INHIBITION BY LAMOTRIGINE OF THE GENERATION OF NITRIC-OXIDE IN RAT FOREBRAIN SLICES

Depolarization of adult rat forebrain slices with veratrine induced th e release of excitatory amino acids (glutamate and aspartate), the syn thesis of nitric oxide (NO), and increases in cyclic GMP(cGMP). The NO synthase inhibitors N-omega-monomethyl-L-arginine and N-omega-nitro-L -arginine methyl ester decreased the release of NO and the levels of c GMP without affecting the release of excitatory amino acids. In contra st, the antiepileptic drug lamotrigine inhibited the release of excita tory amino acids and of NO, and decreased the levels of cGMP without c ausing a significant direct inhibition of the NO synthase. Furthermore , the synthesis of NO and the increases in cGMP induced by veratrine w ere partially blocked by the N-methyl-D-aspartate (NMDA) receptor anta gonist MK-801 but not by 6-nitro-7-sulphamobenzo(f)quinoxaline-2,3-dio ne, a non-NMDA receptor antagonist. Neither of these compounds inhibit ed directly the NO synthase or the release of excitatory amino acids. Thus, these three types of compound act as an inhibitor of voltage-sen sitive sodium channels (lamotrigine), as a receptor antagonist (MK-801 ), or as direct inhibitors of the NO synthase, to block the pathway le ading to increased cGMP after veratrine depolarization. It is likely t hat some of the pharmacological and therapeutic actions shared by thes e three types of compound are, at least in part, a consequence of inhi bition of the synthesis of NO.