The dopaminergic transporter appears to be the primary site of action of drugs of abuse such as amphetamine and cocaine. It functions to catalyze the movement of dopamine from the extracellular to the intracellular milieu of the dopaminergic neuron to terminate the action of dopamine at pre- and post-synaptic receptors. The action of the dopaminergic transporter is generally biased in an inwardly-directed mode, however, various laboratories have shown that its bias can be partially reversed by amphetamine, other substrate analogs, or depolarization of the nerve terminal. In order to investigate and eventually understand the mechanisms related to a change in the functional bias of the dopaminergic transporter, a technique to kinetically resolve the kinetic activity of substrate transport in both directions (simultaneously) is needed. This small grant application proposes to develop and use a double chemical sensor to kinetically resolve and measure the effects of drugs of abuse (amphetamine and cocaine) on the bi-directional transport of dopamine at the dopamine transporter in vitro. The sensor is based on the rotating disk electrode in which two electrodes are mounted in the same assembly for the simultaneous measurement of two substrates for the dopamine transporter, dopamine and tyramine. The anatomical areas that will be studied include the A9 (striatal) and A10 (nucleus accumbens) dopaminergic terminal regions. The rat is the experimental animal of choice in these studies because most of the body of knowledge related to dopaminergic transporter pharmacology and behavior has been obtained with studies in this species.
| Schenk, James O (2002) The functioning neuronal transporter for dopamine: kinetic mechanisms and effects of amphetamines, cocaine and methylphenidate. Prog Drug Res 59:111-31 |
