INTERACTION OF THE ANTIEPILEPTIC DRUG LAMOTRIGINE WITH RECOMBINANT RAT-BRAIN TYPE IIA NA+ CHANNELS AND WITH NATIVE NA+ CHANNELS IN RAT HIPPOCAMPAL-NEURONS

Actions of the new antiepileptic drug lamotrigine (LTG, Lamictal) were characterised using recombinant rat brain type IIA Na+ channels expressed in Chinese hamster ovary (CHO) cells and native Na+ channels in rat hippocampal pyramidal neurones, using whole-cell recording and intracellular recording techniques. In CHO cells, LTC caused a tonic inhibition of Na+ currents in a concentration-dependent and voltage-dependent manner. The half-maximal inhibitory concentration (IC50) of approximately 500 mu M was obtained at a holding potential (V-h) of -90 mV compared with an IC50 of 100 mu M at a V-h of -60 mV. LTG (50 mu M) caused a 10-mV negative shift in the slow, steady-state inactivation curve and delayed considerably the recovery from inactivation, but had no significant effects on the voltage dependence of activation or fast inactivation, suggesting that LTG acts mainly on the slow inactivated state. The affinity for the inactivated channels was estimated at 12 mu M The tonic inhibition was augmented by a use-dependent action in which a further inhibition by the drug developed during rapid repetitive stimulation using a train of 20-ms duration pulses (11 Hz). These results were consistent with the drug action being on firing properties of pyramidal neurones. Only in those epileptiform bursts which caused cumulative inactivation of Na+ spikes did LTG produce a potent inhibition. Our data suggest that the inactivated channel is a primary target for LTG action at therapeutic concentrations.