Effects of acute and chronic lamotrigine treatment on basal and stimulated extracellular amino acids in the hippocampus of freely moving rats

Abstract

The antiepileptic drug lamotrigine (LTG) is a relatively novel anticonvulsant frequently used in polytherapy and increasingly in monotherapy. LTG is believed to act by reducing excitatory glutamate (GLU) release due to an inhibition of Na + channels. In the present study, we have investigated the effects of acute and chronic (up to 21 days) treatment with LTG on basal and either veratridine- or KCl-stimulated release of aspartate (ASP), GLU, taurine (TAU) and GABA in the hippocampus of freely moving rats using microdialysis. Additionally, we have measured LTG concentrations in the plasma, whole brain and extracellular fluid of rats at the same time points. LTG significantly reduced basal ASP and GLU but only at the highest dose used (20 mg/kg) and was entirely without effect on basal TAU or GABA. When either veratridine or 100 mM KCl were added to the infusion medium amino acid release was evoked although the extent of this varied from one amino acid to another. LTG (10 mg/kg) reduced veratridine-evoked release of all four amino acids studied, although this was most marked in the case of GLU. LTG had no effect on KCl-stimulated amino acid release. When given for up to 21 days (2×5 mg/kg/day), LTG had no effect on basal amino acid levels. In contrast, LTG demonstrated over the time period studied an increasingly inhibitory effect on veratridine-evoked amino acid release. This effect of the drug was proportionally much greater in the case of GLU than for the other three amino acids studied. Measurement of plasma, whole brain tissue and extracellular LTG showed that in each of these compartments, it had reached an apparent steady state within 4 days of commencement of treatment and appeared to mirror the neurochemical changes measured. Our estimate of plasma LTG indicates that during chronic study, this was well within the therapeutic range, suggesting that the current neurochemical observations are clinically relevant.