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Effects of volatile anesthetic agents on N-methyl-D-aspartate (NMDA) receptor–mediated excitatory synaptic transmission have not been well characterized. The authors compared effects produced by halothane and isoflurane on electrophysiologic properties of NMDA and non-NMDA receptor–mediated synaptic responses in slices from the rat hippocampus.Field excitatory postsynaptic potentials (fEPSPs) in the CA1 area were recorded with extracellular electrodes after electrical stimulation of Schaffer-collateral-commissural fiber inputs. NMDA or non-NMDA receptor–mediated fEPSPs were pharmacologically isolated using selective antagonists. Clinically relevant concentrations of halothane or isoflurane were applied to slices in an artificial cerebrospinal fluid perfusate. Paired pulse facilitation was used as a measure of presynaptic effects of the anesthetic agents.Clinically relevant concentrations of halothane (1.2 vol% ≈ 0.35 mM) depressed fEPSP amplitudes mediated by NMDA receptors and non-NMDA receptors to a similar degree (mean ± SD: 63.3 ± 14.0% of control, n = 5; 60.2 ± 7.3% of control, n = 7, respectively). In contrast, isoflurane (1.4 vol% ≈ 0.50 mM) preferentially depressed fEPSP amplitudes mediated by NMDA receptors (44.0 ± 7.4% of control, n = 6, P < 0.001) compared with those for non-NMDA receptors (68.7 ± 5.4% of control, n = 6), indicating a selective, additional postsynaptic effect. Paired pulse facilitation of fEPSPs was increased significantly by both anesthetic agents from 1.37 ± 0.13 to 1.91 ± 0.25 (n = 5, P < 0.05 for halothane) and from 1.44 ± 0.04 to 1.64 ± 0.08 (n = 5, P < 0.01 for isoflurane), suggesting that presynaptic mechanisms are also involved in fEPSP depression produced by the anesthetic agents. Neither rise times nor decay times of fEPSPs were changed in the presence of the anesthetic agents.These results indicate that fEPSPs mediated by postsynaptic NMDA receptors are more sensitive to clinically relevant concentrations of isoflurane than are non-NMDA receptor–mediated responses, but this selective effect was not observed for halothane. Both agents also appeared to depress release of glutamate from nerve terminals via presynaptic actions.