Lacosamide is a novel antiepileptic drug which is currently used as an add-on treatment for partial seizures with or without secondary generalisation. Its anti-seizure effect is believed to result from a selective enhancement of the slow inactivation of voltage-gated sodium channels. Lacosamide is effective in the maximal electroshock model, the kindling model and the pentylenetetrazol model. The effect of lacosamide on cortical excitability has not been studied in vivo. Our aim in this study was to evaluate the effect of lacosamide on motor cortex excitability in the cortical stimulation model (CSM). In the CSM, a ramp-shaped pulse train with increasing intensity is delivered through epidural electrodes placed over the motor cortex. The threshold intensity for eliciting forelimb clonus is determined through behavioural observation, and is used as a measure for cortical excitability. Several known antiepileptic drugs including diazepam and carbamazepine increase threshold intensity in this model. Benefits of the CSM are that the activity of a drug can be accurately, rapidly and repeatedly determined in the same animal with a short interval between measurements. The CSM is useful for dose-finding and pharmacokinetic studies. Male Wistar rats (145–220g) were surgically implanted with epidural stimulation electrodes positioned over the motor cortex (AP: -1 mm; ML: +/­3 mm). Following surgery, animals were allowed to recover for one week. Subsequently, all animals were stimulated twice daily for 10 days (ramp pulse 0–1 mA, 50 Hz, pulse width 2 ms) to obtain a stable threshold intensity to elicit forelimb clonus. A first group of 12 stabilized animals underwent intraperitoneal (i.p.) administration of 0, 2.5, 5, 10 and 20 mg/kg lacosamide in a random order on 5 consecutive days. Threshold intensity was determined 1 h before and 30 min, 2 h and 5 h after every injection. To determine whether tolerance to lacosamide occurs after repeated administration, a second group of 12 animals underwent i.p. administration of 20 mg/kg lacosamide once daily on 5 consecutive days. During the stabilization period (stimulation days 1–10), threshold intensity to forelimb clonus decreased from 568 +/­ 73 mA to 394 +/­ 91 mA (n=25). Lacosamide increased the threshold intensity to forelimb clonus in a dose-dependent manner: 2.5, 5, 10 and 20 mg/kg lacosamide increased threshold intensity by 32 +/­ 25 mA, 60 +/­ 41 mA, 111 +/­ 34 mA and 166 +/­ 49 mA respectively. Threshold intensity reached a maximum 30 min after injection of lacosamide and returned to baseline 2 h after injection. Administration of 20 mg/kg lacosamide on 5 consecutive days resulted in a partial attenuation of its effect on cortical excitability: threshold intensity increased by 137 +/­ 43 mA after the first injection, but only by 102 +/­ 33 mA after the fifth. Lacosamide, administered i.p. at doses ranging from 2.5 to 20 mg/kg, decreases cortical excitability in the CSM in a dose-dependent manner. The effect of lacosamide on cortical excitability was maximal 30 min after injection of the drug, and lasted for 2 h. This suggests that lacosamide's half-life may be shorter in rodents than in humans (13 h). Repeated administration of lacosamide on consecutive days resulted in a slight, non-significant trend towards attenuation of its effect on cortical excitability.