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

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

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)49-56
Number of pages8
JournalPsychopharmacology
Volume180
Issue number1
DOIs
StatePublished - 1 Jun 2005

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Clozapine
Serotonin Receptors
Inbred C57BL Mouse
Antipsychotic Agents
pamidronate
olanzapine
Quipazine
Cues
Serotonin Receptor Agonists
Risperidone
Haloperidol
Pharmaceutical Preparations
Serotonin
Ritanserin
Muscarinic Antagonists
Scopolamine Hydrobromide
Dopamine Agonists
Columbidae
Muscarinic Receptors
Amphetamine

Keywords

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

Cite this

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title = "Serotonin receptor mechanisms mediate the discriminative stimulus properties of the atypical antipsychotic clozapine in C57BL/6 mice",
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.",
keywords = "Amphetamine, Antipsychotic drugs, Drug discrimination, Haloperidol, Olanzapine, Quipazine, Risperidone, Ritanserin, Schizophrenia, Scopolamine, Serotonin, Ziprasidone",
author = "Philibin, {Scott D.} and Prus, {Adam J.} and Alan Pehrson and Porter, {Joseph H.}",
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Serotonin receptor mechanisms mediate the discriminative stimulus properties of the atypical antipsychotic clozapine in C57BL/6 mice. / Philibin, Scott D.; Prus, Adam J.; Pehrson, Alan; Porter, Joseph H.

In: Psychopharmacology, Vol. 180, No. 1, 01.06.2005, p. 49-56.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Serotonin receptor mechanisms mediate the discriminative stimulus properties of the atypical antipsychotic clozapine in C57BL/6 mice

AU - Philibin, Scott D.

AU - Prus, Adam J.

AU - Pehrson, Alan

AU - Porter, Joseph H.

PY - 2005/6/1

Y1 - 2005/6/1

N2 - 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.

AB - 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.

KW - Amphetamine

KW - Antipsychotic drugs

KW - Drug discrimination

KW - Haloperidol

KW - Olanzapine

KW - Quipazine

KW - Risperidone

KW - Ritanserin

KW - Schizophrenia

KW - Scopolamine

KW - Serotonin

KW - Ziprasidone

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U2 - 10.1007/s00213-005-2147-0

DO - 10.1007/s00213-005-2147-0

M3 - Article

VL - 180

SP - 49

EP - 56

JO - Psychopharmacology

JF - Psychopharmacology

SN - 0033-3158

IS - 1

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