Hyperactivity and behavioral seizures in rodents following treatment with the dopamine D1 receptor agonists A-86929 and ABT-431.
A-86929 ((-)-trans-9,10-dihydroxy-2-propyl-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 D1 receptor. Both A-86929 and ABT-431 ((-)-trans-9,10-diacetyloxy-2-propyl-4,5,5a,6,7,11b- 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 D1 receptor antagonist, SCH 23390, as well as by higher doses of the dopamine D2 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 ED50 values of 7.1 and 2.7 mumol/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 (ED50 = 34.2 and 35.6 mumol/kg, s.c., respectively), but at doses higher than those required in mice. Moreover, adult rats (3 months) were less sensitive (ED50 = 345 mumol/kg, s.c.) to A-86929-induced seizures than young rats. Comparison of the ED50 values that produced behavioral seizure activity in rats with those previously established to produce contralateral rotation (ED50 = 0.24 mumol/kg, s.c.) in 6-hydroxydopamine-lesioned rat indicates that a significant dose separation exists between these two properties of A-86929.
Shiosaki
K
K
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064, USA. kazumi.shiosaki@abbott.com
Asin
K E
KE
Britton
D R
DR
Giardina
W J
WJ
Bednarz
L
L
Mahan
L
L
Mikusa
J
J
Nikkel
A
A
Wismer
C
C
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D016627:Oxidopamine; D011355:Prodrugs / Q000494:pharmacology*; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015363:Quinolones; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000037:antagonists & inhibitors; D012640:Seizures / Q000139:chemically induced* / Q000523:psychology; D013563:Sympathectomy, Chemical; D013764:Tetrahydronaphthalenes / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013876:Thiophenes
D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D011355:Prodrugs; D011725:Pyridines; D015363:Quinolones; D017447:Receptors, Dopamine D1; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C095428:adrogolide hydrochloride; D016627:Oxidopamine; C095427:A 86929