FELBAMATE MODULATES THE STRYCHNINE-INSENSITIVE GLYCINE RECEPTOR

Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a novel anticonvul sant substance whose mechanism of action is not clearly understood. Th e present investigation examined its ability to modulate the strychnin e-insensitive glycine receptor associated with the N-methyl-D-aspartat e (NMDA) receptor. Felbamate decreased the magnitude of glycine (100 m u M)-enhanced NMDA (100 mu M)-induced intracellular calcium ([Ca2+](i) ) transients in mouse cerebellar granule cells which had been loaded w ith the Ca2+-sensitive fluorescent probe indo-1 acetoxymethyl ester (i ndo-1/AM). This effect of felbamate was concentration dependent, with a maximal effect observed at 300 mu M (65 +/- 4% of control). In the F rings audiogenic seizure-susceptible mouse model of reflex epilepsy, t he 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, administ ration of D-serine (300 nmol, i.c.v.) to felbamate-treated Frings mice produced a parallel right shift in felbamate's anticonvulsant dose-re sponse curve (ED(50)s: 9.4 mg/kg for felbamate vs. 17.7 mg/kg for felb amate + D-serine). The results obtained in this investigation suggest that the ability of felbamate to modulate the strychnine-insensitive g lycine receptor may be physiologically and behaviorally relevant to it s anticonvulsant mechanism of action.