The effects of conventional and novel atypical antipsychotic drugs were compared to clozapine in squirrel monkeys that discriminated IM injections of clozapine (1.0 g/kg) from saline in two-level drug discrimination procedure. Clozapine (0.03-3.0 mg/kg) produced dose-related increases in responding on the clozapine-associated lever with full substitution at the training dose in all monkeys. Dose related increases in responding on the clozapine-associated level and full substitution also were observed with structural analogues of clozapine including perlapine and fluperlapine (0.1-3.0 mg/kg), seroquel (0.1-5.6 mg/kg), and JL 5, JL 8, and JL 18 (0.1-3.0 mg/kg). Other clozapine analogues, including olanzapine, amoxapine, loxapine and clothiapine, and conventional antipsychotic drugs, including phenothiazines such as chlopromazine and thioridazine, produced some clozapine-associated responding up to the highest doses that could be studies, but did not substitute for clozapine. Olanzapine did produce full clozapine-level responding following pretreatment with thedopamine D2-receptor agonist (+)-PHNO (0.003.0.01 mg/kg). Putatively atypical antipsychotic that are structurally unrelated to clozapine including risperidone (0.003-0.1 mg/kg), sertindole (o.03-1.0 mg/kg) and remoxipride (0.1-5.6 mg/kg) similarly failed to substitute for clozapine up to the highest doses. The present results indicate that some, but no all, structural analogs of clozapine that clozapine-like discriminative-stimulus effects and that novel antipsychotic drugs which purportedly have clozapine-like clinical efficacy may not produce its interoceptive stimulus effects.
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