Abstracts

We used transcranial magnetic stimulation (TMS) to study the effects of 7 antiepileptic drugs (AED) on associative long-term potentiation (LTP)-like plasticity and motor learning in eight healthy subjects. LTP was induced by paired associative stimulation and motor learning was investigated in a repeated thumb movement practice protocol. Single oral doses of the following AED were tested in a placebo-controlled double-blind cossover design: 20 mg of diazepam, 1100 mg of gabapentin, 300 mg of lamotrigin, 3000 mg of levetiracetam, 3600 mg of piracetam, 15 mg of tiagabine, and 100 mg of topiramate. Drugs were tested in separate sessions at least one week apart in pseudo-randomized and balanced order. LTP-like plasticity was significantly depressed by those AED, which enhance gamma-butyric acid (GABA) dependent inhibition (tiagabine, diazepam, and in addition levetiracetam). Gabapentin showed a trend towards enhancement of LTP-like plasticity. The testing of effects of AED on motor learning is work in progress. The main finding is that associative LTP-like plasticity in human motor cortex is suppressed by levetiracetam, diazepam and tiagabine. The effects of diazepam and tiagabine are in agreement with the literature, which shows that increase of neurotransmission through the GABAA receptor results in reduction of LTP in rodent hippocampus and neocortex. The suppression of LTP-like plasticity by levetiracetam may also be attributed to its GABAergic mechanisms, which mainly occur through reversal of GABAA receptor inhibition by the negative allosteric modulators zinc and [szlig]-carbolines. An alternative though not mutually exclusive explanation for the effect of levetiracetam is its capability of suppressing repetitive neuronal discharges in various models of epilepsy. A single TMS pulse over motor cortex results in a high-frequency repetitive discharge of corticomotoneuronal cells, which may be a requirement for LTP-like plasticity to develop. The lack of suppression of LTP-like plasticity by other modes of action, in particular the blockade of voltage-gated sodium channels, is in accordance with the animal literature. As a next step, the results of LTP modulation will be compared with the effects of AED on motor learning. Previous studies showed congruence of neuromodulatory effects on LTP and motor learning, suggesting that these two processes share common mechanisms. (Supported by UCB Pharma, Braine l[apos]Alleud, Belgium.)