The dopamine transporter has been identified as the principal brain receptor site best correlated with the rewarding and euphoric properties of cocaine. We have continued studies using site-directed mutagenesis and molecular modelling and have pursued work with pharmacologic structure/activity studies. These joint strategies aim to identify specific amino acids within the dopamine transporter that are more important for cocaine analog binding than for dopamine uptake, and to identify compounds that could interact with these regions to provide dopamine-sparing cocaine antagonists. In this year we have further defined the nature of the interaction of cocaine with the dopamine transporter. We have used these data to define small molecule lead compounds that might interact with these transporter regions to provide dopamine-sparing cocaine antagonism. More complete understanding of the interactions of dopamine and cocaine with the dopamine transporter should lead to the elucidation of better pharmacological agents useful in the treatment of cocaine abuse.