Acute ethanol intoxication is associated with changes in the activity of neurons in the central nervous system. However, the cellular and molecular mechanisms underlying these changes are poorly understood. We have examined the acute effects of ethanol on excitatory synaptic mechanisms in neurons from mammalian central nervous system, and observed that intoxicating concentrations of ethanol can inhibit the ion current activated by the glutamate receptor agonist N-methyl-D-aspartate in cultured neurons from mouse hippocampus, cortex and spinal cord. This inhibition is seen under a variety of experimental recording conditions. On the other hand, ethanol is less effective in inhibiting ion current produced by activation of non-N-methyl-D-aspartate glutamate receptors. Intoxicating concentrations of ethanol also inhibit excitatory synaptic transmission mediated by N-methyl-D-aspartate receptors in hippocampal slices from adult rodents. These observations support the hypothesis that the N-methyl-D-aspartate receptor/ionophore complex is a target for the neural actions of ethanol, and that inhibition of N-methyl-D-aspartate receptor-mediated responses might contribute to acute ethanol intoxication. The possibility that other receptor-gated ion channels may also be sensitive to ethanol is discussed.