SEROTONIN RECEPTORS AND PROTEIN KINASE C IN DEPRESSION

描述(摘自申请者的摘要)：几项研究表明 自杀患者脑内5-羟色胺2A受体的上调 患有或不患有抑郁症的患者以及抑郁症和抑郁症患者的血小板 有自杀倾向的病人。这种上调的意义和机制 5-HT2a受体及其功能后果尚未得到证实 探索过了。研究人员假设5-HT2a的上调 抑郁症患者大脑和血小板中的受体是由 异常的HPA轴。因此，拟议研究的主要目标是 探讨基因上调的意义和机制。 血小板5-HT2a受体及其与脑内5-HT2a的关系 受体，这将通过进行临床和动物实验来实现 学习。 研究人员临床部分的具体目的是研究 5-HT2A型受体数目和5-HT2A型功能后果 血小板中5-羟色胺连接的PI信号系统的关键成分--PKC 取自抑郁症患者和正常对照组。调查员将 进一步探讨5-羟色胺和PKC措施与自杀和自杀的关系 抑郁症患者的冲动/攻击性行为。5-羟色胺的检测 他说，抑郁症患者的上调与HPA功能异常有关 5-HT2a受体测定与血浆皮质醇和 不抑制地塞米松抑制试验(DST)。 拟议中的动物研究的目标是检查异常的 HPA将调节大脑和大脑中的5-HT2A受体和PKC 血小板。这将通过研究5-HT2a受体编号5-HT2a来实现 脑内信使核糖核酸水平，血小板中5-HT2A受体数目，5-羟色胺和 佛波醇肉豆蔻酸酯(PMA)诱导的PKC转位 脑内二丁酸盐(PDBU)结合和PKC活性及免疫标记 大鼠脑和血小板中PKC同工酶的变化 皮质酮(CORT)、地塞米松(DEX)或促肾上腺皮质激素 激素(ACTH)，来自肾上腺切除(ADX)大鼠和治疗后的ADX大鼠 和科特在一起。因此，调查员的研究不仅将澄清 5-HT2a受体和PKC在抑郁症的病理生理学中的作用 也阐明了5-HT2A受体上调的机制 在大脑和血小板中。这些研究可能因此增加我们的 了解抑郁症的病理生理学，有助于识别 抑郁或有自杀倾向的患者。

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.