The subthalamic nucleus plays a critical role in controlling the output of the basal gang!ia. An increased activity of subthalarnic neurons is a key feature of the dopamine-depleted state, and inactivation of these neurons following surgical intervention is effective in alleviating akinesia in Parkinson's disease patients. It is therefore important to understand l) the factors regulating the activity of these neurons under normal conditions, 2) how modification of these mechanisms induced by loss of dopamine cells in the substantia nigra produces an increase in their activity, and 3) if these changes are reversed by established and experimental treatments for Parkinson's disease. In this way it should be possible to develop new pharmacological approaches to therapy which target these neurons. We hypothesize that dopamine depletion induces long-term changes in the response of subthalarnic neurons to glutamatergic, GABAergic and dopaninergic receptor activation. Subthalamic neurons themselves utilize glutamate as a transmitter. Two major targets of these neurons are the substantia nigra zona reticulata and the external pallidum. We will use glutamate release in these structures, measured by microdialysis in conscious animals, as a functional measure of the activity of subthalamic neurons in control and dopamine-depleted states, and in dopamine-depleted animals undergoing one of three treatments: l) chronic L-DOPA administration 2) deep brain stimulation of the subthalamic nucleus 3) chronic implantation of GABA-producing cells in the subthalamic nucleus. The substantia nigra and globus pallidus glutamate release response to activation of glutamate, GABA and dopamine receptors in the subthalamic nucleus will be compared in these different groups of animals. Behavioral analyses will be carried out concomitant with these neurochemical measurements, focusing on measures of orofacial dyskinesia. These in vivo studies will therefore directly interface with the molecular studies of Project l and with the in vitro electrophysiological approach of project 2.
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