N-methyl-D-aspartate (NMDA) receptor dysfunctions are thought to be involved in the pathophysiology of seizures of hippocampal origin. While the cellular effects of excessive NMDA receptor stimulation have been widely studied in vitro, no data are available on the sequence of cellular electrophysiological events that follow the overstimulation of hippocampal NMDA receptors in awake, behaving subjects. Therefore, the present study addressed this problem. Intrahippocampal microdialysis with 500 microM NMDA was performed in freely behaving rats, and the electrical activity of single neurons in the dialysis area were monitored. In all recorded neurons (n = 9), regardless of their type, NMDA induced a long-lasting electrical silence preceded in most cells by a brief but robust firing rate increase. During these firing rate increases, place cells lost the spatial selectivity of their discharges, and a gradual reduction in the amplitude of the action potentials was also observed. Remarkably, electroencephalographic (EEG) seizures developed exclusively after the appearance of cellular electrical silence in the recording/dialysis site. The NMDA-induced electrophysiological changes were reversible. This study demonstrates that the combined single-cell recording-intracerebral microdialysis technique can be readily used for inducing focal epileptiform events in the hippocampus and monitoring the induced cellular electrophysiological events in behaving animals.