Topiramate modulates GABA-evoked currents in murine cortical neurons by a nonbenzodiazepine mechanism.
These studies further investigate the ability of topiramate (TPM) to enhance gamma-aminobutyric acid (GABA)-mediated inhibition through a benzodiazepine-insensitive pathway.



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).



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.).



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.
White
H S
HS
Anticonvulsant Screening Project, Department of Pharmacology and Toxicology, University of Utah, College of Pharmacy, Salt Lake City 84112, USA.
Brown
S D
SD
Woodhead
J H
JH
Skeen
G A
GA
Wolf
H H
HH
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D002998:Clonazepam / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects; D005442:Flumazenil / Q000494:pharmacology; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010433:Pentylenetetrazole / Q000494:pharmacology; D018079:Receptors, GABA / Q000187:drug effects* / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D000077236:Topiramate; D005680:gamma-Aminobutyric Acid / Q000187:drug effects* / Q000494:pharmacology
D000927:Anticonvulsants; D018756:GABA Antagonists; D018757:GABA Modulators; D018079:Receptors, GABA; D000077236:Topiramate; D005632:Fructose; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D002998:Clonazepam; D010433:Pentylenetetrazole