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Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice.
Traut, Janine; Mengual, Jose Prius; Meijer, Elise J; McKillop, Laura E; Alfonsa, Hannah; Hoerder-Suabedissen, Anna; Song, Seo Ho; Fehér, Kristoffer D; Riemann, Dieter; Molnar, Zoltan; Akerman, Colin J; Vyazovskiy, Vladyslav V; Krone, Lukas B.
Affiliation
  • Traut J; Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Mengual JP; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
  • Meijer EJ; Sir Jules Thorn Sleep and Circadian Neuroscience Institute, University of Oxford, Oxford, United Kingdom.
  • McKillop LE; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
  • Alfonsa H; Sir Jules Thorn Sleep and Circadian Neuroscience Institute, University of Oxford, Oxford, United Kingdom.
  • Hoerder-Suabedissen A; The Kavli Institute for Nanoscience Discovery, Oxford, United Kingdom.
  • Song SH; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
  • Fehér KD; Sir Jules Thorn Sleep and Circadian Neuroscience Institute, University of Oxford, Oxford, United Kingdom.
  • Riemann D; The Kavli Institute for Nanoscience Discovery, Oxford, United Kingdom.
  • Molnar Z; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
  • Akerman CJ; Sir Jules Thorn Sleep and Circadian Neuroscience Institute, University of Oxford, Oxford, United Kingdom.
  • Vyazovskiy VV; Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
  • Krone LB; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Elife ; 122023 03 09.
Article in En | MEDLINE | ID: mdl-36892930
Scientists have developed ways to remotely turn on and off populations of neurons in the brain to test the role they play in behaviour. One technique that is frequently used is chemogenetics. In this approach, specific neurons are genetically modified to contain a special 'designer receptor' which switches cells on or off when its corresponding 'designer drug' is present. Recent studies have shown that the drug most commonly used in these experiments, clozapine-N-oxide (CNO), is broken down into small amounts of clozapine, an antipsychotic drug that binds to many natural receptors in the brain and modulates sleep. Nevertheless, CNO is still widely believed to not affect animals' sleep-wake patterns which in turn could influence a range of other brain activities and behaviours. However, there have been reports of animals lacking designer receptors still displaying unusual behaviours when administered CNO. This suggests that the breakdown of CNO to clozapine may cause off-target effects which could be skewing the results of chemogenetic studies. To investigate this possibility, Traut, Mengual et al. treated laboratory mice that do not have a designer receptor with three doses of CNO, and one dose of a new designer drug called compound-21 (C21) that is not broken down to clozapine. They found that high and medium doses of CNO, but also C21 altered the sleep-wake patterns of the mice and their brain activity during sleep. These findings show that CNO and C21 both have sleep-modulating effects on the brain and suggest that these effects are not only due to the production of clozapine, but the drugs binding to off-target natural receptors. To counteract this, Traut, Mengual et al. recommend optimizing the dose of drugs given to mice, and repeating the experiment on a control group which do not have the designer receptor. This will allow researchers to determine which behavioural changes are the result of turning on or off the neuron population of interest, and which are artefacts caused by the drug itself. They also suggest testing how newly developed designer drugs impact sleep before using them in behavioural experiments. Refining chemogenetic studies in these ways may yield more reliable insights about the role specific groups of cells have in the brain.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Clozapine Limits: Animals Language: En Journal: Elife Year: 2023 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Clozapine Limits: Animals Language: En Journal: Elife Year: 2023 Document type: Article Affiliation country: Country of publication: