Cited by 980Photoreceptor and optogenetics researchNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Chemogenetics revealed: DREADD occupancy and activation via converted clozapine

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Gomez, Juan L., Bonaventura, Jordi, Lesniak, Wojciech, Mathews, William B., Sysa-Shah, Polina, Rodriguez, Lionel A., Ellis, Randall J., Richie, Christopher T. +5 more·2017·Science

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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  1. [7]Jann MW, Lam YW, Chang WH, Arch. Int. Pharmacodyn. Ther 328, 243– 250 (1994). 7710309

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Authors
Gomez, J. L., Bonaventura, J., Lesniak, W., Mathews, W. B., Sysa-Shah, P., Rodriguez, L. A., Ellis, R. J., Richie, C. T., Harvey, B. K., Dannals, R. F., Pomper, M. G., Bonci, A., & Michaelides, M.
Affiliations
  • National Institute on Drug Abuse (US)
  • Johns Hopkins University (US)
  • Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
  • National Institutes of Health (US)
Corresponding author
  • Gomez, Juan L.
  • Bonaventura, Jordi
  • Michaelides, Michael
Venue
Science
Published
2017-08-04
Volume
357
Issue
6350
Pages
503-507
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W2745223669
Cited by
980
References
22
Citations by year
2026: 66 · 2025: 72 · 2024: 92 · 2023: 91 · 2022: 99 · 2021: 103 · 2020: 136 · 2019: 140 · 2018: 150 · 2017: 31
FWCI
61.13
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Drug Abuse Intramural Research Program (award313325, ZIA000629, award313326, ZIA000526)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Photoreceptor and optogenetics research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
DREADD, chemogenetics, clozapine-N-oxide, clozapine, designer receptors, receptor occupancy, brain penetration, new psychoactive substances
MeSH terms
Animals, Binding, Competitive, Brain, Clozapine, Genetic Techniques, Humans, Mice, Transgenic, Neurons, Designer Drugs, Receptor, Muscarinic M3, Receptor, Muscarinic M4, Mice, HEK293 Cells

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