The Stress of Chronic Disease: Mineralocorticoid Mediation of Mood

描述（由申请人提供）：当压力源延长或变化，并且不允许其目标调动适当或足够的资源来减轻挑战时，压力源会产生严格的代价。许多慢性疾病的一个特点是，在其漫长的病程中，它们产生神经体液信号，旨在补偿受损的生理功能，但矛盾的是，它们产生额外的疾病。心衰和心理抑郁合并症的高发病率可能提供了一个例子，说明由疾病状态产生的慢性生理应激的产物如何转化为第二种疾病。最近我们一直在研究为什么心衰伴随心理抑郁的发生率如此之高。来自几条证据线的结果使我们假设，在试图维持心力衰竭的心输出量的过程中释放的肾上腺矿化皮质激素通过对中枢神经系统的作用而导致抑郁。本研究拟通过研究心力衰竭和快感缺乏症（抑郁情绪的主要症状）的合并症，以及研究心力衰竭期间产生的矿化皮质激素在诱导愉悦体验减弱中的作用，来检验这一假设。此外，将研究矿物皮质激素本身作为致抑郁剂的作用。本研究的三个具体目标是：1)验证实验性心肌梗死诱导的心力衰竭作为心力衰竭和抑郁共发病的模型；2)研究矿皮质激素在心力衰竭诱导的抑郁中的作用和机制；3)确定矿皮质激素作为致抑郁药物的作用和机制。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。在这些研究的过程中，将更好地了解1)在心肌梗死后早期开始预防性使用选择性5 -羟色胺再摄取抑制剂对心力衰竭相关抑郁症的价值，2)矿皮质激素本身具有致抑郁作用的可能性，以及3)矿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矿皮质激素受体拮抗剂作为抗抑郁药物治疗的可行性。

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.