with the rewarding and euphoric properties of cocaine. MNB scientists cloned the DAT cDNA and gene, and found that deletion of both DAT and SERT are required to eliminate cocaine conditioned place preferences in mice. DAT is required for the actions of each of the current dopamine-selective toxins that produce the best models of Parkinson's disease. Analyses of DAT structure- function relationships, and their relationships with serotonin systems defined through the serotonin receptor subtypes, continued during this year. Work from prior years concerning structure/function relationships of the dopamine tranporter and small molecule substrates and ligands was reported during the year. We also reported further characterization of promoter region haplotypes and their roles in level of expresion variation in vivo. Studies refined the definition of the 5'DAT haplotypes in ways that we reported to correlate with 1)levels of DAT expression in vivo in imaging and 2) levels of DAT expression identified in postmortem human striatal samples. "Triple knockout" mice with alterations of DAT, 5HT1A and 5HT1B receptors produced effects on cocaine reward not identified in single- or double-knockout mice. These insights should continue to help in identification of structure-function relationships relevant to DAT regulation and human individual differences in DAT levels of expression and pharmacology.