In mammalian central neurons, intoxicating concentrations of ethanol inhibit the ion current activated by the glutamate agonist N-methyl-D-aspartate (NMDA). Electrophysiologic analysis of the molecular mechanism involved in this inhibition indicates that ethanol does not inhibit NMDA-activated ion current by voltage-dependent block of the channel, altering the ion selectivity of the channel, or altering the affinity of binding sites for NMDA, glycine or substances known to regulate the function of this channel (Mg2+, Zn2+ and ketamine). The potency for inhibiting the NMDA-activated current by different alcohols is linearly related to their hydrophobicity, suggesting that alcohols may inhibit the NMDA-activated current by a novel type of interaction with a hydrophobic region of the channel.