Serotonin receptor mechanisms mediate the discriminative stimulus properties of the atypical antipsychotic clozapine in C57BL/6 mice

Scott D. Philibin, Adam J. Prus, Alan L. Pehrson, Joseph H. Porter

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Rationale: The atypical antipsychotic drug (APD) clozapine (CLZ) has been shown to have a robust discriminative cue in rats, pigeons, and monkeys in two-choice drug discrimination procedures. Objectives: The present study determined whether a two-choice drug discrimination procedure with CLZ could be established in C57BL/6 mice and whether this procedure could distinguish between atypical and typical APDs. Methods: C57BL/6 male mice were trained to discriminate 2.5 mg/kg CLZ from vehicle in a two-lever drug discrimination procedure. Results: Generalization testing with CLZ produced full substitution at the 2.5- and 5.0-mg/kg doses with an ED50 of 1.14 mg/kg. The atypical APDs olanzapine (ED50=0.24 mg/kg), risperidone (ED 50=0.072 mg/kg), and ziprasidone (ED50=0.33 mg/kg) fully substituted for CLZ's discriminative cue, while the typical APD haloperidol failed to substitute for CLZ. Generalization testing with selective ligands showed that the serotonin (5-HT)2A/2B/2C antagonist ritanserin fully substituted for CLZ (ED50=2.08 mg/kg) and that the 5-HT receptor agonist quipazine significantly attenuated CLZ's discriminative cue without disrupting response rates. The muscarinic receptor antagonist scopolamine, the dopamine agonist amphetamine, and the 5-HT agonist quipazine failed to substitute for CLZ. Conclusions: These results demonstrated that antagonism of 5-HT receptors plays an important role in mediating the discriminative stimulus properties of the atypical APD CLZ in C57BL/6 mice. The atypical APDs olanzapine, risperidone, and ziprasidone fully substituted for CLZ, while the typical APD haloperidol did not. These results suggest that CLZ drug discrimination in C57BL/6 mice may be an effective preclinical behavioral assay for screening atypical from typical antipsychotic drugs.

Original languageEnglish
Pages (from-to)49-56
Number of pages8
Issue number1
Publication statusPublished - 1 Jun 2005



  • Amphetamine
  • Antipsychotic drugs
  • Drug discrimination
  • Haloperidol
  • Olanzapine
  • Quipazine
  • Risperidone
  • Ritanserin
  • Schizophrenia
  • Scopolamine
  • Serotonin
  • Ziprasidone

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