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)
Project #
Application #
Study Section
Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
Program Officer
Meinecke, Douglas L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Schools of Arts and Sciences
Iowa City
United States
Zip Code
Hardy, Rachel N; Simsek, Zinar D; Curry, Brandon et al. (2018) Aging affects isoproterenol-induced water drinking, astrocyte density, and central neuronal activation in female Brown Norway rats. Physiol Behav 192:90-97
McNeal, Neal; Appleton, Katherine M; Johnson, Alan Kim et al. (2017) The protective effects of social bonding on behavioral and pituitary-adrenal axis reactivity to chronic mild stress in prairie voles. Stress 20:175-182
Xue, Baojian; Thunhorst, Robert L; Yu, Yang et al. (2016) Central Renin-Angiotensin System Activation and Inflammation Induced by High-Fat Diet Sensitize Angiotensin II-Elicited Hypertension. Hypertension 67:163-70
Xue, Baojian; Yu, Yang; Zhang, Zhongming et al. (2016) Leptin Mediates High-Fat Diet Sensitization of Angiotensin II-Elicited Hypertension by Upregulating the Brain Renin-Angiotensin System and Inflammation. Hypertension 67:970-6
Thunhorst, Robert L; Xue, Baojian; Beltz, Terry G et al. (2015) Age-related changes in thirst, salt appetite, and arterial blood pressure in response to aldosterone-dexamethasone combination in rats. Am J Physiol Regul Integr Comp Physiol 308:R807-15
Xue, Baojian; Zhang, Zhongming; Beltz, Terry G et al. (2015) Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice. Am J Physiol Regul Integr Comp Physiol 308:R507-16
Johnson, Ralph F; Beltz, Terry G; Johnson, Alan Kim et al. (2015) Effects of fludrocortisone on water and sodium intake of C57BL/6 mice. Am J Physiol Regul Integr Comp Physiol 309:R247-54
Hurley, Seth W; Johnson, Alan Kim (2015) The biopsychology of salt hunger and sodium deficiency. Pflugers Arch 467:445-56
Appleton, K M; Grippo, A J; Beltz, T G et al. (2015) Consumption of a high n-3 polyunsaturated fatty acid diet during gradual mild physiological stress in rats. Prostaglandins Leukot Essent Fatty Acids 95:11-8
Xu, Jie; Johnson, Alan Kim; Thunhorst, Robert L (2015) Thirst and sodium appetite in rats with experimental nephrotic syndrome. Physiol Behav 149:317-23

Showing the most recent 10 out of 40 publications