Electrophysiological techniques were used to study the response of native Xenopus laevis oocytes to intracellular injection and bath application of ethanol. Injection of ethanol produced dose-dependent transient inward currents accompanied by large current fluctuations, with estimated intracellular concentrations ranging from 10 to 300 mM. The response duration varied between 2 and 15 min, with an onset delay of 2-15 s. The inward current sometimes consisted of a fast and a slow component. Bath application of equivalent concentrations elicited similar but considerably smaller responses. The current showed a reversal potential of -20 +/- 10 mV, corresponding to an increase in chloride permeability. The response was eliminated in the presence of low chloride saline and was blocked by the chloride channel inhibitors SITS and DIDS. Ethanol responses were inhibited by the intracellular injection of the calcium chelator EGTA and were unaffected when the extracellular calcium was lowered. It is concluded that ethanol injection into Xenopus oocytes elicits a release of calcium from intracellular stores, which then activates an increased membrane permeability to chloride.