THE SELECTIVE DOPAMINE D1 RECEPTOR AGONIST A-86929 MAINTAINS EFFICACYWITH REPEATED TREATMENT IN RODENT AND PRIMATE MODELS OF PARKINSONS-DISEASE

The ability of the selective dopamine D1 receptor agonist hia-5-azacyc lopent-1-ena[c]-phenanthrene-9,10-diol (A-86929) to induce contralater al rotation after repeated administration was determined in rodent and primate models of Parkinson's disease. Testing was conducted in rats previously given unilateral 6-hydroxydopamine injections and in macaqu es previously given unilateral, intracarotid infusions of the neurotox in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Both treatments have been shown to reduce forebrain dopamine levels on the side of the infu sion. Such animals rotate contralaterally after injections of direct-a cting dopamine receptor agonists. Rats were administered A-86929 (0.11 or 0.22 mu mol/kg s.c.) three times daily for 10 days, with injection s spaced 3 h apart, and rotation was measured across a 9-h period on v arious treatment days. Initially, monkeys were given various doses of A-86929 (0.03, 0.10 or 0.30 mu mol/kg i.m.), and rotation was monitore d for 3 h after each dose. Significant, dose-dependent levels of contr alateral rotation were achieved. Monkeys were next treated three times daily at 3-h intervals with A-86929 (0.3 mu mol/kg). Analysis of tota l, daily rotation scores indicated that the magnitude of the behaviora l response did not change significantly across the 10-day treatment pe riod in monkeys, although it increased in rats (0.22 mu mol/kg). The f irst daily injection tended to elicit greater and longer-lived respons es than the subsequent daily injections in both species. In monkeys, t his was particularly true on the first test day and was not seen by th e last test. This study suggests that a selective D1 receptor agonist, such as A-86929, with full intrinsic activity relative to dopamine, m ay be useful for the treatment of Parkinson's disease.