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

Nat Chem Biol
Authors
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.

Year of Publication
2016
Journal
Nat Chem Biol
Volume
12
Issue
7
Pages
552-8
Date Published
2016 Jul
ISSN
1552-4469
URL
DOI
10.1038/nchembio.2089
PubMed ID
27239788
PubMed Central ID
PMC4912403
Links
Grant list
HHSN271200800025C / MH / NIMH NIH HHS / United States
U01 MH105027 / MH / NIMH NIH HHS / United States
T32 HL007208 / HL / NHLBI NIH HHS / United States
R01 MH086867 / MH / NIMH NIH HHS / United States
R01 GM088040 / GM / NIGMS NIH HHS / United States
R01 AA022583 / AA / NIAAA NIH HHS / United States