This revised level II Research Scientist Development Award (KO2) application involves in vivo electrochemical and microdialysis studies of the extracellular regulation and neurochemistry of dopamine (DA) in the basal ganglia of both normal and lesioned rats and monkeys. These studies address the role of DA in motor behavior and the inherent plasticity and compensatory neurochemical properties of damaged dopaminergic neurons. First, extracellular regulation of potassium-evoked overflow of DA and clearance/diffusion of DA, L-Dopa and D-Dopa will be investigated in the striatum, nucleus accumbens, substantia nigra and ventral tegmental area of the unilateral 6-OHDA-lesioned Fischer 344 rat, using high-speed (5-25 Hz) chronoamperometry coupled with pressure ejection of drugs from micropipettes. Microdialysis studies of the extracellular regulation of potassium-evoked overflow of DA in both normal and 6-OHDA-lesioned rat striatum and substantia nigra be used to further confirm the validity of the electrochemical studies and to investigate changes in the metabolic regulation of DA in the damaged striatum. As part of his scientific development, the applicant will work on the development of semiconductor- based microphobes that can be used for combined in vivo electrochemical and electrophysiological recordings. Secondly, as part of the applicant's further scientific development, extracellular regulation of DA and potassium-evoked overflow of DA will be investigated in the caudate nucleus,putamen and nucleus accumbens of unilateral MPTP-lesioned Rhesus monkeys. In addition, the effects of a glial-derived neurotrophic factor (GDNF), a new dopaminotrophic factor that promotes the survival of DA neurons, will be studied following unilateral infusion of this growth factor into the substantia nigra of unilateral MPTP-treated Rhesus monkeys. All of the proposed studies will contribute to the scientific development of the applicant and a further neurochemical understanding of the plasticity and compensatory properties of DA neurons, and how this relates to DA's role in movement and movement disorders.
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