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Hyperresponsiveness of 5-HT-2 Receptor-Mediated Intracellular Camobilization in Platelets from the Depressed Patients and in C6 Glioma Cells Pretreated with Dexamethasone.

抑郁症患者血小板和地塞米松预处理的 C6 胶质瘤细胞中 5-HT-2 受体介导的细胞内固定化的高反应性。

基本信息

批准号：
01570621
负责人：
MIKUNI Masahiko
金额：
$ 1.34万
依托单位：
Div. of Mental Disorder Res., Natl. Institute of Neurosci., NCNP
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1990
项目状态：
已结题

项目摘要

The increase in intracellular Ca ion concentration induced by 10uM 5-HT in platelets from 11 normal controls was 109+/-6nM, while that from 11 depressed patients was 131+/-5nM, which was significantly higher than that of normal controls. These results are consistent with our previous observation that 5-HT-stimulated inositol phospholipid hydrolysis in platelets from depressed patient is greater than that of normal controls, suggesting that 5-HT-2 receptor function in platelets is enhanced in patients with affective disorders. To clarify what kind of mechanism produces the enhanced 5-HT-2 receptor function in the central nervous system, we also investigated the effect of dexamethasone or ACTH treatment on 5-HT-induced Ca ion mobilization in C6 glioma cells and on the density of 5-HT-2 receptors in rat cerebral cortex. 48-hour treatment with 100nM dexamethasone enhanced 5-HT-2 receptor-mediated Ca ion mobilization in C6 glioma cells and 10-day treatment with ACTH (50ug/day) produced an increase in the density of 5-HT-2 receptors in rat cerebral cortex, suggesting that the disinhibition of Hypothalamo-Pituitary-Adreno-cortical axis may be, in part, responsible for enhancing 5-HT-2 receptor function in the affective disorders. In this preliminary study, we also demonstrated that several antidepressant agents reduced the affinity and increased the rate of H3-GTP binding to crude membranes from rat cerebral cortex as well as these agents enhanced the GTPase activity of reconstituted Co, suggesting that these antidepressants are capable of interacting with G proteins in brain membranes to cause the direct activation.

10 μ M 5-HT引起的11例正常人血小板内Ca ~（2+）浓度升高为109 ± 6 nM，而11例抑郁症患者血小板内Ca ~（2+）浓度升高为131 ± 5 nM，明显高于正常人。这些结果与我们以前的观察一致，即抑郁症患者血小板中5-HT刺激的肌醇磷脂水解大于正常对照，表明情感障碍患者血小板中5-HT-2受体功能增强。为了阐明中枢神经系统中5-HT-2受体功能增强的机制，我们还研究了地塞米松或ACTH处理对5-HT诱导的C6胶质瘤细胞中Ca离子动员和大鼠大脑皮质中5-HT-2受体密度的影响。48-用100 nM地塞米松处理10小时可增强C6胶质瘤细胞中5-HT-2受体介导的Ca离子动员，用ACTH（50 μ g/天）处理10天可使大鼠大脑皮层中5-HT-2受体密度增加，这表明下丘脑-肾上腺素-皮质轴的去抑制可能部分地负责增强情感障碍中5-HT-2受体功能。在这项初步研究中，我们还证明了几种抗抑郁药降低的亲和力，并增加了从大鼠大脑皮层的粗膜H3-GTP结合的速率，以及这些代理商增强GTdR活性的重建钴，这表明这些抗抑郁药能够与G蛋白在脑细胞膜，导致直接激活。