Chemogenetics revealed: DREADD occupancy and activation via converted clozapine
Open accessAbstract
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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About 2% of injected CNO is converted to clozapine.
“Only ~2% of CNO converts to clozapine after injection (Gomez et al., 2017)”
From Anatomically defined and functionally distinct dorsal raphe serotonin sub-systems (2018) · cites this paper as Gomez et al., 2017
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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
- ORCID
- Venue
- Science
- Published
- 2017-08-04
- Volume
- 357
- Issue
- 6350
- Pages
- 503-507
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC7309169
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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