This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Parkinsonism arises from degeneration of dopaminergic neurons in the substantia nigra pars compacta and resulting abnormal neuronal activity patterns in the external and internal pallidal segments and in the subthalamic nucleus (STN). While the development of these pathologic activity patterns has been explained as the result of striatal dopamine loss, due to degeneration of the nigrostriatal tract, recent studies demonstrate that extrastriatal dopamine loss may also play a significant role. Our studies are examining this issue, focusing on the dopamine supply to the primate STN. We have started to analyze the extent of the dopaminergic innervation and characterize the ultrastructural localization of dopamine receptors within STN of normal and MPTP-treated parkinsonian monkeys in 11 Rhesus monkeys. We found that MPTP-treatment reduces the density of dopaminergic fibers in the STN. Ongoing studies characterize the anatomical distribution and density of dopamine receptors in the STN, using electron microscopy. We have also carried out studies of the effects of dopamine receptor ligands on the electrophysiologic STN activity. Studies in one normal animal were completed. This animals is currently being studied in the MPTP-treated state. Studies in rodents have suggested that activation of pre- and postsynaptic dopamine receptors in the STN increases neuronal firing and reduces bursting. Both actions would be considered antiparkinsonian, suggesting that dopamine receptor agonists may exert some of their beneficial antiparkinsonian effects in STN.
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