The dopamine transporter (DAT) has been a principal brain receptor site that has been correlated with the rewarding and euphoric properties of cocaine. It 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 continued during this year with further characterization of the roles of selected amino acid sidechains in transporter functions. These studies have focused on single- and multiple-domaine amino acid changes of interest in the rat dopamine transporter and on characterization of the amino acid changes produced by human allelic variants of the DAT sequence identified in other studies reported during this year. These studies continue to improve identification of selective DAT domains and interacting regions that are important for cocaine analog recognition or for dopamine transport and on regions important for the effects of PKC and MAP kinase pathways on DAT function. They have identified surprisingly-large effects of one of the human DAT allelic variants on DAT expression and function. These insights should help in identification of structure- function features of small molecule compounds possibly active in vivo as cocaine antagonists, structure-function relationships relevant to DAT regulation, and human individual differences in DAT pharmacology.
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