PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

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1) The D-1 dopamine receptor in basal ganglia function. It has previously been assumed that the dopamine receptor responsible for mediating dopamine effects on behavior is the D-2 dopamine receptor; the function of D-1 receptors has been unclear. However, we have shown that the effects of D-2 agonists on the activity of basal ganglia output neurons are significantly potentiated by coadministration of a selective D-1 receptor agonist. Moreoever, effects of D-2 agonists when given alone appear dependent on endogenous dopamine providing some D-1 receptor stimulation. These studies indicate that D-1 and D-2 receptors interact synergistically to affect striatal output and demonstrate the apparent necessity for both receptors to be simultaneously stimulated for the induction of processes previously thought independently mediated by the D-2 receptor. 2) Selective modulation of dopamine autoreceptor function. If dopamine autoreceptors constitute a distinct subset of D-2 dopamine receptors which can be stimulated selectively by a specific agonist, such a drug might have therapeutic advantages in the treatment of tardive dyskinesia, schizophrenia and parkinsonism. We have defined the properties of two new drugs selected for potentially selectivity for dopamine autoreceptors. Both drugs, BHT920 and EMD38362, were found to be more effective agonists at dopamine autoreceptors than at postsynaptic dopamine receptors but each drug has some distinctive properties. These drugs will allow exploration of the therapeutic potential of selective dopamine autoreceptor stimulation and insight into the properties of the dopamine autoreceptors. 3) Consequences of dopamine receptor denervation. Neurophysiological evidence supports the idea that the consequences of stimulating D-1 dopamine receptors are altered by chronic denervation, and shows significant synergistic interactions between the dopamine receptor subtypes occur in the denervated rat. These studies and the effects of bromocriptine in the denervated rat model and in parkinsonian patients suggest that a nonselective dopamine agonist would have a greater efficacy in parkinsonism than an agonist selective for one dopamine receptor subtype.