Topiramate Modulates GABA‐Evoked Currents in Murine Cortical Neurons by a Nonbenzodiazepine Mechanism

Summary: Purpose : These studies further investigate the ability of topiramate (TPM) to enhance γ‐aminobutyric acid (GABA)‐mediated inhibition through a benzodiazepine‐insensitive pathway. Methods : Topiramate (30 and 100 μ M ) enhancement of GABA (1 μ M )‐evoked currents in primary cultures of mouse cortical neurons was studied by using whole‐cell electrophysiologic techniques. Results obtained with TPM (30 μ M ) were compared with those obtained with clonazepam (CZP; 1 μ M ). Results : Topiramate enhanced GABA currents in a subset of cortical neurons tested. In addition, TPM enhanced GABA‐evoked currents in CZP‐insensitive neurons, and CZP was effective in a subset of TPM‐insensitive neurons. Related 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 the benzodiazepine (BZD) antagonist flumazenil (FMZ; 40 mg/kg, i.p.). Conclusions : These results indicate that GABA A ‐receptor sensitivity to TPM is not dependent on the presence of BZD sensitivity. Enhancement of GABA‐mediated inhibition through a BZD‐insensitive pathway may represent one mechanism through which TPM exerts its anticonvulsant action.