EEG was recorded from several brain regions during the i.v. infusion of digitoxigenin to conscious, freely-moving rats. Two seizure episodes were recorded from the ventral hippocampus with the second, more severe seizure characterized by low-frequency (3-6/sec), high-amplitude (0.9-1.5 mV) discharges. Secondary activity was recorded from the mesencephalic and reticular formations. Pretreatment of rats with p-chlorophenylalanine or reserpine prevented the first seizure and markedly delayed the second seizure to appear after 1.85 mg or 4.66 mg digitoxigenin/kg, respectively, compared to 0.79 mg/kg in untreated rats. The pretreatments did not alter the frequency of the discharges but reduced their amplitude to 0.4 -0.75 mV. The results suggest a role for monoamines, and in particular serotonin, in the effect of digitoxigenin to cause hippocampal seizure discharge.