Pharmacological evaluation of SCH-12679: evidence for an in vivo antagonism of D1-dopamine receptors.
The benzazepine compound SCH-12679 has been shown to have clinical efficacy against aggressive behavior in mentally deficient patients. The purpose of the present investigation was to evaluate the potential mechanism of action of SCH-12679. Because of the structural similarity of SCH-12679 to compounds influencing D1-dopamine receptors, even though in vitro studies indicated no direct action on this receptor, investigations focused on the possibility that in vivo SCH-12679 antagonizes the function of this dopamine receptor subtype. After i.p. administration to neonatal-6-hydroxydopamine (6-OHDA)-lesioned rats, SCH-12679 reduced, dose-dependently, the locomotor activity induced by SKF-38393, a D1-dopamine agonist. A dose of SCH-12679 that antagonized the activity induced by SKF-38393 in neonatally lesioned rats also blocked various behaviors observed after administration of this D1-dopamine agonist. SCH-12679 did not alter the activity or behavioral responses induced by quinpirole, a D2-dopamine agonist, when administered to 6-OHDA-lesioned rats. SCH-12679 antagonized the self-mutilation behavior and behavioral responses induced by L-dihydroxyphenylalanine in neonatal-6-OHDA lesioned rats in a manner similar to the prototypic D1-dopamine antagonist SCH-23390 and, like SCH-23390, produced a deficit in avoidance responding in unlesioned rats. SCH-12679 produced a small, transient activation of locomotor activity immediately after administration to neonatal-6-OHDA-lesioned rats that was not observed in unlesioned or adult-6-OHDA-lesioned rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Breese
G R
GR
Biological Sciences Research Center, School of Medicine, University of North Carolina, Chapel Hill.
Criswell
H E
HE
McQuade
R D
RD
Iorio
L C
LC
Mueller
R A
RA
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000374:Aggression / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D018492:Dopamine Antagonists; D005260:Female; D006892:Hydroxydopamines / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology; D016627:Oxidopamine; D011247:Pregnancy; D020891:Raclopride; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012457:Salicylamides / Q000378:metabolism
D014150:Antipsychotic Agents; D001552:Benzazepines; D018492:Dopamine Antagonists; D006892:Hydroxydopamines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012457:Salicylamides; D020891:Raclopride; D007980:Levodopa; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016627:Oxidopamine; C001016:trimopam