Increased γ-aminobutyric acid levels in mouse brain induce loss of righting reflex, but not immobility, in response to noxious stimulation

Sohtaro Katayama, Masahiro Irifune, Nobuhito Kikuchi, Tohru Takarada, Yoshitaka Shimizu, Chie Endo, Takashi Takata, Toshihiro Dohi, Tomoaki Sato, Michio Kawahara

研究成果: ジャーナルへの寄稿記事

16 引用 (Scopus)

抄録

BACKGROUND: The general anesthetic state comprises behavioral and perceptual components, including amnesia, unconsciousness, and immobility. γ-Aminobutyric acidergic (GABAergic) inhibitory neurotransmission is an important target for anesthetic action at the in vitro cellular level. In vivo, however, the functional relevance of enhancing GABAergic neurotransmission in mediating essential components of the general anesthetic state is unknown. Gabaculine is a GABA-transaminase inhibitor that inhibits degradation of released GABA, and consequently increases endogenous GABA in the central nervous system. Here, we examined, behaviorally, the ability of increased GABA levels to produce components of the general anesthetic state. METHODS: All drugs were administered systemically in adult male ddY mice. To assess the general anesthetic components, two end-points were used. One was loss of righting reflex (LORR; as a measure of unconsciousness); the other was loss of movement in response to tail-clamp stimulation (as a measure of immobility). RESULTS: Gabaculine induced LORR in a dose-dependent fashion with a 50% effective dose of 100 (75-134; 95% confidence limits) mg/kg. The behavioral and microdialysis studies revealed that the endogenous GABA-induced LORR occurred in a brain concentration-dependent manner. However, even larger doses of gabaculine (285-400 mg/kg) produced no loss of tail-clamp response. In contrast, all the tested volatile anesthetics concentration-dependently abolished both righting and tail-clamp response, supporting the evidence that volatile anesthetics act on a variety of molecular targets. CONCLUSIONS: These findings indicate that LORR is associated with enhanced GABAergic neurotransmission, but that immobility in response to noxious stimulation is not, suggesting that LORR and immobility are mediated through different neuronal pathways and/or regions in the central nervous system.

元の言語英語
ページ(範囲)1422-1429
ページ数8
ジャーナルAnesthesia and Analgesia
104
発行部数6
DOI
出版物ステータス出版済み - 6 1 2007
外部発表Yes

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Righting Reflex
Aminobutyrates
General Anesthetics
gamma-Aminobutyric Acid
Synaptic Transmission
Anesthetics
Tail
Unconsciousness
Brain
Central Nervous System
4-Aminobutyrate Transaminase
Aptitude
Amnesia
Microdialysis
Pharmaceutical Preparations
gabaculine

All Science Journal Classification (ASJC) codes

  • Anesthesiology and Pain Medicine

これを引用

Increased γ-aminobutyric acid levels in mouse brain induce loss of righting reflex, but not immobility, in response to noxious stimulation. / Katayama, Sohtaro; Irifune, Masahiro; Kikuchi, Nobuhito; Takarada, Tohru; Shimizu, Yoshitaka; Endo, Chie; Takata, Takashi; Dohi, Toshihiro; Sato, Tomoaki; Kawahara, Michio.

:: Anesthesia and Analgesia, 巻 104, 番号 6, 01.06.2007, p. 1422-1429.

研究成果: ジャーナルへの寄稿記事

Katayama, Sohtaro ; Irifune, Masahiro ; Kikuchi, Nobuhito ; Takarada, Tohru ; Shimizu, Yoshitaka ; Endo, Chie ; Takata, Takashi ; Dohi, Toshihiro ; Sato, Tomoaki ; Kawahara, Michio. / Increased γ-aminobutyric acid levels in mouse brain induce loss of righting reflex, but not immobility, in response to noxious stimulation. :: Anesthesia and Analgesia. 2007 ; 巻 104, 番号 6. pp. 1422-1429.
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abstract = "BACKGROUND: The general anesthetic state comprises behavioral and perceptual components, including amnesia, unconsciousness, and immobility. γ-Aminobutyric acidergic (GABAergic) inhibitory neurotransmission is an important target for anesthetic action at the in vitro cellular level. In vivo, however, the functional relevance of enhancing GABAergic neurotransmission in mediating essential components of the general anesthetic state is unknown. Gabaculine is a GABA-transaminase inhibitor that inhibits degradation of released GABA, and consequently increases endogenous GABA in the central nervous system. Here, we examined, behaviorally, the ability of increased GABA levels to produce components of the general anesthetic state. METHODS: All drugs were administered systemically in adult male ddY mice. To assess the general anesthetic components, two end-points were used. One was loss of righting reflex (LORR; as a measure of unconsciousness); the other was loss of movement in response to tail-clamp stimulation (as a measure of immobility). RESULTS: Gabaculine induced LORR in a dose-dependent fashion with a 50{\%} effective dose of 100 (75-134; 95{\%} confidence limits) mg/kg. The behavioral and microdialysis studies revealed that the endogenous GABA-induced LORR occurred in a brain concentration-dependent manner. However, even larger doses of gabaculine (285-400 mg/kg) produced no loss of tail-clamp response. In contrast, all the tested volatile anesthetics concentration-dependently abolished both righting and tail-clamp response, supporting the evidence that volatile anesthetics act on a variety of molecular targets. CONCLUSIONS: These findings indicate that LORR is associated with enhanced GABAergic neurotransmission, but that immobility in response to noxious stimulation is not, suggesting that LORR and immobility are mediated through different neuronal pathways and/or regions in the central nervous system.",
author = "Sohtaro Katayama and Masahiro Irifune and Nobuhito Kikuchi and Tohru Takarada and Yoshitaka Shimizu and Chie Endo and Takashi Takata and Toshihiro Dohi and Tomoaki Sato and Michio Kawahara",
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T1 - Increased γ-aminobutyric acid levels in mouse brain induce loss of righting reflex, but not immobility, in response to noxious stimulation

AU - Katayama, Sohtaro

AU - Irifune, Masahiro

AU - Kikuchi, Nobuhito

AU - Takarada, Tohru

AU - Shimizu, Yoshitaka

AU - Endo, Chie

AU - Takata, Takashi

AU - Dohi, Toshihiro

AU - Sato, Tomoaki

AU - Kawahara, Michio

PY - 2007/6/1

Y1 - 2007/6/1

N2 - BACKGROUND: The general anesthetic state comprises behavioral and perceptual components, including amnesia, unconsciousness, and immobility. γ-Aminobutyric acidergic (GABAergic) inhibitory neurotransmission is an important target for anesthetic action at the in vitro cellular level. In vivo, however, the functional relevance of enhancing GABAergic neurotransmission in mediating essential components of the general anesthetic state is unknown. Gabaculine is a GABA-transaminase inhibitor that inhibits degradation of released GABA, and consequently increases endogenous GABA in the central nervous system. Here, we examined, behaviorally, the ability of increased GABA levels to produce components of the general anesthetic state. METHODS: All drugs were administered systemically in adult male ddY mice. To assess the general anesthetic components, two end-points were used. One was loss of righting reflex (LORR; as a measure of unconsciousness); the other was loss of movement in response to tail-clamp stimulation (as a measure of immobility). RESULTS: Gabaculine induced LORR in a dose-dependent fashion with a 50% effective dose of 100 (75-134; 95% confidence limits) mg/kg. The behavioral and microdialysis studies revealed that the endogenous GABA-induced LORR occurred in a brain concentration-dependent manner. However, even larger doses of gabaculine (285-400 mg/kg) produced no loss of tail-clamp response. In contrast, all the tested volatile anesthetics concentration-dependently abolished both righting and tail-clamp response, supporting the evidence that volatile anesthetics act on a variety of molecular targets. CONCLUSIONS: These findings indicate that LORR is associated with enhanced GABAergic neurotransmission, but that immobility in response to noxious stimulation is not, suggesting that LORR and immobility are mediated through different neuronal pathways and/or regions in the central nervous system.

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