Small-molecule non-peptide antagonists of the PACAP receptor attenuate acute restraint stress-induced anxiety-like behaviors in mice

Yusuke Shintani; Yui Yamano; Manato Kuta; Rei Takeshita; Kazuhiro Takuma; Takuya Okada; Naoki Toyooka; Ichiro Takasaki; Atsuro Miyata; Takashi Kurihara; Hitoshi Hashimoto; Atsuko Hayata-Takano

doi:10.1016/j.bbrc.2022.09.079

Small-molecule non-peptide antagonists of the PACAP receptor attenuate acute restraint stress-induced anxiety-like behaviors in mice

Biochem Biophys Res Commun. 2022 Nov 26:631:146-151. doi: 10.1016/j.bbrc.2022.09.079. Epub 2022 Sep 26.

Authors

Affiliations

¹ Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.
² Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, And University of Fukui, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan; Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka, 565-0871, Japan.
³ Graduate School of Innovative Life Science, University of Toyama, Toyama, 930-0194, 930-8555, Japan; Department of Bio-functional Molecular Engineering, Faculty of Engineering, University of Toyama, Toyama, 930-8555, Japan.
⁴ Graduate School of Innovative Life Science, University of Toyama, Toyama, 930-0194, 930-8555, Japan; Department of Pharmacology, Faculty of Engineering, University of Toyama, Toyama, 930-8555, Japan.
⁵ Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8544, Japan.
⁶ Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, And University of Fukui, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan; Transdimensional Life Imaging Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan; Division of Bioscience, Institute for Datability Science, Osaka University, 2-8 Yamadaoka, Suita, Osaka, 565-0871, Japan; Department of Molecular Pharmaceutical Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. Electronic address: hasimoto@phs.osaka-u.ac.jp.
⁷ Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, And University of Fukui, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan; Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka, 565-0871, Japan. Electronic address: a-hayata@phs.osaka-u.ac.jp.

PMID: 36194909
DOI: 10.1016/j.bbrc.2022.09.079

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved pleiotropic neuropeptide, implicated in emotional stress responses and anxiety-related disorders. Here, we examined whether our recently developed small-molecule non-peptide PACAP receptor antagonists could ameliorate anxiety-like behaviors induced by acute restraint stress in mice. The antagonists PA-9 and its derivative PA-915 improved anxiety-like behaviors in mice subjected to restraint stress. An anxiolytic effect was observed with single acute dose, suggesting their fast-acting properties. PA-915 demonstrated a statistically significant anxiolytic effect whereas fluoxetine did not. These results indicate the potential of PAC1 antagonists as a novel treatment for anxiety.

Keywords: Acute stress; Anxiolytic effect; PAC1 receptor; PACAP; Pituitary adenylate cyclase-activating polypeptide; Small-molecule non-peptide antagonist.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Anxiety Agents* / pharmacology
Anti-Anxiety Agents* / therapeutic use
Anxiety / drug therapy
Fluoxetine
Mice
Pituitary Adenylate Cyclase-Activating Polypeptide* / pharmacology
Pituitary Adenylate Cyclase-Activating Polypeptide* / therapeutic use
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I

Substances

Anti-Anxiety Agents
Pituitary Adenylate Cyclase-Activating Polypeptide
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
Fluoxetine