Multiple actions of the novel anticonvulsant drug topiramate in the rat subiculum in vitro.
We used an in vitro slice preparation to study whether and how the anticonvulsant drug topiramate (TPM, 50-500 microM) modulates the excitability of rat subicular neurons that generate action potential bursts mainly caused by voltage-dependent, Na+-electrogenesis. Subiculum is a gating structure for outputs originating from the hippocampus proper, and thus it may play a role in limbic seizures. In 28/45 neurons, TPM induced a steady hyperpolarization of the resting membrane potential (RMP) that ranged between -2 and -16 mV and was associated with a 24-62% decrease of the apparent membrane input resistance. TPM also depressed the ability of these cells to generate action potential bursts in response to brief (5-150 ms) depolarizing pulses; such an effect was characterized by an increase in the amount of intracellular depolarizing current required for eliciting action potential bursts, and it also occurred when the TPM-induced steady hyperpolarization was compensated by injecting steady depolarizing current. In addition TPM reduced by approx. 50% the regular action potential firing elicited by prolonged (350-1000 ms) depolarizing pulses (n=15 of 27 neurons). Recovery of the TPM-induced changes was not seen during washout for periods of 20-80 min (n=7). Both the steady hyperpolarization of the RMP and the input resistance decrease elicited by TPM were markedly reduced by the GABAA receptor antagonists bicuculline methiodide (10 microM; n=6) or picrotoxin (100 microM; n=2); such an effect was associated with a reduction, but not with blockade of the depressant action exerted by TPM on burst generation. Our findings indicate that TPM reduces subicular cell excitability, and modifies bursting ability and repetitive firing properties. These effects may be ascribed to actions on voltage-gated, Na+ electrogenesis and GABAA receptors. We propose that these changes in excitability may all contribute to the anticonvulsant action of TPM in limbic seizures that occur in temporal lobe epilepsy patients.
Research Group on Cell Biology of Excitable Tissues, Montreal Neurological Institute, Montreal, Quebec, Canada.
H
H
Kawasaki
V
V
Tancredi
G
G
D'Arcangelo
M
M
Avoli
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects*; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D000077236:Topiramate
D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose