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

抑郁症中 5-HT-2 受体刺激转导信号功能障碍的分子药理学研究。

• 批准号: 03454295
• 负责人: MIKUNI Masahiko
• 金额: $ 4.22万
• 依托单位: National Center of Neurology and Psychiatry (NCNP)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-03454295/
• 关键词: Serotonin-2 receptors; Calcium Mobilization; GTP binding protein; Hypothalamo-Pituitary-Adrenal Axis; Dexamethasone; Glucocorticoid Receptor; Depression; 視床下部ー下垂体ー副腎皮質系; セロトニンー2受容体; 細胞体Caイオン; GTP結合蛋白質; 視床下部ー下垂体ー副賢皮質系; C6グリオ-マ細胞

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

在本研究中，它清楚地表明，亚慢性ACTH治疗大鼠额叶皮质5-HT-2受体结合位点的密度增加，这是由肾上腺切除阻止，这表明有可能是一个密切相关的下丘脑-垂体-肾上腺轴功能亢进和5-HT-2受体在情感性精神障碍。地塞米松（DEX）亚慢性处理也降低了大鼠大脑皮质5-HT-2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-HT-2受体的上调。此外，DEX处理6 - 48小时增强C6胶质瘤细胞中5-HT-2受体刺激的肌醇-1，4，5三磷酸形成和Ca动员，以及GTP结合蛋白激活剂NaF诱导的Ca动员，尽管DEX处理降低了5-HT-2受体mRNA表达，表明增强的GTP结合蛋白功能是C6胶质瘤细胞中GTP结合蛋白功能增强的原因之一。 ...更多信息 DEX处理增强5-HT刺激的Ca动员的机制。为了阐明与5-HT-2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C6细胞中5-HT-2受体刺激的Ca动员的影响，发现百日咳毒素不影响5-HT反应，提示5-Ht-2受体-为了了解抑郁症患者糖皮质激素受体敏感性明显缺乏的确切机制，有必要制作HPA轴活性增加的动物模型，其表现为DEX抑制失败，以及大脑皮层中5-HT-2受体密度增加。初步结果表明，产前拥挤压力显着增加5-HT-2受体的密度在出生后12周的后代，以及抵抗抑制immobilizatoin诱导的皮质酮分泌的DEX。少

项目成果

Kagaya,A,Mikuni,M,Muraoka,S,Saitoh,K,Ogawa,T,Shinno,H.: "Homologous desensitization of serotonin-2 receptor-stimulated intracellular Ca mobilization in C6 glioma cells via a mechanism involving calmodulin pathway." J.of Neurochemistry.

Kagaya,A,Mikuni,M,Muraoka,S,Saitoh,K,Okawa,T,Shinno,H.：“通过涉及钙调蛋白途径的机制，对 C6 胶质瘤细胞中 5-羟色胺-2 受体刺激的细胞内 Ca 动员进行同源脱敏。”

Takita, M., Mikuni, M. and Takahashi, K.: "Habituation of lactate-release responding to stressful stimuli in rat prefrontal cortex in vivo." Am. J. Physiology. 263. R722-R727 (1992)

Takita, M.、Mikuni, M. 和 Takahashi, K.：“体内大鼠前额叶皮层应激刺激下乳酸释放的习惯。”

高橋 清久・樋口 輝彦・加藤 進昌・三国 雅彦編: "躁うつ病の薬理生化学〔II〕" 金剛出版,

Kiyohisa Takahashi、Teruhiko Higuchi、Nobumasa Kato、Masahiko Mikuni（编）：“躁狂抑郁症的药理学生物化学[II]”Kongo Publishing，

三国 雅彦,樋口 輝彦,加藤 進昌,高橋 清久 編: "躁うつ病の薬理生化学〔II〕" 金剛出版, 234 (1992)

三国正彦、樋口辉彦、加藤信正、高桥清久（编）：“躁狂抑郁症的药理学生物化学[II]”刚果出版社，234（1992）

Kagaya, K., Mikuni, M., Yamamoto, H., Muraoka, S., Yamawaki, S. and Takahashi, K.: "Heterologous supersensitization between serotonin-2 and alpha-2-adrenergic receptor-mediated intracellular calcium mobilization in human platetlets." J. Neural Transmissio

Kagaya, K.、Mikuni, M.、Yamamoto, H.、Muraoka, S.、Yamawaki, S. 和 Takahashi, K.：“5-羟色胺-2 和 α-2-肾上腺素受体介导的细胞内钙动员之间的异源超敏化