Discriminative-stimulus effects of clozapine in squirrel monkeys: comparison with conventional and novel antipsychotic drugs

Psychopharmacology (Berl). 1997 Aug;132(3):261-9. doi: 10.1007/s002130050344.


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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology*
  • Clozapine / analogs & derivatives
  • Clozapine / pharmacology*
  • Conditioning, Operant*
  • Discrimination, Psychological*
  • Male
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / metabolism
  • Saimiri
  • Structure-Activity Relationship


  • Antipsychotic Agents
  • Receptors, Dopamine D2
  • Clozapine