The assessment of dopaminergic neurotransmission at both the presynaptic and postsynaptic level by in vivo electrochemical and electrophysiological manes, has been the object of investigation in our laboratory during the previous funding period. We intend to continue these investigations and address basic questions about presynaptic and postsynaptic dopaminergic mechanisms. First, high-speed chronoamperometric measures will be used to compare dopamine (DA) diffusion and clearance in normal and unilateral 6- OHDA-lesioned striatum. Our preliminary data suggest a much more extensive diffusion of DA in denervated striatum. In addition, using electrophysiological techniques, we will determine if denervation alters the relative effects of D1 and D2 receptors on caudate neurons as part of the induction of supersensitivity. Secondly, electrochemical methods using Nafion-coated recording electrodes will be used to measure the magnitude and temporal dynamics of potassium-evoked or electrically-induced release of DA in unanesthetized freely-moving animals, for comparison with the data obtained from anesthetized animals. Third, we will continue our ongoing electrophysiological characterization of the differential effects of D1 and D2 receptor activation, with attention both to intracellular transduction and ionic mechanisms and also to effects on both spontaneous and synaptic evoked activity. The role of different second messenger systems in D1 and D2 postsynaptic responses will also be elucidated by pertussis toxin inactivation of certain G-proteins. In addition, the effects of D1 and D2 receptor activation on the potassium-evoked overflow of DA will be measured using in vivo electrochemistry. Finally, the effects of chronic administration of DA agonists to presynaptic and postsynaptic elements in both normal and 6-OHDA lesioned animals will be investigated using electrophysiological, electrochemical and brain microdialysis methods. These experiments will lead to a better understanding of dopamine physiology in the intact and denervated caudate nucleus. Our efforts play two roles in this program project: (1) our in vivo electrochemical measurements of the function of the presynaptic dopaminergic nerve terminal and the electrophysiological assessment of postsynaptic responses to DA will be used by investigators in other projects to assess the function of transplants, and (2) our data from normal, 6-OHDA lesioned, and chronically treated animals will be used as a standard of comparison for the quantitative assessment of the recovery of function from various transplantation operations. Thus, this project will contribute to both the methodology and the data analysis of this program project.
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