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Potentiation by sevoflurane of the γ‐aminobutyric acid‐induced chloride current in acutely dissociated CA1 pyramidal neurones from rat hippocampus
Author(s) -
Wu Jie,
Harata Nobutoshi,
Akaike Norio
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15772.x
Subject(s) - reversal potential , bicuculline , chemistry , gabaa receptor , patch clamp , inhibitory postsynaptic potential , antagonist , biophysics , picrotoxin , gaba receptor antagonist , voltage clamp , membrane potential , strychnine , long term potentiation , endocrinology , medicine , receptor , biochemistry , biology
1 The effects of a new kind of volatile anaesthetic, sevoflurane (Sev), on γ‐aminobutyric acid (GABA)‐gated chloride current ( I C***1 ) in single neurones dissociated from the rat hippocampal CA1 area were examined using the nystatin perforated patch recording configuration under the voltage‐clamp condition. All drugs were applied with a rapid perfusion system, termed the ‘Y‐tube’ method. 2 When the concentrations were higher than 3 × 10 −4 m , Sev, itself, induced an inward current ( I sev ) at a holding potential (V H ) of −40 mV. The concentration‐response curve of I sev was bell‐shaped, with a suppressed peak and plateau currents at high concentrations (above 2 × 10 −3 m ). The reversal potential of I sev ( E sev ) was close to the theoretical Cl − equilibrium potential, indicating that I sev was carried mainly by Cl − . 3 I sev was reversibly blocked by bicuculline (Bic), an antagonist of the GABA A receptor, in a concentration‐dependent manner with a half‐inhibitory concentration (IC 50 ) of 7.2 × 10 −7 m . But I scv was insensitive to strychnine (Str), an antagonist of the glycine receptor. 4 At low concentrations (between 3 × 10 −4 and 10 −3 m ), Sev markedly enhanced the 10 −6 m GABA induced current ( I GABA ) but reduced the I GABA with accelerating desensitization accompanied by a ‘hump’ current after washout at high concentrations (higher than 2 × 10 −3 m ). 5 Sev, 10 −3 m potentiated the current induced by low concentrations of GABA (between 10 −7 and 3 × 10 −6 m ) but reduced the current induced by high concentrations (higher than 10 −5 m ) of GABA with a clear acceleration of I GABA desensitization. 6 Sev, like pentobarbitone (PB), pregnanolone (PGN) or diazepam (DZP), potentiated the 10 −6 m GABA‐induced response without shifting the reversal potential of I GABA . 7 I sev was augmented by PB, PGN, or DZP at concentrations that maximally potentiated I GABA , suggesting that Sev enhanced I GABA at a binding site distinct from that for PB, PGN, or DZP. 8 It is concluded that Sev acts on the GABA A receptor complex mimicking the GABA‐induced chloride current at high concentrations. At low concentrations, Sev enhances GABA‐gated chloride current at a binding site independent of the allosteric modulator sites of barbiturates, benzodiazepines or neurosteroids. The reversible potentiation of the inhibitory GABA A receptor‐mediated Cl − current may result in the depressing of postsynaptic excitability and may, at least in part, underlie the anaesthetic action of Sev.