Molecular Pharmacological Study on the Dysfunction of 5-HT-2 receptor-stimulated Transduction Signaling in Depression.

结果表明，亚慢性ACTH治疗可增加大鼠额叶皮质5-HT-2受体结合部位的密度，而肾上腺切除可阻止这种作用，提示情感性精神障碍的下丘脑-垂体-肾上腺轴功能亢进可能与5-HT-2受体密切相关。地塞米松(DEX)亚慢性处理也降低了大脑皮层5-HT2受体的密度，提示2型糖皮质激素受体参与了ACTH和皮质酮亚慢性处理诱导的5-HT2受体的上调。此外，地塞米松处理6-48小时可增强C6胶质瘤细胞中5-羟色胺-2受体刺激的三磷酸肌醇的形成和钙动员，以及氟化钠诱导的钙动员，而5-羟色胺-2受体的表达被地塞米松处理后降低，提示这种增强的谷氨酸氨基转移酶结合蛋白功能是…的一种。进一步探讨了地塞米松促进5-羟色胺刺激的钙动员的机制。为了阐明与5-HT2受体偶联的GTP结合蛋白的药理学特征，我们研究了百日咳毒素对5-Ht-2受体刺激的C6细胞钙动员的影响，发现百日咳毒素不影响5-羟色胺的反应，提示5-Ht-2受体偶联的GTP结合蛋白可能属于GTP结合蛋白家族。为了了解抑郁症患者明显缺乏糖皮质激素受体敏感性的确切机制，有必要建立一种动物模型，其HPA轴活性增加，表明DEX抑制失败。大脑皮层5-羟色胺-2受体密度增加。初步结果表明，出生前拥挤应激显著增加出生后12周仔鼠大脑皮质5-Ht-2受体的密度，并增强对地塞米松抑制皮质酮分泌的抵抗力。较少

In the present study, it was clearly demonstrated that subchronic ACTH treatment increased the density of 5-HT-2 receptor binding sites in rat frontal cortex, which was prevented by adrenalectomy, suggesting there may be a tight corelation between both hyperfunction of hypothalamopituitary-adrenal axis and 5-HT-2 receptors in affective disorders. Subcronic treatment with dexamethasone(DEX) also reduced the density of 5-HT-2 receptors in rat cerebral cortex, suggesting that type 2 glucocorticoid receptors are involved in the up-regulation of 5-HT-2 receptors induced by subchronic treatment with ACTH and corticosterone. In addition, DEX treatment for 6 - 48 hrs potentiated 5-HT-2 receptor-stimulated inositol-1,4,5 trisphosphate formation and Ca mobilization in C6 glioma cells and GTP binding protein activator, NaF-induced Ca mobilization as well, although 5-HT-2 receptor mRNA expression was reduced by this DEX treatment, suggesting that the enhanced GTP binding protein function is one of … More the mechanisms which are responsible for the enhancement of 5-Ht-stimulated Ca mobilization induced by DEX treatment. To clarify a pharmacological profile of the GTP binding protein coupled to 5-HT-2 receptors, we investigated the effect of Pertussis toxin on 5-Ht-2 receptor-stimulated Ca mobilization in C6 cells, and found Pertussis toxin did not affect 5-HT response, suggesting that the 5-Ht-2 receptor-coupled GTP binding protein may belong to Gq family of GTP binding proteins.In order to know the precise mechanisms of the apparent lack of gluco-corticoid receptor sensitivity observed in depression, it is necessary to make a animal model which have increased activity of the HPA axis, indicated by failure to DEX suppression, and increased density of 5-HT-2 receptors in cerebral cortex. Preliminary results suggest that prenatal crowding stress significantly increased the density of 5-Ht-2 receptors in cerebral cortex of postnatal 12 weeks offspring, as well as resistance to suppress immobilizatoin-induced corticosterone secretion by DEX. Less