ROLE OF NITRIC-OXIDE AND CYCLIC-GMP IN THE DIZOCILPINE-INDUCED IMPAIRMENT OF SPONTANEOUS-ALTERNATION BEHAVIOR IN MICE

The activation of N-methyl-D-aspartate receptors induces the synthesis of nitric oxide, which activates soluble guanylate cyclase and leads to the formation of cyclic GMP in the brain. The inhibition of nitric oxide production, as well as the blockade of N-methyl-D-aspartate rece ptors, has been reported to prevent the induction of hippocampal long- term potentiation and learning and memory formation in vivo, although the effects of inhibitors of nitric oxide synthase are still controver sial. We investigated the putative role of nitric oxide and cyclic GMP in dizocilpine-induced memory impairment in mice. The nitric oxide sy nthase inhibitors, N-G-nitro-L-arginine methyl ester and 7-nitro indaz ole, as well as dizocilpine, a non-competitive N-methyl-D-aspartate re ceptor antagonist, dose-dependently impaired spatial working memory in mice, assessed by their spontaneous alternation behavior in a Y-maze. The inhibitory effects of both N-G-nitro-L-arginine methyl ester and dizocilpine on their behavior were completely reversed by 8-bromo-cycl ic GMP. Cyclic GMP levels in the cerebellum were reduced by treatment with dizocilpine. N-G-Nitro-L-arginine methyl ester and 7-nitro indazo le reduced cyclic GMP levels in the cerebral cortex/hippocampus and ce rebellum and the suppressive effect of N-G-nitro-L-arginine methyl est er on cyclic GMP levels in the cerebral cortex/hippocampus was reverse d by co-treatment with L-arginine. Cyclic AMP levels in the brain were not affected by treatment with either dizocilpine, N-G-nitro-L-argini ne methyl ester, or 7-nitro indazole. Neither N-G-nitro-L-arginine met hyl ester nor L-arginine had any effect on monoamine and acetylcholine metabolism in the brain. These results suggest that the reduction in nitric oxide/cyclic GMP production in the brain may be responsible for dizocilpine-induced impairment of spontaneous alternation behavior in a Y-maze. Copyright 1996 IBRO. Published by Elsevier Science Ltd.