POTENTIATION BY SEVOFLURANE OF THE GAMMA-AMINOBUTYRIC ACID-INDUCED CHLORIDE CURRENT IN ACUTELY DISSOCIATED CA1 PYRAMIDAL NEURONS FROM RAT HIPPOCAMPUS

1 The effects of a new kind of volatile anaesthetic, sevoflurane (Sev) , on gamma-aminobutyric acid (GABA)-gated chloride current (I-Cl) in s ingle neurones dissociated from the rat hippocampal CA1 area were exam ined using the nystatin perforated patch recording configuration under the voltage-clamp condition. All drugs were applied with a rapid perf usion system, termed the 'Y-tube' method. 2 When the concentrations we re higher than 3 x 10(-4) M, Sev, itself, induced an inward current (I -Sev) at a holding potential (V-H) Of -40 mV. The concentration-respon se curve of I-Sev was bell-shaped, with a suppressed peak and plateau currents at high concentrations (above 2 x 10(-3) M). The reversal pot ential 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 wa s reversibly blocked by bicuculline (Bic), an antagonist of the GABA(A ) receptor, in a concentration-dependent manner with a half-inhibitory concentration (IC50) Of 7.2 x 10(-7) M. But I-Sev was insensitive to strychnine (Str), an antagonist of the glycine receptor. 4 At low conc entrations (between 3 x 10(-4) and 10(-3) M), Sev markedly enhanced th e 10(-6) M GABA induced current (I-GABA) but reduced the I-GABA With a ccelerating desensitization accompanied by a 'hump' current after wash out at high concentrations (higher than 2 x 10(-3) M). 5 Sev, 10(-3) M potentiated the current induced by low concentrations of GABA (betwee n 10(-7) and 3 x 10(-6) M) but reduced the current induced by high con centrations (higher than 10(-5) M) of GABA with a clear acceleration o f I-GABA desensitization. 6 Sev, like pentobarbitone (PB), pregnanolon e (PGN) or diazepam (DZP), potentiated the 10(-6) M GABA-induced respo nse without shifting the reversal potential of I-GABA. 7 I-Sev was aug mented by PB, PGN, or DZP at concentrations that maximally potentiated I-GABA, suggesting that Sev enhanced I-GABA at a binding site distinc t from that for PB, PGN, or DZP. 8 It is concluded that Sev acts on th e GABA(A) receptor complex mimicking the GABA-induced chloride current at high concentrations. At low concentrations, Sev enhances GABA-gate d chloride current at a binding site independent of the allosteric mod ulator sites of barbiturates, benzodiazepines or neurosteroids. The re versible 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.