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Chemogenetics Revealed: DREADD Occupancy and Activation Via Converted Clozapine

Overview
Journal Science
Specialty Science
Date 2017 Aug 5
PMID 28774929
Citations 522
Authors
Juan L Gomez
Jordi Bonaventura
Wojciech Lesniak
William B Mathews
Polina Sysa-Shah
Lionel A Rodriguez
Randall J Ellis
Christopher T Richie
Brandon K Harvey
Robert F Dannals
Martin G Pomper
Antonello Bonci
Michael Michaelides
Affiliations
Soon will be listed here.
Abstract

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.

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