The dihydropyridine calcium channel antagonist, nimodipine has antiepileptic and anticonvulsive properties that are thought to be mediated through neuronal calcium channel blockade. The dihydropyridine binding site can be positively and negatively allosterically regulated by the benzothiazepines and the phenylalkylamines/piperazines, respectively. We investigated this binding interaction at the physiologic level by examining the effects of diltiazem (a benzothiazepine) and flunarizine (a piperazine) on the antiseizure activity of nimodipine. Seizures were induced with pentylenetetrazole in awake rats with chronically implanted EEG electrodes. Calcium channel antagonists were administered intracerebroventricularly 30 min after pentylenetetrazole at doses given at 15 min intervals. Diltiazem and flunarizine alone lacked antiseizure properties. The calculated ED50 values for nimodipine were: nimodipine alone = 135 micrograms; nimodipine + diltiazem (100 micrograms) = 67 micrograms. Nimodipine + flunarizine (10 micrograms) completely suppressed nimodipine's antiseizure activity. These findings may reflect the interaction observed among these agents at binding sites associated with the calcium channel and supports the idea that dihydropyridines mediate their antiseizure actions through neuronal calcium channel antagonism.