The Stress of Chronic Disease: Mineralocorticoid Mediation of Mood

Summary

Principal Investigator: Alan Kim Johnson
Abstract: 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.
Funding Period: 2009-12-01 - 2014-11-30
more information: NIH RePORT

Top Publications

  1. pmc Mineralocorticoid receptor antagonism prevents hedonic deficits induced by a chronic sodium appetite
    Michael J Morris
    Department of Psychology, Integrative Physiology and Pharmacology, and the Cardiovascular Center, The University of Iowa, Iowa City, IA 52242 1407, USA
    Behav Neurosci 124:211-24. 2010
  2. pmc Early interference with p44/42 mitogen-activated protein kinase signaling in hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension
    Yang Yu
    Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242
    Hypertension 61:842-9. 2013
  3. pmc Estrogen receptor-β in the paraventricular nucleus and rostroventrolateral medulla plays an essential protective role in aldosterone/salt-induced hypertension in female rats
    Baojian Xue
    Department of Psychology, The University of Iowa, 11 Seashore Hall E, Iowa City, IA 52242, USA
    Hypertension 61:1255-62. 2013
  4. ncbi Anger and the heart: perspectives on cardiac risk, mechanisms and interventions
    Jerry Suls
    Department of Psychology, University of Iowa, Iowa City, IA 52242, USA
    Prog Cardiovasc Dis 55:538-47. 2013
  5. pmc Subfornical organ mediates sympathetic and hemodynamic responses to blood-borne proinflammatory cytokines
    Shun Guang Wei
    Department of Internal Medicine, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA
    Hypertension 62:118-25. 2013
  6. pmc Estradiol modulates anhedonia and behavioral despair in rats and negative affect in a subgroup of women at high risk for postpartum depression
    Crystal Edler Schiller
    Department of Psychiatry, University of North Carolina at Chapel Hill, 10514 Neurosciences Hospital, 101 Manning Drive, Campus Box 7160, Chapel Hill, NC 27599 7160, USA
    Physiol Behav 119:137-44. 2013
  7. pmc Central endogenous angiotensin-(1-7) protects against aldosterone/NaCl-induced hypertension in female rats
    Baojian Xue
    Department of Psychology, University of Iowa, Iowa City, Iowa
    Am J Physiol Heart Circ Physiol 305:H699-705. 2013
  8. pmc Integration of thermal and osmotic regulation of water homeostasis: the role of TRPV channels
    Celia D Sladek
    Department of Physiology and Biophysics, University of Colorado School of Medicine, Aurora, Colorado and
    Am J Physiol Regul Integr Comp Physiol 305:R669-78. 2013
  9. ncbi Dissociation of thirst and sodium appetite in the furo/cap model of extracellular dehydration and a role for N-methyl-D-aspartate receptors in the sensitization of sodium appetite
    Seth W Hurley
    Department of Psychology
    Behav Neurosci 127:890-8. 2013
  10. ncbi Angiotensinergic and cholinergic receptors of the subfornical organ mediate sodium intake induced by GABAergic activation of the lateral parabrachial nucleus
    C F Roncari
    Department of Physiology and Pathology, School of Dentistry, Sao Paulo State University, UNESP, Araraquara, SP, Brazil Department of Psychology, The Cardiovascular Center, University of Iowa, Iowa City, IA, USA Department of Pharmacology, The Cardiovascular Center, University of Iowa, Iowa City, IA, USA
    Neuroscience 262:1-8. 2014

Research Grants

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
  2. MBSR Symptom Cluster Trial for Breast Cancer Survivors
    Cecile A Lengacher; Fiscal Year: 2013

Detail Information

Publications26

  1. pmc Mineralocorticoid receptor antagonism prevents hedonic deficits induced by a chronic sodium appetite
    Michael J Morris
    Department of Psychology, Integrative Physiology and Pharmacology, and the Cardiovascular Center, The University of Iowa, Iowa City, IA 52242 1407, USA
    Behav Neurosci 124:211-24. 2010
    ..We conclude that an unresolved sodium appetite will reduce responding for rewards and that experimental manipulations that reduce sodium appetite (e.g., access to saline or blockade of MR) decrease hedonic deficits...
  2. pmc Early interference with p44/42 mitogen-activated protein kinase signaling in hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension
    Yang Yu
    Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242
    Hypertension 61:842-9. 2013
    ..MAPK signaling in PVN may be a novel target for early intervention in the progression of ANG II-dependent hypertension...
  3. pmc Estrogen receptor-β in the paraventricular nucleus and rostroventrolateral medulla plays an essential protective role in aldosterone/salt-induced hypertension in female rats
    Baojian Xue
    Department of Psychology, The University of Iowa, 11 Seashore Hall E, Iowa City, IA 52242, USA
    Hypertension 61:1255-62. 2013
    ..The brain regions responsible for the protective effects of estrogen interaction with ERα in Aldo-induced hypertension still need to be determined...
  4. ncbi Anger and the heart: perspectives on cardiac risk, mechanisms and interventions
    Jerry Suls
    Department of Psychology, University of Iowa, Iowa City, IA 52242, USA
    Prog Cardiovasc Dis 55:538-47. 2013
    ..Limitations, including third-variable explanations and overlap among the negative emotions, and implications for cardiology and behavioral medicine research and practice are discussed...
  5. pmc Subfornical organ mediates sympathetic and hemodynamic responses to blood-borne proinflammatory cytokines
    Shun Guang Wei
    Department of Internal Medicine, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA
    Hypertension 62:118-25. 2013
    ..These data suggest that SFO is a predominant site in the brain at which circulating proinflammatory cytokines act to elicit cardiovascular and sympathetic responses...
  6. pmc Estradiol modulates anhedonia and behavioral despair in rats and negative affect in a subgroup of women at high risk for postpartum depression
    Crystal Edler Schiller
    Department of Psychiatry, University of North Carolina at Chapel Hill, 10514 Neurosciences Hospital, 101 Manning Drive, Campus Box 7160, Chapel Hill, NC 27599 7160, USA
    Physiol Behav 119:137-44. 2013
    ..Despite important cross-species differences, both the rat and human studies provided evidence of the effects of estradiol on perinatal depressive symptoms...
  7. pmc Central endogenous angiotensin-(1-7) protects against aldosterone/NaCl-induced hypertension in female rats
    Baojian Xue
    Department of Psychology, University of Iowa, Iowa City, Iowa
    Am J Physiol Heart Circ Physiol 305:H699-705. 2013
    ....
  8. pmc Integration of thermal and osmotic regulation of water homeostasis: the role of TRPV channels
    Celia D Sladek
    Department of Physiology and Biophysics, University of Colorado School of Medicine, Aurora, Colorado and
    Am J Physiol Regul Integr Comp Physiol 305:R669-78. 2013
    ....
  9. ncbi Dissociation of thirst and sodium appetite in the furo/cap model of extracellular dehydration and a role for N-methyl-D-aspartate receptors in the sensitization of sodium appetite
    Seth W Hurley
    Department of Psychology
    Behav Neurosci 127:890-8. 2013
    ..The involvement of NMDA-Rs provides support for the possibility that sensitization of sodium appetite is mediated by neuroplasticity...
  10. ncbi Angiotensinergic and cholinergic receptors of the subfornical organ mediate sodium intake induced by GABAergic activation of the lateral parabrachial nucleus
    C F Roncari
    Department of Physiology and Pathology, School of Dentistry, Sao Paulo State University, UNESP, Araraquara, SP, Brazil Department of Psychology, The Cardiovascular Center, University of Iowa, Iowa City, IA, USA Department of Pharmacology, The Cardiovascular Center, University of Iowa, Iowa City, IA, USA
    Neuroscience 262:1-8. 2014
    ..They also show that there are cells in the SFO activated by both angiotensinergic and cholinergic stimuli, perhaps those involved in the responses to muscimol into the LPBN...
  11. pmc Role of the lateral parabrachial nucleus in the control of sodium appetite
    Jose V Menani
    Department of Physiology and Pathology, School of Dentistry, Universidade Estadual Paulista, Araraquara, Sao Paulo, Brazil and Departments of Psychology, Pharmacology and Health, and Human Physiology and the Cardiovascular Center, University of Iowa, Iowa City, Iowa
    Am J Physiol Regul Integr Comp Physiol 306:R201-10. 2014
    ..To summarize, a model of LPBN inhibitory actions on forebrain facilitatory components for the control of sodium appetite is presented in this review. ..
  12. pmc Activity of protein kinase C-α within the subfornical organ is necessary for fluid intake in response to brain angiotensin
    Jeffrey P Coble
    From the Departments of Pharmacology J P C, J L G, C D S, Psychology R F J, A K J, and Anatomy and Cell Biology M D C, Roy J and Lucille A Carver College of Medicine, University of Iowa
    Hypertension 64:141-8. 2014
    ....
  13. pmc Aldosterone acting through the central nervous system sensitizes angiotensin II-induced hypertension
    Baojian Xue
    Department of Psychology, Cardiovascular Center, University of Iowa, 11 Seashore Hall E, Iowa City, IA 52242, USA
    Hypertension 60:1023-30. 2012
    ..Taken together, these results indicate that Aldo pretreatment cross-sensitizes the development of Ang II-induced hypertension probably by mechanisms that involve the central nervous system...
  14. ncbi Voluntary running-wheel exercise decreases the threshold for rewarding intracranial self-stimulation
    Michael J Morris
    Department of Psychology, The University of Iowa, Iowa City 52242 1407, USA
    Behav Neurosci 126:582-7. 2012
    ..We conclude that long-term voluntary exercise increases sensitivity to rewarding stimuli, which may contribute to its antidepressant properties...
  15. pmc Drinking and arterial blood pressure responses to ANG II in young and old rats
    Robert L Thunhorst
    Dept of Psychology, Univ of Iowa, 11 Seashore Hall E, Iowa City, IA 52242 1407, USA
    Am J Physiol Regul Integr Comp Physiol 299:R1135-41. 2010
    ..In summary, young rats appear to be more sensitive to the inhibitory effects of increased arterial blood pressure on water drinking than are older animals...
  16. pmc The brain Renin-angiotensin system controls divergent efferent mechanisms to regulate fluid and energy balance
    Justin L Grobe
    Department of Internal Medicine, University of Iowa, Iowa City, 52242, USA
    Cell Metab 12:431-42. 2010
    ..adrenergic blockade or restoration of circulating angiotensin-II, but not adrenalectomy, normalized metabolic rate. Our data point to contrasting mechanisms by which the brain RAS regulates fluid intake and energy expenditure...
  17. pmc Central interactions of aldosterone and angiotensin II in aldosterone- and angiotensin II-induced hypertension
    Baojian Xue
    Department of Psychology, Cardiovascular Center, University of Iowa, 11 Seashore Hall E, Iowa City, IA 52242, USA
    Am J Physiol Heart Circ Physiol 300:H555-64. 2011
    ..The pressor effects produced by systemic ANG II or Aldo involve increased central ROS and sympathetic outflow...
  18. pmc Cancer induces inflammation and depressive-like behavior in the mouse: modulation by social housing
    Donald M Lamkin
    Department of Psychology, University of Iowa, IA, USA
    Brain Behav Immun 25:555-64. 2011
    ..It is concluded that tumor elicits anhedonic depressive-like behavior in a murine model of ovarian cancer. This may have important implications for etiology of depression in the clinical cancer setting...
  19. pmc Effects of β-adrenergic receptor agonists on drinking and arterial blood pressure in young and old rats
    Robert L Thunhorst
    Dept of Psychology, Univ of Iowa, 11 Seashore Hall E, Iowa City, IA 52242 1407, USA
    Am J Physiol Regul Integr Comp Physiol 300:R1001-8. 2011
    ..In conclusion, there are age-related differences in β-adrenergic receptor-mediated drinking that can be explained only in part by age-related differences in renin secretion after β-adrenergic receptor stimulation...
  20. pmc Behavioral cross-sensitization between DOCA-induced sodium appetite and cocaine-induced locomotor behavior
    Martin J Acerbo
    Departments of Psychology, Pharmacology, and Health and Human Physiology, and the Cardiovascular Center, The University of Iowa, Iowa City, IA 52242, USA
    Pharmacol Biochem Behav 98:440-8. 2011
    ..The underlying mechanisms accounting for this relationship may be the fact that psychostimulants and an unresolved craving for sodium can act as potent stressors...
  21. pmc Altered ADAR 2 equilibrium and 5HT(2C) R editing in the prefrontal cortex of ADAR 2 transgenic mice
    M Singh
    Department of Internal Medicine, University of Iowa, Iowa City, USA
    Genes Brain Behav 10:637-47. 2011
    ..These results altogether suggest that altered 5HT(2C) R function could be contributing to enhanced depression-like behavior of ADAR2 transgenic mice and further implicate ADAR2 as a contributing factor in cases of affective disorder...
  22. ncbi Changes in taste reactivity to intra-oral hypertonic NaCl after lateral parabrachial injections of an α2-adrenergic receptor agonist
    Carina A F Andrade
    Department of Physiology and Pathology, School of Dentistry, UNESP, Araraquara, SP, 14801 903, Brazil
    Physiol Behav 104:702-8. 2011
    ..The maintained positive rewarding qualities of 0.3 M NaCl are likely to account for why LPBN moxonidine treated rats show such a remarkable salt appetite when assayed by the volume of hypertonic 0.3 M NaCl consumed...
  23. pmc PVN adenovirus-siRNA injections silencing either NOX2 or NOX4 attenuate aldosterone/NaCl-induced hypertension in mice
    Baojian Xue
    Departments of Psychology, University of Iowa, Iowa City, IA 52242, USA
    Am J Physiol Heart Circ Physiol 302:H733-41. 2012
    ..These data indicate that both NOX2 and NOX4 in the PVN contribute to elevated sympathetic activity and the hypertensivogenic actions induced by mineralocorticoid excess...
  24. pmc Sensitization of slow pressor angiotensin II (Ang II)-initiated hypertension: induction of sensitization by prior Ang II treatment
    Baojian Xue
    Department of Psychology, University of Iowa, 11 Seashore Hall E, Iowa City, IA 52242, USA
    Hypertension 59:459-66. 2012
    ....
  25. ncbi Opioid mechanisms that mediate the palatability of and appetite for salt in sodium replete and deficient states
    Elisa S Na
    Department of Psychology, The University of Iowa, Iowa City, IA 52242 1407, USA
    Physiol Behav 106:164-70. 2012
    ..The results indicate that endogenous opioids alter the processing of central information to affect hedonic mechanisms that influence behaviors related to sodium consumption and palatability...
  26. pmc Yes! Sex matters: sex, the brain and blood pressure
    Meredith Hay
    Department of Physiology, University of Arizona, 1501 N Campbell Rd Bldg 201, Rm 4103, Tucson, AZ, 85724, USA
    Curr Hypertens Rep 16:458. 2014
    ....

Research Grants30

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  2. MBSR Symptom Cluster Trial for Breast Cancer Survivors
    Cecile A Lengacher; Fiscal Year: 2013
    ..If this intervention is shown to be efficacious, the possibility exists of extending its use to minimize morbidity for other types of cancers, as well as severe non-cancer health disorders. ..