Role of brain histamine on refractory schizophrenia

脑组织胺对难治性精神分裂症的作用

• 批准号: 11470199
• 负责人: ITO Chihiro
• 金额: $ 9.86万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470199/
• 关键词: Schizophrenia; Histamine; Knock-out mice; Polymorphism; PET; 覚醒剤精神病; 逆耐性現象; メタンフェタミン

Schizophrenia resistant to the treatments with D2 antagonists is supposed to have the possible changes of extradopaminergic systems. Meanwhile, histamine was recently suggested to be a neurotransmitter in the mammalian brains, which regulates many brain functions. We have recently found the interesting results about the role of brain histamine on schizophrenia in basic and clinical studies. Methamphetamine-induced behavioral sensitization, which has been well established as the animal model of schizophrenia, induced the enhanced histamine turnover and histamine H1 and H2 receptor mRNA. Behavioral sensitization was also rapidly completed in the histidine decarboxylase deficient mice and both the H1 and H2 receptors deficient mice than in the wild typed mice. In clinical studies, the levels of N-tele-methylhistamine, a major brain HA metabolite, were elevated in the cerebrospinal fluid of schizophrenics. Moreover, the H1 receptor gene variant was related to schizophrenia, and H1 receptor binding sites decreased in schizophrenics. Therefore, the dysfunction of HA neuron system may participate in the extradopaminergic brain dysfunction of schizophrenia, and HA agents may improve the refractory schizophrenia.

精神分裂症对D2拮抗剂治疗的耐药可能有其外胺能系统的改变。与此同时，组胺最近被认为是哺乳动物大脑中的一种神经递质，它调节着许多大脑功能。我们最近在基础和临床研究中发现了关于脑组胺在精神分裂症中的作用的有趣结果。甲基苯丙胺诱导的行为致敏是一种已经建立的精神分裂症动物模型，它可以诱导组胺转换和组胺H1和H2受体mRNA的增加。组氨酸脱羧酶缺陷小鼠以及H1和H2受体缺陷小鼠的行为致敏也比野生型小鼠更快完成。在临床研究中，精神分裂症患者脑脊液中的n -远端甲基组胺水平升高，n -远端甲基组胺是脑HA的主要代谢物。此外，H1受体基因变异与精神分裂症有关，精神分裂症患者H1受体结合位点减少。因此，HA神经元系统功能障碍可能参与了精神分裂症的多巴胺能外脑功能障碍，HA药物可能改善难治性精神分裂症。

项目成果

Ito C: "The role of brain histamine in acute and chronic stresses"Biomed. Pharmacother.. 54・5. 263-267 (2000)

伊藤 C：“脑组胺在急性和慢性应激中的作用”Biomed. 54・5（2000）。

Ito C: "Brain histamine as protective system for the formation of neural sensitization. In : Histamine Research in the New Millenium"Elsevier Science. 483-486 (2001)

Ito C：“大脑组胺作为神经敏化形成的保护系统。见：新千年的组胺研究”Elsevier Science。

Ito C.: "The role of brain histamine in acute and chronic stresses"Biomed. Pharmacother.. 54. 263-267 (2000)

Ito C.：“脑组胺在急性和慢性应激中的作用”Biomed。

Ito C: "Novel antipsychotics discovery using DNA microarray"Int. Psychiat. Today.. 10・3. 7-9 (2001)

伊藤 C：“利用 DNA 微阵列发现新的抗精神病药物”Int.Today.. 10・3（2001 年）

Kubota Y: "Transient increases of histamine H1 and H2 receptor mRNA levels in the rat striatum after chronic administration of methamphetamine"Neurosci. Lett.. 275. 37-40 (1999)

Kubota Y：“长期服用甲基苯丙胺后，大鼠纹状体中组胺 H1 和 H2 受体 mRNA 水平短暂增加”Neurosci。