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. We study dopaminergic transmission in the substantia nigra pars reticulata (SNr) of normal and parkinsonian animals, with anatomic and electrophysiologic techniques. During this period of funding, we carried out experiments of the distribution of D2-receptors in SNr. These studies are still ongoing, but the first results show that D2-receptors immunoreactivity is found predominately on unmyelinated axons and on dendrites in the SNr. D2-immunoreactive glial processes were also found in the SNr. We also continued our work on the functional effects of activation or inactivation of D2-like receptors in the SNr. We locally injected D2-like receptor agonists and antagonists in two normal animals and recorded the neuronal activity in the vicinity of the injection site. The spiking activity of all of the recorded cells was inhibited by the agonist, but not affected by the antagonist. The known (inhibitory) pharmacologic effects of D2-like receptor activation and the distribution of these receptors suggest that the effects mediated through D2-like receptor agonists are due to inhibition of glutamatergic inputs to SNr cells (likely arising from the subthalamic nucleus). We are currently in the process of treating our animals with MPTP to assess the effects of the agonist in parkinsonism. The findings are clinically significant, because most of the clinically used dopamine receptor agonists act at D2-like receptors. Our results suggest that these compounds may strongly affect basal ganglia output at extrastriatal sites. The beneficial motor effects of these drugs may mostly result from actions within the motor circuit of the basal ganglia (and may, therefore, predominately involve the internal pallidal segment (GPi)), while actions at the level of the SNr may explain some of the unwanted side effects of these medications, particularly their propensity of producing psychosis.
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