Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: Role of 5-HT2A serotonergic and α1 adrenergic antagonism

Scott D. Philibin, D. Matthew Walentiny, Sarah A. Vunck, Adam J. Prus, Herbert Y. Meltzer, Joseph H. Porter

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Rationale: The discriminative stimulus properties of the atypical antipsychotic drug (APD) clozapine (CLZ) have recently been studied in C57BL/6 mice, a common background strain for genetic alterations. However, further evaluation is needed to fully characterize CLZ's discriminative cue in this strain of mice. Objectives: The objectives of the study were to confirm the previous findings using a shorter pretreatment time and to further characterize the receptor mechanisms mediating the discriminative stimulus properties of CLZ by testing APDs, selective ligands, and N-desmethylclozapine (CLZ's major metabolite) in C57BL/6 mice. Materials and methods: C57BL/6 male mice were trained to discriminate 2.5 mg/kg CLZ (s.c.) from vehicle in a two-lever drug discrimination task. Results: Generalization testing with CLZ yielded an ED 50∈=∈1.19 mg/kg. Substitution testing with APDs showed that the atypical APDs quetiapine, sertindole, zotepine, iloperidone, and melperone fully substituted for CLZ (≥80% CLZ-appropriate responding), but aripiprazole did not. The typical APDs chlorpromazine and thioridazine substituted for CLZ (fluphenazine and perphenazine did not). The serotonin (5-HT) 2A antagonist M100907 and the α1-adrenoceptor antagonist prazosin fully substituted for CLZ. The H1 histaminergic antagonist pyrilamine, dopamine agonist amphetamine, and the selective serotonin reuptake inhibitor fluoxetine did not substitute for CLZ. While N-desmethylclozapine did not substitute for CLZ when tested alone, N-desmethylclozapine plus a low dose of CLZ combined in an additive manner produced full substitution. Conclusions: CLZ's discriminative cue in C57BL/6 mice is a "compound" cue mediated in part by antagonism of 5-HT2A and α1 receptors.

Original languageEnglish (US)
Pages (from-to)303-315
Number of pages13
JournalPsychopharmacology
Volume203
Issue number2
DOIs
StatePublished - Apr 2009

Keywords

  • Antipsychotic drugs
  • Aripiprazole
  • Chlorpromazine
  • Clozapine
  • Fluoxetine
  • Fluphenazine
  • Iloperidone
  • M100907
  • Melperone
  • N-Desmethylclozapine
  • Norepinephrine
  • Olanzapine
  • Perphenazine
  • Prazosin
  • Pyrilamine
  • Quetiapine
  • Serotonin
  • Sertindole
  • Thioridazine
  • Zotepine

ASJC Scopus subject areas

  • Pharmacology

Fingerprint Dive into the research topics of 'Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: Role of 5-HT<sub>2A</sub> serotonergic and α<sub>1</sub> adrenergic antagonism'. Together they form a unique fingerprint.

Cite this