The Stress of Chronic Disease: Mineralocorticoid Mediation of Mood

慢性病的压力：盐皮质激素调节情绪

• 批准号: 8197355
• 负责人: ALAN Kim JOHNSON
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197355
• 关键词: Abbreviations; Address; Adrenal Glands; Aldosterone; Anhedonia; Animal Model; Antidepressive Agents; Arrhythmia; Attenuated; Behavior; Behavioral; Bibliography; Brain; Cardiac Output; Cardiology; Cardiovascular Physiology; Cardiovascular system; Characteristics; Chronic; Chronic Disease; Comorbidity; Data; Depressed mood; Development; Disease; Endocrine; Event; Frequencies; Generations; Heart; Heart failure; Hormonal; Hormones; Human; Incidence; Infarction; Investigation; Laboratory Rat; Lead; Mediation; Mental Depression; Methods; Mineralocorticoid Receptor; Mineralocorticoids; Modeling; Mood Disorders; Moods; Myocardial Infarction; Nature; Neuraxis; Neurosciences; Pathology; Patients; Physiological; Play; Probability; Protocols documentation; Psychopharmacology; Recurrence; Research; Resources; Role; Selective Serotonin Reuptake Inhibitor; Series; Serotonin; Signal Transduction; Stimulus; Stress; Sudden Death; Sympathetic Nervous System; Syndrome; System; Testing; Text; Translating; base; biological adaptation to stress; experience; indexing; interest; pleasure; pre-clinical; pre-clinical research; prophylactic; psychologic; public health relevance; research study; response; reuptake; stressor; theories

DESCRIPTION (provided by applicant): Stressors exert an exacting toll when they are prolonged or varied and do not permit their target to mobilize appropriate or sufficient resources to attenuate the challenge. A characteristic of many chronic diseases is that throughout their prolonged course they generate neurohumoral signals intended to compensate for compromised physiological function, but they paradoxically generate additional disorders. The high incidence of the co-morbidity of heart failure and psychological depression may provide an example of how the product of the chronic physiological stress produced by a disease state gets translated into a second disorder. Recently we have been addressing the question of why there is such a high incidence of psychological depression accompanying heart failure. The results from several converging lines of evidence lead us to hypothesize that adrenal mineralocorticoids released in the course of attempting to maintain the cardiac output of a failing heart are depressivogenic through their action on the central nervous system. The present application proposes to test this hypothesis by studying the co-morbidity of heart failure and anhedonia, a cardinal sign of depressed mood, and by investigating the role of mineralocorticoids generated during heart failure in inducing the attenuated experience of pleasure. In addition, the role of mineralocorticoids themselves as depressivogenic agents will be investigated. The three specific aims to be achieved by the proposed research are to: 1) test experimental myocardial infarction-induced heart failure as a model for the co-morbidity of heart failure and depression, 2) investigate the role and mechanisms of mineralocorticoids in heart failure-induced depression, and 3) determine the role and mechanisms of mineralocorticoids as depressivogenic agents. Protocols employing methods from behavioral neuroscience, preclinical psychopharmacology, experimental cardiology, and cardiovascular physiology will be used to answer a series of key experimental questions. In the course of these studies a better understanding will be achieved of the 1) value of prophylactic use of selective serotonin reuptake inhibitors beginning early after myocardial infarction on heart failure-related depression, 2) likelihood that mineralocorticoids have a depressivogenic action on their own, and 3) potential antidepressant actions of mineralocorticoid receptor antagonists. Importantly, this preclinical research will test the feasibility of using a clinically approved mineralocorticoid receptor antagonist as an antidepressant pharmacotherapeutic. PUBLIC HEALTH RELEVANCE: This application addresses the question of why heart failure and psychological depression display such an unexpectedly high incidence of co-morbidity. The proposed experiments will investigate the role of heart failure-induced aldosterone release as a depressivogenic hormonal mechanism.

描述（由申请人提供）：压力源在延长或变化时会造成严重的损失，并且不允许其目标动员适当或足够的资源来减轻挑战。许多慢性疾病的一个特征是，在整个过程中，它们产生了旨在补偿损害生理功能的神经肿瘤信号，但它们矛盾地产生了其他疾病。心力衰竭和心理抑郁症的合并症的高发率可能提供了一个例子，说明疾病状态产生的慢性生理压力的产物如何转化为第二种疾病。最近，我们一直在解决一个问题，为什么心理抑郁症发生如此高的心力衰竭。来自几种融合的证据线的结果使我们假设在试图维持失败心脏的心脏输出过程中释放的肾上腺矿物皮质激素通过其对中枢神经系统的作用是降低的。本应用建议通过研究心力衰竭和Anhedonia的合并症，情绪低落的基础迹象，并研究心力衰竭在诱发愉悦感减弱的经历中产生的矿物皮质激素的作用，来检验这一假设。此外，将研究矿物皮质激素本身作为降压剂的作用。拟议的研究要实现的三个具体目标是：1）测试实验性心肌梗死引起的心力衰竭，作为心脏衰竭和抑郁症的合并症的模型，2）研究矿物皮质激素在心脏衰竭诱导的抑郁症中的作用和机制，3）确定矿物质类药物的作用和机制，以下类药物的作用和机制。采用行为神经科学，临床前心理药理学，实验心脏病学和心血管生理学方法的方法的方案将用于回答一系列关键的实验问题。在这些研究的过程中，将对1）预防性使用选择性血清素再摄取抑制剂的价值从心肌衰竭相关性抑郁症开始，2）矿物皮质激素可能会自身具有抑郁剂的作用，并且有3）潜在的抗矿物质的抗矿物质部体。重要的是，这项临床前研究将测试使用临床认可的矿物皮质受体拮抗剂作为抗抑郁药药物治疗的可行性。 公共卫生相关性：该应用程序解决了为什么心力衰竭和心理抑郁症表现出如此出乎意料的合并症发生率如此高的问题。提出的实验将研究心力衰竭诱导的醛固酮释放作为降压生成激素机制的作用。