K. Yamada et al., ROLE OF NITRIC-OXIDE AND CYCLIC-GMP IN THE DIZOCILPINE-INDUCED IMPAIRMENT OF SPONTANEOUS-ALTERNATION BEHAVIOR IN MICE, Neuroscience, 74(2), 1996, pp. 365-374
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.