Water-Soluble DREADD Agonist CNO Protocol

To avoid the use of the toxic solvent dimethyl sulfoxide (DMSO), which is typically used for the preparation of CNO products in concentrations of up to 15% (Campbell and Marchant, 2018 (link)), we opted for the use of a water-soluble salt preparation of CNO, CNO dihydrochloride (Tocris, Bio-Techne LTD, Abingdon, UK, catalog no.: 6329) dissolved in sterile saline. The dihydrochloride preparation of CNO undergoes less back-metabolism to clozapine but has a higher bioavailability compared to CNO-DMSO as indicated by pharmacokinetic work in rhesus macaques (Allen et al., 2019 (link)). This product has previously been used in sleep studies on mice at concentrations between 1 and 5 mg/kg (Fernandez et al., 2018 (link); Stucynski et al., 2021 (link)). For C21 injections we used the water-soluble version of DREADD agonist C21 (C21 dihydrochloride, Tocris, Bio-Techne LTD, Abingdon, UK, catalog no.: HB6124). We chose a dose of 3 mg/kg because a detailed pharmacokinetic assessment of this product at this specific concentration as well as behavioural testing in a five-choice serial-reaction-time task did not reveal any behavioural effects at this dose (Jendryka et al., 2019 (link)).

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Traut J., Mengual J.P., Meijer E.J., McKillop L.E., Alfonsa H., Hoerder-Suabedissen A., Song S.H., Fehér K.D., Riemann D., Molnar Z., Akerman C.J., Vyazovskiy V.V, & Krone L.B. (2023). Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice. eLife, 12, e84740.

Publication 2023

CNO dihydrochloride

Clozapine Dimethyl sulfoxide Metabolism Mice Rhesus macaques Saline Salt Sleep studies Solvent Sterile

Corresponding Organization :

Other organizations : Neuroscience Institute, University of Freiburg, University of Oxford, Kavli Energy NanoScience Institute, Geneva College, University of Bern

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Variable analysis

independent variables

Type of DREADD agonist used: CNO dihydrochloride or C21 dihydrochloride

dependent variables

Measured outcomes not explicitly mentioned

control variables

Solvent used: Sterile saline
Concentration of CNO dihydrochloride: 1-5 mg/kg
Concentration of C21 dihydrochloride: 3 mg/kg

controls

Positive control: None specified
Negative control: None specified

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