Drug abuse in the United States has increased dramatically over the last 30 years. A consistent pattern appears to involve the abuse of drugs known to be, at least in part, inhibitors of the dopaminergic transporter which mediates the uptake of this neurotransmitter into neurons. In this proposed study we plan to determine how the drug of abuse, cocaine, affects neuronal release and reuptake of dopamine as well as the multisubstrate kinetic mechanism of the transporter protein mediating uptake. This information is needed to better understand how the drugs of abuse affect dopamine signaling in space and time. The work proposed will include defining, in studies in vitro using rotating disk electrode voltammetry, the kinetic mechanisms of the inward and outward functioning transporter, studying the presynaptic receptor-mediated control of transporter function, and defining the electrogenic properties of the transporter. Studies will be conducted in tissues from the striatum and the nucleus accumbens. Once elucidated we shall investigate how these properties are altered by acute and repeated treatments with cocaine. The effects observed with cocaine will be compared to results obtained with other inhibitors of dopamine transport, including but not limited to GBR- 12909, nomifensine, and mazindol. Kinetic observations observed in vitro will be compared to those observed in vivo using in vivo voltammetry. The animal model used in these studies is the rat because much of the experimental behavioral and biochemical work related to the dopaminergic system and its involvement in drug abuse has been conducted with this species as the experimental subject. Furthermore, a strong correlation between the binding of drugs of abuse to the rat dopaminergic transporter and the induction of self-administration behaviors has been made.
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