The antiepileptic drug riluzole is a use-dependent blocker of voltage-gated Na+ channels and selectively depresses action potential-driven glutamate over γ-aminobutyric acid (GABA) release. Here we report that in addition to its presynaptic effect, riluzole at higher concentrations also strongly potentiates postsynaptic GABAA responses both in cultured hippocampal neurons and in Xenopus oocytes expressing recombinant receptors. Although peak inhibitory postsynaptic currents (IPSCs) of autaptic hippocampal neurons were inhibited, 20-100 μM riluzole significantly prolonged the decay of IPSCs, resulting in little change in total charge transfer. The effect was dose-dependent and reversible. Riluzole selectively increased miniature IPSC fast and slow decay time constants, without affecting their relative proportions. Miniature IPSC peak amplitude, rise time and frequency were unaffected, indicating a postsynaptic mechanism. In the Xenopus oocyte expression system, riluzole potentiated GABA responses by lowering the EC50 for GABA activation. Riluzole directly gated a GABAA current that was partially blocked by bicuculline and gabazine. Pharmacological experiments suggest that the action of riluzole did not involve a benzodiazepine, barbiturate, or neurosteroid site. Instead, riluzole-induced potentiation was inhibited by the lactone antagonist α-isopropyl-α-methyl-γ-butyrolatone (α-IMGBL). While most anticonvulsants either block voltage-gated Na+ channels or potentiate GABAA receptors, our results suggest that riluzole may define an advantageous class of anticonvulsants with both effects.
- GABA receptors
- Inhibitory postsynaptic current