Pharmacologic evaluation of SCH-39166, A-69024, NO-0756, and SCH-23390 in neonatal-6-OHDA-lesioned rats. Further evidence that self-mutilatory behavior induced by L-dopa is related to D1 dopamine receptors.
The purpose of the present investigation was to explore further the hypothesis that the self-injurious behavior induced by L-dihydroxyphenylalanine (L-DOPA) in neonatal-6-hydroxydopamine (OHDA)-lesioned rats is associated with an action on D1 dopamine receptors. This was accomplished by examining the behavioral responses induced by SKF-38393, quinpirole, and L-DOPA after treatment with the D1 antagonist SCH-23390 and three new pharmacologic agents, SCH-39166, NO-0756, and A-69024, reported to be D1 antagonists. All putative D1 antagonists were found to antagonize the action of SKF-38393 without reducing the increased locomotion and behavioral responses induced by quinpirole, consistent with an in vivo action on D1 receptors. The potency hierarchy of the compounds against the action of SKF-38393 on activity, from strongest to weakest, was: SCH-39166 equaled SCH-23390 and these were greater than NO-0756, which was greater than A-69024. All compounds were found to antagonize L-DOPA-induced self-mutilatory behavior (SMB) in neonatal-6-OHDA-lesioned rats in a dose-related manner. The potency hierarchy against this behavior, from strongest to weakest, was: SCH-23390, SCH-39166, NO-0756, and A-69024. The correlation between the ED50 for the ability of these drugs to antagonize SKF-38393-induced activity and their ability to reduce SMB by L-DOPA was greater than 0.99. In conclusion, the present findings provide additional evidence in vivo that NO-0756, SCH-39166, and A-69024 are selective D1 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
Criswell
H E
HE
Brain and Development Research Center, School of Medicine, University of North Carolina, Chapel Hill 27599.
Mueller
R A
RA
Breese
G R
GR
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001552:Benzazepines / Q000494:pharmacology; D018492:Dopamine Antagonists; D004305:Dose-Response Relationship, Drug; D004873:Ergolines / Q000494:pharmacology; D005260:Female; D007980:Levodopa / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine; D010208:Papaverine / Q000031:analogs & derivatives / Q000494:pharmacology; D019257:Quinpirole; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors* / Q000187:drug effects; D012652:Self Mutilation / Q000523:psychology*; D013563:Sympathectomy, Chemical; D044005:Tetrahydroisoquinolines
D001552:Benzazepines; D018492:Dopamine Antagonists; D004873:Ergolines; D017447:Receptors, Dopamine D1; D044005:Tetrahydroisoquinolines; C058081:ecopipam; C076525:NO 756; D019257:Quinpirole; D007980:Levodopa; C061450:A 69024; D016627:Oxidopamine; D010208:Papaverine