The effect of the neurosteroid dehydroepiandrosterone sulfate on inhibitory synaptic transmission was studied in area CA1 of the rat hippocampus using an in vitro hippocampal slice preparation. Synaptic responses elicited by stimulation of Schaffer collateral fibers were recorded extracellularly as population spikes in the somatic region and as synaptic field potentials in the dendritic region. Bath application of dehydroepiandrosterone sulfate (10 microM) enhanced the synaptically evoked somatic population spike with no effect on the dendritic synaptic potential. Isolation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor-mediated component of the synaptic response by addition of antagonists of N-methyl-D-aspartate and GABA receptors to the perfusion saline demonstrated that dehydroepiandrosterone sulfate had no effect on this component of the dendritic synaptic potential. In contrast, dehydroepiandrosterone sulfate antagonized GABA receptor-mediated inhibitory effects in the somatic region, resulting in an augmentation of the somatic population spike amplitude. Paired-pulse facilitation was unaltered by dehydroepiandrosterone sulfate, thus arguing against possible presynaptic sites of dehydroepiandrosterone sulfate's actions. These results indicate that dehydroepiandrosterone sulfate can alter synaptic transmission in the hippocampus through selective postsynaptic actions on inhibitory synaptic transmission. A synaptic effect of dehydroepiandrosterone sulfate is consistent with a neuromodulatory role for this neurosteroid in the central nervous system, and may contribute to the reported effects of dehydroepiandrosterone sulfate on cognitive processes such as learning and memory.