Journal article
Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice
- Abstract:
- Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remote control of targeted cell populations using chemical actuators that bind to modified receptors. Despite the popularity of DREADDs in neuroscience and sleep research, potential effects of the DREADD actuator clozapine-N-oxide (CNO) on sleep have never been systematically tested. Here, we show that intraperitoneal injections of commonly used CNO doses (1, 5, and 10 mg/kg) alter sleep in wild-type male laboratory mice. Using electroencephalography (EEG) and electromyography (EMG) to analyse sleep, we found a dose-dependent suppression of rapid eye movement (REM) sleep, changes in EEG spectral power during non-REM (NREM) sleep, and altered sleep architecture in a pattern previously reported for clozapine. Effects of CNO on sleep could arise from back-metabolism to clozapine or binding to endogenous neurotransmitter receptors. Interestingly, we found that the novel DREADD actuator, compound 21 (C21, 3 mg/kg), similarly modulates sleep despite a lack of back-metabolism to clozapine. Our results demonstrate that both CNO and C21 can modulate sleep of mice not expressing DREADD receptors. This implies that back-metabolism to clozapine is not the sole mechanism underlying side effects of chemogenetic actuators. Therefore, any chemogenetic experiment should include a DREADD-free control group injected with the same CNO, C21, or newly developed actuator. We suggest that electrophysiological sleep assessment could serve as a sensitive tool to test the biological inertness of novel chemogenetic actuators.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 5.3MB, Terms of use)
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- Publisher copy:
- 10.7554/eLife.84740
Authors
+ Medical Research Council
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- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MR/S01134X/1
- Publisher:
- eLife Sciences Publications
- Journal:
- eLife More from this journal
- Volume:
- 12
- Article number:
- e84740
- Publication date:
- 2023-03-09
- Acceptance date:
- 2023-01-03
- DOI:
- EISSN:
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2050-084X
- Language:
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English
- Pubs id:
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1544834
- Local pid:
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pubs:1544834
- Deposit date:
-
2024-06-18
- ARK identifier:
Terms of use
- Copyright holder:
- Traut et al.
- Copyright date:
- 2023
- Rights statement:
- © Traut, Mengual et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
- Notes:
- This research was funded in whole or in part by the Medical Research Council (MR/S01134X/1). For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
- Licence:
- CC Attribution (CC BY)
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