INHIBITION BY LEVETIRACETAM OF A NON-GABA(A) RECEPTOR-ASSOCIATED EPILEPTIFORM EFFECT OF BICUCULLINE IN RAT HIPPOCAMPUS

1 Extracellular recording of field potentials, evoked by commissural s timulation in hippocampal area CA3 of anaesthetized rats, was performe d in order to study the mode of action of the novel antiepileptic drug levetiracetam (ucb LO59). 2 The amplitude of orthodromic field popula tion spike (PS2) markedly increased and repetitive population spikes a ppeared when the recording micropipette contained either bicuculline m ethiodide (BMI), or the specific GABA(A) antagonist gabazine (SR-95531 ). 3 BMI-induced increases in PS2 were reduced in a dose-dependent man ner by to 320 mu mol kg(-1) levetiracetam i.v., with a U-shape dose-re sponse relationship. However, levetiracetam did not reduce the increas es in PS2 produced by gabazine. 4 Clonazepam (1 mg kg(-1), i.p.), carb amazepine (20 mg kg(-1), i.p.) and valproate (200 mg kg(-1) i.v.) were ineffective in preventing BMI-induced increases in PS2, while the cal cium channel antagonist flunarizine, 50 mu mol kg(-1), i.p., reduced P S2 increments caused by BMI. The L-type calcium channel blocker nifedi pine, 100 mu mol kg(-1), i.p., was without effect. Similar to levetira cetam, flunarizine did not reduce the increases in PS2 induced by gaba zine. 5 These data suggest that the increased excitability of CA3 neur ones, caused by BMI administered in situ, involves calcium-dependent p rocesses not associated with blockade of GABAA receptors. The inhibiti on by levetiracetam of this calcium-dependent effect of BMI might cont ribute to the antiepileptic effects of the drug.