This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Degeneration of the dopaminergic nigrostriatal tract results in Parkinson's disease. 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 study explores whether these findings also apply to the STN-SNc relationship in primates, with the hypothesis that STN activation will result in increased burst discharges in SNc and increased striatal dopamine levels, while STN inactivation will result in the opposite. A combination of electrophysiologic, microdialysis and anatomic methods is used to assess effects of transient manipulations of STN activity, induced by intra-STN injections of GABA receptor agonists or antagonists on the neuronal activity in SNc and SNr and on striatal dopamine levels. Similarly, effects of lesions of STN are being studied to assess the impact of these commonly used neurosurgical interventions on SNc activity, and on striatal DA levels. In the case of STN lesions, the density of glutamate and GABA receptors in SNc will also be determined as a measure of the strength of glutamatergic and GABAergic inputs. These studies provide insight into the STN-SNc interaction under normal and parkinsonian conditions. They also help to understand the mechanisms of action of neurosurgical treatments aimed at STN in parkinsonian patients.
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