Elsevier

Neuroscience

Volume 74, Issue 2, 19 July 1996, Pages 365-374
Neuroscience

Role of nitric oxide and cyclic GMP in the dizocilpine-induced impairment of spontaneous alternation behavior in mice

https://doi.org/10.1016/0306-4522(96)00161-3Get rights and content

Abstract

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 receptors, 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 controversial. We investigated the putative role of nitric oxide and cyclic GMP in dizocilpine-induced memory impairment in mice. The nitric oxide synthase inhibitors, NG-nitro-l-arginine methyl ester and 7-nitro indazole, as well as dizocilpine, a non-competitive N-methyl-d-aspartate receptor antagonist, dose-dependently impaired spatial working memory in mice, assessed by their spontaneous alternation behavior in a Y-maze. The inhibitory effects of both NG-nitro-l-arginine methyl ester and dizocilpine on their behavior were completely reversed by 8-bromo-cyclic GMP. Cyclic GMP levels in the cerebellum were reduced by treatment with dizocilpine. NG-Nitro-l-arginine methyl ester and 7-nitro indazole reduced cyclic GMP levels in the cerebral cortex/hippocampus and cerebellum, and the suppressive effect of NG-nitro-l-arginine methyl ester on cyclic GMP levels in the cerebral cortex/hippocampus was reversed by co-treatment with l-arginine. Cyclic AMP levels in the brain were not affected by treatment with either dizocilpine, NG-nitro-l-arginine methyl ester, or 7-nitro indazole. Neither NG-nitro-l-arginine methyl 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.

Section snippets

Materials

The animals used in this study were male mice of the ddY strain (six weeks old; Nihon SCL, Shizuoka, Japan) weighing 30–33 g. All animals were kept in a regulated environment (23±0.5°C; 50±0.5% humidity) with a 12-h light/dark cycle (light on between 9.00 a.m. and 9.00 p.m.) and had free access to food and water. l-NAME, l-arginine, and Br-cGMP were purchased from Sigma (St Louis, MO, U.S.A.). Dizocilpine [(+)-MK-801] and 7-NI were obtained from Research Biochemicals International (Natick, MA,

Effects of dizocilpine, NG-nitro-l-arginine methyl ester, and 7-nitro indazole on spontaneous alternation behavior

During the 8-min session, vehicle-treated control mice showed approximately 30 arm entries and 73% spontaneous alternation (Fig. 1 and Table 1). Dizocilpine and l-NAME impaired the spontaneous alternation in a dose-dependent manner, significantly inhibiting this behavior at doses of 0.1 mg/kg and 100 mg/kg, respectively. Dizocilpine (0.1 mg/kg), but not l-NAME, significantly increased the number of arm entries (Fig. 1). 7-NI also dose-dependently impaired the spontaneous alternation behavior (F3,

Discussion

We have previously shown that dizocilpine and l-NAME impaired the spontaneous alternation behavior of mice in the Y-maze.[53]It is known that NO synthase inhibitors such as l-NAME cause hypertension following systemic injection.[42]In contrast, 7-NI, at doses up to 80 mg/kg, is reported to have no effect on mean arterial pressure in the anesthetized mouse.[33]Since we observed that 7-NI significantly and dose-dependently impaired the spontaneous alternation behavior at doses up to 75 mg/kg, it is

Conclusions

The present results suggest that reduction in NO/cGMP formation in the brain may be responsible for the dizocilpine-induced impairment of spatial working memory. Furthermore, the results suggest that acute inhibition of NO production has no effect on monoamine and acetylcholine metabolism in the brain.

Acknowledgements

This study was supported, in part, by an SRF Grant for Biomedical Research and by grants from the Japanese Ministry of Health and Welfare Foundation for Gerontological Science Research (94A-2405), the Uehara Memorial Foundation, the Ishida Foundation, and the Ministry of Education, Science and Culture, Japan (No. 07557009).

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