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 confirm that Dl stimulation typically exerts an inhibitory effect on striatal neurons with dopaminergic innervation intact. In contrast, the majority of striatal neurons in tissue ipsilateral to 6 week 6-hydroxydopamine (6-OHDA) lesions respond to a Dl agonist, SKF 38393, with an increase in excitability, suggesting that a dramatic difference in the function of the striatal Dl receptors or coupled intracellular processes occurs following dopaminergic denervation. If confirmed, these findings will be the first in vitro evidence to indicate that chronic dopaminergic denervation changes the predominant effect of D1 stimulation in the striatum from inhibition to excitation. 2) Consequences of Dopamine Depletion in the Basal Ganglia. Two strategies for depleting dopamine, 6-OHDA-induced dopamine cell lesion and subchronic treatment with reserpine, are thought to induce comparable behavioral indications of dopamine receptor supersensitivity. However, in 6-OHDA-lesioned rats, a Dl agonist produces a decrease in rate in the substantia nigra pars reticulata while in the reserpine-treated rats an increase in the firing rates of cells in the substantia nigra pars reticulata occurs. Thus, through as yet unidentified processes, these two strategies for depleting dopamine exert different effects on Dl-mediated mechanisms resulting in opposite changes in basal ganglia output. 3) Role of Excitatory Amino Acid Receptor Subtypes, AMPA and NMDA in Basal Ganglia Function. The NMDA antagonist MK 801 alters the effects of apomorphine on type I caudate neurons and on Type II globus pallidus neurons. MK 801 also completely blocks the Dl agonist SKF 38393's inhibitory effect on dopamine cells and excitatory effect on reticulata cells in reserpine-treated rats. in addition, MK 801 blocks the inhibitory effect of the Dl agonist on reticulata cells in 6-OHDA lesioned rats. These results provide evidence for an apparent dependence of dopamine-mediated effects in the basal ganglia on tonic glutamatergic activity and indicate that blockade of NMDA receptors "upstream" from the globus pallidus interferes with dopamine-mediated neuronal transmission through the neostriatum. In contrast, the AMPA antagonist, NBQX inhibits the firing rate of both Type I caudate neurons and Type 11 globus pallidus cells but does not alter their response to apomorphine.