Topiramate modulates GABA-evoked currents in murine cortical neurons by a nonbenzodiazepine mechanism

Purpose: These studies further investigate the ability of topiramate (TPM) to enhance gamma-aminobutyric acid (GABA)-mediated inhibition through a ben zodiazepine-insensitive pathway. Methods: Topiramate (30 and 100 mu M) enhancement of GABA (1 mu M)-evoked c urrents in primary cultures of mouse cortical neurons was studied by using whole-cell electrophysiologic techniques. Results obtained with TPM (30 mu M) were compared with those obtained with clonazepam (CZP; 1 mu M). Results: Topiramate enhanced GABA currents in a subset of cortical neurons tested. In addition, TPM enhanced GABA-evoked currents in CZP-insensitive n eurons, and CZP was effective in a subset of TPM-insensitive neurons. Relat ed studies in vivo demonstrated that intraperitoneal (i.p.) administration of either TPM (25 mg/kg) or CZP (0.012 mg/kg) increases pentylenetetrazol ( PTZ) seizure threshold. This effect of CZP, but not TPM, was reversed by th e benzodiazepine (BZD) antagonist flumazenil (FMZ; 40 mg/kg, i.p.). Conclusions: These results indicate that GABA(A)-receptor sensitivity to TP M is not dependent on the presence of BZD sensitivity. Enhancement of GABA- mediated inhibition through a BZD-insensitive pathway may represent one mec hanism through which TPM exerts its anticonvulsant action.