"Serotonin Receptor Mechanisms Mediate the Discriminative Stimulus Prop" by Scott D. Philibin, Adam J. Prus et al.
 

Serotonin Receptor Mechanisms Mediate the Discriminative Stimulus Properties of the Atypical Antipsychotic Clozapine in C57BL/6 Mice

Document Type

Article

Publication Date

6-1-2005

Journal / Book Title

Psychopharmacology

Abstract

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.

DOI

10.1007/s00213-005-2147-0

Published Citation

Philibin, S.D., Prus, A.J., Pehrson, A.L. et al. Serotonin receptor mechanisms mediate the discriminative stimulus properties of the atypical antipsychotic clozapine in C57BL/6 mice. Psychopharmacology 180, 49–56 (2005). https://doi.org/10.1007/s00213-005-2147-0

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