Carisbamate (RWJ-333369) inhibits glutamate transmission in the granule cell of the dentate gyrus

Abstract

Carisbamate (CRS, RWJ-333369) is a novel antiepileptic drug awaiting approval for use in the treatment of partial and generalized seizures. Our aim was to determine whether CRS modulates synaptic transmission in the dentate gyrus (DG) and the underlying mechanism. The whole-cell patch-clamp method was used to record AMPA receptor- and NMDA receptor-mediated excitatory postsynaptic currents (EPSCAMPA and EPSCNMDA) and GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in granule cells of the DG in brain slices prepared from 3- to 5-week-old male Wistar rats. CRS (30–300μM) inhibited the evoked EPSCAMPA and EPSCNMDA by the same extent (20%) with significantly altered CV−2, suggesting presynaptic modulation. It did not significantly change the inward currents induced by AMPA application. The inhibitory effect of CRS on the evoked EPSCAMPA was not occluded by selective voltage-gated Ca2+ channel blockers, ruling out the involvement of presynaptic Ca2+ channels. The frequency, but not the amplitude, of spontaneous EPSCAMPA was significantly reduced by CRS. However, CRS did not alter either the frequency or the amplitude of TTX-insensitive miniature EPSCAMPA, indicating an action potential-dependent mechanism was involved. In addition, CRS (100 or 300μM) did not significantly change the amplitude of the evoked IPSCs. To summarize, our results suggest that CRS reduces glutamatergic transmission by an action potential-dependent presynaptic mechanism and consequently inhibits excitatory synaptic strength in the DG without affecting GABAergic transmission. This effect may contribute to the antiepileptic action observed clinically at therapeutic concentrations of CRS.