FELBAMATE INHIBITS [H-3] T-BUTYLBICYCLOORTHOBENZOATE (TBOB) BINDING AND ENHANCES CL- CURRENT AT THE GAMMA-AMINOBUTYRIC ACID(A) (GABA(A)) RECEPTOR

We investigated the interaction of felbamate (FBM) with gamma-aminobut yric acid type A receptors using receptor autoradiography with [H-3]t- butylbicycloorthobenzoate (TBOB) and whole-cell patch-clamp recordings of cultured mouse cortical neurons. FBM produced dose-dependent inhib ition of [H-3]TBOB binding with IC50 values of approximately 250 mu M. Saturation analysis in the presence of FBM revealed increased K-d and decreased B-max. Dissociation initiated by picrotoxin (PTX) was accel erated by FBM. The regional pattern of [H-3]TBOB binding inhibition by FBM was different from the regional modulation of [H-3]TBOB binding p roduced by gamma-aminobutyric acid (GABA) agonists, bicuculline, zinc or neurosteroids. With electrophysiological recordings, FBM enhanced G ABA-elicited Cl- currents at GABA concentrations of 10 mu M but not 3 mu M or 100 mu M. FBM enhancement was not blocked by the benzodiazepin e antagonist flumazenil, and FBM did not affect pentobarbital potentia tion of GABA-elicited currents. FBM also had no effect on PTX inhibiti on of GABA-elicited Cl- currents. These results suggest that FBM poten tiates gamma-aminobutyric acid type A receptor function, at least in p art, by acting at a site hat interacts with the PTX site but is distin ct from the PTX barbiturate, GABA, benzodiazepine, zinc and neurostero id sites.