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The effect of the novel antiepileptic drug levetiracetam on caffeine (10 mM)-induced intracellular calcium ([Ca2+]i) response was investigated in rat hippocampal neurons in culture, with the aim of exploring the cellular mechanisms of this new drug. Levetiracetam significantly reduced caffeine-induced [Ca2+]i response, with maximum inhibition at 32 μM. The R-enantiomer of levetiracetam, ucb L060, which is devoid of anticonvulsant activity, at 32μM had no effect on caffeine-induced [Ca2+]i response. Caffeine 10 mM also induced epileptiform field potentials in rat hippocampal slices in vitro: single stimuli evoked repetitive population spikes and spontaneous field bursts regularly occurred. Levetiracetam (32 μM) significantly inhibited the amplitudes and the number of caffeine-induced repeated population spikes and delayed the appearance of spontaneous bursts, while ucb L060 (32 μM) completely lacked anti-caffeine activity. These results suggest that the inhibition of caffeine-induced Ca2+ release from intra-neuronal stores might be an excitability-reducing effect of levetiracetam, contributing to its antiepileptic activity.