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

Epilepsia. 2000;41(S1):17-20.


Purpose: These studies further investigate the ability of topiramate (TPM) to enhance gamma-aminobutyric acid (GABA)-mediated inhibition through a benzodiazepine-insensitive pathway.

Methods: Topiramate (30 and 100 microM) enhancement of GABA (1 microM)-evoked currents in primary cultures of mouse cortical neurons was studied by using whole-cell electrophysiologic techniques. Results obtained with TPM (30 microM) were compared with those obtained with clonazepam (CZP; 1 microM).

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Anticonvulsants / pharmacology*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Clonazepam / pharmacology
  • Evoked Potentials / drug effects
  • Flumazenil / pharmacology
  • Fructose / analogs & derivatives*
  • Fructose / pharmacology
  • GABA Antagonists / pharmacology*
  • GABA Modulators / pharmacology
  • Mice
  • Neurons / drug effects*
  • Neurons / physiology
  • Patch-Clamp Techniques
  • Pentylenetetrazole / pharmacology
  • Receptors, GABA / drug effects*
  • Receptors, GABA / physiology
  • Seizures / chemically induced
  • Seizures / prevention & control
  • Topiramate
  • gamma-Aminobutyric Acid / drug effects*
  • gamma-Aminobutyric Acid / pharmacology


  • Anticonvulsants
  • GABA Antagonists
  • GABA Modulators
  • Receptors, GABA
  • Topiramate
  • Fructose
  • Flumazenil
  • gamma-Aminobutyric Acid
  • Clonazepam
  • Pentylenetetrazole