Clozapine antagonism of D-1 and D-2 dopamine receptor-mediated behaviors

Abstract

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.