Neocortical potassium currents are enhanced by the antiepileptic drug lamotrigine

Purpose: We used field-potential recordings in slices of rat cerebral cortex along with whole-cell patch recordings from rat neocortical cells in culture to test the hypothesis that the antiepileptic drug (AED) lamotrigine (LTG) modulates K⁺-mediated, hyperpolarizing currents. Methods: Extracellular field-potential recordings were performed in neocortical slices obtained from Wistar rats aged 25-50 days. Rat neocortical neurons in culture were subjected to the whole-cell mode of voltage clamping under experimental conditions designed to study voltage-gated K⁺ currents. Results: In the in vitro slice preparation, LTG (100-400 μM) reduced and/or abolished epileptiform discharges induced by 4-aminopyridine (4AP, 100 μM; n = 10), at doses that were significantly higher than those required to affect epileptiform activity recorded in Mg²⁺-free medium (n = 8). We also discovered that in cultured cortical cells, LTG (100-500 μM; n = 13) increased a transient, 4AP-sensitive, outward current elicited by depolarizing commands in medium containing voltagegated Ca²⁺ and Na⁺ channel antagonists. Moreover, we did not observe any change in a late, tetraethylammonium-sensitive outward current. Conclusions: Our data indicate that LTG, in addition to the well-known reduction of voltage-gated Na⁺ currents, potentiates 4AP-sensitive, K⁺-mediated hyperpolarizing conductances in cortical neurons. This mechanism of action contributes to the anticonvulsant effects exerted by LTG in experimental models of epileptiform discharge, and presumably in clinical practice.