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Nat Chem Biol. 2016 Jul;12(7):552-8. doi: 10.1038/nchembio.2089. Epub 2016 May 30.

σ1 receptor ligands control a switch between passive and active threat responses.

Rennekamp AJ1,2,3,4,5, Huang XP6,7, Wang Y1,2,3,4,5, Patel S1,2,3,4,5, Lorello PJ8,9, Cade L1,2,3,4,5, Gonzales AP1,2,3,4,5, Yeh JR1,2,3, Caldarone BJ8,9, Roth BL6,7,10, Kokel D11, Peterson RT1,2,3,4,5.

Author information

1
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
2
Department of Medicine, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
3
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
5
Broad Institute, Cambridge, Massachusetts, USA.
6
National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
7
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
8
NeuroBehavior Laboratory, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Boston, Massachusetts, USA.
9
Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
10
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
11
Department of Physiology, University of California, San Francisco, San Francisco, California, USA.

Abstract

Humans and many animals show 'freezing' behavior in response to threatening stimuli. In humans, inappropriate threat responses are fundamental characteristics of several mental illnesses. To identify small molecules that modulate threat responses, we developed a high-throughput behavioral assay in zebrafish (Danio rerio) and evaluated 10,000 compounds for their effects on freezing behavior. We found three classes of compounds that switch the threat response from freezing to escape-like behavior. We then screened these for binding activity across 45 candidate targets. Using target profile clustering, we identified the sigma-1 (σ1) receptor as having a role in the mechanism of behavioral switching and confirmed that known σ1 ligands also disrupt freezing behavior. Furthermore, mutation of the gene encoding σ1 prevented the behavioral effect of escape-inducing compounds. One compound, which we call finazine, potently bound mammalian σ1 and altered threat-response behavior in mice. Thus, pharmacological and genetic interrogation of the freezing response revealed σ1 as a mediator of threat responses in vertebrates.

PMID:
27239788
PMCID:
PMC4912403
DOI:
10.1038/nchembio.2089
[Indexed for MEDLINE]
Free PMC Article

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