SEROTONIN RECEPTORS AND PROTEIN KINASE C IN DEPRESSION

抑郁症中的血清素受体和蛋白激酶 C

• 批准号: 2501461
• 负责人: Ghanshyam N Pandey
• 金额: $ 16.91万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2501461
• 关键词: adrenocorticotropic hormone; aggression; autoradiography; blood chemistry; clinical research; corticosterone; depression; dexamethasone suppression test; enzyme activity; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; impulsive behavior; interview; laboratory rat; mental disorder diagnosis; pathologic process; platelets; polymerase chain reaction; protein kinase C; questionnaires; radioimmunoassay; receptor expression; serotonin receptor; statistics /biometry; suicide; western blottings

DESCRIPTION (Adapted from applicant's abstract): Several studies suggest upregulation of serotonin2A (5-HT2A) receptors in the brain of suicide victims with or without depression and in platelets of depressed and suicidal patients. The significance and the mechanisms of this upregulation of 5-HT2A receptors and their functional consequences have not been explored. The investigator hypothesizes that the upregulation of 5-HT2A receptors in the brain and in platelets of depressed patients is caused by an abnormal HPA axis. The major objectives of the proposed studies are thus to examine the significance and the mechanisms of the upregulation of platelet 5-HT2A receptors and its relationship to the brain 5-HT2A receptors, which will be achieved by conducting a clinical and an animal study. The specific aims of the investigator's clinical component are to study 5-HT2A receptor number and the 5-HT2A functional consequences as well as PKC, a key component in the 5-HT-linked PI signaling system, in platelets obtained from depressed patients and normal controls. The investigator will further examine the relationship of 5-HT and PKC measures with suicidal and impulsive/ aggressive behavior in depressed patients. To examine of 5-HT2A upregulation in depressed patients is related to abnormal HPA function, he will correlate 5-HT2A receptor measures with plasma cortisol and nonsuppression of the dexamethasone suppression test (DST). The objectives of the proposed animal studies are to examine if an abnormal HPA will modulate 5-HT2A receptors and PKC both in the brain and in platelets. This will be achieved by studying 5-HT2A receptor number, 5-HT2A mRNA levels in the brain, 5-HT2A receptor number in platelets, 5-HT- and phorbol myristate acetate (PMA)-induced PKC translocation, (3H)phorbol dibutyrate (PDBU) binding and PKC activity in the brain, and immunolabeling of PKC isozymes in the brain and in platelets obtained from rats treated with corticosterone (CORT), dexamethasone (DEX), or adrenocorticotropical hormone (ACTH), and from adrenalectomized (ADX) rats and in ADX rats treated with CORT. The investigator's study will thus not only clarify the role of 5-HT2A receptors and PKC in the pathophysiology of depression, but it will also elucidate the mechanisms by which 5-HT2A receptors are upregulated both in the brain and in platelets. These studies may thus increase our understanding of the pathophysiology of depression and may help identify depressed or suicide-prone patients.

描述（改编自申请人摘要）：几项研究表明 自杀者脑内5-HT 2A受体的上调 有或没有抑郁症的受害者，以及抑郁症和 自杀的病人 这种上调的意义和机制 5-HT2A受体及其功能性后果尚未被 探讨了 研究者假设5-HT 2A的上调 抑郁症患者大脑和血小板中的受体是由 HPA轴异常 因此，拟议研究的主要目的如下 为了研究上调的意义和机制， 血小板5-HT2A受体及其与脑5-HT2A的关系 受体，这将通过进行临床和动物 study. 研究者临床部分的具体目标是研究 5-HT2A受体数量和5-HT2A功能后果以及 血小板中5-HT-连接的PI信号系统的关键组分PKC 从抑郁症患者和正常对照组中获得。 研究者将 进一步研究5-HT和PKC指标与自杀和 抑郁症患者的冲动/攻击行为。 检测5-HT2A 抑郁症患者的上调与HPA功能异常有关， 将5-HT2A受体测量与血浆皮质醇相关联， 地塞米松抑制试验（DST）无抑制。 拟议动物研究的目的是检查是否存在异常 HPA可调节脑内和脑内的5-HT 2A受体和PKC。 血小板 这将通过研究5-HT2A受体数量、5-HT2A 脑中mRNA水平、血小板中5-HT 2A受体数量、5-HT-和 佛波醇肉豆蔻酸酯（PMA）诱导的PKC转位，（3H）佛波醇 二丁酸（PDBU）结合和PKC活性，以及免疫标记 PKC同工酶在脑和血小板中的表达 与皮质酮（CORT）、地塞米松（DEX）或肾上腺皮质激素联合使用 肾上腺切除（ADX）大鼠和ADX处理大鼠 关于CORT 因此，研究人员的研究不仅将阐明 5-HT2A受体和PKC在抑郁症的病理生理学中的作用，但它将 还阐明了5-HT 2A受体上调的机制， 在大脑和血小板中。 因此，这些研究可能会增加我们的 了解抑郁症的病理生理学，并可能有助于识别 抑郁或有自杀倾向的病人。