LAMOTRIGINE REDUCES VOLTAGE-GATED SODIUM CURRENTS IN RAT CENTRAL NEURONS IN CULTURE

Purpose: To study the mechanism or mechanisms of action of lamotrigine (LTG) and, in particular, to establish its effects on the function of NA(+) channels in mammalian central neurons. Methods: Rat cerebellar granule cells in culture were subjected to the whole-cell mode of volt age clamping under experimental conditions designed to study voltage-g ated Na+ currents. Results: Extracellular application of LTG (10-500 m u M, n = 21) decreased in a dose-related manner a tetrodotoxin-sensiti ve inward current that was elicited by depolarizing commands (from -80 to +20mV). The peak amplitude of this Na+-mediated current was dimini shed by 38.8 +/- 12.2% (mean +/- SD, n = 6) during application of 100 mu M LTG, and the dose-response curve of this effect indicated an IC50 of 145 mu M. The reduction in the inward currents produced by LTG was not associate with any significant change in the current decay, where as the voltage dependency of the steady-state inactivation shifted tow ard more negative values (midpoint of the inactivation curve: -47.5 an d -59.0 mV under control conditions and during application of 100 mu M LTG, respectively, n = 4). Conclusions: Our findings indicate that LT G reduces the amplitude of voltage-gated Na+ inward current in rat cer ebellar granule cells and induces a negative shift of the steady-state inactivation curve. Both mechanisms may be instrumental in controllin g the repetitive firing of action potentials (AP) that occurs in neuro nal networks during seizure activity.