The ability of the selective
dopamine D1 receptor agonist (5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-aza
cyclopent-1-ena[c]-
phenanthrene-9,10-diol (A-86929) to induce contralateral 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 macaques previously given unilateral, intracarotid infusions of the
neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Both treatments have been shown to reduce forebrain
dopamine levels on the side of the infusion. Such animals rotate contralaterally after
injections of direct-acting
dopamine receptor agonists. Rats were administered
A-86929 (0.11 or 0.22 micromol/kg s.c.) three times daily for 10 days, with
injections spaced 3 h apart, and rotation was measured across a 9-h period on various treatment days. Initially, monkeys were given various doses of
A-86929 (0.03, 0.10 or 0.30 micromol/kg i.m.), and rotation was monitored for 3 h after each dose. Significant, dose-dependent levels of contralateral rotation were achieved. Monkeys were next treated three times daily at 3-h intervals with
A-86929 (0.3 micromol/kg). Analysis of total, daily rotation scores indicated that the magnitude of the behavioral response did not change significantly across the 10-day treatment period in monkeys, although it increased in rats (0.22 micromol/kg). The first daily injection tended to elicit greater and longer-lived responses than the subsequent daily
injections in both species. In monkeys, this was particularly true on the first test day and was not seen by the last test. This study suggests that a selective D1 receptor agonist, such as
A-86929, with full intrinsic activity relative to
dopamine, may be useful for the treatment of
Parkinson's disease.