Chronic lamotrigine treatment increases rat hippocampal GABA shunt activity and elevates cerebral taurine levels.
The mechanism of action of the antiepileptic drug lamotrigine has previously been investigated only in acute experiments and is thought to involve inhibition of voltage-dependent sodium channels. However, lamotrigine is effective against more forms of epilepsies than other antiepileptic drugs that also inhibit sodium channels. We investigated whether chronic lamotrigine treatment may affect cerebral amino acid levels. Rats received lamotrigine, 10 mg/kg/day, for 90 days. The hippocampal level of GABA increased 25%, and the activities of glutamate decarboxylase and succinic semialdehyde/GABA transaminase increased 12 and 21% (p< 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 alpha-ketoglutarate dehydrogenase, remained at control values. Serum lamotrigine was 41.7+/-1.5 microM (mean+/-S.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.
Hassel
B
B
Division for Environmental Toxicology, Norwegian Defence Research Establishment, P.O.Box 25, N-2007, Kjeller, Norway. bjornar.hassel@ffi.no
Taubøll
E
E
Gjerstad
L
L
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000201:enzymology / Q000378:metabolism; D018698:Glutamic Acid / Q000493:pharmacokinetics; D006624:Hippocampus / Q000378:metabolism*; D000077213:Lamotrigine; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011510:Proteolipids / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013654:Taurine / Q000378:metabolism*; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000493:pharmacokinetics
D000596:Amino Acids; D000927:Anticonvulsants; D009419:Nerve Tissue Proteins; D011510:Proteolipids; D014227:Triazines; C020485:proteoliposomes; D013654:Taurine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000077213:Lamotrigine