Presynaptic and postsynaptic actions of halothane at glutamatergic synapses in the mouse hippocampus.
Whole-cell patch-clamp recordings in adult mouse hippocampal slices were used to test the mechanism by which the volatile anesthetic halothane inhibits glutamate receptor-mediated synaptic transmission. Non-N-methyl-D-aspartate (nonNMDA) and NMDA receptor-mediated currents in CA1 pyramidal cells were pharmacologically isolated by bath application of D,L-2-amino-5-phosphonovaleric acid (APV; 100 microM) or 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX; 5 microM), respectively. Halothane blocked both nonNMDA and NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) to a similar extent (IC50 values of 0.66 and 0.57 mM, respectively). Partial blockade of the EPSCs by lowering the extracellular concentration of calcium ([Ca2+]o), but not by application of CNQX (1 microM), was accompanied by an increase in paired-pulse facilitation (PPF). Halothane-induced blockade of the EPSCs also was associated with an increase in PPF. The effects of halothane on alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and NMDA receptor-mediated currents induced by agonist iontophoresis, were compared. AMPA-induced currents were blocked with an IC50 of 1.7 mM. NMDA-induced currents were significantly less sensitive to halothane (IC50 of 5.9 mM). The effect of halothane on iontophoretic AMPA dose-response curves was tested. Halothane suppressed the maximal response to AMPA without affecting its EC50, suggesting a noncompetitive mechanism of inhibition. All effects of halothane were reversible upon termination of the exposure to the drug. These data suggest that halothane blocks central glutamatergic synaptic transmission by presynaptically inhibiting glutamate release and postsynaptically blocking the AMPA subtype of glutamate receptors.
Department of Physiology, Hebrew University-Hadassah School of Medicine, Jerusalem, Israel.
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Kirson
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Yaari
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Perouansky
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000502:physiology*; D006221:Halothane / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007478:Iontophoresis; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017661:Receptors, Presynaptic / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects*
D018685:Anesthetics, Inhalation; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D017661:Receptors, Presynaptic; D018698:Glutamic Acid; D006221:Halothane