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 (>or=80% condition-appropriate responding) for both the 1.25 mg/kg CLZ dose (ED50=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 (>or=60% and <or=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.
authors.affiliation: Department of Psychology, Virginia Commonwealth University, Richmond, VA 23284-2018, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Prus
authors.forename: S D
authors.initials: SD
authors.lastname: Philibin
authors.forename: A L
authors.initials: AL
authors.lastname: Pehrson
authors.forename: J H
authors.initials: JH
authors.lastname: Porter
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D003024:Clozapine / Q000008:administration & dosage* / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects*; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005795:Generalization, Stimulus / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine