Generalization to atypical antipsychotic drugs depends on training dose in rats trained to discriminate 1.25 mg/kg clozapine versus 5.0 mg/kg clozapine versus vehicle in a three-choice drug discrimination task

A. J. Prus, S. D. Philibin, Alan Pehrson, J. H. Porter

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13 Citations (Scopus)

Abstract

The prototypical atypical antipsychotic drug (APD) clozapine (CLZ) elicits a discriminative cue that appears to be similar to the stimulus properties elicited by atypical, but not typical, antipsychotic drugs in two-choice drug discrimination procedures. However, the ability of CLZ to generalize to atypical APDs depends on the training dose, since several atypical APDs (e.g. sertindole, risperidone) do not substitute for a 5.0 mg/kg CLZ training dose in rats, but do so for a 1.25 mg/kg CLZ training dose. Yet, a 1.25 mg/kg CLZ discriminative stimulus has not generalized to all atypical APDs either (e.g. quetiapine); thus, both 1.25 mg/kg and 5.0 mg/kg CLZ discriminative stimuli may be necessary to provide a better screen for atypical APDs. The present study sought to determine whether a three-choice 1.25 mg/kg CLZ versus 5.0 mg/kg CLZ versus vehicle drug discrimination task in rats might better distinguish atypical from typical APDs. Adult male Sprague-Dawley rats were trained in this three-choice drug discrimination task with a fixed ratio 30 reinforcement schedule for food. Clozapine produced full substitution (≥ 80% condition-appropriate responding) for both the 1.25 mg/kg CLZ dose (ED 50 = 0.09 mg/kg) and the 5.0 mg/kg CLZ dose (ED50 = 2.71 mg/kg). The atypical APD olanzapine produced full substitution for the 5.0 mg/kg CLZ dose, but not for the 1.25 mg/kg CLZ dose (ED50 = 1.55 mg/kg). In contrast, the atypical APD quetiapine produced full substitution for the 1.25 mg/kg CLZ dose (ED50 = 0.13 mg/kg), but not for the 5.0 mg/kg CLZ dose. Similarly, the atypical APD sertindole produced full substitution for only the 1.25 mg/kg CLZ dose (ED50 = 0.94 mg/kg). Risperidone, another atypical APD, produced partial substitution (≥ 60% and ≤, 80% condition-appropriate responding) for the 1.25 mg/kg CLZ dose, and failed to substitute for the 5.0 mg/kg CLZ dose. The atypical APD ziprasidone and the typical APDs haloperidol and chlorpromazine failed to substitute for either CLZ training dose. These results demonstrated that the 1.25 mg/kg CLZ training dose provides partial or full stimulus generalization to more atypical APDs than does the 5.0 mg/kg CLZ training dose. Full substitution by olanzapine for only the 5.0 mg/kg CLZ dose suggests that this higher training dose is also important for screening atypical APDs.

Original languageEnglish
Pages (from-to)511-520
Number of pages10
JournalBehavioural Pharmacology
Volume16
Issue number7
DOIs
StatePublished - 1 Nov 2005

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Clozapine
Antipsychotic Agents
pamidronate
Pharmaceutical Preparations
olanzapine
Generalization (Psychology)
Discrimination (Psychology)
Risperidone
Stimulus Generalization
Reinforcement Schedule

Keywords

  • Antipsychotic
  • Chlorpromazine
  • Clozapine
  • Haloperidol
  • Olanzapine
  • Quetiapine
  • Rat
  • Risperidone
  • Schizophrenia
  • Sertindole
  • Three-choice drug discrimination
  • Ziprasidone

Cite this

@article{9f5b4fe34688400fb87267bcaa6cfeb6,
title = "Generalization to atypical antipsychotic drugs depends on training dose in rats trained to discriminate 1.25 mg/kg clozapine versus 5.0 mg/kg clozapine versus vehicle in a three-choice drug discrimination task",
abstract = "The prototypical atypical antipsychotic drug (APD) clozapine (CLZ) elicits a discriminative cue that appears to be similar to the stimulus properties elicited by atypical, but not typical, antipsychotic drugs in two-choice drug discrimination procedures. However, the ability of CLZ to generalize to atypical APDs depends on the training dose, since several atypical APDs (e.g. sertindole, risperidone) do not substitute for a 5.0 mg/kg CLZ training dose in rats, but do so for a 1.25 mg/kg CLZ training dose. Yet, a 1.25 mg/kg CLZ discriminative stimulus has not generalized to all atypical APDs either (e.g. quetiapine); thus, both 1.25 mg/kg and 5.0 mg/kg CLZ discriminative stimuli may be necessary to provide a better screen for atypical APDs. The present study sought to determine whether a three-choice 1.25 mg/kg CLZ versus 5.0 mg/kg CLZ versus vehicle drug discrimination task in rats might better distinguish atypical from typical APDs. Adult male Sprague-Dawley rats were trained in this three-choice drug discrimination task with a fixed ratio 30 reinforcement schedule for food. Clozapine produced full substitution (≥ 80{\%} condition-appropriate responding) for both the 1.25 mg/kg CLZ dose (ED 50 = 0.09 mg/kg) and the 5.0 mg/kg CLZ dose (ED50 = 2.71 mg/kg). The atypical APD olanzapine produced full substitution for the 5.0 mg/kg CLZ dose, but not for the 1.25 mg/kg CLZ dose (ED50 = 1.55 mg/kg). In contrast, the atypical APD quetiapine produced full substitution for the 1.25 mg/kg CLZ dose (ED50 = 0.13 mg/kg), but not for the 5.0 mg/kg CLZ dose. Similarly, the atypical APD sertindole produced full substitution for only the 1.25 mg/kg CLZ dose (ED50 = 0.94 mg/kg). Risperidone, another atypical APD, produced partial substitution (≥ 60{\%} and ≤, 80{\%} condition-appropriate responding) for the 1.25 mg/kg CLZ dose, and failed to substitute for the 5.0 mg/kg CLZ dose. The atypical APD ziprasidone and the typical APDs haloperidol and chlorpromazine failed to substitute for either CLZ training dose. These results demonstrated that the 1.25 mg/kg CLZ training dose provides partial or full stimulus generalization to more atypical APDs than does the 5.0 mg/kg CLZ training dose. Full substitution by olanzapine for only the 5.0 mg/kg CLZ dose suggests that this higher training dose is also important for screening atypical APDs.",
keywords = "Antipsychotic, Chlorpromazine, Clozapine, Haloperidol, Olanzapine, Quetiapine, Rat, Risperidone, Schizophrenia, Sertindole, Three-choice drug discrimination, Ziprasidone",
author = "Prus, {A. J.} and Philibin, {S. D.} and Alan Pehrson and Porter, {J. H.}",
year = "2005",
month = "11",
day = "1",
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language = "English",
volume = "16",
pages = "511--520",
journal = "Behavioural Pharmacology",
issn = "0955-8810",
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}

Generalization to atypical antipsychotic drugs depends on training dose in rats trained to discriminate 1.25 mg/kg clozapine versus 5.0 mg/kg clozapine versus vehicle in a three-choice drug discrimination task. / Prus, A. J.; Philibin, S. D.; Pehrson, Alan; Porter, J. H.

In: Behavioural Pharmacology, Vol. 16, No. 7, 01.11.2005, p. 511-520.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Generalization to atypical antipsychotic drugs depends on training dose in rats trained to discriminate 1.25 mg/kg clozapine versus 5.0 mg/kg clozapine versus vehicle in a three-choice drug discrimination task

AU - Prus, A. J.

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AB - The prototypical atypical antipsychotic drug (APD) clozapine (CLZ) elicits a discriminative cue that appears to be similar to the stimulus properties elicited by atypical, but not typical, antipsychotic drugs in two-choice drug discrimination procedures. However, the ability of CLZ to generalize to atypical APDs depends on the training dose, since several atypical APDs (e.g. sertindole, risperidone) do not substitute for a 5.0 mg/kg CLZ training dose in rats, but do so for a 1.25 mg/kg CLZ training dose. Yet, a 1.25 mg/kg CLZ discriminative stimulus has not generalized to all atypical APDs either (e.g. quetiapine); thus, both 1.25 mg/kg and 5.0 mg/kg CLZ discriminative stimuli may be necessary to provide a better screen for atypical APDs. The present study sought to determine whether a three-choice 1.25 mg/kg CLZ versus 5.0 mg/kg CLZ versus vehicle drug discrimination task in rats might better distinguish atypical from typical APDs. Adult male Sprague-Dawley rats were trained in this three-choice drug discrimination task with a fixed ratio 30 reinforcement schedule for food. Clozapine produced full substitution (≥ 80% condition-appropriate responding) for both the 1.25 mg/kg CLZ dose (ED 50 = 0.09 mg/kg) and the 5.0 mg/kg CLZ dose (ED50 = 2.71 mg/kg). The atypical APD olanzapine produced full substitution for the 5.0 mg/kg CLZ dose, but not for the 1.25 mg/kg CLZ dose (ED50 = 1.55 mg/kg). In contrast, the atypical APD quetiapine produced full substitution for the 1.25 mg/kg CLZ dose (ED50 = 0.13 mg/kg), but not for the 5.0 mg/kg CLZ dose. Similarly, the atypical APD sertindole produced full substitution for only the 1.25 mg/kg CLZ dose (ED50 = 0.94 mg/kg). Risperidone, another atypical APD, produced partial substitution (≥ 60% and ≤, 80% condition-appropriate responding) for the 1.25 mg/kg CLZ dose, and failed to substitute for the 5.0 mg/kg CLZ dose. The atypical APD ziprasidone and the typical APDs haloperidol and chlorpromazine failed to substitute for either CLZ training dose. These results demonstrated that the 1.25 mg/kg CLZ training dose provides partial or full stimulus generalization to more atypical APDs than does the 5.0 mg/kg CLZ training dose. Full substitution by olanzapine for only the 5.0 mg/kg CLZ dose suggests that this higher training dose is also important for screening atypical APDs.

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KW - Chlorpromazine

KW - Clozapine

KW - Haloperidol

KW - Olanzapine

KW - Quetiapine

KW - Rat

KW - Risperidone

KW - Schizophrenia

KW - Sertindole

KW - Three-choice drug discrimination

KW - Ziprasidone

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DO - 10.1097/01.fbp.0000172735.73876.06

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