TY - JOUR
T1 - Presynaptic and postsynaptic actions of halothane at glutamatergic synapses in the mouse hippocampus
AU - Kirson, Eilon D.
AU - Yaari, Yoel
AU - Perouansky, Misha
PY - 1998
Y1 - 1998
N2 - 1. 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 μM) or 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX; 5 μM), respectively. 2. 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). 3. Partial blockade of the EPSCs by lowering the extracellular concentration of calcium ([Ca2+](O)), but not by application of CNQX (1 μM), was accompanied by an increase in paired-pulse facilitation (PPF). Halothane-induced blockade of the EPSCs also was associated with an increase in PPF. 4. The effects of halothane on α-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). 5 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. 6. All effects of halothane were reversible upon termination of the exposure to the drug. 7. These data suggest that halothane blocks central glutamatergic synaptic transmission by presynaptically inhibiting glutamate release and postsynaptically blocking the AMPA subtype of glutamate receptors.
AB - 1. 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 μM) or 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX; 5 μM), respectively. 2. 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). 3. Partial blockade of the EPSCs by lowering the extracellular concentration of calcium ([Ca2+](O)), but not by application of CNQX (1 μM), was accompanied by an increase in paired-pulse facilitation (PPF). Halothane-induced blockade of the EPSCs also was associated with an increase in PPF. 4. The effects of halothane on α-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). 5 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. 6. All effects of halothane were reversible upon termination of the exposure to the drug. 7. These data suggest that halothane blocks central glutamatergic synaptic transmission by presynaptically inhibiting glutamate release and postsynaptically blocking the AMPA subtype of glutamate receptors.
KW - AMPA
KW - Halothane
KW - Hippocampus
KW - Mouse
KW - Paired pulse facilitation
KW - Volatile anesthetic
UR - http://www.scopus.com/inward/record.url?scp=0031818612&partnerID=8YFLogxK
U2 - 10.1038/sj.bjp.0701996
DO - 10.1038/sj.bjp.0701996
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C2 - 9756375
AN - SCOPUS:0031818612
SN - 0007-1188
VL - 124
SP - 1607
EP - 1614
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 8
ER -