The main goal of the proposal is to determine the mechanism of action and structural basis for cocaine inhibition of neuronal nicotinic receptors (nAChRs). Although evidence from a number of studies makes clear the importance of cocaine inhibition of the dopamine transporter in mediating many of the addictive and locomotor effects of cocaine, our preliminary data indicate that cocaine can inhibit nicotinic receptors in a subtype-dependent manner at concentrations which are potentially relevant in mediating some of the toxicity associated with cocaine use. It is becoming increasingly apparent that the primary function of brain nicotinic receptors is to modulate the release of other neurotransmitters via presynaptic effects. Thus, it is possible that some of cocaine's effects could be related to inhibition of transmitter release via direct interactions with neuronal nAChRs. The proposal makes use of the Xenopus oocyte expression system in conjunction with single channel recording, laser pulse photolysis and molecular biology to characterize cocaine inhibition of nicotinic receptors. The applicant will gain training in the analysis of single channel and macroscopic receptor kinetics as well as additional experience in molecular biology. In order to understand the wide spectrum of cocaine effects on brain function, it will be necessary to consider the potential for cocaine effects at sites in addition to those associated with inhibition of the dopamine transporter, including binding to neuronal nicotinic receptors.