Several substances with significant abuse liability in man are known to interact with the nigrostriatal and mesolimbic dopamine pathways of the brain. Examples of such substances include cocaine, amphetamine, and phencyclidine. Detailed knowledge of the manner in which these drugs affect dopaminergic transmission is, therefore, of central importance in understanding the mechanisms that underlie substance abuse. For instance, understanding those mechanisms is a prerequisite for developing new therapeutic strategies for drug abusers. The objective of this application is to investigate how substances of abuse affect the spatiotemporal distribution of dopamine concentrations in the extracellular space of brain structures that received dopaminergic innervation. That distribution is regulated by the kinetics of dopamine release, molecular diffusion, and dopamine uptake. The possibility exists, therefore, that drugs might change not just the level of dopamine in the extracellular space but also it spatiotemporal distribution. Information on this aspect of dopaminergic transmission does not presently exist. This research will be conducted by using dopamine-selective microsensors that offer both high spatial and high temporal resolution. With these devices, the impact of drugs on the regulation of the spatiotemporal distribution of dopamine in the extracellular space of the caudate nucleus and nucleus accumbens of the rat will be observed.
