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

Matthew N. McCarroll, Leo Gendelev, Reid Kinser, Jack Taylor, Giancarlo Bruni, Douglas Myers-Turnbull, Cole Helsell, Amanda Carbajal, Capria Rinaldi, Hye Jin Kang, Jung Ho Gong, Jason K. Sello, Susumu Tomita, Randall T. Peterson, Michael J. Keiser () and David Kokel ()
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Matthew N. McCarroll: University of California
Leo Gendelev: University of California
Reid Kinser: University of California
Jack Taylor: University of California
Giancarlo Bruni: Massachusetts General Hospital, Harvard Medical School
Douglas Myers-Turnbull: University of California
Cole Helsell: University of California
Amanda Carbajal: San Francisco State University
Capria Rinaldi: University of California
Hye Jin Kang: University of North Carolina Chapel Hill Medical School
Jung Ho Gong: Brown University
Jason K. Sello: Brown University
Susumu Tomita: Yale University School of Medicine
Randall T. Peterson: Massachusetts General Hospital, Harvard Medical School
Michael J. Keiser: University of California
David Kokel: University of California

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11936-w

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