Discriminative stimulus properties of the atypical neuroleptic clozapine in rats: tests with subtype selective receptor ligands

The interoceptive stimulus induced by clozapine (5 mg/kg, i.p.) has been ch aracterized in an operant drug discrimination procedure in the rat using a aide range of receptor subtype-selective agonists and antagonists. Only the muscarinic receptor antagonist scopolamine generalized fully to clozapine (> 80%). partial generalization (defined here as 40% maximal generalization ) was seen with the D-1 receptor antagonist SCH 23390 (43% maximal generali zation), the alpha(1)-adrenoceptor antagonist prazosin (67%) and the alpha( 2)-adrenoceptor antagonist methoxyidazoxan (42%). All other specific agents tested induced <25% maximal generalization, including the alpha(2)-adrenoc eptor antagonist yohimbine (24%), the histamine H-1 receptor antagonist mep yramine (21%), the D-2 antagonist typical neuroleptic haloperidol (23%), th e D-4 receptor antagonist L-745,870 (14%), the 5-hydroxytryptamine-1A (5-HT 1A) receptor agonist S-14506 (8%), the 5-HT2A receptor antagonists ketanser in (0%) and M100907 (12%), the 5-HT2B/2C receptor antagonists SE 200646A (8 %) and SDZ SER 082 (6%), and the 5-HT3 receptor antagonist ondansetron (0%) . The clozapine discriminative stimulus was not blocked by the dopamine D-1 receptor antagonist SCH 23390, or by the 5-HT1A receptor antagonist WAY 10 0635, when given concomitantly with clozapine. Although the results suggest that muscarinic antagonism plays a major role in the clozapine cue, the re sults have to be considered in the light of the full generalization to cloz apine seen with various antipsychotic agents which have very low affinity f or muscarinic receptors, including zotepine, quetiapine, JL13 and PNU 96415 (a finding replicated in rats from the same breeding colony as those which generalized to scopolamine). Thus, generalization to clozapine for antipsy chotics with multiple affinities but with low muscarinic affinity is probab ly mediated by additive or perhaps supra-additive actions at other receptor s, although extensive studies with various combinations of drug mixtures ar e required to validate this hypothesis. Behav Pharmacol 1998; 9:699-710 (C) 1998 Lippincott Williams & Wilkins.