Epilepsy Research 43 (2001) 153 – 163 Chronic lamotrigine treatment increases rat hippocampal GABA shunt activity and elevates cerebral taurine levels Bjørnar Hassel a, *, Erik Taubøll b , Leif Gjerstad b a Di6ision for En6ironmental Toxicology, Norwegian Defence Research Establishment, P.O.Box 25 , N- 2007 Kjeller, Norway b Neurological Department, NationalHospital, Oslo, Norway Received 22 June 2000; received in revised form 13 October 2000; accepted 15 October 2000 Abstract The mechanism of action of the antiepileptic drug lamotrigine has previously been investigated only in acute experiments and is thought to involve inhibition ofvoltage-dependent sodium channels. However,lamotrigine is effective against more formsof epilepsies than otherantiepileptic drugs that also inhibitsodium channels. We investigated whether chronic lamotrigine treatment may affect cerebral amino acid levels. Rats received lamotrigine, 10 mg/kg/day,for 90 days.The hippocampalevelof GABA increased 25%,and the activitiesof glutamate decarboxylase and succinicsemialdehyde/GABA transaminase increased 12 and 21% (p B 0.05), respectively, indicating increased GABA turnover. The uptake of GABA and glutamate into proteoliposomes remained unaltered. The level of taurine increased 27% in the hippocampus and 16% in the frontal and parietal cortices. The activities of hexokinase and a-ketoglutarate dehydrogenase, remained at controlvalues.Serum lamotrigine was 41.7 91.5 mM (mean9S.E.M.), which is within the range seen in epileptic patients. Acute experiments with 5, 20 or 100 mg lamotrigine/kg, caused no changes in brain amino acid levels. The results suggest that chronic lamotrigine treatment increases GABAergic activity in the hippocampus. The cerebral increase in taurine, which has neuromodulatory properties, may contribute to the antiepileptic effect of lamotrigine. © 2001 Elsevier Science B.V. All rights reserved. Keywords : Lamotrigine; GABA; Taurine;Glutamic acid decarboxylase; Hippocampus; Epilepsy www.elsevier.com/locate/epilepsyres 1.Introduction The mechanism ofaction of lamotrigine has only been studied in acute animal experiments or in vitro, and the antiepilepticeffecthas been attributed to inhibition of voltage-dependent sodium channels (Leach et al., 1986;Cheung et al., 1992;Lang et al., 1993;Xie et al., 1995), which in turn could inhibit release of transmitter glutamate (Leach et al., 1986;Lizasoain etal., 1995;Waldmeieret al., 1996).Interestingly, the therapeutic effect of lamotrigine is different from that of other antiepilepticdrugs that act on sodium channels, such asphenytoin and carba- mazepine. For instance, lamotrigine is effective in the treatmentof childhood absenceepilepsy, * Corresponding author. Tel: + 47-63-807846; fax: +47-63- 807509. E-mail address : bjornar.hassel@ffi.no (B. Hassel). 0920-1211/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved. PII: S 0 9 2 0 - 1 2 1 1 ( 0 0 ) 0 0 1 9 6 - 0