Physiological significance of histamine H3-receptor as hetero-recetor in the brain.

组胺 H3 受体作为大脑异质受体的生理意义。

• 批准号: 07680843
• 负责人: YAMATODANI Atsushi
• 金额: $ 1.41万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07680843/
• 关键词: Histamine H3-receptors; Presynaptic receptor; Heteroreceptor; GABA transporter; Thioperamide; Microdialysis; Motion sickness; Anesthesia; ヒスタミン; H3-受容体; 培養神経細胞; クロベンプロピット; プレシナプス性受容体; H_3-受容体; 神経細胞培養; ニューロケム装置

This project was planned to investigate our hypothesis that the brain histaminergic system plays some of its physiological functions through H3-receptors located on other neuronal systems as heteroreceptor. Using a microdialysis and a Neurochem analysis apparatus, we examined the effects of H3-ligands on the neurotransmitter release. And we found that thioperamide, the most popular H3-antagonist, increased release of GABA form the rat hypothalamus. This increase was Ca2+-independent and H3-agonist could not inhibit the effect. Furthermore, clobenpropit, a more specific H3-antagonist, did not increase GABA release. Thus we concluded that thioperamide increased extracellular concentration of GABA by possibly inhibition of GABA transporter. Thioperamide has been used in many investigations of physiological roles of brain histaminergic system as a pharmacological tool to increase histamine release in the brain. Present result indicates that these previous reports should be reexamined to exclude possible participation of GABA in the results.Next, we explore the possibility of H3-ligands as some therapeutic drug. By animal experiments using rats, we found that H3-antagonists were effective in prevention of motion sickness. The effect of H3-ligands as supplemental agents of anesthesia was also examined.

本项目旨在研究我们的假设，即大脑组胺能系统通过位于其他神经元系统上的H3受体作为异源受体发挥其某些生理功能。使用微透析和Neurochem分析仪器，我们研究了H3-配体对神经递质释放的影响。我们发现，硫代哌丁胺，最常用的H3-拮抗剂，增加释放GABA的大鼠下丘脑。这种增加是不依赖于Ca ~（2+）的，H_3-激动剂不能抑制这种作用。此外，clobenpropit，一个更具体的H3-拮抗剂，没有增加GABA的释放。因此，我们得出结论，硫代哌丁胺可能通过抑制GABA转运蛋白来增加细胞外GABA浓度。硫代哌丁胺作为一种增加脑组织组胺释放的药理学工具，已被用于脑组织组胺能系统生理作用的许多研究中。目前的结果表明，这些以前的报告应重新审查，以排除可能的参与GABA的结果。接下来，我们探讨的可能性，H3-配体作为一些治疗药物。通过大鼠动物实验，我们发现H3-受体拮抗剂在预防运动病方面是有效的。还检查了H3-配体作为麻醉补充剂的效果。

项目成果

A. Yamatodani et al.: "New vistas on histamine arousal hypothesis : Microdialysis studies." Meth. Find. Exp. Clin. Pharmacol.18 Suppl. A. 113-117 (1996)

A. Yamatodani 等人：“组胺唤醒假说的新前景：微透析研究。”

K. Okakura-Mochizuki, et al.: "Endogenous GABA modulate histamine release from the anterior hypothalamus of the rat." J. Neurochem.67 (1). 171-176 (1996)

K. Okakura-Mochizuki 等人：“内源性 GABA 调节大鼠下丘脑前部的组胺释放。”

A.Horii et al.: "Vestibular modulation of the septo-hippocampal cholinergic system of rats." Acta Otolaryngol.(Stockh) Suppl 520. 395-398 (1995)

A.Horii 等人：“大鼠隔海马胆碱能系统的前庭调节。”

K.Okakura-Mochizuki: "Endogenous GABA modulate histamine release from the anterior hypothalamus of the rat." J.Neurochem.67・1. 171-176 (1996)

K.Okakura-Mochizuki：“内源性 GABA 调节大鼠下丘脑前部的组胺释放。”J.Neurochem.67·1（1996）。

N.Takeda,S.Hasegawa,他: "Neuropharmacological mechanisms of emesis.II. Effects of antiemetic drugs on cisplatine-induced pica in rats." Meth.Find.Exp.Clin.Pharmacol.17. 647-652 (1995)

N.Takeda、S.Hasekawa 等人：“呕吐的神经药理学机制。II。止吐药物对顺铂引起的大鼠异食癖的影响。Meth.Find.Exp.Clin.Pharmacol.17（1995 年）” ）