Biochemical and Biophysical Research Communications, Vol.309, No.4, 893-899, 2003
Biphasic action of midazolam on GABA(A) receptor-mediated responses in rat sacral dorsal commissural neurons
The effect of the benzodiazepine agonist midazolam on gamma-aminobutyric acid(A) (GABA(A)) receptor-mediated currents was investigated in neurons acutely dissociated from the rat sacral dorsal commissural nucleus (SDCN) using the nystatin-perforated patch-recording configuration under voltage-clamp conditions. Midazolam displayed a biphasic effect on GABA responses. Low concentrations of midazolam (1 nM-10 muM) reversibly potentiated GABA (3 muM)-activated Cl- currents (I-GABA) in a bell-shaped manner, with the maximal facilitary effect at 0.1 muM; whereas at higher concentrations (above 10 muM), midazolam had an antagonistic effect on I-GABA. Our further study indicated that midazolam changed GABA(A) receptor affinity to GABA and the effects of midazolam on I-GABA were voltage-independent. The benzodiazepine receptor antagonist, flumazenil, abolished the facilitary effect of low concentrations of midazolam rather than the antagonism of I-GABA induced by high doses of midazolam. In addition, activation of protein kinase C prevented the inhibitory effect of midazolam at higher concentrations, but did not influence the effect of midazolam at low concentrations. These results indicate that midazolam interacts with another distinct site other than the central benzodiazepine receptors on GABA(A) receptors as an antagonist at higher concentrations in SDCN neurons. (C) 2003 Elsevier Inc. All rights reserved.