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.

该项目计划研究我们的假设，即大脑组胺能系统通过位于其他神经元系统上的 H3 受体作为异质受体发挥其某些生理功能。使用微透析和 Neurochem 分析装置，我们检查了 H3 配体对神经递质释放的影响。我们发现硫哌丁胺（最常用的 H3 拮抗剂）可增加大鼠下丘脑 GABA 的释放。这种增加不依赖于Ca2+，并且H3-激动剂不能抑制该作用。此外，clobenpropit（一种更特异的 H3 拮抗剂）不会增加 GABA 的释放。因此我们得出结论，硫哌丁胺可能通过抑制 GABA 转运蛋白来增加细胞外 GABA 浓度。硫哌丁胺已被用于大脑组胺能系统的生理作用的许多研究中，作为增加大脑中组胺释放的药理学工具。目前的结果表明，应该重新审查这些先前的报告，以排除 GABA 可能参与结果。接下来，我们探讨 H3-配体作为某些治疗药物的可能性。通过大鼠动物实验，我们发现H3拮抗剂可以有效预防晕动病。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）。

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

A. Horii 等人：“大鼠隔海马胆碱能系统的前庭调节。”