A failure of early paired pulse depression often precedes the onset of intermittent spontaneous seizures in animal models of status epilepticus. In the present study, changes in the strength of early and late paired pulse depression of dentate granule cell field potentials were compared in the unanesthetized rat during the initiation of a single afterdischarge (AD) evoked by perforant path stimulation (0.1 ms pulse duration, 5 Hz, 12-18 s duration, 50-1000 microA). Late paired pulse depression was measured by sequential changes in the population spike (PS) amplitude during 5 Hz stimulation (200 ms interpulse interpulse interval, IPI). When 5 Hz stimulation triggered an AD, the population spike (PS) was initially depressed and then increased to above pre-train values, indicating a loss of late paired pulse depression by the middle of the train. Early paired pulse depression was measured by inserting paired pulses (20 ms IPI) at spaced intervals throughout the 5 Hz train. In contrast to late paired pulse depression, early paired pulse depression remained at maximum strength until an abrupt failure was detected coincident with AD initiation. Two experimental treatments shown to increase the strength of late paired pulse depression, administration of the N-methyl-D-aspartate antagonist, MK-801 (0.25 mg/kg, i.p.), and the development of kindled seizures, produced an increase in AD thresholds and in the initial depression in the PS amplitude during 5 Hz stimulation. Together, these results suggest that a failure of late paired pulse depression may be a precipitating event in AD initiation triggered by 5 Hz stimulation in the unanesthetized rat.