Discriminative stimulus properties of N-desmethylclozapine, the major active metabolite of the atypical antipsychotic clozapine, in C57BL/6 mice

Jason M. Wiebelhaus, Sarah A. Vunck, Herbert Y Meltzer, Joseph H. Porter*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

N-desmethylclozapine (NDMC) is the major active metabolite of the atypical antipsychotic drug clozapine and may contribute to the therapeutic efficacy of clozapine. Although they share many pharmacological features, it is noteworthy that NDMC is a partial dopamine D 2 and cholinergic muscarinic M 1/M 4 agonist, whereas clozapine is a weak dopamine D 2 receptor inverse agonist/antagonist and a nonselective muscarinic antagonist. To better understand the in-vivo pharmacological mechanisms of these drugs, male C57BL/6NHsd-wild-type mice were trained to discriminate 10.0 mg/kg NDMC from vehicle in a two-lever drug discrimination procedure for food reward. It was found that the parent drug clozapine fully substituted for NDMC, whereas the typical antipsychotic drug haloperidol (dopamine D 2 antagonist) and the atypical antipsychotic drug aripiprazole (D 2 partial agonist) did not substitute for NDMC. These results demonstrated that clozapine and its major metabolite NDMC share in-vivo behavioral properties (i.e. discriminative stimulus properties) that are likely due to shared pharmacological mechanisms that differ from other antipsychotic drugs. The discriminative stimulus properties of NDMC probably reflect a compound cue similar to that of its parent drug clozapine due to its diverse binding profile.

Original languageEnglish (US)
Pages (from-to)262-270
Number of pages9
JournalBehavioural Pharmacology
Volume23
Issue number3
DOIs
StatePublished - Jun 1 2012

Keywords

  • Antipsychotic drugs
  • Aripiprazole
  • Clozapine
  • Discriminative stimulus
  • Drug discrimination
  • Haloperidol
  • Mouse
  • N-desmethylclozapine

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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