The effect of ethanol on current activated by extracellular adenosine 5'-triphosphate (ATP) was studied in freshly isolated adult rat hippocampal CA1 neurons using whole-cell patch-clamp recording. ATP activated an inward current with an EC(50) value of 18 microM. The inward current was also activated by 2-methylthio ATP (2-MeSATP) and alpha,beta-methylene ATP (alpha,beta-MeATP), inhibited by pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), and potentiated by Zn(2+). Ethanol inhibited current activated by 10 microM ATP with an IC(50) value of 83 mM in a voltage-independent manner. Ethanol, 100 mM, shifted the ATP concentration-response curve to the right, increasing the EC(50) value for ATP from 18 to 33 microM, but did not reduce the maximal response to ATP. The results suggest that ethanol can inhibit the function of P2X receptors in adult rat hippocampal neurons by decreasing the apparent affinity of the binding site for ATP.