Angela J. Grippo

Biological mechanisms in the relationship between depression and heart disease

Psychological depression is shown to be associated with several aspects of coronary artery disease (CAD), including arrhythmias, myocardial infarction, heart failure and sudden death. The physiological mechanisms accounting for this association are unclear. Hypothalamic-pituitary-adrenal dysregulation, diminished heart rate variability, altered blood platelet function and noncompliance with medial treatments have been proposed as mechanisms underlying depression and cardiovascular disease. Recent evidence also suggests that reduced baroreflex sensitivity, impaired immune function, chronic fatigue and the co-morbidity of depression and anxiety may be involved in the relationship between depression and cardiovascular dysregulation. An experimental strategy using animal models for investigating underlying physiological abnormalities in depression is presented. A key to understanding the bidirectional association between depression and heart disease is to determine whether there are common changes in brain systems that are associated with these conditions. Such approaches may hold promise for advancing our understanding of the interaction between this mood disorder and CAD.

Neuroendocrine and cytokine profile of chronic mild stress-induced anhedonia

A bidirectional relationship exists between depression and cardiovascular disease. Patients with major depression are more likely to develop cardiac events, and patients with myocardial infarction and heart failure are more likely to develop depression. A feature common to both clinical syndromes is activation of proinflammatory cytokines and stress hormones, including the hypothalamic-pituitary-adrenal axis and the renin-angiotensin-aldosterone system. In the present study we examined the hypothesis that exposure to chronic mild stress (CMS), an experimental model of depression that induces anhedonia in rats, is sufficient to activate the production of proinflammatory cytokines and stress hormones that are detrimental to the heart and vascular system. Four weeks of exposure of male, Sprague-Dawley rats to mild unpredictable environmental stressors resulted in anhedonia which was operationally defined as a reduction in sucrose intake without a concomitant effect on water intake. Humoral assays indicated increased plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), plasma renin activity, aldosterone, and corticosterone in the CMS exposed rats. Tissue TNF-alpha and IL-1beta were increased in the hypothalamus, and TNF-alpha was increased in the pituitary gland. These humoral responses to CMS, associated with anhedonia as an index of depression in the rat, are likely to be associated with neurohumoral mechanisms that may contribute to adverse cardiac events. The findings provide a basis for examining more directly the interactions among the central, endocrine, and immune systems in depression associated with heart disease.

Behavioral and cardiovascular changes in the chronic mild stress model of depression.

Depression is a multifaceted psychological disorder that involves changes in behavior, neuroendocrine function, and physiological responses. The present study investigated multiple behavioral and cardiovascular consequences in the chronic mild stress (CMS) rodent model of depression. Rats were exposed to 4 weeks of CMS followed by 4 weeks of a stress-free recovery period. Sucrose intake, a measure of anhedonia, and spontaneous locomotor activity were measured weekly throughout the study, and cardiovascular function tests were conducted at the completion of the protocol. The results indicate that CMS results in anhedonia and reduced locomotor activity, as well as elevated heart rate (HR), reduced HR variability, and elevated sympathetic cardiac tone. The behavioral effects of CMS recovered to baseline (prestress) levels during the recovery period; however, cardiovascular changes were observed following the recovery of sucrose intake and activity levels. The present findings suggest that behavioral changes that are indicative of anhedonia and locomotor alterations associated with depression are dissociable from long-term cardiovascular changes induced by CMS.

The Effects of Chronic Fluoxetine Treatment on Chronic Mild Stress-Induced Cardiovascular Changes and Anhedonia

BACKGROUNDnDepression has a complex bidirectional association with heart disease. Previously we have shown notable cardiovascular changes in the chronic mild stress (CMS) rodent model of depression. Here we investigated the effects of a serotonin-specific reuptake inhibitor on a behavioral index of depression (anhedonia) and cardiac function in rats exposed to CMS.nnnMETHODSnMale Sprague-Dawley rats were exposed to either 4 weeks of control conditions or CMS, consisting of unpredictable periods of mild stressors, while being treated concurrently with 4 weeks of daily fluoxetine (10 mg/kg, sc) or vehicle.nnnRESULTSnChronic fluoxetine treatment prevented anhedonia in rats exposed to CMS, versus the CMS group treated with vehicle. However, treatment with fluoxetine in the CMS group only partially prevented specific cardiovascular changes associated with CMS, including elevated resting heart rate (HR), exaggerated pressor and HR responses to air jet stress, reduced cardiac output and stroke volume, and HR exaggerated responses to beta-adrenergic receptor blockade.nnnCONCLUSIONSnThese findings provide evidence that 4 weeks of fluoxetine treatment can prevent behavioral responses and can partially prevent cardiovascular changes associated with CMS, providing insight into the role of serotonin in the link between depression and cardiovascular dysfunction.

A Comparative Developmental Study of Impulsivity in Rats and Humans: The Role of Reward Sensitivity

Abstract: The present study was conducted to test the hypothesis that differences in reward sensitivity between adolescents and adults account for differences in impulsivity. In a comparative study, we examined preferences for various concentrations of sucrose solutions as an operational measure of reward sensitivity in adolescent and adult rats and humans. Humans also completed self‐report measures of impulsivity and reward sensitivity. There was some indication that adolescents preferred sweeter solutions compared to adults. Also, adolescents scored substantially higher on impulsivity. However, adolescents and adults did not differ in self‐ratings of reward sensitivity and personality scores were not consistently related to sucrose preferences. The data highlight some of the benefits and issues that arise with developing comparative measures in humans and animals. Future comparative research using alternative behavioral paradigms is necessary to determine if and how changes in reward sensitivity influence developmental shifts in impulsivity.

The effects of deoxycorticosterone-induced sodium appetite on hedonic behaviors in the rat.

The authors tested the hypothesis that chronic treatment with a dose of deoxycorticosterone acetate (DOCA) known to elicit a robust sodium appetite can negatively affect the hedonic state of rats. Daily treatment with DOCA with no opportunity to ingest saline produced a rightward shift in the midpoint (effective current 50) of lateral hypothalamic self-stimulation (LHSS) current-response functions and reduced intakes of a palatable sucrose solution. Providing rats with 0.3 M saline during DOCA treatment prevented the rightward shift in LHSS response functions and the decrease in sucrose intake. The authors concluded that a chronic sodium appetite, with no opportunity to attenuate the appetite, can elicit a reduced responsiveness to reward.

Reduced hedonic behavior and altered cardiovascular function induced by mild sodium depletion in rats

Interactions among sodium homeostasis, fatigue, mood, and cardiovascular regulation have been described previously. The present study investigates the effects of sodium deficiency on an index of mood (hypohedonia; Experiment 1), cardiovascular function (Experiment 2), and plasma electrolytes (Experiment 3) in rats. Following 48 hr of sodium depletion with a diuretic (furosemide) and a sodium deficient diet, rats displayed hypohedonia evidenced by reduced responding for rewarding electrical brain stimulation into the hypothalamus. Also, sodium depletion produced increased heart rate and reduced heart rate variability. Plasma sodium levels were lower in sodium-depleted rats versus control rats, whereas potassium levels were unchanged. Thus, mild sodium depletion produces hypohedonia and cardiovascular alterations, which has implications for understanding behavioral and cardiovascular consequences of sodium deficiency.

Sucrose ingestion elicits reduced Fos expression in the nucleus accumbens of anhedonic rats.

Chronic mild stress (CMS), an animal model of depression associated with anhedonia, was used to examine nucleus accumbens (NAc) activation associated with a rewarding stimulus. Following 4 weeks of CMS in rats, NAc Fos-immunoreactivity was measured after ingestion of a fixed volume of sucrose. Fewer Fos-positive neurons were observed in the NAc in CMS versus control rats. These findings have implications for the mechanisms underlying reduced responding to pleasurable stimuli associated with depression.

Hindlimb Unloading Elicits Anhedonia and Sympathovagal Imbalance

The hindlimb-unloaded (HU) rat model elicits cardiovascular deconditioning and simulates the physiological adaptations to microgravity or prolonged bed rest in humans. Although psychological deficits have been documented following bed rest and spaceflight in humans, few studies have explored the psychological effects of cardiovascular deconditioning in animal models. Given the bidirectional link established between cardiac autonomic imbalance and psychological depression in both humans and in animal models, we hypothesized that hindlimb unloading would elicit an alteration in sympathovagal tone and behavioral indexes of psychological depression. Male, Sprague-Dawley rats confined to 14 days of HU displayed anhedonia (a core feature of human depression) compared with casted control (CC) animals evidenced by reduced sucrose preference (CC: 81 +/- 2.9% baseline vs. HU: 58 +/- 4.5% baseline) and reduced (rightward shift) operant responding for rewarding electrical brain stimulation (CC: 4.4 +/- 0.3 muA vs. 7.3 +/- 1.0 muA). Cardiac autonomic blockade revealed elevated sympathetic [CC: -54 +/- 14.1 change in (Delta) beats/min vs. HU: -118 +/- 7.6 Delta beats/min] and reduced parasympathetic (CC: 45 +/- 11.8 Delta beats/min vs. HU: 8 +/- 7.3 Delta beats/min) cardiac tone in HU rats. Heart rate variability was reduced (CC: 10 +/- 1.4 ms vs. HU: 7 +/- 0.7 ms), and spectral analysis of blood pressure indicated loss of total, low-, and high-frequency power, consistent with attenuated baroreflex function. These data indicate that cardiovascular deconditioning results in sympathovagal imbalance and behavioral signs consistent with psychological depression. These findings further elucidate the pathophysiological link between cardiovascular diseases and affective disorders.

Angiotensin II-induced drinking and pressor responses to central or systemic irbesartan and losartan

Angiotensin II (ANG II) is a peptide hormone that is important for maintaining blood pressure and body fluid homeostasis. Two nonpeptide angiotensin type 1 (AT(1)) receptor antagonists, irbesartan and losartan, were compared for their antidipsogenic and antihypertensive efficacy in both normotensive and hypertensive rats. ANG II-induced drinking and pressor responses were examined following central or systemic administration of irbesartan and losartan. Both agents inhibited the drinking response to ANG II in normotensive rats. Irbesartan was more effective than losartan at inhibiting pressor responses to ANG II in normotensive and hypertensive rats. These data indicate that centrally administered irbesartan may be somewhat more effective as an AT(1) receptor antagonist than losartan. However, evaluating the antihypertensive efficacy of these drugs when administered systemically is complex due to several pharmacokinetic factors (e.g., metabolism and lipophilicity).