The cellular mechanisms by which ethanol affects nervous system function are poorly understood. However, evidence has been accumulating that ethanol can affect the function of neurotransmitter-gated ion channels. Extracellular ATP has recently been reported to produce excitatory actions in the peripheral and central nervous systems by activating ligand-gated ion channels. We studied the effect of ethanol on membrane ion current activated by extracellular ATP in isolated bullfrog dorsal root ganglion neurons, by means of the whole-cell patch-clamp technique. The amplitude of the ATP-activated current was decreased by ethanol in a concentration-dependent manner over the range of 3-500 mM. The average inhibition of 1 microM ATP-activated current by 100 mM ethanol was 64 +/- 3%, and the concentration of ethanol that produced 50% inhibition was 68 mM. Ethanol inhibition of ATP-activated current was not dependent on membrane potential from -80 to +40 mV, and ethanol did not change the reversal potential of ATP-activated current. Ethanol (100 or 400 mM) shifted the ATP concentration-response curve to the right, increasing the EC50 for ATP from 3.0 microM to 6.0 microM or 22.3 microM, respectively, but did not reduce the maximal response to ATP. The results suggest that ethanol inhibits ATP-activated current by increasing the apparent dissociation constant for the ATP receptor.