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Nat Commun. 2019 Sep 9;10(1):4078. doi: 10.1038/s41467-019-11936-w.

Zebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation.

Author information

1
Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94143, USA.
2
Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
3
Department of Systems Biology, Harvard Medical School, 149 13th Street, Charlestown, MA, 02129, USA.
4
Department of Biology, San Francisco State University, San Francisco, CA, USA.
5
Department of Pharmacology and NIMH Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC, 27759, USA.
6
Department of Chemistry, Brown University, Providence, RI, 02912, USA.
7
Department of Cellular and Molecular Physiology, Department of Neuroscience, Yale University School of Medicine, New Haven, CT, 06510, USA.
8
Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, 84112, USA.
9
Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94143, USA. keiser@keiserlab.org.
10
Departments of Pharmaceutical Chemistry and of Bioengineering & Therapeutic Sciences, University of California, San Francisco, CA, 94158, USA. keiser@keiserlab.org.
11
Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94143, USA. david.kokel@ucsf.edu.
12
Department of Physiology, University of California, San Francisco, CA, 94158, USA. david.kokel@ucsf.edu.

Abstract

Anesthetics are generally associated with sedation, but some anesthetics can also increase brain and motor activity-a phenomenon known as paradoxical excitation. Previous studies have identified GABAA receptors as the primary targets of most anesthetic drugs, but how these compounds produce paradoxical excitation is poorly understood. To identify and understand such compounds, we applied a behavior-based drug profiling approach. Here, we show that a subset of central nervous system depressants cause paradoxical excitation in zebrafish. Using this behavior as a readout, we screened thousands of compounds and identified dozens of hits that caused paradoxical excitation. Many hit compounds modulated human GABAA receptors, while others appeared to modulate different neuronal targets, including the human serotonin-6 receptor. Ligands at these receptors generally decreased neuronal activity, but paradoxically increased activity in the caudal hindbrain. Together, these studies identify ligands, targets, and neurons affecting sedation and paradoxical excitation in vivo in zebrafish.

PMID:
31501447
PMCID:
PMC6733874
DOI:
10.1038/s41467-019-11936-w
[Indexed for MEDLINE]
Free PMC Article

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