PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

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Investigations into the role of dopamine (DA) in basal ganglia (BG) function in FY97 have focused on the subthalamic nucleus (STN), an area emerging as critical to the generation of Parkinson's disease (PD) symptomatology, and regions directly innervated by the STN, the substantia nigra pars reticulata (SNpr) and globus pallidus (GP). Extracellular single unit recording studies in intact rats with a series of full D1 receptor agonists have confirmed previous results obtained with a partial D1 agonist (SKF 38393) demonstrating that D1 receptor stimulation markedly enhances STN activity but does not exert consistent effects on SNpr and GP neurons in the absence of agonist-induced increases in D2 receptor stimulation. STN firing rates are also increased by systemically administered D1/D2 agonists but require a specific order of receptor stimulation; D2 agonists do not alter STN firing rates. These effects are inconsistent with current models of basal ganglia function and argue for important dopaminergic effects on basal ganglia output mediated via interactions with glutamatergic corticosubthalamic projections and/or direct effects on STN neurons. In a rodent model of PD [unilateral 6-hydroxydopamine(6-OHDA)-induced lesion of the median forebrain bundle], effects of DA D1/D2 agonists on STN activity are qualitatively altered. Consistent with the observation that STN lesion reduces the symptomatology of PD in man, extracellular single unit recordings in rats show STN neuronal firing rates are doubled after DA cell lesion, and reduced by systemic administration of L-DOPA or DA D1/D2 receptor agonists. These findings together with the observation that unilateral STN lesion markedly attenuates DA agonist- induced rotation in this rodent model of PD argues that STN neurons are critically involved in the hypo- and hyperactivity associated with altered levels of DA receptor stimulation in PD. Ongoing studies are focused on identifying how changes in STN activity mediate these effects. Results to date show the firing pattern of STN neurons in 6- OHDA lesioned rats becomes less burst-like; glutamatergic NMDA antagonists further reduce burst activity and attenuate D1 agonist- induced increases in STN firing rates. In the SNpr, studies of neuronal firing rate and pattern in 6-OHDA-lesioned rats have produced the unexpected finding that DA agonist induced rotational behavior does not correlate with decreases in SNpr neuronal firing rates. Dramatic changes in firing pattern have been observed, however, which involve DA agonist-induced oscillations in instantaneous frequency in the range of 0.25 - 0.05 Hz in SNpr as well as other BG nuclei. New techniques for quantifying this previously undescribed attribute of BG neuronal activity have been developed in FY97 and are being used to quantitate the effects of altering DA receptor stimulation on these oscillations within the basal ganglia nuclei.