Clozapine antagonism of D-1 and D-2 dopamine receptor-mediated behaviors.
When tested in rats supersensitive to dopamine agonists, the atypical neuroleptic clozapine displayed pharmacological properties expected of both a D-1 and D-2 receptor antagonist. The locomotor response induced by the D-1 receptor agonist SKF-38393 in neonatal-6-hydroxydopamine (6-OHDA)-lesioned rats was reversed in a dose-related fashion, although a complete blockade of this behavior was not observed indicative for only a partial antagonism of D-1 receptor function. Clozapine also blocked the self mutilation resulting from L-dihydroxyphenylalanine (L-DOPA) administration to neonatal-6-OHDA-lesioned rats, an effect previously linked to D-1 receptor activation. At higher doses, clozapine blocked the locomotor activity elicited by the D-2 agonist LY-171555 in adult-6-OHDA-lesioned rats. Therefore, the action of clozapine on D-1 as well as D-2 receptor-mediated behaviors contributes to its pharmacological effects. The ability of clozapine to stop self-mutilatory behavior in neonatal-6-OHDA-lesioned rats suggests that this drug might be an effective treatment for self-injurious behavior associated with the Lesch-Nyhan syndrome and mental retardation.
Criswell
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HE
Biological Sciences Research Center, University of North Carolina, School of Medicine, Chapel Hill 27599.
Mueller
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RA
Breese
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GA
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D001067:Appetite Depressants / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology*; D003984:Dibenzazepines / Q000494:pharmacology*; D004873:Ergolines / Q000494:pharmacology; D005260:Female; D006892:Hydroxydopamines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine; D011247:Pregnancy; D019257:Quinpirole; D051381:Rats; D011919:Rats, Inbred Strains; D011950:Receptors, Cholinergic / Q000187:drug effects; D011954:Receptors, Dopamine / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects
D001067:Appetite Depressants; D001552:Benzazepines; D003984:Dibenzazepines; D004873:Ergolines; D006892:Hydroxydopamines; D011950:Receptors, Cholinergic; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D019257:Quinpirole; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016627:Oxidopamine; D003024:Clozapine