The effects of anticonvulsant agents on 4-aminopyridine induced epileptiform activity in rat hippocampus in vitro.

Six anticonvulsant drugs, phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), U-54494A, losigamone (LOS), and D-20443, were studied using rat hippocampal slices and standard electrophysiological techniques. The K+ channel blocker, 4-aminopyridine (4-AP), was used as neuronal stimulant. The extracellular parameters evaluated in areas CA3 and CA1 were: (1) interictal-type bursting, (2) evoked population spike (PS) amplitude, (3) latency to PS onset, and (4) duration of the excitatory postsynaptic potential (EPSP). VPA was ineffective in altering any of the parameters. PHT and CBZ partially reversed the increase in EPSP duration produced by 4-AP in area CA3, while the spontaneous bursting was not affected. The experimental drugs, U-54494A, LOS, and D-20443 (dihydrochloride salt of D-23129 from Asta Medica), tended to reverse to varying degrees the 4-AP effects, especially the increase in the EPSP duration. U-54494A tended to depress responses even under control conditions. LOS partially reversed the 4-AP excitation, but abolished bursting in only one of five slices. D-20443 abolished bursting in all slices. It also partially reversed the 4-AP induced increase in the EPSP duration without depressing the normal evoked potential. The results show that 4-AP induced changes in vitro can help differentiate drugs with similar in vivo spectrums of anticonvulsant activity. While the drug induced changes may not truly define the mechanisms of action of these promising new agents, these experimental anticonvulsants can be differentiated from standard agents using the experimental paradigm in this study.