FUNCTION OF DOPAMINE IN THE PRIMATE SUBSTANTIA NIGRA

Emory University, Atlanta GA

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Abstract

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. We carried out further studies of the anatomic distribution of D2-receptors in SNr, and have expanded the studies to include the other major extrastriatal basal ganglia nuclei, the internal and external pallidal segments (GPi, GPe). The results show that D2-receptor immunoreactivity is found predominately on unmyelinated axons and dendrites in both nuclei. D2-immunoreactive glial processes were also found. We also continued our studies of activation or inactivation of D2-like receptors in these nuclei. We locally injected D2-like receptor agonists and antagonists in two normal animals and two MPTP-treated (parkinsonian) animals, and recorded the neuronal activity in the vicinity of the injection site. Most GPe cells increased their activity in response to quinpirole injections, while the firing rate of GPi and SNr cells decreased. The predominant increase of the discharge rates of GPe neurons may result from activation of presynaptic D2 receptors on striato-pallidal terminals, reducing the release of GABA in GPe. Postsynaptic D4 receptors may also be involved, acting to reduce GABAergic inhibition. The inhibitory effects on GPi/SNr could be mediated through presynaptic inhibition of glutamate release from terminals of inputs from the subthalamic nucleus. Sulpiride injections into GPe, GPi or SNr in normal animals had no effect. 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 GPi), while actions at the level of the SNr may explain some of the unwanted side effects of these medications, such as psychosis.