Activation of muscarinic cholinergic receptors produces oscillations in the hippocampal slice that resemble the theta rhythm, but also may produce abnormal synchronous activity that is more characteristic of epileptiform activity. We used pilocarpine, a muscarinic agonist and convulsant, and an elevation in extracellular potassium (5-7.5 mM) to produce synchronous neuronal activity that was prolonged (>2 s) and mimicked synchronization noted during seizures in vivo (ictal activity). In the CA3 region of adult rat hippocampal slices, prolonged ictal oscillations consisted of rhythmic field potentials occurring at 4-10 Hz for up to 30 s (ictal duration) that occurred in a regular periodic pattern every 12-166 s (ictal interval). The duration and interval between ictal oscillations were measured before and after application of drugs to define determinants of ictal occurrence. High threshold calcium channel antagonists (nifedipine and verapamil) blocked ictal activity. Release of calcium from intracellular stores also appeared to be important for ictal synchronization because ictal activity was blocked by dantrolene, an inhibitor of calcium release from intracellular stores, and by thapsigargin which blocks the ATPase that maintains intracellular calcium stores. These suppressive effects appeared to be postsynaptic because nifedipine, dantrolene, and thapsigargin had no effect on evoked fEPSPs. Enhancement of presynaptic inhibition by activation of GABA(B) or adenosine A(1) receptors suppressed ictal activity and depressed the amplitude of evoked population synaptic potentials. The results point to an important role for high threshold calcium channels and release of calcium from intracellular stores in addition to strength of synaptic connections in generation of prolonged oscillations that underlie seizure activity.