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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
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Meinecke, Douglas L
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University of Iowa
Schools of Arts and Sciences
Iowa City
United States
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Clayton, Sarah C; Zhang, Zhongming; Beltz, Terry et al. (2014) CNS neuroplasticity and salt-sensitive hypertension induced by prior treatment with subpressor doses of ANG II or aldosterone. Am J Physiol Regul Integr Comp Physiol 306:R908-17
Roncari, C F; David, R B; Johnson, R F et al. (2014) Angiotensinergic and cholinergic receptors of the subfornical organ mediate sodium intake induced by GABAergic activation of the lateral parabrachial nucleus. Neuroscience 262:1-8
Coble, Jeffrey P; Johnson, Ralph F; Cassell, Martin D et al. (2014) Activity of protein kinase C-? within the subfornical organ is necessary for fluid intake in response to brain angiotensin. Hypertension 64:141-8
Xue, Baojian; Zhang, Zhongming; Beltz, Terry G et al. (2014) Estrogen regulation of the brain renin-angiotensin system in protection against angiotensin II-induced sensitization of hypertension. Am J Physiol Heart Circ Physiol 307:H191-8
Hay, Meredith; Xue, Baojian; Johnson, Alan Kim (2014) Yes! Sex matters: sex, the brain and blood pressure. Curr Hypertens Rep 16:458
Menani, Jose V; De Luca Jr, Laurival A; Johnson, Alan Kim (2014) Role of the lateral parabrachial nucleus in the control of sodium appetite. Am J Physiol Regul Integr Comp Physiol 306:R201-10
Suls, Jerry (2013) Anger and the heart: perspectives on cardiac risk, mechanisms and interventions. Prog Cardiovasc Dis 55:538-47
Xue, Baojian; Zhang, Zhongming; Johnson, Ralph F et al. (2013) Central endogenous angiotensin-(1-7) protects against aldosterone/NaCl-induced hypertension in female rats. Am J Physiol Heart Circ Physiol 305:H699-705
Xue, Baojian; Zhang, Zhongming; Beltz, Terry G et al. (2013) Estrogen receptor-* in the paraventricular nucleus and rostroventrolateral medulla plays an essential protective role in aldosterone/salt-induced hypertension in female rats. Hypertension 61:1255-62
Sladek, Celia D; Johnson, Alan Kim (2013) Integration of thermal and osmotic regulation of water homeostasis: the role of TRPV channels. Am J Physiol Regul Integr Comp Physiol 305:R669-78

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