Continuous administration decreases and pulsatile administration increases behavioral sensitivity to a novel dopamine D2 agonist (U-91356A) in MPTP-exposed monkeys.

Abstract

We compared the behavioral effects of a novel and highly selective dopamine D2 receptor agonist, U-91356A, administered to 6 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-exposed parkinsonian monkeys for 27 days following an intermittent (n = 3) or continuous (n = 3) schedule, using subcutaneous osmotic minipumps for the latter group. Each group received equivalent amount of drug daily. Dopamine D1 and D2 receptor binding assays were performed on striatal tissue homogenates with tritiated selective antagonists and were compared with those of 3 healthy control animals and 3 MPTP-exposed monkeys treated in parallel with daily doses of levodopa and 2 additional MPTP-exposed monkeys otherwise untreated. U-91356A quickly relieved all parkinsonian features and greatly stimulated locomotion in all animals. The pulsatile administration group showed progressive sensitization to the drug, and all 3 animals developed chorea during the first week of treatment that subsequently increased in intensity. The same pattern was seen in the levodopa-treated animals. In contrast, an apparent, incomplete tachyphylaxis were observed in 2 of 3 animals in the continuous infusion group during the first 10 days of treatment. Only 1 of these animals developed minimal and transient choreic dyskinesia. An apparent decrease of D2 receptor binding was observed. No upregulation of dopamine receptors occurred in the dyskinetic monkeys of the pulsatile group, but a tendency toward upregulation of putaminal D1 receptors was observed in the levodopa-treated, dyskinetic animals. These results confirm that the mode of administration of dopaminergic agents may result in a markedly different clinical outcome.(ABSTRACT TRUNCATED AT 250 WORDS)