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

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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.