FELBAMATE INCREASES [H-3]GLYCINE BINDING IN RAT-BRAIN AND SECTIONS OFHUMAN POSTMORTEM BRAIN

The anticonvulsant compound felbamate (2-phenyl-1,3-propanediol dicarb amate; FBM) appears to inhibit the function of the N-methyI-D-aspartat e (NMDA) receptor complex through an interaction with the strychnine-i nsensitive glycine recognition site. Since we have demonstrated previo usly that FBM inhibits the binding of [H-3]5,7-dichlorokynurenic acid (DCKA), a competitive antagonist at the glycine site, we assessed the ability of FBM to modulate the binding of an agonist, [H-3]glycine, to rat forebrain membranes and human brain sections. In contrast to its ability to inhibit [H-3]5,7-DCKA binding, FBM increased [H-3]glycine b inding (20 nM; EC50 = 485 mu M; E-max = 211% of control; n(H) = 1.8). FBM, but not carbamazepine, phenytoin, valproic acid or phenobarbital, also increased [3H]glycine binding (50 nM; EC50 = 142 mu M; E-max = 1 57% of control; n(H) = 1.6) in human cortex sections. Autoradiographic analysis of human brain slices demonstrated that FBM produced the lar gest increases in [H-3]glycine binding in the cortex, hippocampus and the parahippocampal gyrus. Because various ions can influence the bind ing of glycine-site ligands, we assessed their effects on FBM-modulati on of [H-3]glycine binding. FBM-enhanced [H-3]glycine binding was atte nuated by Zn++ and not inhibited by Mg++ in human brain. These results suggest that FBM increases [H-3]glycine binding in a manner sensitive to ions which modulate the NMDA receptor. These data support the hypo thesis that FBM produces anticonvulsant and neuroprotective effects by inhibiting NMDA receptor function, likely through an allosteric modul ation of the glycine site.