Rapid and long-lasting antidepressant-like effects of the pituitary adenylate cyclase-activating polypeptide receptor antagonist PA-915 in chronic stress mouse models

Shintani, Yusuke; Hayata-Takano, Atsuko; Takasaki, Ichiro; Kurihara, Takashi; Miyata, Atsuro; Yamano, Yui; Ikuta, Manato; Takeshita, Rei; Murata, Kenichiro; Oguri, Taisei; Asaka, Chiaki; Nunomura, Kazuto; Lin, Bangzhong; Nakagawa, Shinsaku; Okada, Takuya; Toyooka, Naoki; Takumi, Toru; Ago, Yukio; Takuma, Kazuhiro; Hashimoto, Hitoshi

doi:https://doi.org/10.1038/s41380-025-03209-4

Rapid and long-lasting antidepressant-like effects of the pituitary adenylate cyclase-activating polypeptide receptor antagonist PA-915 in chronic stress mouse models

Shintani, Yusuke; Hayata-Takano, Atsuko; Takasaki, Ichiro et al.

Molecular Psychiatry, 2025

Number of Access:4（2025-11-13 23:50 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/103008

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Title	Rapid and long-lasting antidepressant-like effects of the pituitary adenylate cyclase-activating polypeptide receptor antagonist PA-915 in chronic stress mouse models
Creator	NRID 1000050984267 1000050984267 CreatorName Shintani, Yusuke
	NRID 1000070390812 1000070390812 researchmap permalink atsuko-hayata atsuko-hayata Scopus Author ID 55151498300 55151498300 ORCID 0000-0002-4992-2845 0000-0002-4992-2845 CreatorName Hayata-Takano, Atsuko
	NRID 1000000397176 1000000397176 CreatorName Takasaki, Ichiro
	NRID 1000060282745 1000060282745 CreatorName Kurihara, Takashi
	NRID 1000060183969 1000060183969 CreatorName Miyata, Atsuro
	CreatorName Yamano, Yui
	CreatorName Ikuta, Manato
	CreatorName Takeshita, Rei
	CreatorName Murata, Kenichiro
	CreatorName Oguri, Taisei
	CreatorName Asaka, Chiaki
	ORCID 0000-0002-6444-3244 0000-0002-6444-3244 researchmap permalink nunomurakazuto nunomurakazuto CreatorName Nunomura, Kazuto
	ORCID 0000-0001-5877-949X 0000-0001-5877-949X researchmap permalink linbangzhong linbangzhong Scopus Author ID 57200092216 57200092216 CreatorName Lin, Bangzhong
	NRID 1000070207728 1000070207728 researchmap permalink read0042859 read0042859 CreatorName Nakagawa, Shinsaku
	NRID 1000070848613 1000070848613 CreatorName Okada, Takuya
	NRID 1000010217565 1000010217565 CreatorName Toyooka, Naoki
	NRID 1000000222092 1000000222092 CreatorName Takumi, Toru
	NRID 1000050403027 1000050403027 CreatorName Ago, Yukio
	NRID 1000090289025 1000090289025 ORCID 0000-0001-6484-1122 0000-0001-6484-1122 researchmap permalink read0201718 read0201718 Scopus Author ID 7005554636 7005554636 CreatorName Takuma, Kazuhiro
	NRID 1000030240849 1000030240849 ORCID 0000-0001-6548-4016 0000-0001-6548-4016 researchmap permalink hitoshi-hashimoto hitoshi-hashimoto Scopus Author ID 35352982100 35352982100 CreatorName Hashimoto, Hitoshi
Description	Shintani Y., Hayata-Takano A., Takasaki I., et al. Rapid and long-lasting antidepressant-like effects of the pituitary adenylate cyclase-activating polypeptide receptor antagonist PA-915 in chronic stress mouse models. Molecular Psychiatry (2025); https://doi.org/10.1038/s41380-025-03209-4.
Abstract	Stress-related disorders, such as depression and anxiety, have been one of the most important medical issues. Accumulating evidence suggests that the activation of the pituitary adenylate cyclase-activating polypeptide and its receptor PAC1 are involved in the stress axis and the development of stress-related disorders. We recently developed PA-915, a small-molecule, non-peptide, high-affinity PAC1 antagonist, and demonstrated that it significantly suppresses anxiety-like behavior in acute stress-induced mice. In this study, we aimed to investigate the behavioral effects of PA-915 in chronic stress-induced mouse models of depression, which included repeated social defeat stress, repeated corticosterone administration, and social isolation rearing. PA-915 ameliorated the increased immobility time in the forced swim test in these stress-induced mice. In repeated social defeat stress mice, PA-915 improved anxiety-like and depression-like behaviors and cognitive dysfunction, as assessed by the light-dark, open field, elevated plus maze, sucrose preference, forced swim, Y-maze, and novel object recognition tests. In addition, we evaluated the usefulness of PA-915 as an antidepressant and compared it with ketamine and fluoxetine. In the sucrose preference test, an antidepressant-like effect was observed for 8 weeks in mice that received a single dose of PA-915, which was a similar effect observed with ketamine. In non-stressed control mice, PA-915 did not induce behavioral abnormalities, such as hyperlocomotion, cognitive dysfunction, or dependency. The present results show that PA-915 improves anxiety-like behaviors and cognitive impairment and exerts rapid and long-lasting antidepressant effects in chronic stress-induced mouse models of anxiety and depression, proposing a promising treatment option for stress-related disorders.
Publisher	Springer Nature
Source Title	Molecular Psychiatry
Date of Issued	2025-09-04
Language	English
Handle URL	https://hdl.handle.net/11094/103008
PISSN	13594184
eISSN	14765578
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1038/s41380-025-03209-4
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Molecular Psychiatry. 2025
DC.title	Rapid and long-lasting antidepressant-like effects of the pituitary adenylate cyclase-activating polypeptide receptor antagonist PA-915 in chronic stress mouse models
DC.creator	Shintani, Yusuke
	Hayata-Takano, Atsuko
	Takasaki, Ichiro
	Kurihara, Takashi
	Miyata, Atsuro
	Yamano, Yui
	Ikuta, Manato
	Takeshita, Rei
	Murata, Kenichiro
	Oguri, Taisei
	Asaka, Chiaki
	Nunomura, Kazuto
	Lin, Bangzhong
	Nakagawa, Shinsaku
	Okada, Takuya
	Toyooka, Naoki
	Takumi, Toru
	Ago, Yukio
	Takuma, Kazuhiro
	Hashimoto, Hitoshi
DC.publisher	Springer Nature
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-09-04
DC.identifier	https://doi.org/10.1038/s41380-025-03209-4
DC.description	Shintani Y., Hayata-Takano A., Takasaki I., et al. Rapid and long-lasting antidepressant-like effects of the pituitary adenylate cyclase-activating polypeptide receptor antagonist PA-915 in chronic stress mouse models. Molecular Psychiatry (2025); https://doi.org/10.1038/s41380-025-03209-4.
DCTERMS.abstract	Stress-related disorders, such as depression and anxiety, have been one of the most important medical issues. Accumulating evidence suggests that the activation of the pituitary adenylate cyclase-activating polypeptide and its receptor PAC1 are involved in the stress axis and the development of stress-related disorders. We recently developed PA-915, a small-molecule, non-peptide, high-affinity PAC1 antagonist, and demonstrated that it significantly suppresses anxiety-like behavior in acute stress-induced mice. In this study, we aimed to investigate the behavioral effects of PA-915 in chronic stress-induced mouse models of depression, which included repeated social defeat stress, repeated corticosterone administration, and social isolation rearing. PA-915 ameliorated the increased immobility time in the forced swim test in these stress-induced mice. In repeated social defeat stress mice, PA-915 improved anxiety-like and depression-like behaviors and cognitive dysfunction, as assessed by the light-dark, open field, elevated plus maze, sucrose preference, forced swim, Y-maze, and novel object recognition tests. In addition, we evaluated the usefulness of PA-915 as an antidepressant and compared it with ketamine and fluoxetine. In the sucrose preference test, an antidepressant-like effect was observed for 8 weeks in mice that received a single dose of PA-915, which was a similar effect observed with ketamine. In non-stressed control mice, PA-915 did not induce behavioral abnormalities, such as hyperlocomotion, cognitive dysfunction, or dependency. The present results show that PA-915 improves anxiety-like behaviors and cognitive impairment and exerts rapid and long-lasting antidepressant effects in chronic stress-induced mouse models of anxiety and depression, proposing a promising treatment option for stress-related disorders.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	103008
citation_title	Rapid and long-lasting antidepressant-like effects of the pituitary adenylate cyclase-activating polypeptide receptor antagonist PA-915 in chronic stress mouse models
citation_author	Shintani, Yusuke
	Hayata-Takano, Atsuko
	Takasaki, Ichiro
	Kurihara, Takashi
	Miyata, Atsuro
	Yamano, Yui
	Ikuta, Manato
	Takeshita, Rei
	Murata, Kenichiro
	Oguri, Taisei
	Asaka, Chiaki
	Nunomura, Kazuto
	Lin, Bangzhong
	Nakagawa, Shinsaku
	Okada, Takuya
	Toyooka, Naoki
	Takumi, Toru
	Ago, Yukio
	Takuma, Kazuhiro
	Hashimoto, Hitoshi
citation_publisher	Springer Nature
citation_language	English
citation_date	2025-09-04
citation_journal_title	Molecular Psychiatry
citation_doi	https://doi.org/10.1038/s41380-025-03209-4
citation_public_url	https://hdl.handle.net/11094/103008

Rapid and long-lasting antidepressant-like effects of the pituitary adenylate cyclase-activating polypeptide receptor antagonist PA-915 in chronic stress mouse models

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