title: Discriminative-stimulus effects of clozapine in squirrel monkeys: comparison with conventional and novel antipsychotic drugs.
abstract: The effects of conventional and novel atypical antipsychotic drugs were compared to clozapine in squirrel monkeys that discriminated I.M. injections of clozapine (1.0 mg/kg) from saline in a two-lever 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 lever 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 chlorpromazine and thioridazine, produced some clozapine-associated responding up to the highest doses that could be studied, but did not substitute for clozapine. Olanzapine did produce full clozapine-lever responding following pretreatment with the dopamine D2-receptor agonist (+)-PHNO (0.003-0.01 mg/kg). Putatively atypical antipsychotics that are structurally unrelated to clozapine including risperidone (0.003-0.1 mg/kg), sertindole (0.03-1.0 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 not all, structural analogs of clozapine have clozapine-like discriminative-stimulus effects and that novel antipsychotic drugs which purportedly have clozapine-like clinical efficacy may not produce its interoceptive stimulus effects.
authors.affiliation: New England Regional Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Carey
authors.forename: J
authors.initials: J
authors.lastname: Bergman
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology*; D003216:Conditioning, Operant; D004192:Discrimination, Psychological; D008297:Male; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D012453:Saimiri; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D017448:Receptors, Dopamine D2; D003024:Clozapine