CONTINUOUS ADMINISTRATION DECREASES AND PULSATILE ADMINISTRATION INCREASES BEHAVIORAL SENSITIVITY TO A NOVEL DOPAMINE D-2 AGONIST (U-91356A) IN MPTP-EXPOSED MONKEYS

We compared the behavioral effects of a novel and highly selective dop amine D-2 receptor agonist, U-91356A, administered to 6 1-methyl-4-phe nyl-1,2,3,6-tetrahydropyridine (MPTP)-exposed parkinsonian monkeys for 27 days following an intermittent (n = 3) or continuous (n = 3) sched ule, using subcutaneous osmotic minipumps for the latter group. Each g roup received equivalent amount of drug daily. Dopamine D-1 and D-2 re ceptor binding assays were performed on striatal tissue homogenates wi th tritiated selective antagonists and were compared with those of 3 h ealthy control animals and 3 MPTP-exposed monkeys treated in parallel with daily doses of levodopa and 2 additional MPTP-exposed monkeys oth erwise untreated. U-91356A quickly relieved all parkinsonian features and greatly stimulated locomotion in all animals. The pulsatile admini stration group showed progressive sensitization to the drug, and all 3 animals developed chorea during the first week of treatment that subs equently increased in intensity. The same pattern was seen in the levo dopa-treated animals. In contrast, an apparent, incomplete tachyphylax is were observed in 2 of 3 animals in the continuous infusion group du ring the first 10 days of treatment. Only 1 of these animals developed minimal and transient choreic dyskinesia. An apparent decrease of D-2 receptor binding was observed. No upregulation of dopamine receptors occurred in the dyskinetic monkeys of the pulsatile group, but a tende ncy toward upregulation of putaminal D-1 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. Changes in dopamine receptors do not appe ar to be clearly linked to dyskinesia but may play a role in desensiti zation.