The sensitivity of N-methyl-D-aspartate- (NMDA) induced whole-cell and single-channel currents to Pb2+ was studied in neurons acutely dissociated from the hippocampus of 3- to 30-day-old rats. The amplitude of NMDA-induced whole-cell currents in the neurons increased with age of the animals until they were 10 to 12 days old, thereafter remaining nearly unchanged. As in cultured hippocampal neurons, Pb2+ at both 10 and 30 microM inhibited NMDA-induced currents, and the sensitivity of the currents to Pb2+ decreased with age of the rats. The sensitivity correlated with the age-related expression of two components of the NMDA-induced currents, one that was fast decaying and more prominent in younger neurons, and the other slowly decaying. Inhibition of the fast component by Pb2+ was always greater than that of the slow component, which may explain the greater sensitivity of younger neurones to Pb2+. may explain the greater sensitivity of younger neurons to Pb2+. The use of trypsin during acute dissociation of the neurons did not qualitatively alter the findings, although in the trypsin-treated neurons the currents were 65% smaller, and the EC50 for NMDA and glycine for the slow component were both about two times greater than in the untreated neurons; in the case of the fast component, the EC50s for NMDA and for glycine were not significantly altered. In outside-out patches excised from acutely dissociated hippocampal neurons, Pb2+ decreased the frequency of NMDA-activated channel openings without altering the mean channel open time. Our results are in agreement with those reported for embryonic neurons that developed in culture, and indicate that NMDA receptors expressed in hippocampal neurons of young animals are key target sites for the neurotoxic actions of Pb2+.