K. Shiosaki et al., HYPERACTIVITY AND BEHAVIORAL SEIZURES IN RODENTS FOLLOWING TREATMENT WITH THE DOPAMINE D-1 RECEPTOR AGONISTS A-86929 AND ABT-431, European journal of pharmacology, 317(2-3), 1996, pp. 183-190
A-86929 ahydro-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 xahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydroc
hloride), the diacetyl prodrug derivative of A-86929, were evaluated f
or their effects on behavioral excitability in rodents. In rats, A-869
29 produced a dose-dependent increase in locomotor activity that was a
ttenuated 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 h
yperactivity which did not change in magnitude across days. Acute admi
nistration 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., respectiv
ely, 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 sen
sitive (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-hydroxydop
amine-Iesioned rat indicates that a significant dose separation exists
between these two properties of A-86929.