The synthesis of a large series of substituted cocaine analogs in recent years has allowed structure-activity analysis of the mechanisms by which cocaine binds to the dopamine transporter and inhibits dopamine uptake in vitro, a process considered central to the behavioral stimulant and reinforcing properties of cocaine. Because cocaine interacts with other sites in the brain which may potentiate its actions on dopamine neurons, the ability of cocaine analogs which differ in potency and selectivity at these sites to elevate extracellular dopamine levels in vivo is of great interest. Recently investigators have reported the synthesis of a cocaine analog which inhibits dopamine uptake and dopamine transporter binding in vitro with high affinity, but which lacks the behavioral stimulant and discriminative stimulus properties of cocaine. The effects of this compound and other cocaine analogs on extracellular dopamine levels in vivo are unknown. The objective of this proposal is to address the importance of neurotransmitter interactions in mesolimbic dopamine systems on the behavioral and neurochemical effects of cocaine and structurally related analogs in vivo. To this end the experiments described below are designed to compare the potencies and efficacies of cocaine and cocaine analogs as inhibitors of dopamine uptake in vitro with their potencies and efficacies to elevate extracellular dopamine and to stimulate locomotor activity in vivo.
