The long-term objective of this proposal is to study the real-time diffusion and fate of substances in the extracellular microenvironment of the brain. Diffusion will be measured with ion-selective micro-electrodes (ISMs), carbon fiber voltammetric microelectrodes (CFVMs), which are both working in this laboratory, and quantitative optical imaging (QOI) which will be developed. The specific aims are: 1. Characterization of basic diffusion properties in selected brain regions under different conditions. Using ISMs and QOI three investigations will made: a) Diffusion in selected neural lobes of an invertebrate, the cuttlefish, for comparison with existing vertebrate data to determine the ubiquity of diffusion parameters. b) Diffusion in the optic nerve of the rat to make a comparison between white and grey matter. c) Diffusion in the isolated turtle cerebellum bathed in media of different osmotic strength to delineate the effects of extracellular space volume on diffusion. These studies will clarify fundamental diffusion mechanisms and provide a basis for future studies of altered states in anoxic or ischemic pathologies and diffusion in the developing and ageing brain. 2. Dopamine diffusion in the striatum and the general problem of uptake. Nafion coated CFVMs and high speed cyclic voltammetry will be used to measure dopamine diffusion in slices from normal and 6-hydrooxydopamine unilaterally lesioned rat striatum. Control diffusion parameters will be measured with ISMs and QOI. Equations for Michelis-Menten uptake kinetics in complex media will be developed and applied to the analysis of dopamine migration. Diffusion and uptake of dopamine in the striatum is a key to replacement therapies for Parkinson's disease, which is simulated by the proposed lesion. Active uptake of substances commonly modifies diffusion in many parts of the brain. 3. Migration of substances at ventricular interfaces. QOI and ISMs will be used to look at substances moving across the ventricular and sub-ventricular interfaces in the isolated and perfused turtle brain. Diffusion across ventricular surfaces is a likely route for neuromodulators and is commonly employed for the administration of drugs and chemotherapy agents.