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

10 μ m 5-HT诱导11例正常人血小板细胞内Ca离子浓度升高109+/-6nM， 11例抑郁症患者血小板细胞内Ca离子浓度升高131+/-5nM，均显著高于正常对照组。这些结果与我们之前的观察一致，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5-HT-2受体功能在情感性障碍患者中得到增强。为了阐明中枢神经系统5-HT-2受体功能增强的机制，我们还研究了地塞米松或ACTH对5- ht诱导的C6胶质瘤细胞钙离子动员和大鼠大脑皮层5-HT-2受体密度的影响。100nM地塞米松治疗48小时可增强C6胶质瘤细胞中5-HT-2受体介导的钙离子动员，ACTH治疗10天（50ug/天）可增加大鼠大脑皮层中5-HT-2受体的密度，提示下丘脑-垂体-肾上腺-皮质轴的去抑制可能是情感性障碍中5-HT-2受体功能增强的部分原因。在这项初步研究中，我们还证明了几种抗抑郁药物降低了H3-GTP与大鼠大脑皮层粗膜的亲和力，增加了H3-GTP与粗膜的结合率，并且这些药物增强了重组Co的GTPase活性，这表明这些抗抑郁药物能够与脑膜中的G蛋白相互作用，导致直接激活。

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.