Vol. 286, Issue 2, 991-999, August 1998

Felbamate Increases [³H]Glycine Binding in Rat Brain and Sections of Human Postmortem Brain

R. Tyler McCabe, R. Duane Sofia, Richard T. Layer, Kevin A. Leiner, Richard L. M. Faull, Neelam Narang and James K. Wamsley

Cognetix, Inc., Salt Lake City, Utah (R.T.M., R.T.L.); Wallace Laboratories, Division of Carter-Wallace, Inc., Cranbury, New Jersey (R.D.S.); Department of Biology, Texas A&M Universtity, College Station, Texas (K.A.L.); Department of Anatomy, University of Auckland, Auckland, New Zealand (R.L.M.F.); Department of Microbiology, USDA, Washington D.C. (N.N.) and Departments of Psychiatry and Pharmacology, New York Medical College, Valhalla, New York (J.K.W.)

The anticonvulsant compound felbamate (2-phenyl-1,3-propanediol dicarbamate; FBM) appears to inhibit the function of the N-methyl-D-aspartate (NMDA) receptor complex through an interaction with the strychnine-insensitive glycine recognition site. Since we have demonstrated previously that FBM inhibits the binding of [³H]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, [³H]glycine, to rat forebrain membranes and human brain sections. In contrast to its ability to inhibit [³H]5,7-DCKA binding, FBM increased [³H]glycine binding (20 nM; EC₅₀ = 485 µM; 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 µM; E_max = 157% of control; n_H = 1.6) in human cortex sections. Autoradiographic analysis of human brain slices demonstrated that FBM produced the largest increases in [³H]glycine binding in the cortex, hippocampus and the parahippocampal gyrus. Because various ions can influence the binding of glycine-site ligands, we assessed their effects on FBM-modulation of [³H]glycine binding. FBM-enhanced [³H]glycine binding was attenuated by Zn⁺⁺ and not inhibited by Mg⁺⁺ in human brain. These results suggest that FBM increases [³H]glycine binding in a manner sensitive to ions which modulate the NMDA receptor. These data support the hypothesis that FBM produces anticonvulsant and neuroprotective effects by inhibiting NMDA receptor function, likely through an allosteric modulation of the glycine site.