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Science. 2017 Aug 4;357(6350):503-507. doi: 10.1126/science.aan2475.

Chemogenetics revealed: DREADD occupancy and activation via converted clozapine.

Author information

1
Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse (NIDA) Intramural Research Program, Baltimore, MD 21224, USA.
2
Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
3
Optogenetics and Transgenic Technology Core, NIDA Intramural Research Program, Baltimore, MD 21224, USA.
4
Synaptic Plasticity Section, NIDA Intramural Research Program, Baltimore, MD 21224, USA.
5
Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse (NIDA) Intramural Research Program, Baltimore, MD 21224, USA. mike.michaelides@nih.gov.
6
Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.

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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PMID:
28774929
DOI:
10.1126/science.aan2475
[Indexed for MEDLINE]

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