1. The effect of ethanol on the function of P2X(4) receptors expressed in Xenopus oocytes was studied using two-electrode voltage-clamp recording. 2. The amplitude of current activated by 1 microM ATP was decreased by ethanol in a concentration-dependent manner over the concentration range 1 - 500 mM. The concentration of ethanol that produced 50% inhibition (IC(50)) of current activated by 1 microM ATP was 58 mM. 3. Ethanol inhibition of ATP-activated current was not dependent on membrane potential from -60 to +20 mV, and ethanol did not change the reversal potential of ATP-activated current. 4. Ethanol, 50 mM, shifted the ATP concentration-response curve to the right, increasing the EC(50) for ATP from 9.1 to 16.0 microM, but did not reduce the maximal response to ATP. 5. The results suggest that ethanol may inhibit P2X(4) receptors by decreasing the apparent affinity of the binding site for ATP. 6. Since the P2X(4) receptor is the most abundant P2X subunit in the brain, these receptors could be important effectors of ethanol action in the central nervous system.