Purpose: Stiripentol (STP) is currently an efficient drug for add‐on therapy in infantile epilepsies because it improves the efficacy of antiepileptic drugs (AEDs) through its potent inhibition of liver cytochromes P450. In addition, STP directly reduces seizures in several animal models of epilepsy, suggesting that it might also have anticonvulsive effects of its own. However, its underlying mechanisms of action are unknown.

Methods: We examined the interactions of STP with γ‐aminobutyric acid (GABA) transmission by using patch‐clamp methods in CA3 pyramidal neurons in the neonatal rat.

Results: STP markedly increased miniature inhibitory postsynaptic current (mIPSC) decay‐time constant in a concentration‐dependent manner. The prolongation of mIPSC duration does not result from an interaction with GABA transporters because it persisted in the presence of GAT‐1 inhibitors (SKF‐89976A and NO‐711). An interaction with benzodiazepine or neurosteroid binding sites also was excluded because STP‐mediated increase of decay time was still observed when these sites were initially saturated (by clobazam, zolpidem, or pregnanolone) or blocked (by flumazenil or dehydroepiandrosterone sulfate), respectively. In contrast, saturating barbiturate sites with pentobarbital clearly occluded this effect of STP, suggesting that STP and barbiturates interact at the same locus. This was directly confirmed by using outside‐out patches, because STP increased the duration and not the frequency of opening of GABA_A channels.

Conclusions: At clinically relevant concentrations, STP enhances central GABA transmission through a barbiturate‐like effect, suggesting that STP should possess an antiepileptic effect by itself.