Felbamate modulates the strychnine-insensitive glycine receptor

Abstract

Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a novel anticonvulsant substance whose mechanism of action is not clearly understood. The present investigation examined its ability to modulate the strychnine-insensitive glycine receptor associated with the N-methyl-D-aspartate (NMDA) receptor. Felbamate decreased the magnitude of glycine (100 microM)-enhanced NMDA (100 microM)-induced intracellular calcium ([Ca2+]i) transients in mouse cerebellar granule cells which had been loaded with the Ca(2+)-sensitive fluorescent probe indo-1 acetoxymethyl ester (indo-1/AM). This effect of felbamate was concentration dependent, with a maximal effect observed at 300 microM (65 +/- 4% of control). In the Frings audiogenic seizure-susceptible mouse model of reflex epilepsy, the glycine agonist D-serine (150 nmol, i.c.v.) completely blocked the anticonvulsant activity of a maximally effective dose of felbamate (19 mg/kg, i.p.). This effect of D-serine could be reversed by increasing the administered dose of felbamate to 29 mg/kg. Furthermore, administration of D-serine (300 nmol, i.c.v.) to felbamate-treated Frings mice produced a parallel right shift in felbamate's anticonvulsant dose-response curve (ED50s: 9.4 mg/kg for felbamate vs. 17.7 mg/kg for felbamate + D-serine). The results obtained in this investigation suggest that the ability of felbamate to modulate the strychnine-insensitive glycine receptor may be physiologically and behaviorally relevant to its anticonvulsant mechanism of action.