H S White1, S D Brown, J H Woodhead, G A Skeen, H H Wolf. 1. Anticonvulsant Screening Project, Department of Pharmacology and Toxicology, University of Utah, College of Pharmacy, Salt Lake City 84112, USA.
Abstract
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.
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.
Authors: Constance M Moore; Megan Wardrop; Blaise deB Frederick; Perry F Renshaw Journal: Psychopharmacology (Berl) Date: 2006-08-31 Impact factor: 4.530
Authors: Henry R Kranzler; Jonathan Covault; Richard Feinn; Stephen Armeli; Howard Tennen; Albert J Arias; Joel Gelernter; Timothy Pond; Cheryl Oncken; Kyle M Kampman Journal: Am J Psychiatry Date: 2014-04 Impact factor: 18.112