Caffeine (50 microM) increases the amplitude of the basal field potential (BFP) due to orthodromic stimulation of CA1 pyramidal neurons in rat hippocampal slices. This effect is absent if (1) the adenosine agonist L-phenyl-isopropyladenosine (L-PIA) (0.5 microM) is added to the perfusion with caffeine, and (2) low calcium (0.1 mM)-high magnesium (5mM) solutions are used. The calcium blocker verapamil (0.05-0.2 mM) does not modify the caffeine-induced effects. Higher concentrations of caffeine (0.2-0.5 mM) elicit the appearance of an epileptiform bursting, whose duration is inhibited at almost the 50% by 0.5 microM of L-PIA and unaffected by verapamil (0.2 mM) and nifedipine (0.05-0.10 mM). 5 microM of L-PIA, low calcium (0.1 mM)-high magnesium (5 mM) solution and verapamil (0.2 mM) are able to inhibit at almost the 50% the epileptiform bursting duration due to the potassium blocker 4-aminopyridine (4-AP). Nifedipine (0.05-0.1 mM) does not affect the 4-AP effects. L-PIA (0.5-2 microM) but not verapamil (0.2 mM) and nifedipine (0.1 mM) inhibits at almost the 50% the penicillin (1 mM) epileptiform bursting duration. The data indicate a different antagonistic influence of purinergic drugs and verapamil, on different models of epilepsy in rat hippocampal slices. In addition, the lack of antagonism between purinergic drugs and verapamil suggests different sites of action of the drugs.