PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

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1) Dl and D2 Dopamine Receptors in Basal Ganglia: In Vitro Studies. Studies in striatal slices utilizing intracellular recording techniques find patterns of evoked spike activity and the direction/extent of rectification in current-voltage relationship data are not altered in striatal neurons following 6- week (DA) cell lesion. However, among neurons exhibiting nominal rectification in current-a-voltage relations, a time constant describing the early onset of hyperpolarizing membrane transients was significantly smaller than in control. SKF38393 effects on neuronal excitability are altered after DA cell lesion but this drug's action is unrelated to Dl receptors, raising questions about in vitro use of SKF 38393 as prototypic D1 agonist. 2) In Vivo Effects of Dopamine Agonists: Globus Pallidus. Two distinct globus pallidus cell types have been identified based on their extracellular waveforms and response to DA receptor stimulation. The cells' opposite responses to systemic apomorphine raises questions about basal ganglia circuitry. 3) Consequences of Dopamine Depletion in the Basal Ganglia . Evidence for variability in D1- mediated effects observed: after reserpine treatment, Dl agonist administration leads to an increase in the firing rate of the substantia nigra pars reticulata neurons, an effect exactly opposite to that observed in the 6-OHDA lesioned rats. Moreover, the net result of stimulating both receptor subtypes in the reserpinized preparation was, in fact, opposite to the result obtained when only Dl receptors were stimulated. 4) Role of Excitatory Amino Acid Receptor Subtypes, AMPA, and NMDA in Basal Ganglia Function. The NMDA antagonist dizocilpine had no effect on spontaneous activity in the striatum, globus pallidus, and substantia nigra pars reticulata. Although entopeduncular neurons were partially inhibited by dizocilpine(MK 801). In contrast, the AMPA antagonist NBQX produced a dose-related partial inhibition of activity in the globus pallidus, substantia nigra pars reticulata, and caudate neurons when given systemically. Local infusion of NBQX reduced pallidal activity and partially blocked effects of activating the subthalamic nuclei. Thus, tonic glutamate input serves as a driving force behind some spontaneous activity in various nuclei in the basal ganglia. Studies with glutamate antagonists ketamine and MK801 have indicated that MK801 does not appear to be an effective anesthetic; ketamine anesthesia is neither associated with nor results in a diffuse blockade of the NMDA receptor complex.