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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.<\/jats:p>","DOI":"10.7554\/elife.84740","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T12:15:20Z","timestamp":1675080920000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.84740","source":"Crossref","is-referenced-by-count":38,"title":["Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2169-2670","authenticated-orcid":true,"given":"Janine","family":"Traut","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0245cg223","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg","place":["Freiburg, 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