The Stress of Chronic Disease: Mineralocorticoid Mediation of Mood

慢性病的压力：盐皮质激素调节情绪

基本信息

批准号：
7782875
负责人：
ALAN Kim JOHNSON
金额：
$ 33.75万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
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/7782875
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

项目摘要

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）：当压力源持续存在或变化时，会产生严重的后果，并且不允许其目标调动适当或足够的资源来减轻挑战。许多慢性疾病的一个特点是，在其漫长的病程中，它们会产生神经体液信号，旨在补偿受损的生理功能，但矛盾的是，它们会产生额外的疾病。心力衰竭和心理抑郁并存的高发病率可能提供了一个例子，说明疾病状态产生的慢性生理应激产物如何转化为第二种疾病。最近我们一直在解决为什么伴随心力衰竭的心理抑郁发生率如此之高的问题。多个证据的汇集结果使我们推测，在试图维持衰竭心脏的心输出量的过程中释放的肾上腺盐皮质激素通过其对中枢神经系统的作用而产生抑郁症。本申请提出通过研究心力衰竭和快感缺乏（抑郁情绪的主要症状）的共病，并通过研究心力衰竭期间产生的盐皮质激素在诱导快乐体验减弱中的作用来检验该假设。此外，还将研究盐皮质激素本身作为抑郁剂的作用。该研究要实现的三个具体目标是：1）测试实验性心肌梗塞诱发的心力衰竭作为心力衰竭和抑郁症共病的模型，2）研究盐皮质激素在心力衰竭中的作用和机制-诱导的抑郁症，以及3)确定盐皮质激素作为抑郁剂的作用和机制。采用行为神经科学、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。在这些研究过程中，我们将更好地了解 1) 心肌梗死后早期开始预防性使用选择性血清素再摄取抑制剂对心力衰竭相关抑郁症的价值，2) 盐皮质激素本身具有致抑郁作用的可能性， 3）盐皮质激素受体拮抗剂的潜在抗抑郁作用。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。公共卫生相关性：本申请解决了为什么心力衰竭和心理抑郁的共病发生率如此之高的问题。拟议的实验将研究心力衰竭引起的醛固酮释放作为抑制性激素机制的作用。