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

Autor: McCarroll MN; Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94143, USA., Gendelev L; Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94143, USA., Kinser R; Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94143, USA., Taylor J; Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94143, USA., Bruni G; Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.; Department of Systems Biology, Harvard Medical School, 149 13th Street, Charlestown, MA, 02129, USA., Myers-Turnbull D; Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94143, USA., Helsell C; Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94143, USA., Carbajal A; Department of Biology, San Francisco State University, San Francisco, CA, USA., Rinaldi C; Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94143, USA., Kang HJ; Department of Pharmacology and NIMH Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC, 27759, USA., Gong JH; Department of Chemistry, Brown University, Providence, RI, 02912, USA., Sello JK; Department of Chemistry, Brown University, Providence, RI, 02912, USA., Tomita S; Department of Cellular and Molecular Physiology, Department of Neuroscience, Yale University School of Medicine, New Haven, CT, 06510, USA., Peterson RT; Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.; Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, 84112, USA., Keiser MJ; Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94143, USA. keiser@keiserlab.org.; Departments of Pharmaceutical Chemistry and of Bioengineering & Therapeutic Sciences, University of California, San Francisco, CA, 94158, USA. keiser@keiserlab.org., Kokel D; Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94143, USA. david.kokel@ucsf.edu.; Department of Physiology, University of California, San Francisco, CA, 94158, USA. david.kokel@ucsf.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2019 Sep 09; Vol. 10 (1), pp. 4078. Date of Electronic Publication: 2019 Sep 09.
DOI: 10.1038/s41467-019-11936-w
Abstrakt: 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 GABA A 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 GABA A 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.
Databáze: MEDLINE