ANTAGONISM OF CONVULSIONS BUT FAILURE TO ENHANCE GABA(A) RECEPTOR FUNCTION BY FELBAMATE IN MICE TOLERANT TO DIAZEPAM

The transfer of tolerance between drugs may indicate a common mode of action. The development of cross-tolerance to the anticonvulsant effec t of felbamate after long-term treatment of mice with diazepam, a posi tive modulator of gamma-aminobutyric acid (GABA)-mediated transmission , was therefore studied in order to clarify the mechanism of this acti on of felbamate. A challenge injection of felbamate, administered 36 h after the last dose of chronic diazepam treatment, antagonized convul sions elicited by administration of isoniazid. In contrast, felbamate had no effect on the isoniazid-induced increase in t-[S-35]butylbicycl ophosphorothionate binding to cerebral cortical membranes of diazepam- tolerant mice. These results suggest that the action of felbamate on G ABAergic transmission is not required for the anticonvulsant effect of this drug. This conclusion is consistent with studies that have indic ated that the antiepileptic activity of felbamate depends on its modul atory activity at excitatory amino acid receptors.