New perspectives in research for histaminergic functions in CNS

1. 克隆了大鼠、豚鼠和人的组胺H1受体基因，分别获得了486,488和487个氨基酸。研究了磷酯上调人H1受体的作用机制。位点定向突变表明，Asp107、Asn198和Tyr431在组胺与H1受体的结合中起重要作用。奎宁是细胞色素P450-IID的配体，不与表达的H1受体结合，但中枢和外周组织有奎宁敏感位点，H1拮抗剂也与这些位点结合。人脑H1受体的正电子发射断层扫描（PET）显示，部分复杂发作患者的大脑癫痫灶周围的密度增加。与性别和年龄匹配的正常志愿者相比，阿尔茨海默病和多发性梗死性痴呆患者大脑中的H1受体减少。3 .三羟基组氨酸类似物，一种可能的组胺能特异性神经毒素，不破坏大鼠下丘脑的组胺能神经元，但一种特异性的NMDA-1拮抗剂，伊伯腾酸，破坏了神经元。采用微透析技术研究了新型H3受体激动剂伊梅匹普和新型H3受体拮抗剂氯苯propit对大鼠脑组织胺和GABA释放的影响。Immepip抑制组胺的释放，但不影响GABA的释放。氯苯propit促进组胺的释放，但不影响GABA的释放。另一方面，硫哌丁胺，一种原始的H3拮抗剂，增加了组胺和GABA的释放。氯苯普罗比硫哌丁胺更能缩短小鼠电惊厥的持续时间。

1. The genes of histamine H1 receptors of rats, guinea-pigs and humnans were cloned : The numbers of amino acids of the respective H1 receptors were 486,488 and 487. The mechanism of the up-regulation of human H1 receptors by phorbol ester was studied. Site directed mutagenesis showed that Asp107, Asn198 and Tyr431 are important in the binding of histamine to H1 receptors. Quinine, a ligand for cytochrome P450-IID,was not bound to expressed H1 receptors, but central and peripheral tissues had quinine sensitive sites to which H1 antagonists were also bound.2. The positron emission tomography (PET) of H1 receptors in human brains showed that the density is increased around the epileptic foci in brains of patients with partial complex seizure. H1 receptors decreased in brains of patients of Alzheimer's disease and multi-infarct dementia when compared with those of sex-and age-matched normal volunteers.3. A trihydroxyhistidine analog, a possible histamiergic specific neurotoxin, did not destroy the histaminergic neurons in the hypothalamus of rats, but ibotenate, a specific NMDA-1 antagonist, destroyed the neurons.4. The effects of immepip, a new H3 agonist and clobenpropit, a new H3 antagonist on the releases of histamine and GABA were studied by microdialysis technique in rat brains. Immepip inhibited histamine release, but did not affect GABA release. Clobenpropit enhanced histamine release, but did not affect GABA release. On the other hand, thioperamide, an original H3 antagonist, increased the releases of both histamine and GABA.Clobenpropit shortened the duration of electroconvulsion in mice in a greater degree than thioperamide.