Hyperactivity and behavioral seizures in rodents following treatment with the dopamine D-1 receptor agonists A-86929 and ABT-431

A-86929 ((-)-trans-9,10-dihydroxy-2-propy1-4,5,5a,6,7,11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene) is a potent and selective full agonist at the dopamine D-1 receptor. Both A-86929 and ABT-431 ((-)-trans-9,10-diacetyloxy-2-propyl-4,5,5a,6,11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride), the diacetyl prodrug derivative of A-86929, were evaluated for their effects on behavioral excitability in rodents. In rats, A-86929 produced a dose-dependent increase in locomotor activity that was attenuated by the selective dopamine D-1 receptor antagonist, SCH 23390, as well as by higher:doses of the dopamine D-1 receptor antagonist, haloperidol. Repeated administration of A-86929 over 6 days produced hyperactivity which did not change in magnitude across days. Acute administration of A-86929 and ABT-431 to mice produced behavioral seizure activity, with ED(50) values of 7.1 and 2.7 mu mol/kg, s.c., respectively, that was blocked by SCH 23390. Young rats (35-37 days) exhibited behavioral seizures following A-86929 and ABT-431 treatment (ED(50) = 34.2 and 35.6 mu mol/kg, s.c., respectively), but at doses higher than those required in mice. Moreover, adult rats (3 months) were less sensitive (ED(50) = 345 mu mol/kg, s.c.) to A-86929-induced seizures than young rats. Comparison of the ED(50) values that produced behavioral seizure activity in rats with those previously established to produce contralateral rotation (ED(50) = 0.24 mu mol/kg, s.c.) in 6-hydroxydopamine-Iesioned rat indicates that a significant dose separation exists between these two properties of A-86929.