The purpose of this investigation was to study the effect of isoflurane on excitatory synaptic transmission. Rat hippocampal slices maintained in vitro were used as a model. Isoflurane caused a dose-dependent reduction of the excitatory postsynaptic potential (EPSP); 1.5% isoflurane reduced the EPSP by 35 +/- 9% (mean +/- s.d.) and 3% by 57 +/- 11%. Neither spontaneous nor potassium-stimulated efflux of the glutamate analogue D-(3H)aspartate was changed, but the content of D-(3H)aspartate in slices loaded during isoflurane was reduced to 83 +/- 12% of control (P less than 0.05). The intracellularly recorded response to direct application of glutamate increased by 37 +/- 20% during isoflurane (3%) and 50 +/- 5% during halothane (2%). Isoflurane (3%) enhanced the response to the glutamate receptor agonist quisqualate by 44 +/- 19%, whereas the N-methyl-D-aspartate response was unchanged. Isoflurane enhanced the tetanic depression of the population spike. The present results suggest that isoflurane reduces excitatory synaptic transmission by a presynaptic mechanism.