Modulation of gamma-aminobutyric acid type A receptor-mediated spontaneous inhibitory postsynaptic currents in auditory cortex by midazolam and isoflurane.
BACKGROUND
Anesthetic agents that target gamma-aminobutyric acid type A (GABA(A)) 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 GABA(A) receptors to effects on cortical physiology is unclear. The authors compared effects of the GABA(A) 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 degrees C. GABA(A) 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 microM on sIPSCs, whereas midazolam at 0.1 and 1 microM 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 GABA(A) sIPSCs in pyramidal cells is consistent with effects on auditory evoked response in vivo. By contrast, comparable effects of midazolam on GABA(A) 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.
Verbny
Yakov I
YI
Department of Anesthesiology, University of Wisconsin, Madison 53706, USA.
Merriam
Elliott B
EB
Banks
Matthew I
MI
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001303:Auditory Cortex / Q000187:drug effects*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005260:Female; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008808:Mice, Inbred CBA; D008874:Midazolam / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*
D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D011963:Receptors, GABA-A; D007530:Isoflurane; D008874:Midazolam