The DREADD agonist clozapine N-oxide (CNO) is reverse-metabolized to clozapine and produces clozapine-like interoceptive stimulus effects in rats and mice

• Type of Material: Article
• Authors: Daniel F. Manvich, Emory University; Kevin A. Webster, Virginia Commonwealth University; Stephanie L. Foster, Emory University; Martilias S. Farrell, University of North Carolina; James C Ritchie, Emory University; James C. Porter, Virginia Commonwealth University; David Weinshenker, Emory University
• Language: English
• Date: 2018-03-01
• Publisher: Nature Publishing Group: Open Access Journals - Option C
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-018-22116-z
• Title of Journal or Parent Work: Scientific Report
• ISSN: 2045-2322
• Volume: 8
• Issue: 1
• Start Page: 3840
• End Page: 3840
• Grant/Funding Information: This work was supported by grants from the National Institutes of Health (DA039991 to D.F.M., DA038453, DA040788, AG047667, and NS102306 to D.W.).
• Keywords: Multidisciplinary Sciences; COCAINE; DESIGNER DRUGS; CHEMOGENETICS; DOPAMINE-BETA-HYDROXYLASE; Science & Technology; TYPICAL ANTIPSYCHOTIC-DRUGS; Science & Technology - Other Topics
• Research Categories: Biology, Genetics; Health Sciences, Medicine and Surgery; Health Sciences, Pathology

Abstract

Clozapine-N-oxide (CNO) has long been the ligand of choice for selectively activating Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). However, recent studies have challenged the long-held assertion that CNO is otherwise pharmacologically inert. The present study aimed to 1) determine whether CNO is reverse-metabolized to its parent compound clozapine in mice (as has recently been reported in rats), and 2) determine whether CNO exerts clozapine-like interoceptive stimulus effects in rats and/or mice. Following administration of 10.0 mg/kg CNO, pharmacokinetic analyses replicated recent reports of back-conversion to clozapine in rats and revealed that this phenomenon also occurs in mice. In rats and mice trained to discriminate 1.25 mg/kg clozapine from vehicle, CNO (1.0-20.0 mg/kg) produced partial substitution for the clozapine stimulus on average, with full substitution being detected in some individual animals of both species at doses frequently used to activate DREADDs. The present demonstration that CNO is converted to clozapine and exerts clozapine-like behavioral effects in both mice and rats further emphasizes the need for appropriate control groups in studies employing DREADDs, and highlights the utility of the drug discrimination procedure as a tool with which to screen the off-target effects of novel DREADD agonists.