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Front. Neurosci. | doi: 10.3389/fnins.2019.00187

The chemogenetic receptor ligand Clozapine N-oxide induces in vivo neuroreceptor occupancy and reduces striatal glutamate levels

Simone Baerentzen1, 2,  Agata Casado-Sainz1, Denise Lange3, Vladimir Shalgunov1, 2,  Isabel M. Tejada1, Mengfei Xiong1, 2, Elina T. L'Estrade1, 2, 4, Fraser G. Edgar2, Hedok Lee5, Matthias M. Herth1, 2 and  Mikael Palner1, 2*
  • 1Neurobiology Research Unit, Rigshospitalet, Denmark
  • 2Center of Translational Neuromedicine, University of Copenhagen, Denmark
  • 3Copenhagen University Hospital, Denmark
  • 4Radiation and Nuclear Medicine Physics Unit, Skåne University Hospital, Sweden
  • 5Department of Anesthesiology and Pediatric Anesthesiology, Yale University, United States

Chemogenetic studies with the ligand clozapine N-oxide (CNO) are predicated upon the assumption that CNO is devoid of actions at natural neuroreceptors. However, recent evidence shows that CNO may be converted back to clozapine (CLZ) in vivo, which could yield plasma concentrations that may be sufficient to occupy inter alia dopamine D2/3 and serotonin 5HT2A receptors in living brain. To test this phenomenon, we measured striatal dopamine D2/3 receptor occupancy with [18F]fallypride PET and serotonin 5HT2A occupancy ex vivo using [18F]MH.MZ. We found a CNO dose-dependent effect on the availability of both neuroreceptor sites. In parallel MR spectroscopy experiments, we found that CNO reduced creatine + phosphcreatine (Cr+PCr) and increased N-acetylaspartate + N-acetylaspartylglutamate (NAA+NAAG) signals in the prefrontal cortex, and also reduced the glutamate signal in dorsal striatum, with peak effect at 2 mg/kg. Thus, our findings suggest that conversion of CNO to CLZ in living rats imparts significant occupancy at endogenous neuroreceptors and significant changes to neurometabolite levels.

Keywords: DREADD, CNO, Clozapine, Dopamine receptor, serotonin receptor, Glutamate, MRS (magnetic resonance spectroscopy), chemogenetics, D2 receptor, 5-HT2A receptor, Glutamine

Received: 06 Jul 2018; Accepted: 15 Feb 2019.

Edited by:

Pascal Bonaventure, Janssen Research and Development, United States

Reviewed by:

Rodrigo España, College of Medicine, Drexel University, United States
Clinton Canal, Mercer University, United States  

Copyright: © 2019 Baerentzen, Casado-Sainz, Lange, Shalgunov, Tejada, Xiong, L'Estrade, Edgar, Lee, Herth and Palner. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Mikael Palner, Rigshospitalet, Neurobiology Research Unit, Copenhagen, 2100, Denmark,