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 ant iconvulsant drug topiramate (TPM, 50-500 mu M) modulates the excitabil ity of rat subicular neurons that generate action potential bursts mai nly caused by voltage-dependent, Na+-electrogenesis. Subiculum is a ga ting structure for outputs originating from the hippocampus proper, an d thus it may play a role in limbic seizures. In 28/45 neurons, TPM in duced a steady hyperpolarization of the resting membrane potential (RM P) 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 res ponse to brief (5-150 ms) depolarizing pulses, such an effect was char acterized by an increase in the amount of intracellular depolarizing c urrent required for eliciting action potential bursts, and it also occ urred when the TPM-induced steady hyperpolarization was compensated by injecting steady depolarizing current. In addition TPM reduced by app rox. 50% the regular action potential firing elicited by prolonged (35 0-1000 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 inpu t resistance decrease elicited by TPM were markedly reduced by the GAB A(A) receptor antagonists bicuculline methiodide (10 mu M; n = 6) or p icrotoxin (100 mu M; n = 2); such an effect was associated with a redu ction, but not with blockade of the depressant action exerted by TPM o n burst generation. Our findings indicate that TPM reduces subicular c ell excitability, and modifies bursting ability and repetitive firing properties. These effects may be ascribed to actions on voltage-gated, Na+ electrogenesis and GABA(A) receptors. We propose that these chang es in excitability may all contribute to the anticonvulsant action of TPM in limbic seizures that occur in temporal lobe epilepsy patients. (C) 1998 Elsevier Science B.V. All rights reserved.