SIMILAR POTENCY OF CARBAMAZEPINE, OXCARBAZEPINE, AND LAMOTRIGINE IN INHIBITING THE RELEASE OF GLUTAMATE AND OTHER NEUROTRANSMITTERS

We compared the effects of the antiepileptic drugs carbamazepine, oxca rbazepine, and lamotrigine on the release from rat brain slices of end ogenous glutamate, [H-3]-GABA, and [H-3]-dopamine, elicited by the Na channel opener, veratrine, and of the same transmitters as well as [H -3]-noradrenaline, [H-3]-5-hydroxytryptamine, and [H-3]-acetylcholine, elicited by electrical stimulation. The three antiepileptic drugs inh ibited veratrine-induced release of endogenous glutamate, [H-3]-GABA, and [H-3]-dopamine, with IC50 values between 23 and 150 mu M, in or ne ar the concentration range in which they interact with Na+ channels, a nd there was little difference between the compounds. They were five t o seven times less potent in inhibiting electrically as compared with veratrine-stimulated release of [H-3]-GABA and [H-3]-dopamine; similar ly, carbamazepine and tetrodotoxin were more potent in inhibiting vera trine-induced as compared with electrically induced release of endogen ous glutamate. Carbamazepine, oxcarbazepine, and lamotrigine also inhi bited electrically stimulated release of [H-3]-5-hydroxytryptamine (IC 50 values, 150 to 250 mu M) and [H-3]-acetylcholine (IC50 values, 50 t o 150 mu M); [H-3]-noradrenaline release was affected to a lesser degr ee. The active concentration ranges of these drugs with respect to inh ibition of veratrine-stimulated neurotransmitter release matched the t herapeutic plasma and brain concentrations. It is uncertain whether th ese effects are relevant in vivo at anticonvulsant doses, because the drugs are markedly less potent in inhibiting the more physiologic rele ase elicited by electrical stimulation. Therefore, the hypothesis that inhibition of glutamate release is the mechanism of anticonvulsant ac tion of lamotrigine (or carbamazepine and oxcarbazepine) is doubtful. Other consequences of Na+ channel blockade may have an important role.