Chemogenetics revealed: DREADD occupancy and activation via converted clozapine

The chemogenetic technology DREADD (designer receptors exclusively activated by designer drugs) is widely used for remote manipulation of neuronal activity in freely moving animals. DREADD technology posits the use of “designer receptors,” which are exclusively activated by the “designer drug” cloza...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2017-08, Vol.357 (6350), p.503-507
Main Authors: Gomez, Juan L., Bonaventura, Jordi, Lesniak, Wojciech, Mathews, William B., Sysa-Shah, Polina, Rodriguez, Lionel A., Ellis, Randall J., Richie, Christopher T., Harvey, Brandon K., Dannals, Robert F., Pomper, Martin G., Bonci, Antonello, Michaelides, Michael
Format: Article
Language:English
Subjects:
Affinity
Anatomy
Animals
Binding, Competitive
Brain
Brain - drug effects
Brain - metabolism
Central nervous system
Clozapine
Clozapine - administration & dosage
Clozapine - analogs & derivatives
Clozapine - pharmacokinetics
Clozapine - pharmacology
Designer Drugs - administration & dosage
Designer Drugs - pharmacokinetics
Designer Drugs - pharmacology
Drugs
Emission measurements
Genetic Techniques
HEK293 Cells
Humans
Mice
Mice, Transgenic
Narcotics
Neurons - drug effects
Positron emission
Positron emission tomography
Receptor, Muscarinic M3 - metabolism
Receptor, Muscarinic M4 - metabolism
Receptors
Technology
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Summary:The chemogenetic technology DREADD (designer receptors exclusively activated by designer drugs) is widely used for remote manipulation of neuronal activity in freely moving animals. DREADD technology posits the use of “designer receptors,” which are exclusively activated by the “designer drug” clozapine N-oxide (CNO). Nevertheless, the in vivo mechanism of action of CNO at DREADDs has never been confirmed. CNO does not enter the brain after systemic drug injections and shows low affinity for DREADDs. Clozapine, to which CNO rapidly converts in vivo, shows high DREADD affinity and potency. Upon systemic CNO injections, converted clozapine readily enters the brain and occupies central nervous system–expressed DREADDs, whereas systemic subthreshold clozapine injections induce preferential DREADD-mediated behaviors.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aan2475