Background: Anesthetic agents that target γ-aminobutyric acid type A (GABAA) receptors modulate cortical auditory evoked responses in vivo, but the cellular targets involved are unidentified. Also, for agents with multiple protein targets, the relative contribution of modulation of GABAA receptors to effects on cortical physiology is unclear. The authors compared effects of the GABAA receptor-specific drug midazolam with the volatile anesthetic isoflurane on spontaneous inhibitory postsynaptic currents (sIPSCs) in pyramidal cells of auditory cortex.
Methods: Whole cell recordings were obtained in murine brain slices at 34°C. GABAA sIPSCs were isolated by blocking ionotropic glutamate receptors. Effects of midazolam and isoflurane on time course, amplitude, and frequency of sIPSCs were measured.
Results: The authors detected no effect of midazolam at 0.01 μm on sIPSCs, whereas midazolam at 0.1 and 1 μm prolonged the decay of sIPSCs by approximately 25 and 70%, respectively. Isoflurane at 0.1, 0.25, and 0.5 mm prolonged sIPSCs by approximately 45, 150, and 240%, respectively. No drug-specific effects were observed on rise time or frequency of sIPSCs. Isoflurane at 0.5 mm caused a significant decrease in sIPSC amplitude.
Conclusions: The dose dependence of isoflurane effects on GABAA sIPSCs in pyramidal cells is consistent with effects on auditory evoked response in vivo. By contrast, comparable effects of midazolam on GABAA sIPSCs arise at concentrations exceeding those currently thought to be achieved in vivo, suggesting that the cellular targets of midazolam reside elsewhere in the thalamocortical circuit or that the concentration of midazolam reached in the brain is higher than currently believed.