Depression, Epinephrine, Serotonin, & Platelet Function

抑郁症，肾上腺素，血清素，

• 批准号: 6621590
• 负责人: DOMINIQUE L. MUSSELMAN
• 金额: $ 38.02万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-04 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6621590
• 关键词: adenosine diphosphate; adenosine triphosphate; autocrine; behavioral /social science research tag; calcium flux; cell adhesion; desipramine; disease /disorder proneness /risk; epinephrine; fibrinogen; flow cytometry; human subject; integrins; ligands; major depression; male; mental disorder chemotherapy; myocardial ischemia /hypoxia; paroxetine; patient oriented research; platelet aggregation; psychopharmacology; psychophysiology; selectins; serotonin; serotonin receptor; thrombin receptor; thromboxanes

Several studies have shown that major depression and associated symptoms, such as hopelessness, are a major independent risk factor in development of ischemic heart disease (IHD), and for death after an index myocardial infarction. Not only do platelets play a central role in hemostasis, atherosclerosis, and acute coronary syndromes, but patients with major depression exhibit increased numbers of the functional platelet GPIIb/IIIa receptor, the receptor for fibrinogen and other ligands, and the final common pathway by which platelet aggregation and adhesion occurs. The overall goal is to determine in patients with major depression, the specific molecular pathways, and relative contributions of these pathways, whereby the platelet GPIIb/IIIa receptor is converted from a low- affinity to high-affinity conformation. To accomplish this goal, we will scrutinize in men with unipolar, recurrent, major depression, not only depression severity and platelet GPIIb/IIIa receptors, but characterize platelet autocrine "feed forward" pathways via: platelet serotonin (5HT) and 5HT2 receptors, platelet adenosine triphosphate (ATP) release, and urinary excretion of 11-dehydrothromboxane beta2: (1) under controlled basal conditions, (2) after the Trier Social Stress Test (a sustained mental stressor which will stimulate platelet function via peripheral release of the platelet agonist epinephrine). Moreover we will determine the molecular mechanisms whereby antidepressant treatment reduces numbers of high-affinity GPIIb/IIIa receptors, using randomized, double-blind, treatment with paroxetine (a selective 5HT reuptake inhibitor) in comparison to desipramine (a noradrenergic tricyclic). State-of- the-art techniques will be used, including fluorescence activated flow cytometry (FAFC), platelet calcium mobilization, and evaluation of in vitro antidepressant direct "drug effects" of upon platelet function. Novel information will be gleaned regarding not only the biological basis for the increased vulnerability of depressed patients to IHD, but also potential thrombovascular targets whereby psychopharmacologic interventions might reduce the future risk of heart attack and sudden death in patients with major depression.

多项研究表明，重度抑郁症和相关症状（例如绝望）是缺血性心脏病（IHD）以及心肌梗死后死亡的主要独立危险因素。 血小板不仅在止血、动脉粥样硬化和急性冠状动脉综合征中发挥核心作用，而且重度抑郁症患者的功能性血小板 GPIIb/IIIa 受体、纤维蛋白原和其他配体的受体以及最终的共同途径的数量增加。血小板发生聚集和粘附。 总体目标是确定重度抑郁症患者的具体分子途径以及这些途径的相对贡献，从而使血小板 GPIIb/IIIa 受体从低亲和力构象转变为高亲和力构象。 为了实现这一目标，我们将仔细检查患有单相、复发性重度抑郁症的男性，不仅检查抑郁症的严重程度和血小板 GPIIb/IIIa 受体，还将通过以下方式表征血小板自分泌“前馈”途径：血小板血清素 (5HT) 和 5HT2 受体、血小板三磷酸腺苷 (ATP) 释放和 11-脱氢血栓β2 的尿排泄：(1) 在受控基础条件下，(2)特里尔社会压力测试（一种持续的精神压力源，将通过血小板激动剂肾上腺素的外周释放刺激血小板功能）后。此外，我们将使用帕罗西汀（一种选择性 5HT 再摄取抑制剂）与地昔帕明（一种去甲肾上腺素三环类药物）进行随机、双盲治疗，确定抗抑郁治疗减少高亲和力 GPIIb/IIIa 受体数量的分子机制。 将使用最先进的技术，包括荧光激活流式细胞术（FAFC）、血小板钙动员以及体外抗抑郁药对血小板功能的直接“药物效应”的评估。 我们将收集新的信息，不仅涉及抑郁症患者易患 IHD 的生物学基础，还涉及潜在的血栓血管目标，通过这些目标，精神药物干预可能会降低重度抑郁症患者未来心脏病发作和猝死的风险。