Felbamate modulates the strychnine-insensitive glycine receptor.
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.
White
H S
HS
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112.
Harmsworth
W L
WL
Sofia
R D
RD
Wolf
H H
HH
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000078328:Felbamate; D005998:Glycine / Q000494:pharmacology; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000494:pharmacology*; D018009:Receptors, Glycine / Q000502:physiology*; D012694:Serine / Q000494:pharmacology; D013331:Strychnine / Q000494:pharmacology*
D000927:Anticonvulsants; D048448:Phenylcarbamates; D011409:Propylene Glycols; D018009:Receptors, Glycine; D012694:Serine; D016202:N-Methylaspartate; D013331:Strychnine; D002118:Calcium; D005998:Glycine; D000078328:Felbamate