PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

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1) Roles of D-1 and D-2 Dopamine Receptors in Basal Ganglia. Concurrent D-1 and D-2 receptor stimulation is necessary for full expression of postsynaptic receptor-mediated effects of dopamine and dopamine agonists in the basal ganglia. Current results have indicated the interaction between the two receptor subtypes cannot be localized to the globus pallidus or the substantia nigra; it appears to take place in the striatum. 2) D-2 Autoreceptor/ D-2 Postsynaptic receptor Studies. The therapeutic potential of dopamine autoreceptor-selective drugs is of current concern. One factor contributing to the apparent ability of dopamine agonists with limited efficacy to selectively affect the dopamine autoreceptors is the existence of a greater D- 2 receptor reserve at dopamine autoreceptor sites relative to postsynaptic dopamine receptor sites. Two dopamine antagonists reported to selectively affect the autoreceptors do not appear selective for dopamine autoreceptors in our neurophysiological investigations. Thus, several factors make it possible for a drug to selectively affect dopamine autoreceptor-mediated function but current evidence does not suggest that the two receptors are structurally different. 3) Consequences of Dopamine Cell Degeneration in the Basal Ganglia. In an animal model of Parkinsonism, we have found neurophysiological evidence for functional up-regulation of GABA receptors in the nigra and down-regulation of these receptors and opioid receptors in the globus pallidus, correlating with decreased tonic level of activity in striatal input to the nigra and increased tonic inhibitory input to the globus pallidus. Support for the continued loss of dopamine terminals as a factor contributing to altered I-DOPA thresholds in advanced Parkinsonism was found in rats with bilateral dopamine cell lesions where I-DOPA is less effective than in unilaterally lesioned rats, presumably because of the small contralateral dopaminergic innervation unaffected by the unilateral lesion. 4) Role of the Pedunculopontine Tegmental Nucleus. A marked reduction in the number of spontaneously active dopamine cells was found in rats following kainic acid lesions of the pedunculopontine tegmental nucleus. Thus, this nucleus appears to exert a very significant tonic influence on substantia nigra dopamine cell activity.