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


OBJECTIVE
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 (ED50=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.
Philibin
Scott D
SD
Department of Psychology, Virginia Commonwealth University, 808 West Franklin Street, PO Box 842018, Richmond, VA 23284-2018, USA.
Prus
Adam J
AJ
Pehrson
Alan L
AL
Porter
Joseph H
JH
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D044348:Receptors, Serotonin, 5-HT2 / Q000187:drug effects / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D014150:Antipsychotic Agents; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D044348:Receptors, Serotonin, 5-HT2; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D003024:Clozapine