Isobolographic analysis of the interactions between midazolam and propofolat GABA(A) receptors in embryonic mouse neurons

Background: Clinical studies suggest that midazolam and propofol interact s ynergistically to induce hypnosis, but these drugs do not interact synergis tically to prevent movement in response to noxious stimuli. The mechanisms underlying these interactions are not certain but may occur at the level of the gamma-aminobutyric acid A (GABA(A)) receptor. Methods: The authors evaluated the interactions between propofol and midazo lam in modulating GABA(A) receptor activity in embryonic hippocampal neuron s. The effects of midazolam and propofol on peak current evoked by submaxim al concentrations of GABA were studied using the patch clamp method. Isobol ographic analysis was undertaken by constructing concentration-response cur ves for midazolam and propofol alone and then evaluating the potency of com binations of midazolam and propofol. In other experiments, the concentratio n of GABA was increased and flurazepam was substituted for midazolam. Results: Isobolographic analysis confirmed that midazolam and propofol inte ract synergistically to enhance currents evoked by low concentrations of GA BA (1 mu M) Hen-ever, when the concentration of GABA was increased to 3 mu M, the interaction was additive. The interaction between flurazepam and pro pofol was also additive for enhancement of currents evoked by 3 mu M GABA. Conclusions: The interaction between midazolam and propofol was critically dependent on the concentration of GABA: Synergism was evident at low concen trations of GABA, but an additive interaction was apparent when the concent ration of GABA was increased. Changes in GABA(A) receptor function may unde rlie the synergistic interaction between propofol and midazolam for clinica l effects such as hypnosis. The clinical implication of the results is that the benefits of synergism observed at one concentration ratio of these dru gs map not be apparent at another.