Degeneration of the dopaminergic nigrostriatal tract results in Parkinson's disease. Over the last years, rodent studies have provided evidence that the activity of the source neurons of the nigrostriatal tract in the substantia nigra pars compacta (SNc) is modulated by afferents from the subthalamic nucleus (STN). Increased STN output, a central feature of most models of parkinsonian pathophysiology, could impact SNc function in early parkinsonism, helping to compensate for the loss of striatal dopamine by increased driving of nigrostriatal neurons. In rodents, STN and SNc are linked via excitatory glutamatergic projections, or via inhibitory pathways involving GABAergic neurons in the substantia nigra pars reticulata (SNr). Activation of the excitatory projections results in increased bursting in SNc, whereas activation of the inhibitory projections lowers the average discharge rates in SNc. Our preliminary data in primates have also demonstrated excitatory and inhibitory effects of STN stimulation on SNc activity, and have indicated that striatal DA levels may be increased with STN stimulation and reduced with STN inactivation. Effects on striatal dopamine may be explained by the direct synaptic STN-SNc interaction, by actions mediated via long loop circuits through thalamus and cortex, as well as by presynaptic mechanisms. The proposed experiments will explore the STN-SNc relationship in primates, with the general hypothesis that STN activation will result in increased burst discharges in SNc and increased dopamine levels in the striatum, while STN inactivation will result in the opposite. A combination of electrophysiologic, microdialysis and anatomic methods will be used to assess effects of transient manipulations of STN activity, induced by intra-STN injections of the GABA receptor agonist muscimol or the GABA receptor antagonist bicuculline, on the neuronal activity in SNc and SNr and on striatal dopainine levels (S.A. V 1/2). Similarly, effects of """"""""deep brain"""""""" stimulation and lesions of STN will be studied to assess the impact of these commonly used neurosurgical interventions on SNc and SNr activity, and on striatal DA. In the case of STN lesions, the density of glutamate and GABA receptors in SNc will also be determined (immunoautoradiography) as an inverse measure of the strength of glutamatergic and GABAergic inputs to SNc. These studies will provide insight into the role of the STN-SNc interaction under normal and parkinsonian conditions and will help to understand the mechanisms of action of neurosurgical treatments aimed at SIN in parkinsonian patients.
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