title: σ1 receptor ligands control a switch between passive and active threat responses.
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.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.|Department of Medicine, Massachusetts General Hospital, Charlestown, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Andrew J
authors.identifier: 0000-0001-6174-7253
authors.initials: AJ
authors.lastname: Rennekamp
authors.affiliation: National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.|Department of Medicine, Massachusetts General Hospital, Charlestown, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: You
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.|Department of Medicine, Massachusetts General Hospital, Charlestown, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Patel
authors.affiliation: NeuroBehavior Laboratory, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lorello
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.|Department of Medicine, Massachusetts General Hospital, Charlestown, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Cade
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.|Department of Medicine, Massachusetts General Hospital, Charlestown, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Andrew P W
authors.initials: AP
authors.lastname: Gonzales
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.|Department of Medicine, Massachusetts General Hospital, Charlestown, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jing-Ruey Joanna
authors.initials: JR
authors.lastname: Yeh
authors.affiliation: NeuroBehavior Laboratory, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Caldarone
authors.affiliation: National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Department of Physiology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Kokel
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.|Department of Medicine, Massachusetts General Hospital, Charlestown, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Randall T
authors.initials: RT
authors.lastname: Peterson
mesh_terms: D000813:Anilides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004924:Escape Reaction / Q000187:drug effects* / Q000528:radiation effects; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects* / Q000528:radiation effects; D057166:High-Throughput Screening Assays; D007814:Larva / Q000187:drug effects* / Q000528:radiation effects; D008024:Ligands; D008027:Light; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017480:Receptors, sigma / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D015027:Zebrafish / Q000254:growth & development; D000097605:Sigma-1 Receptor
chemical_list: D000813:Anilides; D008024:Ligands; D010879:Piperazines; D017480:Receptors, sigma; D054852:Small Molecule Libraries; D000097605:Sigma-1 Receptor; C000618761:finazine