Yamada K, Hiramatsu M, Noda Y, Mamiya T, Murai M, Kameyama T, Komori Y, Nikai T, Sugihara H, Nabeshima T
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Japan.
Neuroscience. 1996 Sep;74(2):365-74. doi: 10.1016/0306-4522(96)00161-3.
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.
N-甲基-D-天冬氨酸受体的激活会诱导一氧化氮的合成，一氧化氮会激活可溶性鸟苷酸环化酶并导致大脑中环状鸟苷单磷酸的形成。据报道，抑制一氧化氮的产生以及阻断N-甲基-D-天冬氨酸受体可防止体内海马体长期增强以及学习和记忆形成，尽管一氧化氮合酶抑制剂的作用仍存在争议。我们研究了一氧化氮和环状鸟苷单磷酸在小鼠地佐环平诱导的记忆损伤中的假定作用。一氧化氮合酶抑制剂NG-硝基-L-精氨酸甲酯和7-硝基吲唑，以及非竞争性N-甲基-D-天冬氨酸受体拮抗剂地佐环平，通过小鼠在Y迷宫中的自发交替行为评估，剂量依赖性地损害小鼠的空间工作记忆。8-溴环状鸟苷单磷酸完全逆转了NG-硝基-L-精氨酸甲酯和地佐环平对其行为的抑制作用。地佐环平治疗可降低小脑的环状鸟苷单磷酸水平。NG-硝基-L-精氨酸甲酯和7-硝基吲唑降低了大脑皮层/海马体和小脑的环状鸟苷单磷酸水平，L-精氨酸共同治疗可逆转NG-硝基-L-精氨酸甲酯对大脑皮层/海马体环状鸟苷单磷酸水平的抑制作用。地佐环平、NG-硝基-L-精氨酸甲酯或7-硝基吲唑治疗均未影响大脑中的环磷酸腺苷水平。NG-硝基-L-精氨酸甲酯和L-精氨酸对大脑中的单胺和乙酰胆碱代谢均无影响。这些结果表明，大脑中一氧化氮/环状鸟苷单磷酸生成的减少可能是地佐环平诱导的Y迷宫中自发交替行为损伤的原因。
