Acute administration of ketamine attenuates the impairment of social behaviors induced by social defeat stress exposure as juveniles via activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors

Sho Hasegawa, Akira Yoshimi, Akihiro Mouri, Yoji Uchida, Hirotake Hida, Masayoshi Mishina, Kiyofumi Yamada, Norio Ozaki, Toshitaka Nabeshima, Yukihiro Noda

Research output: Contribution to journalArticle

Abstract

The impairment of social behaviors induced by social defeat stress exposure as juveniles is resistant to some antidepressants and an antipsychotic, although the underlying mechanisms and/or therapeutic target are not yet clear. In this study, we investigated the involvement of the glutamatergic neuronal system in the impairment of social behaviors in this model, as this system is known to be involved in many central pathologies. Acute administration of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and subsequent stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, attenuated the expression of impairment of social behaviors. Lack of the NMDA receptor GluN2A subunit or acute administration of ifenprodil, an NMDA receptor GluN2B subunit antagonist, did not cause an effect. There were no significant changes in NMDA function, as determined by the ratios of phosphorylated NMDA receptor subunits in the prefrontal cortex and hippocampus. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione, a selective AMPA receptor antagonist, prevented the effect of ketamine on the expression of impairment of social behaviors. On the contrary, the ratio of phosphorylated AMPA receptor GluA1 subunit in the hippocampus was significantly increased in the non-tested, defeated group. Ketamine increased the level of total protein, but not the ratio of phosphorylated GluA1 in the hippocampus of the non-tested, defeated group. In conclusion, exposure to social defeat stress as juveniles may induce the expression of impairment of social behaviors in adolescents via functional changes in GluA1. Activators of AMPA receptor signaling, such as ketamine, may constitute a novel treatment strategy for stress-related psychiatric disorders in adolescents with adverse juvenile experiences.

LanguageEnglish
Pages107-116
Number of pages10
JournalNeuropharmacology
Volume148
DOIs
Publication statusPublished - 01-04-2019

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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
AMPA Receptors
Social Behavior
Ketamine
N-Methyl-D-Aspartate Receptors
Hippocampus
N-Methylaspartate
Prefrontal Cortex
Antidepressive Agents
Antipsychotic Agents
Psychiatry
Pathology
Therapeutics
Proteins

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

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title = "Acute administration of ketamine attenuates the impairment of social behaviors induced by social defeat stress exposure as juveniles via activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors",
abstract = "The impairment of social behaviors induced by social defeat stress exposure as juveniles is resistant to some antidepressants and an antipsychotic, although the underlying mechanisms and/or therapeutic target are not yet clear. In this study, we investigated the involvement of the glutamatergic neuronal system in the impairment of social behaviors in this model, as this system is known to be involved in many central pathologies. Acute administration of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and subsequent stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, attenuated the expression of impairment of social behaviors. Lack of the NMDA receptor GluN2A subunit or acute administration of ifenprodil, an NMDA receptor GluN2B subunit antagonist, did not cause an effect. There were no significant changes in NMDA function, as determined by the ratios of phosphorylated NMDA receptor subunits in the prefrontal cortex and hippocampus. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione, a selective AMPA receptor antagonist, prevented the effect of ketamine on the expression of impairment of social behaviors. On the contrary, the ratio of phosphorylated AMPA receptor GluA1 subunit in the hippocampus was significantly increased in the non-tested, defeated group. Ketamine increased the level of total protein, but not the ratio of phosphorylated GluA1 in the hippocampus of the non-tested, defeated group. In conclusion, exposure to social defeat stress as juveniles may induce the expression of impairment of social behaviors in adolescents via functional changes in GluA1. Activators of AMPA receptor signaling, such as ketamine, may constitute a novel treatment strategy for stress-related psychiatric disorders in adolescents with adverse juvenile experiences.",
author = "Sho Hasegawa and Akira Yoshimi and Akihiro Mouri and Yoji Uchida and Hirotake Hida and Masayoshi Mishina and Kiyofumi Yamada and Norio Ozaki and Toshitaka Nabeshima and Yukihiro Noda",
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Acute administration of ketamine attenuates the impairment of social behaviors induced by social defeat stress exposure as juveniles via activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. / Hasegawa, Sho; Yoshimi, Akira; Mouri, Akihiro; Uchida, Yoji; Hida, Hirotake; Mishina, Masayoshi; Yamada, Kiyofumi; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro.

In: Neuropharmacology, Vol. 148, 01.04.2019, p. 107-116.

Research output: Contribution to journalArticle

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T1 - Acute administration of ketamine attenuates the impairment of social behaviors induced by social defeat stress exposure as juveniles via activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors

AU - Hasegawa, Sho

AU - Yoshimi, Akira

AU - Mouri, Akihiro

AU - Uchida, Yoji

AU - Hida, Hirotake

AU - Mishina, Masayoshi

AU - Yamada, Kiyofumi

AU - Ozaki, Norio

AU - Nabeshima, Toshitaka

AU - Noda, Yukihiro

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