Modulation of GABAergic synaptic transmission by the non-benzodiazepine anxiolytic etifoxine

Rémy Schlichter; Volodymyr Rybalchenko; Pierrick Poisbeau; Marc Verleye; Jean Marie Gillardin

doi:10.1016/S0028-3908(99)00253-1

Modulation of GABAergic synaptic transmission by the non-benzodiazepine anxiolytic etifoxine

Rémy Schlichter, Volodymyr Rybalchenko, Pierrick Poisbeau, Marc Verleye, Jean Marie Gillardin

Research output: Contribution to journal › Article › peer-review

105 Scopus citations

Abstract

We have investigated the effects of 2-ethylamino-6-chloro-4-methyl-4-phenyl-4H-3,1-benzoxazine hydrochloride (etifoxine) on GABA(A) receptor function. Etifoxine displaced [³⁵S]TBPS (t-butylbicyclophosphorothionate) from GABA(A) receptors of rat cortical membranes with an IC₅₀ of 6.7±0.8 μM and [³H]PK11195 from peripheral (mitochondrial)-type benzodiazepine receptors (PBRs) of rat heart homogenates with an IC₅₀ of 27.3±1.0 μM. Etifoxine displayed anxiolytic properties in an anticonflict test in rats, and potentiated GABA(A) receptor-mediated membrane currents elicited by submaximal (5-10 μM) but not saturating (0.5 mM) concentrations of GABA in cultured rat hypothalamic and spinal cord dorsal horn neurones. In hypothalamic cultures, etifoxine induced a dose-dependent inward current for concentrations >1 μM which reflected the post-synaptic potentiation of a small (~20 pA) tonic and bicuculline-sensitive GABA(A) receptor-gated Cl^- current. Etifoxine also increased the frequency of spontaneous and miniature GABAergic inhibitory post-synaptic currents without changing their amplitude and kinetic characteristics. Both effects of etifoxine were insensitive to flumazenil (10 μM), an antagonist of central-type benzodiazepine sites present at GABA(A) receptors, but were partly inhibited by PK11195 (10 μM) an antagonist of PBRs which control the synthesis of neurosteroids. Our results indicate that etifoxine potentiates GABA(A) receptor-function by a direct allosteric effect and by an indirect mechanism involving the activation of PBRs. Copyright (C) 2000 Elsevier Science Ltd.

Original language	English (US)
Pages (from-to)	1523-1535
Number of pages	13
Journal	Neuropharmacology
Volume	39
Issue number	9
DOIs	https://doi.org/10.1016/S0028-3908(99)00253-1
State	Published - Aug 2000

Keywords

Anxiolytic
Inhibitory post-synaptic current (IPSC)
Neurosteroid
PK11195
Peripheral benzodiazepine receptor (PBR)

ASJC Scopus subject areas

Pharmacology
Cellular and Molecular Neuroscience

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10.1016/S0028-3908(99)00253-1

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title = "Modulation of GABAergic synaptic transmission by the non-benzodiazepine anxiolytic etifoxine",

abstract = "We have investigated the effects of 2-ethylamino-6-chloro-4-methyl-4-phenyl-4H-3,1-benzoxazine hydrochloride (etifoxine) on GABA(A) receptor function. Etifoxine displaced [35S]TBPS (t-butylbicyclophosphorothionate) from GABA(A) receptors of rat cortical membranes with an IC50 of 6.7±0.8 μM and [3H]PK11195 from peripheral (mitochondrial)-type benzodiazepine receptors (PBRs) of rat heart homogenates with an IC50 of 27.3±1.0 μM. Etifoxine displayed anxiolytic properties in an anticonflict test in rats, and potentiated GABA(A) receptor-mediated membrane currents elicited by submaximal (5-10 μM) but not saturating (0.5 mM) concentrations of GABA in cultured rat hypothalamic and spinal cord dorsal horn neurones. In hypothalamic cultures, etifoxine induced a dose-dependent inward current for concentrations >1 μM which reflected the post-synaptic potentiation of a small (~20 pA) tonic and bicuculline-sensitive GABA(A) receptor-gated Cl- current. Etifoxine also increased the frequency of spontaneous and miniature GABAergic inhibitory post-synaptic currents without changing their amplitude and kinetic characteristics. Both effects of etifoxine were insensitive to flumazenil (10 μM), an antagonist of central-type benzodiazepine sites present at GABA(A) receptors, but were partly inhibited by PK11195 (10 μM) an antagonist of PBRs which control the synthesis of neurosteroids. Our results indicate that etifoxine potentiates GABA(A) receptor-function by a direct allosteric effect and by an indirect mechanism involving the activation of PBRs. Copyright (C) 2000 Elsevier Science Ltd.",

keywords = "Anxiolytic, Inhibitory post-synaptic current (IPSC), Neurosteroid, PK11195, Peripheral benzodiazepine receptor (PBR)",

author = "R{\'e}my Schlichter and Volodymyr Rybalchenko and Pierrick Poisbeau and Marc Verleye and Gillardin, {Jean Marie}",

note = "Funding Information: We wish to thank D. Di Scala, Y. Schwab and E. Jover for providing hypothalamic cultures, and Roche (Basel, Switzerland) for the gift of flumazenil. Many thanks to Yves De Konninck (McGill University, Montreal, Canada) for making available to us his synaptic current analysis program. This work was supported by University Louis Pasteur, CNRS (Centre National de la Recherche Scientifique), and Biocodex Laboratories.",

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doi = "10.1016/S0028-3908(99)00253-1",

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AU - Schlichter, Rémy

AU - Rybalchenko, Volodymyr

AU - Poisbeau, Pierrick

AU - Verleye, Marc

AU - Gillardin, Jean Marie

N1 - Funding Information: We wish to thank D. Di Scala, Y. Schwab and E. Jover for providing hypothalamic cultures, and Roche (Basel, Switzerland) for the gift of flumazenil. Many thanks to Yves De Konninck (McGill University, Montreal, Canada) for making available to us his synaptic current analysis program. This work was supported by University Louis Pasteur, CNRS (Centre National de la Recherche Scientifique), and Biocodex Laboratories.

PY - 2000/8

Y1 - 2000/8

N2 - We have investigated the effects of 2-ethylamino-6-chloro-4-methyl-4-phenyl-4H-3,1-benzoxazine hydrochloride (etifoxine) on GABA(A) receptor function. Etifoxine displaced [35S]TBPS (t-butylbicyclophosphorothionate) from GABA(A) receptors of rat cortical membranes with an IC50 of 6.7±0.8 μM and [3H]PK11195 from peripheral (mitochondrial)-type benzodiazepine receptors (PBRs) of rat heart homogenates with an IC50 of 27.3±1.0 μM. Etifoxine displayed anxiolytic properties in an anticonflict test in rats, and potentiated GABA(A) receptor-mediated membrane currents elicited by submaximal (5-10 μM) but not saturating (0.5 mM) concentrations of GABA in cultured rat hypothalamic and spinal cord dorsal horn neurones. In hypothalamic cultures, etifoxine induced a dose-dependent inward current for concentrations >1 μM which reflected the post-synaptic potentiation of a small (~20 pA) tonic and bicuculline-sensitive GABA(A) receptor-gated Cl- current. Etifoxine also increased the frequency of spontaneous and miniature GABAergic inhibitory post-synaptic currents without changing their amplitude and kinetic characteristics. Both effects of etifoxine were insensitive to flumazenil (10 μM), an antagonist of central-type benzodiazepine sites present at GABA(A) receptors, but were partly inhibited by PK11195 (10 μM) an antagonist of PBRs which control the synthesis of neurosteroids. Our results indicate that etifoxine potentiates GABA(A) receptor-function by a direct allosteric effect and by an indirect mechanism involving the activation of PBRs. Copyright (C) 2000 Elsevier Science Ltd.

AB - We have investigated the effects of 2-ethylamino-6-chloro-4-methyl-4-phenyl-4H-3,1-benzoxazine hydrochloride (etifoxine) on GABA(A) receptor function. Etifoxine displaced [35S]TBPS (t-butylbicyclophosphorothionate) from GABA(A) receptors of rat cortical membranes with an IC50 of 6.7±0.8 μM and [3H]PK11195 from peripheral (mitochondrial)-type benzodiazepine receptors (PBRs) of rat heart homogenates with an IC50 of 27.3±1.0 μM. Etifoxine displayed anxiolytic properties in an anticonflict test in rats, and potentiated GABA(A) receptor-mediated membrane currents elicited by submaximal (5-10 μM) but not saturating (0.5 mM) concentrations of GABA in cultured rat hypothalamic and spinal cord dorsal horn neurones. In hypothalamic cultures, etifoxine induced a dose-dependent inward current for concentrations >1 μM which reflected the post-synaptic potentiation of a small (~20 pA) tonic and bicuculline-sensitive GABA(A) receptor-gated Cl- current. Etifoxine also increased the frequency of spontaneous and miniature GABAergic inhibitory post-synaptic currents without changing their amplitude and kinetic characteristics. Both effects of etifoxine were insensitive to flumazenil (10 μM), an antagonist of central-type benzodiazepine sites present at GABA(A) receptors, but were partly inhibited by PK11195 (10 μM) an antagonist of PBRs which control the synthesis of neurosteroids. Our results indicate that etifoxine potentiates GABA(A) receptor-function by a direct allosteric effect and by an indirect mechanism involving the activation of PBRs. Copyright (C) 2000 Elsevier Science Ltd.

KW - Anxiolytic

KW - Inhibitory post-synaptic current (IPSC)

KW - Neurosteroid

KW - PK11195

KW - Peripheral benzodiazepine receptor (PBR)

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Modulation of GABAergic synaptic transmission by the non-benzodiazepine anxiolytic etifoxine

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