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The Chemogenetic Receptor Ligand Clozapine N-Oxide Induces in vivo Neuroreceptor Occupancy and Reduces Striatal Glutamate Levels

Bærentzen, S. and Casado-Sainz, A. and Lange, D. and Shalgunov, V. and Martinez Tejada, I. and Xiong, M. and L’Estrade, E.T. and Edgar, F.G. and Lee, H. and Herth, M.M. and Palner, M. (2019) The Chemogenetic Receptor Ligand Clozapine N-Oxide Induces in vivo Neuroreceptor Occupancy and Reduces Striatal Glutamate Levels. Frontiers in Neuroscience, 13, p. 187. Frontiers Media S.A.. doi: 10.3389/fnins.2019.00187. ISSN 1662-4548.

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Official URL: https://www.frontiersin.org/articles/10.3389/fnins.2019.00187/full

Abstract

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 dosedependent effect on the availability of both neuroreceptor sites. In parallel MR spectroscopy experiments, we found that CNO reduced creatine C phosphcreatine (CrCPCr) and increased N-acetylaspartate C N-acetylaspartylglutamate (NAACNAAG) 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.

Item URL in elib:https://elib.dlr.de/136541/
Document Type:Article
Title:The Chemogenetic Receptor Ligand Clozapine N-Oxide Induces in vivo Neuroreceptor Occupancy and Reduces Striatal Glutamate Levels
Authors:
AuthorsInstitution or Email of AuthorsAuthor's ORCID iD
Bærentzen, S.UNSPECIFIEDUNSPECIFIED
Casado-Sainz, A.UNSPECIFIEDUNSPECIFIED
Lange, D.denise.lange (at) dlr.deUNSPECIFIED
Shalgunov, V.UNSPECIFIEDUNSPECIFIED
Martinez Tejada, I.UNSPECIFIEDUNSPECIFIED
Xiong, M.UNSPECIFIEDUNSPECIFIED
L’Estrade, E.T.UNSPECIFIEDUNSPECIFIED
Edgar, F.G.UNSPECIFIEDUNSPECIFIED
Lee, H.UNSPECIFIEDUNSPECIFIED
Herth, M.M.UNSPECIFIEDUNSPECIFIED
Palner, M.UNSPECIFIEDUNSPECIFIED
Date:2019
Journal or Publication Title:Frontiers in Neuroscience
Refereed publication:Yes
Open Access:Yes
Gold Open Access:Yes
In SCOPUS:Yes
In ISI Web of Science:Yes
Volume:13
DOI :10.3389/fnins.2019.00187
Page Range:p. 187
Publisher:Frontiers Media S.A.
ISSN:1662-4548
Status:Published
Keywords:DREADD, CNO, clozapine, dopamine receptors, serotonin receptors, glutamate
HGF - Research field:Aeronautics, Space and Transport
HGF - Program:Aeronautics
HGF - Program Themes:air traffic management and operations
DLR - Research area:Aeronautics
DLR - Program:L AO - Air Traffic Management and Operation
DLR - Research theme (Project):L - Human factors and safety in Aeronautics (old)
Location: Köln-Porz
Institutes and Institutions:Institute of Aerospace Medicine > Sleep and Human Factors Research
Deposited By: Sender, Alina
Deposited On:08 Oct 2020 11:12
Last Modified:08 Oct 2020 11:12

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