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)：当压力源持续时间较长或变化较大，并且不允许其目标调动适当或足够的资源来减轻挑战时，应激源会造成严重的损失。许多慢性病的一个特点是，在漫长的病程中，它们会产生神经体液信号，旨在补偿受损的生理功能，但它们却矛盾地产生了额外的疾病。心力衰竭和心理抑郁并存的高发病率可能为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提供了一个例子。最近，我们一直在探讨为什么心力衰竭时会有如此高的心理抑郁发生率。来自几个证据汇聚的结果使我们假设，在试图维持衰竭心脏的心输出量的过程中释放的肾上腺矿质皮质激素是通过对中枢神经系统的作用而导致抑郁的。目前的应用建议通过研究心力衰竭和快感缺乏的共同发病率来检验这一假设，而快感缺乏是抑郁情绪的主要标志，并通过调查心力衰竭期间产生的矿质皮质激素在诱导减弱的愉悦体验中的作用来检验这一假说。此外，还将研究矿物皮质激素本身作为降压剂的作用。这项研究的三个具体目标是：1)测试实验性心肌梗死所致心力衰竭作为心力衰竭和抑郁并存的模型；2)研究盐皮质激素在心力衰竭引起的抑郁中的作用和机制；3)确定盐皮质激素作为降压剂的作用和机制。将使用来自行为神经科学、临床前精神药理学、实验心脏病学和心血管生理学的方法来回答一系列关键的实验问题。在这些研究过程中，人们将更好地了解1)心肌梗死后早期开始使用选择性5-羟色胺再摄取抑制剂对心力衰竭相关性抑郁的预防价值，2)盐皮质激素本身具有降压作用的可能性，以及3)盐皮质激素受体拮抗剂潜在的抗抑郁作用。重要的是，这项临床前研究将测试使用临床批准的盐皮质激素受体拮抗剂作为抗抑郁药物治疗的可行性。 与公共健康相关：这项应用解决了为什么心力衰竭和心理抑郁表现出出人意料的高发病率共病的问题。这项拟议的实验将研究心力衰竭诱导的醛固酮释放作为导致抑郁的激素机制的作用。