Experimental and theoretical investigation of striatal dopamine concentration measured by voltammetry and microdialysis

The widespread use of voltammetric microelectrodes and microdialysis probes as analytical tools for brain research requires understanding how these devices function in the complicated physiochemical environment of the brain. This dissertation describes the progress we have made in advancing this understanding. In one study, carbon fiber microelectrodes were either implanted directly into brain or were mounted into the outlet of microdialysis probes that were implanted in the brain. This allowed voltammetry and microdialysis to be used under identical in vivo conditions to monitor electrically-evoked dopamine, before and after uptake inhibition. These experiments have led to the development of a numerical model that rationalizes the observations reported herein and allows in vivo voltammetry and microdialysis results to be interpreted within a single theoretical framework. Next, finite differences simulations were used to solve this model under a variety of boundary condition appropriate for the simulation of microdialysis and voltammetry. The simulations qualitatively agree with both voltammetry and microdialysis results obtained in our laboratory, as well as with steady state microdialysis results. Two of the key conclusions drawn from these results are that microdialysis extraction and recovery ratios are unequal, and that recovery increases dramatically with uptake inhibition. The numerical model described above was further used to consider whether the limited diffusion distance of dopamine in vivo produces spatial heterogeneity in extracellular dopamine concentration on a dimensional scale of a few micrometers. Spatially resolved measurements of electrically-evoked dopamine were performed in the brain with carbon fiber microdisk electrodes before and after the administration of drugs that selectively affect dopamine release and uptake. The comparison between the outcome of these experiments and the predictions derived from the model suggests that the extracellular dopamine concentration is spatially heterogeneous on a micrometer scale. Lastly, electron microscopy was used to examine the tissue surrounding microelectrode implantation site in the brain. The results of these experiments reveal that intact synapses are present within micrometers of where the electrode had been implanted, contrasting with the extensive damage seen around microdialysis probe implantation sites. These observations further explain the differences in the results obtained by voltammetry and microdialysis in vivo.