Anticonvulsant actions of lamotrigine on spontaneous thalamocortical rhythms.

Abstract

This study examined the actions of lamotrigine (LTG) on epileptiform discharges resembling generalized absence (GA) and primary generalized tonic-clonic (GTC) seizures in rat thalamocortical (TC) brain slices and attempted to characterize further the cellular mechanisms of action of LTG on neuronal ionic conductances. Rat TC slices generated spontaneous generalized epileptiform discharges after perfusion with a medium containing no added Mg(2+). Using multiple channel extracellular field-potential recordings in thalamus and cortex, the effects of LTG were characterized on two principal variants of activity that are similar to spike-wave discharges (SWDs) of GA epilepsy and GTC seizure discharges. These were termed simple TC burst complexes (sTBCs) and complex TC burst complexes (cTBCs), respectively. With whole-cell patch-clamp recording techniques in acutely dissociated TC neurons, the effects of LTG on GABA (gamma-aminobutyric acid)(A)-receptor-mediated currents and the low-threshold calcium current (I(T)) were examined. In field-potential recording studies in TC slices, both sTBCs and cTBCs were blocked by clinically relevant concentrations of LTG. In patch-clamp recording studies, LTG was found to be ineffective in the modulation of both GABA(A) receptors (GABARs) and I(T) in TC neurons. The efficacy of LTG on both variants of epileptiform discharges in TC slices clearly parallels its broad human clinical spectrum of action. This demonstrates that neurons within the TC system constitute one probable therapeutic target of LTG. However, LTG did not block either GABAR-mediated responses or I(T) in TC neurons. Modulation of these conductances represent likely cellular mechanisms of action of other antiepileptic drugs effective in the control of GA epilepsy. This suggests that LTG may have as yet uncharacterized effects that could combine with its previously defined sodium channel-blocking actions to explain its clinical utility in the control GA seizures.