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Stress and Salt Appetite
C H A P T E R
27 Stress and Salt Appetite Michael J. McKinley, Philip J. Ryan Florey Institute of Neuroscience and Mental Health, University of Melbourne, VIC, Australia
O U T L I N E Stress-Induced Salt Appetite in Animals
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ACTH-Induced Salt Appetite
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Hormones Influencing Salt Appetite in Stressed Animals 385 Adrenocorticotropic Hormone 385 Renin, Angiotensin, Aldosterone
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Salt or sodium appetite, the urge that motivates animals to seek out and ingest NaCl containing foods or fluids, is manifested in response to a number of different physiological conditions. Salt appetite may be generated as a response to excessive loss of sodium in body fluids such as sweat or from the gastrointestinal tract during vomiting or diarrhea or in urine following diuretic treatment1,2; salt appetite is also evident during pregnancy and lactation.3,4 By driving animals to restore sodium balance in these conditions, salt appetite may be viewed as a homeostatic emotion. However, need-free intake of salt is also observed when animals ingest NaCl in excess of bodily need because its ingestion provides a pleasurable taste experience. This hedonic intake is especially evident in homo sapiens; however, taste preference for
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salt may vary across individual conspecifics.5 If stress is a stimulus to salt appetite, as some animal studies indicate, it is not immediately apparent whether such salt intake would be considered homeostatic or hedonic. This chapter reviews the evidence that stress is a stimulus to salt appetite and explores the neuroendocrine mechanisms that could mediate such a response. Initially, we review evidence from animal studies on the effects of stress, either psychological or physical, on salt intake. A survey of effects of stress hormones (adrenocorticotrophic hormone [ACTH], corticosteroids, renineangiotensin) on salt intake follows; as well we review the effect of increased plasma sodium levels on anxiety and stress. The chapter concludes with a review of salt appetite in humans and how stress may influence it.
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Copyright © 2019 Elsevier Inc. All rights reserved.
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KEY POINTS • Many mammals develop an urge to ingest salt (NaCl), i.e. salt appetite, in response to sodium depletion. • Physical or psychological stresses have been shown to cause an increased intake of NaCl in rabbits, mice and rats. • Hormonal signals, and the hypothalamicpituitary-adrenal system in particular ,may mediate stress-induced salt appetite. • Salt appetite in humans is less well-defined compared with many other animal species and is usually manifested as an increased liking of, or preference for, salted food or beverages. • To date, laboratory studies have failed to demonstrate an influence of stress on salt intake in humans. However, a definitive conclusion on this requires further investigation.
STRESS-INDUCED SALT APPETITE IN ANIMALS The first observation of stress-induced salt appetite was an unintended consequence of attempts to make intravenous infusions in rabbits. In order to study the way reproductive hormones influence the intake of different mineral salt solutions by wild rabbits, Denton and Nelson attached jackets around the animals so that they could fix small infusion pumps to their backs to enable the administration of hormones.6,7 However, the rabbits succeeded in removing the jackets within 24 h, and they were unable to obtain a stable baseline of salt intake. Not to be thwarted, the design of the jackets was improved. While these investigators did succeed in producing a jacket that could not be removed by the rabbits, the study had to be abandoned because a huge increase in intake of 0.5 mol/L NaCl solution occurred which continued for 10 days until the jackets were removed6,7; after this time, the high intake of salt solution returned to baseline within
1e2 days. It may have been serendipitous that these rabbits had been captured in the wild and brought into a laboratory situation, as they were probably primed to respond to any stressful condition imposed on them. Having jackets placed around their bodies, which they continually attempted to remove, would likely have been an extremely stressful procedure. Thus Denton and Nelson concluded that continual stress of having jackets around them probably caused the large increase in salt intake.6,7 They suggested that stress may have been responsible for earlier observations by others8 that salt intake was increased in response to subcutaneous injection of formalin in rats. Following these initial observations, further investigations of the effects of different stressors, both physical and psychological, were made in laboratory mice and rats. Most but not all these investigations confirmed that stress was indeed a stimulus to salt appetite. Laboratory mice were shown consistently to respond to stress with an increased intake of salt solution, regardless of the strain studied. Male Swiss-Webster mice were subjected to two different stressors, food deprivation for 24 h prior to testing their salt appetite or immobilization stress brought about by taping the mice back down to a metal cage top for 15 min before an observation period of 2 h. As a consequence of these stressors, intake of 0.3 mol/L NaCl more than doubled after immobilization or quadrupled following food deprivation.9 Peripheral administration of the opioid antagonist naloxone inhibited the stressinduced intake of NaCl,9 indicating a role for opioid receptors in stress-induced salt appetite. Another strain, male BALB/c mice, was subjected to a severe psychological stressdtotal immobilization.10 These mice were prevented from crawling around their home cage by fixing them to a wire rod by means of adhesive tape wrapped around the torso. They were suspended on the wire rod above a running wheel, thereby allowing exercise without any movement around the cage over a period of 8 days; however, they were within reach of food, water, and 0.2 mol/L NaCl solution. On the initial day of total immobilization, both water and NaCl intake were virtually absent. However, in the
STRESS-INDUCED SALT APPETITE IN ANIMALS
following 2 days, while water intake was still depressed, the intake of NaCl more than tripled. For three of the remaining 5 days of total immobilization, the Na intake of immobilized rats was significantly greater than control rats, while water intake was largely similar to the control group.10 When the animals were killed at the completion of the 8 days of total immobilization, the mean thymus weight was only one-third that of control mice. The authors considered the small thymus indicated increased glucocorticoid secretion and stress in the immobilized group. By contrast, in another group of mice, the less stressful procedure of wrapping tape around the torso for 7 days without immobilizing them did not cause increased intake of NaCl solution nor was water intake affected during the 7 days of taping.10 These data suggest that stress needs to reach a certain threshold intensity before sodium appetite is generated in mice. The effect of stress on salt intake has also been investigated in several rat strains. Normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and F1 crosses of SHR and WKY rats were subjected to a social stress in which two adult King-Holtzman male rats were introduced into cages for 2 h. All four strains increased the intake of either 0.5% or 1.0% NaCl solution. SHR rats had a higher baseline NaCl intake as well as a greater salt intake in response to the intruder stress compared with the other three strains.11 Pharmacological blockade of sympathetic nerves by treatment with reserpine, clonidine, or propranolol suppressed stress-induced increase in salt intake,11 indicating a role for sympathetic nerve activity in stress-induced salt appetite. In a further investigation of salt appetite in intruder stressed WKY and SHR rats, male rats exhibited a larger increase in salt intake in response to this psychosocial stress compared with female WKY and SHR rats.12 In comparison to mice and hamsters, restraint stress is not a reliable stimulus to salt appetite in rats.13 Moreover, it may even inhibit salt appetite because 2 h per day of restraint on a wooden board for 13 days caused a reduction in intake of saline solution in male Wistar rats.13 As well, when SpragueeDawley rats were restrained
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within a Perspex tube for 1e3 h per day for up to three consecutive days, they did not consistently increase the intake of or preference for NaCl at concentrations of 0.1e0.15 mol/L.14 Significant loss of body weight by the restrained group of rats (but not the control group) indicated that these rats had been stressed. Bensi et al.14 showed that renal sodium retention results from restraint stress probably due to increased renal sympathetic nerve activity. They suggested that the antinatriuretic effect of restraint would cause positive sodium balance that may have inhibited salt intake, thereby affording a reason why restraint stress was not an effective stimulus to salt appetite in the rat. An aspect of these investigations into the effects of stress, as well as the effects of sodium depletion and other natriorexigenic stimuli on sodium appetite that is rarely considered, is the practice of testing the effects of these stimuli on the intake of pure solutions of NaCl; the concentrations of NaCl used are usually within the range of 0.1e0.5 mol/L that encompasses palatable to aversive concentration of NaCl for the sodium replete animal.1 While much useful information has been acquired using this technique, it should be noted that the only animals that would ever encounter such solutions of NaCl are those within a laboratory. In nature, animals never have access to pure solutions of NaCl, and only those with habitats close to the sea or mineral springs may even ingest mixtures of salt solutions. The normal source of NaCl for the overwhelming majority of mammals is food, yet there are no studies of the effect of stress on the drive for, or ingestion of, salted food. Interestingly, if rats are given a choice of foods with varying Na content, sodium depletion results in the animals changing their diet to ingest more salted food.15,16 However, this response to sodium depletion needs to be qualified. If rats are given a choice of eating salted or unsalted food, the initial ingestive response observed during the first day that they are sodium depleted is reduced intake of unsalted food (normally preferred by rats) rather than increased ingestion of salted food.16 Thus unsalted food became aversive before a true salt appetite developed.
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Dehydration resulting from water deprivation may be profoundly stressful if the dehydration is severe. When rats given a choice of salted and unsalted food were deprived of water, food intake was reduced considerably, as expected, but not uniformly. Only the intake of salted food was inhibited,16 so much so, that the intake of salted food was virtually abolished with little change in the intake of unsalted food by dehydrated rats.16 Thus the stress of dehydration resulted in salted food becoming aversive (or unsalted food becoming much more palatable). Yet, if the intake of solutions of NaCl had been tested at the end of the period of fluid deprivation, such an effect would not have been observed.17,18
ACTH-INDUCED SALT APPETITE Activation of the hypothalamoepituitarye adrenal axis is a major neuroendocrine response to stress.19 If the induction of salt appetite is one of the behavioral consequence of stress, the question arises whether the secretion of ACTH, with subsequent secretion of adrenal glucocorticoid and mineralocorticoid hormones, has a role in stress-induced salt appetite. Studies showing that endogenously administered ACTH could cause increased intake of NaCl solution in four mammalian species (rabbits,20 rats,21 sheep,22,23 and mice10,24) suggest that this is likely. In the only study of the effects of ACTH on salt intake in a primate, intramuscular injection of porcine or synthetic ACTH at 80 IU/day in baboons did not cause any increase in the intake of 0.3 mol/ L NaCl during 5 days of treatment25 although these animals did respond to diuretic-induced sodium depletion with a robust increase in salt intake. Central administration of two other stress-related peptide hormones, corticotropinreleasing hormone (CRH) and urocortin, did not stimulate any increased salt intake in baboons.25 When Wistar rats were treated intramuscularly with a long-acting preparation of ACTH for 5 days, their intake of 0.5 mol/L NaCl solution increased 2 days after the commencement of ACTH treatment. By 5 days of treatment,
the intake of NaCl had increased 20-fold from <1 mmol/day to a mean of 19 mmol/ day.21 These animals were turning over an amount of Na approximately equivalent to their total body Na each day. The overall Na balance of these rats was measured each day during the experiment, and no evidence of negative Na balance was observed, so the salt appetite was unlikely to be secondary to Na loss. Furthermore, the salt appetite was specific for Na because when offered a choice of Na, Ca, K, and Mg salts, ACTH treatment only increased intake of NaCl solution. ACTH was ineffective at stimulating salt intake in bilaterally adrenalectomized rats, whether or not they received maintenance doses of glucocorticoid and mineralocorticoid hormones.21 Thus the salt appetite was likely to be secondary to ACTH-induced adrenal steroid secretion. Wild rabbits that had been brought into the laboratory exhibited a 10-fold increase in salt intake when treated with ACTH for 1 week.20 Bilateral adrenalectomy greatly reduced but did not abolish salt intake in response to ACTH treatment in these animals, indicating that although ACTH may have a minor extra-adrenal effect, adrenal steroids probably play a major role in mediating ACTH-induced salt appetite in rabbits.20 As well, peripherally administered corticosterone or cortisol stimulated the salt appetite of these animals, consistent with such a proposal.20 More detailed investigations of the adrenal steroids that may mediate ACTH-induced salt appetite have been made in sheep and mice. These animals also manifested a large, specific increase in intake of 0.5 mol/L NaCl when injected intramuscularly with long-acting ACTH daily for 5 days.10,22,23 In sheep, the salt appetite preceded any increase in Na excretion by the kidney; therefore it was not secondary to sodium depletion. Similar to rats, salt intake in response to ACTH was abolished by bilateral adrenalectomy22; the adrenalectomized sheep were maintained on replacement steroid (aldosterone and cortisol) treatment by intravenous infusion.22 However, ACTH-induced salt intake could be reproduced in adrenalectomized sheep
RENIN, ANGIOTENSIN, ALDOSTERONE
by intravenous infusion of a combination of steroids comprising cortisol, corticosterone, 11deoxycortisol, deoxycorticosterone, and aldosterone at doses contrived to achieve blood levels of these hormones similar to those observed when ACTH was administered to intact sheep.22 Intravenous infusion of this combined steroid mixture also stimulated a strong salt appetite in intact sheep showing that the salt appetite associated with ACTH treatment is mediated by the action of glucocorticoid and/or mineralocorticoid hormones probably acting directly on the brain.22 By contrast to the action of ACTH on salt appetite, intracerebroventricular administration of other hormones and neuropeptides associated with stress (CRH and urocortin) either inhibited or had no effect on salt intake in sheep.23 To study which specific steroids may be driving ACTH-induced Na appetite, further studies were made in mice. As observed in sheep, peripheral administration of a combination of aldosterone, corticosterone, deoxycorticosterone, and 11-deoxycortisol could reproduce the increased salt intake caused by ACTH treatment in mice.23 When each of these steroids was administered individually, both aldosterone and corticosterone stimulated an increase in salt intake during the first 2 days of treatment, but this effect was modest and not sustained; 11-Deoxycortisol was ineffective. More robust and sustained increase in salt intake resulted from deoxycorticosterone treatment, but the effect was still not as large as that caused by ACTH treatment.23 The investigators concluded that the additive effects of aldosterone, corticosterone, and deoxycorticosterone acting on the brain could probably explain why ACTH stimulated salt appetite in mice.
HORMONES INFLUENCING SALT APPETITE IN STRESSED ANIMALS Adrenocorticotropic Hormone Could endogenously secreted ACTH drive secretion of adrenal corticosteroids to play a role in stress-induced salt appetite? There are no investigations that directly address this question; however, studies of salt intake in
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hypophysectomized rats25 show the feasibility of such an explanation. Salt appetite in rats was investigated using subcutaneous injection of formalin to cause sequestration of plasma from the circulation into the interstitium, thereby inducing hypovolemia. However, this is a painful procedure and has been considered to be a stressor because blood corticosterone levels rise threefold, and abnormal behaviors are observed.1 Rats began to ingest normally aversive concentrations of 0.51 mol/L NaCl within 2 h of the formalin injection,8 which was attributed to the hypovolemia.8,26 However, when hypovolemia was caused by a less stressful procedure, viz subcutaneous injection of polyethylene glycol to sequester extracellular fluid, salt intake did not increase until many hours later,27 suggesting that the initial phase of the salt intake in response to formalin was not the result of hypovolemia but may have been a stress response. Compared with sham-operated rats, increased salt intake in response to formalin injection in hypophysectomized rats was delayed by several hours.26 Since no ACTH would have been secreted in the hypophysectomized rats, it is likely that the initial phase of the salt appetite of formalin-treated rats is mediated by ACTH secretion causing secretion of adrenal steroids that act centrally to drive salt appetite.
RENIN, ANGIOTENSIN, ALDOSTERONE In sodium-depleted rats, salt appetite is stimulated through the synergistic action of circulating angiotensin II on forebrain subfornical organ neurons and aldosterone on hindbrain neurons in the nucleus tractus solitarii (NTS) that express mineralocorticoid receptors and the enzyme 11-hydroxysteroid dehydrogenase 2.2 In stressed animals, sympathetic nerve activation leads to renin secretion by the kidney with subsequent generation of blood-borne angiotensin II and stimulation of aldosterone secretion by the adrenal cortex.28e30 Thus the blood levels of two circulating hormones, angiotensin II and aldosterone, known to be implicated in the physiological genesis of salt appetite, are elevated in stressed
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animals. In mice, either sympathetic blockade with propranolol or reserpine treatment that will inhibit stress-induced renin secretion, or captopril treatment, that blocks generation of angiotensin II, have been shown to inhibit stress-induced NaCl intake.9,11 These data are consistent with a role for blood-borne angiotensin II and aldosterone in stress-induced salt appetite. ACTH also increases circulating levels of aldosterone and deoxycorticosterone (which should both act on the mineralocorticoid receptors in the NTS). Therefore it seems likely that hormones of the HPA axis, via ACTH and adrenal corticosteroids, together with the sympathetic nervous system via the renineangiotensinealdosterone system, act in combination to drive salt appetite in stressful conditions.
THE EFFECTS OF INCREASED SODIUM LEVELS ON STRESS AND ANXIETY If stress increases salt intake, what might be the consequences of such behavior? There is evidence that animals reduce anxiety-like behavior and blunt the secretion of stress hormones in response to increased plasma sodium levels. For example, acute intraperitoneal injection of hypertonic NaCl into rodents blunted the secretion of corticosterone in response to physical restraint, attenuated cardiovascular responses, and reduced Fos expression (a marker of activated neurons) in CRH-producing neurons in the hypothalamic paraventricular nucleus (PVH).31e33 As well, there was decreased anxiety-like behavior in social interaction and elevated plus maze tests and increased Fos expression in oxytocin-containing neurons of the PVH.31e33 Chronic salt-loading also attenuated activation of the HPA axis, with a significant reduction in plasma corticosterone during recovery from restraint stress and decreased CRH messenger RNA in the anterior part but not the posterior part of the PVH.34 These results suggest that animals may increase their salt intake under stressful conditions in order to reduce anxiety and blood levels of stress hormones.
STRESS AND HUMAN SALT APPETITE Unlike thirst and hunger, salt appetite has long been an enigmatic and ill-defined entity in humans. There are a few well-documented cases of strong desires or cravings for salted foods and beverages in human subjects. Wilkins and Richter described the remarkable but tragic case of a child who was afflicted with undiagnosed adrenocortical insufficiency causing a salt-wasting condition.35 From the age of 11 months, this child sought out and consumed strongly salted foods such as salted crackers, bacon, olives, salted potato chips, and fish; he rejected (by vomiting it) any other food that was not salted. As well, he would obtain salt from the shaker and ingest approximately a teaspoon of salt per day. When he was 3½ years of age, he was admitted to hospital, where he was denied access to NaCl. He died suddenly after 7 days of salt deprivation. Wilkins and Richter concluded that the salt hunger exhibited by this child was crucial for his survival.35 Other reports of strong craving for salted foods have been reported, but these cases are uncommon and predominantly, but not exclusively, in children.36e38 A major problem that arises in assessing salt appetite in humans is that unlike thirst and hunger for food, where ratings such as on a visual analog scale can be made, there is no clear appreciation of how the feeling or desire to ingest salted food is perceived or rated. Several investigators have noted that the salt appetite of humans cannot be compared with that exhibited by animals such as rats, mice, or sheep because of the high sodium intake of normal sodium-replete humans resulting from the ubiquitous salting of food.5,39 It has not been possible to measure an increased sodium intake in humans in response to sodium depletion resulting from such conditions as hemorrhage, diuretics, vomiting, or excessive sweating.5 However, there is evidence that when human subjects are sodium depleted by means of diuretic treatment, they report that the pleasantness or desirability of foods rated
REFERENCES
as being more salty increased, whereas the pleasantness of those that were unsalted or sweet fell.39 This increased preference or liking of salt has also been observed in sodium-depleted patients with low aldosterone secretion due to congenital adrenal hyperplasia and 21hydroxylase deficiency.40 Another reliable cause of increased preference for salted food is perinatal sodium and water loss due to maternal nausea and vomiting associated with pregnancy.5,40 Unlike rodents, the threshold of salt taste sensitivity and the intensity of salt taste did not change with sodium depletion.39,40 Thus sodium appetite in human subjects seems to be expressed in hedonic terms, and its study in stressed individuals has been based on preference ratings of salted foods. In regard to the influence of stress on salt appetite, Henry proposed that the overall salt intake of a society may reflect the general level of stress arising from psychosocial factors within that population.41 His supposition was based in part on evidence from closely related Polynesian groups in the Cook Islands who were either living a traditional atoll-dwelling subsistence lifestyle in Pukapuka “without clocks beside their lagoon” or had been exposed to more societal stress in Raratonga with its cash economy, repressive authority, and modern-day hustle and haste. The atoll-dwellers of Pukapuka ingested half the amount of salt than did the town-dwelling Raratongans, even though salt was plentiful there.42 Such data suggest links between stress and salt appetite; however, such a proposal relies on the validity of several assumptions which may not be sustained on careful examination. Five experimental studies of the effect of psychological stress on salt intake in human subjects were reviewed by Torres et al.43 They concluded that it was unlikely that stress contributed to the genesis of salt appetite in human subjects. Consistent with this conclusion were findings that stress associated with exams (assessed by Institute for Personality and Ability Testing IPAT scale) increased significantly in 17 medical students, but there was no increase in the preference for salted soup or the amount of salted snacks eaten by these subjects.5 In one of the
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studies reviewed by Torres et al.,43 subjects rated as having a personality with a high hostility rating manifested a greater preference for salted food than those given a low hostility rating, regardless of whether or not they were subjected to an acute stress44 (harassment during a mathematical task). Interestingly, there is evidence that depression and salt intake are correlated in humans, and the hypothesis has been advanced that the intake of salt, ingested as a selfmedication in depression, may ameliorate the depressed state.45 The studies in human subjects mentioned previously were limited to acute, short duration stressors that were relatively mild or not clearly defined in a questionnaire. Almost certainly, the intensity and duration of the stressors utilized in those studies would have been low relative to many of life’s more intense and enduring stressors such as the death of a child or spouse, chronic pain, constant hostile interpersonal threats, or danger to one’s safety and survival during a war. It would be of interest to know whether such severe and chronic stress could influence salt preference in humans. Both ethical and practical considerations make it unlikely that the effect of severe, prolonged stress on salt appetite could be investigated in the laboratory. Describing the studies on human stress and salt appetite up to 2014 as “scrappy,” Lesham46 concluded that “the case for a substantive role for sodium intake in alleviating stress in humans or for stress promoting our intake of salt, although tantalizing as a potential explanation of great importance, remains unproven.” No further progress on this topic has occurred in the subsequent few years to modify that summary. Clearly, more carefully conducted field investigations of salt preference and salt intake in stressed human populations and individuals are needed.
References 1. Denton DA. The Hunger for Salt. Berlin: Springer Verlag; 1982. 2. Hurley SW, Johnson AK. The biopsychology of salt hunger and sodium deficiency. Pflugers Arch. 2015;467: 445e456.
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3. Richter CP, Barelare B. Nutritional requirements of pregnant and lactating rats studied by the self-selection method. Am J Physiol. 1938;121:185e188. 4. Denton DA, Nelson JF. Effects of pregnancy and lactation on the mineral appetites of wild rabbits [Oryctolagus cuniculus (L)]. Endocrinology. 1970;88:31e40. 5. Leshem M. Biobehavior of the human love of salt. Neurosci Biobehav Rev. 2009;33:1e17. 6. Denton DA, Nelson JF. The influence of reproductive processes on salt appetite. In: Biological and Behavioral Aspects of Salt Intake. London: Academic Press; 1980: 229e246. 7. Coghlan JP, Fei DT, McKinley MJ, et al. Stress, ACTH, salt intake and hypertension. Clin Exp Hypertens. 1984; 6:403e415. 8. Jaloweic JE, Stricker EM. Restoration of body fluid balance following acute sodium deficiency in rats. J Comp Physiol Psychol. 1970:94e102. 9. Kuta CC, Bryant HU, Zabik JE, Yim GKW. Stress, endogenous opioids and salt intake. Appetite. 1984;5:53e60. 10. Denton DA, Blair-West JR, McBurnie MI, Miller JAFP, Weisinger RS, Williams RM. Effect of adrenocorticotrophic hormone on sodium appetite in mice. Am J Physiol Regul Integr Comp Physiol. 1999;46: R1033eR1040. 11. Bourjeli N, Turner M, Stinner J. Sympathetic nervous system influences salt appetite in four strains of rats. Physiol Behav. 1995;58:437e443. 12. Ely D, Herman M, Ely L, Barrett L, Milstead A. Sodium intake is increased by social stress and the Y chromosome and reduced by clonidine. Am J Physiol Regul Integr Comp Physiol. 2000;278:R407eR412. 13. Howell LA, Harris RBS, Clarke C, Youngblood BD, Ryan DH, Gilbertson TA. The effects of restraint stress on intake of preferred and nonpreferred solutions in rodents. Physiol Behav. 1999;65:697e704. 14. Bensi N, Bertuzzi M, Armario A, Gauna HF. Chronic immobilization stress reduces sodium intake and renal excretion in rats. Physiol Behav. 1997;62: 1391e1396. 15. Bertino M, Tordoff MG. Sodium depletion increases rat’s preferences for salted food. Behav Neurosci. 1988; 102:565e573. 16. McKinley MJ. Adaptive appetites for salted and unsalted food in rats: differential effects of sodium depletion, DOCA and dehydration. Am J Physiol. 2013; 304:R1149eR1160. 17. Weisinger RS, Denton DA, McKinley MJ, Nelson JF. Dehydration-induced sodium appetite in rats. Physiol Behav. 1985;34:45e50. 18. DeLuca LA, Pereira-derderian DT, Vendramani RC, David RB, Menani JV. Water deprivation-induced sodium appetite. Physiol Behav. 2010;100:535e544. 19. Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci. 2009;10:397e409.
20. Blaine EH, Covelli MD, Denton DA, Nelson JF, Shulkes AA. The role of ACTH and adrenal glucocorticoids in the salt appetite of wild rabbits [Oryctolagus cuniculus (L)]. Endocrinology. 1975;97:793e801. 21. Weisinger RS, Denton DA, McKinley MJ, Nelson JF. ACTH induced sodium appetite in the rat. Pharmac Biochem Behav. 1978;8:339e342. 22. Weisinger RS, Coghlan JP, Denton DA, et al. ACTHelicited sodium appetite in sheep. Am J Physiol. 1980; 239:E45eE50. 23. Weisinger RS, Blair-West JR, Burns P, et al. The inhibitory effect of hormones associated with stress on Na appetite of sheep. Proc Natl Acad Sci U S A. 2000;97: 2922e2927. 24. Shade RE, Blair-West JR, Carey KD, et al. Ingestive responses to administration of stress hormones in baboons. Am J Physiol. 2002;282:R10eR18. 25. Blair-West JR, Denton DA, McBurnie M, Tarjan E, Weisinger RS. Influence of adrenal steroid hormones on sodium appetite of Balb/c mice. Appetite. 1995;24: 11e24. 26. Jaloweic JE, Stricker EM, Wolf G. Restoration of sodium balance in hypophysectomised rats after acute sodium deficiency. Physiol Behav. 1970;5:1145e1149. 27. Stricker EM, Jalowiec JE. Restoration of intravascular fluid volume following acute hypovolemia in rats. Am J Physiol. 1970;218:191e196. 28. Clamage DM, Sanford CS, Vander AJ, Mouw DR. Effects of psychosocial stress on plasma renin activity in rats. Am J Physiol. 1976;231:1290e1294. 29. Van de Kar LD. Forebrain pathways mediating stressinduced renin secretion. Clin Exp Pharmacol Physiol. 1996;23:166e178. 30. Ceremuzynski L, Klos J, Barcikowski B, HerbaczynskaCedro K. Calcium channel blocker prevents stressinduced activation of renin and aldosterone in conscious pig. Cardiovasc Drug Ther. 1991;5:643e646. 31. Krause EG, de Kloet AD, Flak JN, et al. Hydration state controls stress responsiveness and social behaviour. J Neurosci. 2011;31:5470e5476. 32. Frazier CJ, Pati J, Hiller H, et al. Acute hypernatremia exerts an inhibitory oxytocinergic tone that is associated with anxiolytic mood in rats. Endocrinology. 2013;154: 2457e2467. 33. Smith JA, Wang L, Hiller H, Taylor CD, de Kloet AD, Krause EG. Acute hypernatremia promotes anxiolysis and attenuates stress-induced activation of the hypothalamicepituitary-adrenal axis in male mice. Physiol Behav. 2014;136:91e96. 34. Krause EG, Pati D, Frazier CJ. Chronic salt-loading reduces basal excitatory input to CRH neurons in the paraventricular nucleus and accelerates recovery from restraint stress in male mice. Physiol Behav. 2017;176: 189e194. 35. Wilkins L, Richter CP. A great craving for salt by a child with cortico adrenal insufficiency. JAMA. 1940;114:866.
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36. Spiro AJ, Pineas JW, Moore CL. A new mitochondrial myopathy in a patient with salt craving. Arch Neurol. 1970;22:259e269. 37. Grossman H, Kennedy E, McCamman S, Rice K, Hellerstein S. Salt appetite in children with sickle cell disease. J Pediatr. 1977;90:671e672. 38. Hinz LE, Kline GA, Dias VC. Addison’s disease in evolution: an illustrative case and literature review. Endocrine Pract. 2014;20:e176ee179. 39. Beauchamp GK, Bertino M, Burke D, Engelman K. Experimental sodium depletion and salt taste in normal human volunteers. Am J Clin Nutr. 1990;51:881e889. 40. Kochli A, Tenenbaum-Rakover Y, Leshem M. Increased salt appetite in patients with congenital adrenal hyperplasia 21-hydroxylase deficiency. Am J Physiol. 2004;288: R1673eR1681. 41. Henry JP. Stress, salt and hypertension. Soc Sci Med. 1988;26:293e302.
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42. Prior AM, Grimley Evans J, Harvey HPB, Davidson F. Lindsey M. Sodium intake and blood pressure in two Polynesian populations. New Eng J Med. 1968;279: 515e520. 43. Torres SJ, Turner AI, Nowson CA. Does stress induce salt intake? Brit J Nutrit. 2010;103:1562e1568. 44. Miller SB, Friese M, Dolgoy L, Sita A, Lavoie K, Campbell T. Hostility, sodium consumption, and cardiovascular response to interpersonal stress. Psychosom Med. 1998;60:71e77. 45. Goldstein P, Lesham M. Dietary sodium, added salt, and serum sodium associations with growth and depression in the U.S. general population. Appetite. 2014;79:83e90. 46. Leshem M. The human penchant for deranged salt balance. In: De Luca LA, Menani JV, Johnson AK, eds. Neurobiology of Body Fluid Homeostasis: Transduction and Integration. Boca Raton: CRC Press/Taylor Francis; 2014:1e22.
27 Stress and Salt Appetite Michael J. McKinley, Philip J. Ryan Florey Institute of Neuroscience and Mental Health, University of Melbourne, VIC, Australia
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Hormones Influencing Salt Appetite in Stressed Animals 385 Adrenocorticotropic Hormone 385 Renin, Angiotensin, Aldosterone
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Salt or sodium appetite, the urge that motivates animals to seek out and ingest NaCl containing foods or fluids, is manifested in response to a number of different physiological conditions. Salt appetite may be generated as a response to excessive loss of sodium in body fluids such as sweat or from the gastrointestinal tract during vomiting or diarrhea or in urine following diuretic treatment1,2; salt appetite is also evident during pregnancy and lactation.3,4 By driving animals to restore sodium balance in these conditions, salt appetite may be viewed as a homeostatic emotion. However, need-free intake of salt is also observed when animals ingest NaCl in excess of bodily need because its ingestion provides a pleasurable taste experience. This hedonic intake is especially evident in homo sapiens; however, taste preference for
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salt may vary across individual conspecifics.5 If stress is a stimulus to salt appetite, as some animal studies indicate, it is not immediately apparent whether such salt intake would be considered homeostatic or hedonic. This chapter reviews the evidence that stress is a stimulus to salt appetite and explores the neuroendocrine mechanisms that could mediate such a response. Initially, we review evidence from animal studies on the effects of stress, either psychological or physical, on salt intake. A survey of effects of stress hormones (adrenocorticotrophic hormone [ACTH], corticosteroids, renineangiotensin) on salt intake follows; as well we review the effect of increased plasma sodium levels on anxiety and stress. The chapter concludes with a review of salt appetite in humans and how stress may influence it.
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Copyright © 2019 Elsevier Inc. All rights reserved.
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KEY POINTS • Many mammals develop an urge to ingest salt (NaCl), i.e. salt appetite, in response to sodium depletion. • Physical or psychological stresses have been shown to cause an increased intake of NaCl in rabbits, mice and rats. • Hormonal signals, and the hypothalamicpituitary-adrenal system in particular ,may mediate stress-induced salt appetite. • Salt appetite in humans is less well-defined compared with many other animal species and is usually manifested as an increased liking of, or preference for, salted food or beverages. • To date, laboratory studies have failed to demonstrate an influence of stress on salt intake in humans. However, a definitive conclusion on this requires further investigation.
STRESS-INDUCED SALT APPETITE IN ANIMALS The first observation of stress-induced salt appetite was an unintended consequence of attempts to make intravenous infusions in rabbits. In order to study the way reproductive hormones influence the intake of different mineral salt solutions by wild rabbits, Denton and Nelson attached jackets around the animals so that they could fix small infusion pumps to their backs to enable the administration of hormones.6,7 However, the rabbits succeeded in removing the jackets within 24 h, and they were unable to obtain a stable baseline of salt intake. Not to be thwarted, the design of the jackets was improved. While these investigators did succeed in producing a jacket that could not be removed by the rabbits, the study had to be abandoned because a huge increase in intake of 0.5 mol/L NaCl solution occurred which continued for 10 days until the jackets were removed6,7; after this time, the high intake of salt solution returned to baseline within
1e2 days. It may have been serendipitous that these rabbits had been captured in the wild and brought into a laboratory situation, as they were probably primed to respond to any stressful condition imposed on them. Having jackets placed around their bodies, which they continually attempted to remove, would likely have been an extremely stressful procedure. Thus Denton and Nelson concluded that continual stress of having jackets around them probably caused the large increase in salt intake.6,7 They suggested that stress may have been responsible for earlier observations by others8 that salt intake was increased in response to subcutaneous injection of formalin in rats. Following these initial observations, further investigations of the effects of different stressors, both physical and psychological, were made in laboratory mice and rats. Most but not all these investigations confirmed that stress was indeed a stimulus to salt appetite. Laboratory mice were shown consistently to respond to stress with an increased intake of salt solution, regardless of the strain studied. Male Swiss-Webster mice were subjected to two different stressors, food deprivation for 24 h prior to testing their salt appetite or immobilization stress brought about by taping the mice back down to a metal cage top for 15 min before an observation period of 2 h. As a consequence of these stressors, intake of 0.3 mol/L NaCl more than doubled after immobilization or quadrupled following food deprivation.9 Peripheral administration of the opioid antagonist naloxone inhibited the stressinduced intake of NaCl,9 indicating a role for opioid receptors in stress-induced salt appetite. Another strain, male BALB/c mice, was subjected to a severe psychological stressdtotal immobilization.10 These mice were prevented from crawling around their home cage by fixing them to a wire rod by means of adhesive tape wrapped around the torso. They were suspended on the wire rod above a running wheel, thereby allowing exercise without any movement around the cage over a period of 8 days; however, they were within reach of food, water, and 0.2 mol/L NaCl solution. On the initial day of total immobilization, both water and NaCl intake were virtually absent. However, in the
STRESS-INDUCED SALT APPETITE IN ANIMALS
following 2 days, while water intake was still depressed, the intake of NaCl more than tripled. For three of the remaining 5 days of total immobilization, the Na intake of immobilized rats was significantly greater than control rats, while water intake was largely similar to the control group.10 When the animals were killed at the completion of the 8 days of total immobilization, the mean thymus weight was only one-third that of control mice. The authors considered the small thymus indicated increased glucocorticoid secretion and stress in the immobilized group. By contrast, in another group of mice, the less stressful procedure of wrapping tape around the torso for 7 days without immobilizing them did not cause increased intake of NaCl solution nor was water intake affected during the 7 days of taping.10 These data suggest that stress needs to reach a certain threshold intensity before sodium appetite is generated in mice. The effect of stress on salt intake has also been investigated in several rat strains. Normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and F1 crosses of SHR and WKY rats were subjected to a social stress in which two adult King-Holtzman male rats were introduced into cages for 2 h. All four strains increased the intake of either 0.5% or 1.0% NaCl solution. SHR rats had a higher baseline NaCl intake as well as a greater salt intake in response to the intruder stress compared with the other three strains.11 Pharmacological blockade of sympathetic nerves by treatment with reserpine, clonidine, or propranolol suppressed stress-induced increase in salt intake,11 indicating a role for sympathetic nerve activity in stress-induced salt appetite. In a further investigation of salt appetite in intruder stressed WKY and SHR rats, male rats exhibited a larger increase in salt intake in response to this psychosocial stress compared with female WKY and SHR rats.12 In comparison to mice and hamsters, restraint stress is not a reliable stimulus to salt appetite in rats.13 Moreover, it may even inhibit salt appetite because 2 h per day of restraint on a wooden board for 13 days caused a reduction in intake of saline solution in male Wistar rats.13 As well, when SpragueeDawley rats were restrained
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within a Perspex tube for 1e3 h per day for up to three consecutive days, they did not consistently increase the intake of or preference for NaCl at concentrations of 0.1e0.15 mol/L.14 Significant loss of body weight by the restrained group of rats (but not the control group) indicated that these rats had been stressed. Bensi et al.14 showed that renal sodium retention results from restraint stress probably due to increased renal sympathetic nerve activity. They suggested that the antinatriuretic effect of restraint would cause positive sodium balance that may have inhibited salt intake, thereby affording a reason why restraint stress was not an effective stimulus to salt appetite in the rat. An aspect of these investigations into the effects of stress, as well as the effects of sodium depletion and other natriorexigenic stimuli on sodium appetite that is rarely considered, is the practice of testing the effects of these stimuli on the intake of pure solutions of NaCl; the concentrations of NaCl used are usually within the range of 0.1e0.5 mol/L that encompasses palatable to aversive concentration of NaCl for the sodium replete animal.1 While much useful information has been acquired using this technique, it should be noted that the only animals that would ever encounter such solutions of NaCl are those within a laboratory. In nature, animals never have access to pure solutions of NaCl, and only those with habitats close to the sea or mineral springs may even ingest mixtures of salt solutions. The normal source of NaCl for the overwhelming majority of mammals is food, yet there are no studies of the effect of stress on the drive for, or ingestion of, salted food. Interestingly, if rats are given a choice of foods with varying Na content, sodium depletion results in the animals changing their diet to ingest more salted food.15,16 However, this response to sodium depletion needs to be qualified. If rats are given a choice of eating salted or unsalted food, the initial ingestive response observed during the first day that they are sodium depleted is reduced intake of unsalted food (normally preferred by rats) rather than increased ingestion of salted food.16 Thus unsalted food became aversive before a true salt appetite developed.
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Dehydration resulting from water deprivation may be profoundly stressful if the dehydration is severe. When rats given a choice of salted and unsalted food were deprived of water, food intake was reduced considerably, as expected, but not uniformly. Only the intake of salted food was inhibited,16 so much so, that the intake of salted food was virtually abolished with little change in the intake of unsalted food by dehydrated rats.16 Thus the stress of dehydration resulted in salted food becoming aversive (or unsalted food becoming much more palatable). Yet, if the intake of solutions of NaCl had been tested at the end of the period of fluid deprivation, such an effect would not have been observed.17,18
ACTH-INDUCED SALT APPETITE Activation of the hypothalamoepituitarye adrenal axis is a major neuroendocrine response to stress.19 If the induction of salt appetite is one of the behavioral consequence of stress, the question arises whether the secretion of ACTH, with subsequent secretion of adrenal glucocorticoid and mineralocorticoid hormones, has a role in stress-induced salt appetite. Studies showing that endogenously administered ACTH could cause increased intake of NaCl solution in four mammalian species (rabbits,20 rats,21 sheep,22,23 and mice10,24) suggest that this is likely. In the only study of the effects of ACTH on salt intake in a primate, intramuscular injection of porcine or synthetic ACTH at 80 IU/day in baboons did not cause any increase in the intake of 0.3 mol/ L NaCl during 5 days of treatment25 although these animals did respond to diuretic-induced sodium depletion with a robust increase in salt intake. Central administration of two other stress-related peptide hormones, corticotropinreleasing hormone (CRH) and urocortin, did not stimulate any increased salt intake in baboons.25 When Wistar rats were treated intramuscularly with a long-acting preparation of ACTH for 5 days, their intake of 0.5 mol/L NaCl solution increased 2 days after the commencement of ACTH treatment. By 5 days of treatment,
the intake of NaCl had increased 20-fold from <1 mmol/day to a mean of 19 mmol/ day.21 These animals were turning over an amount of Na approximately equivalent to their total body Na each day. The overall Na balance of these rats was measured each day during the experiment, and no evidence of negative Na balance was observed, so the salt appetite was unlikely to be secondary to Na loss. Furthermore, the salt appetite was specific for Na because when offered a choice of Na, Ca, K, and Mg salts, ACTH treatment only increased intake of NaCl solution. ACTH was ineffective at stimulating salt intake in bilaterally adrenalectomized rats, whether or not they received maintenance doses of glucocorticoid and mineralocorticoid hormones.21 Thus the salt appetite was likely to be secondary to ACTH-induced adrenal steroid secretion. Wild rabbits that had been brought into the laboratory exhibited a 10-fold increase in salt intake when treated with ACTH for 1 week.20 Bilateral adrenalectomy greatly reduced but did not abolish salt intake in response to ACTH treatment in these animals, indicating that although ACTH may have a minor extra-adrenal effect, adrenal steroids probably play a major role in mediating ACTH-induced salt appetite in rabbits.20 As well, peripherally administered corticosterone or cortisol stimulated the salt appetite of these animals, consistent with such a proposal.20 More detailed investigations of the adrenal steroids that may mediate ACTH-induced salt appetite have been made in sheep and mice. These animals also manifested a large, specific increase in intake of 0.5 mol/L NaCl when injected intramuscularly with long-acting ACTH daily for 5 days.10,22,23 In sheep, the salt appetite preceded any increase in Na excretion by the kidney; therefore it was not secondary to sodium depletion. Similar to rats, salt intake in response to ACTH was abolished by bilateral adrenalectomy22; the adrenalectomized sheep were maintained on replacement steroid (aldosterone and cortisol) treatment by intravenous infusion.22 However, ACTH-induced salt intake could be reproduced in adrenalectomized sheep
RENIN, ANGIOTENSIN, ALDOSTERONE
by intravenous infusion of a combination of steroids comprising cortisol, corticosterone, 11deoxycortisol, deoxycorticosterone, and aldosterone at doses contrived to achieve blood levels of these hormones similar to those observed when ACTH was administered to intact sheep.22 Intravenous infusion of this combined steroid mixture also stimulated a strong salt appetite in intact sheep showing that the salt appetite associated with ACTH treatment is mediated by the action of glucocorticoid and/or mineralocorticoid hormones probably acting directly on the brain.22 By contrast to the action of ACTH on salt appetite, intracerebroventricular administration of other hormones and neuropeptides associated with stress (CRH and urocortin) either inhibited or had no effect on salt intake in sheep.23 To study which specific steroids may be driving ACTH-induced Na appetite, further studies were made in mice. As observed in sheep, peripheral administration of a combination of aldosterone, corticosterone, deoxycorticosterone, and 11-deoxycortisol could reproduce the increased salt intake caused by ACTH treatment in mice.23 When each of these steroids was administered individually, both aldosterone and corticosterone stimulated an increase in salt intake during the first 2 days of treatment, but this effect was modest and not sustained; 11-Deoxycortisol was ineffective. More robust and sustained increase in salt intake resulted from deoxycorticosterone treatment, but the effect was still not as large as that caused by ACTH treatment.23 The investigators concluded that the additive effects of aldosterone, corticosterone, and deoxycorticosterone acting on the brain could probably explain why ACTH stimulated salt appetite in mice.
HORMONES INFLUENCING SALT APPETITE IN STRESSED ANIMALS Adrenocorticotropic Hormone Could endogenously secreted ACTH drive secretion of adrenal corticosteroids to play a role in stress-induced salt appetite? There are no investigations that directly address this question; however, studies of salt intake in
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hypophysectomized rats25 show the feasibility of such an explanation. Salt appetite in rats was investigated using subcutaneous injection of formalin to cause sequestration of plasma from the circulation into the interstitium, thereby inducing hypovolemia. However, this is a painful procedure and has been considered to be a stressor because blood corticosterone levels rise threefold, and abnormal behaviors are observed.1 Rats began to ingest normally aversive concentrations of 0.51 mol/L NaCl within 2 h of the formalin injection,8 which was attributed to the hypovolemia.8,26 However, when hypovolemia was caused by a less stressful procedure, viz subcutaneous injection of polyethylene glycol to sequester extracellular fluid, salt intake did not increase until many hours later,27 suggesting that the initial phase of the salt intake in response to formalin was not the result of hypovolemia but may have been a stress response. Compared with sham-operated rats, increased salt intake in response to formalin injection in hypophysectomized rats was delayed by several hours.26 Since no ACTH would have been secreted in the hypophysectomized rats, it is likely that the initial phase of the salt appetite of formalin-treated rats is mediated by ACTH secretion causing secretion of adrenal steroids that act centrally to drive salt appetite.
RENIN, ANGIOTENSIN, ALDOSTERONE In sodium-depleted rats, salt appetite is stimulated through the synergistic action of circulating angiotensin II on forebrain subfornical organ neurons and aldosterone on hindbrain neurons in the nucleus tractus solitarii (NTS) that express mineralocorticoid receptors and the enzyme 11-hydroxysteroid dehydrogenase 2.2 In stressed animals, sympathetic nerve activation leads to renin secretion by the kidney with subsequent generation of blood-borne angiotensin II and stimulation of aldosterone secretion by the adrenal cortex.28e30 Thus the blood levels of two circulating hormones, angiotensin II and aldosterone, known to be implicated in the physiological genesis of salt appetite, are elevated in stressed
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animals. In mice, either sympathetic blockade with propranolol or reserpine treatment that will inhibit stress-induced renin secretion, or captopril treatment, that blocks generation of angiotensin II, have been shown to inhibit stress-induced NaCl intake.9,11 These data are consistent with a role for blood-borne angiotensin II and aldosterone in stress-induced salt appetite. ACTH also increases circulating levels of aldosterone and deoxycorticosterone (which should both act on the mineralocorticoid receptors in the NTS). Therefore it seems likely that hormones of the HPA axis, via ACTH and adrenal corticosteroids, together with the sympathetic nervous system via the renineangiotensinealdosterone system, act in combination to drive salt appetite in stressful conditions.
THE EFFECTS OF INCREASED SODIUM LEVELS ON STRESS AND ANXIETY If stress increases salt intake, what might be the consequences of such behavior? There is evidence that animals reduce anxiety-like behavior and blunt the secretion of stress hormones in response to increased plasma sodium levels. For example, acute intraperitoneal injection of hypertonic NaCl into rodents blunted the secretion of corticosterone in response to physical restraint, attenuated cardiovascular responses, and reduced Fos expression (a marker of activated neurons) in CRH-producing neurons in the hypothalamic paraventricular nucleus (PVH).31e33 As well, there was decreased anxiety-like behavior in social interaction and elevated plus maze tests and increased Fos expression in oxytocin-containing neurons of the PVH.31e33 Chronic salt-loading also attenuated activation of the HPA axis, with a significant reduction in plasma corticosterone during recovery from restraint stress and decreased CRH messenger RNA in the anterior part but not the posterior part of the PVH.34 These results suggest that animals may increase their salt intake under stressful conditions in order to reduce anxiety and blood levels of stress hormones.
STRESS AND HUMAN SALT APPETITE Unlike thirst and hunger, salt appetite has long been an enigmatic and ill-defined entity in humans. There are a few well-documented cases of strong desires or cravings for salted foods and beverages in human subjects. Wilkins and Richter described the remarkable but tragic case of a child who was afflicted with undiagnosed adrenocortical insufficiency causing a salt-wasting condition.35 From the age of 11 months, this child sought out and consumed strongly salted foods such as salted crackers, bacon, olives, salted potato chips, and fish; he rejected (by vomiting it) any other food that was not salted. As well, he would obtain salt from the shaker and ingest approximately a teaspoon of salt per day. When he was 3½ years of age, he was admitted to hospital, where he was denied access to NaCl. He died suddenly after 7 days of salt deprivation. Wilkins and Richter concluded that the salt hunger exhibited by this child was crucial for his survival.35 Other reports of strong craving for salted foods have been reported, but these cases are uncommon and predominantly, but not exclusively, in children.36e38 A major problem that arises in assessing salt appetite in humans is that unlike thirst and hunger for food, where ratings such as on a visual analog scale can be made, there is no clear appreciation of how the feeling or desire to ingest salted food is perceived or rated. Several investigators have noted that the salt appetite of humans cannot be compared with that exhibited by animals such as rats, mice, or sheep because of the high sodium intake of normal sodium-replete humans resulting from the ubiquitous salting of food.5,39 It has not been possible to measure an increased sodium intake in humans in response to sodium depletion resulting from such conditions as hemorrhage, diuretics, vomiting, or excessive sweating.5 However, there is evidence that when human subjects are sodium depleted by means of diuretic treatment, they report that the pleasantness or desirability of foods rated
REFERENCES
as being more salty increased, whereas the pleasantness of those that were unsalted or sweet fell.39 This increased preference or liking of salt has also been observed in sodium-depleted patients with low aldosterone secretion due to congenital adrenal hyperplasia and 21hydroxylase deficiency.40 Another reliable cause of increased preference for salted food is perinatal sodium and water loss due to maternal nausea and vomiting associated with pregnancy.5,40 Unlike rodents, the threshold of salt taste sensitivity and the intensity of salt taste did not change with sodium depletion.39,40 Thus sodium appetite in human subjects seems to be expressed in hedonic terms, and its study in stressed individuals has been based on preference ratings of salted foods. In regard to the influence of stress on salt appetite, Henry proposed that the overall salt intake of a society may reflect the general level of stress arising from psychosocial factors within that population.41 His supposition was based in part on evidence from closely related Polynesian groups in the Cook Islands who were either living a traditional atoll-dwelling subsistence lifestyle in Pukapuka “without clocks beside their lagoon” or had been exposed to more societal stress in Raratonga with its cash economy, repressive authority, and modern-day hustle and haste. The atoll-dwellers of Pukapuka ingested half the amount of salt than did the town-dwelling Raratongans, even though salt was plentiful there.42 Such data suggest links between stress and salt appetite; however, such a proposal relies on the validity of several assumptions which may not be sustained on careful examination. Five experimental studies of the effect of psychological stress on salt intake in human subjects were reviewed by Torres et al.43 They concluded that it was unlikely that stress contributed to the genesis of salt appetite in human subjects. Consistent with this conclusion were findings that stress associated with exams (assessed by Institute for Personality and Ability Testing IPAT scale) increased significantly in 17 medical students, but there was no increase in the preference for salted soup or the amount of salted snacks eaten by these subjects.5 In one of the
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studies reviewed by Torres et al.,43 subjects rated as having a personality with a high hostility rating manifested a greater preference for salted food than those given a low hostility rating, regardless of whether or not they were subjected to an acute stress44 (harassment during a mathematical task). Interestingly, there is evidence that depression and salt intake are correlated in humans, and the hypothesis has been advanced that the intake of salt, ingested as a selfmedication in depression, may ameliorate the depressed state.45 The studies in human subjects mentioned previously were limited to acute, short duration stressors that were relatively mild or not clearly defined in a questionnaire. Almost certainly, the intensity and duration of the stressors utilized in those studies would have been low relative to many of life’s more intense and enduring stressors such as the death of a child or spouse, chronic pain, constant hostile interpersonal threats, or danger to one’s safety and survival during a war. It would be of interest to know whether such severe and chronic stress could influence salt preference in humans. Both ethical and practical considerations make it unlikely that the effect of severe, prolonged stress on salt appetite could be investigated in the laboratory. Describing the studies on human stress and salt appetite up to 2014 as “scrappy,” Lesham46 concluded that “the case for a substantive role for sodium intake in alleviating stress in humans or for stress promoting our intake of salt, although tantalizing as a potential explanation of great importance, remains unproven.” No further progress on this topic has occurred in the subsequent few years to modify that summary. Clearly, more carefully conducted field investigations of salt preference and salt intake in stressed human populations and individuals are needed.
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3. Richter CP, Barelare B. Nutritional requirements of pregnant and lactating rats studied by the self-selection method. Am J Physiol. 1938;121:185e188. 4. Denton DA, Nelson JF. Effects of pregnancy and lactation on the mineral appetites of wild rabbits [Oryctolagus cuniculus (L)]. Endocrinology. 1970;88:31e40. 5. Leshem M. Biobehavior of the human love of salt. Neurosci Biobehav Rev. 2009;33:1e17. 6. Denton DA, Nelson JF. The influence of reproductive processes on salt appetite. In: Biological and Behavioral Aspects of Salt Intake. London: Academic Press; 1980: 229e246. 7. Coghlan JP, Fei DT, McKinley MJ, et al. Stress, ACTH, salt intake and hypertension. Clin Exp Hypertens. 1984; 6:403e415. 8. Jaloweic JE, Stricker EM. Restoration of body fluid balance following acute sodium deficiency in rats. J Comp Physiol Psychol. 1970:94e102. 9. Kuta CC, Bryant HU, Zabik JE, Yim GKW. Stress, endogenous opioids and salt intake. Appetite. 1984;5:53e60. 10. Denton DA, Blair-West JR, McBurnie MI, Miller JAFP, Weisinger RS, Williams RM. Effect of adrenocorticotrophic hormone on sodium appetite in mice. Am J Physiol Regul Integr Comp Physiol. 1999;46: R1033eR1040. 11. Bourjeli N, Turner M, Stinner J. Sympathetic nervous system influences salt appetite in four strains of rats. Physiol Behav. 1995;58:437e443. 12. Ely D, Herman M, Ely L, Barrett L, Milstead A. Sodium intake is increased by social stress and the Y chromosome and reduced by clonidine. Am J Physiol Regul Integr Comp Physiol. 2000;278:R407eR412. 13. Howell LA, Harris RBS, Clarke C, Youngblood BD, Ryan DH, Gilbertson TA. The effects of restraint stress on intake of preferred and nonpreferred solutions in rodents. Physiol Behav. 1999;65:697e704. 14. Bensi N, Bertuzzi M, Armario A, Gauna HF. Chronic immobilization stress reduces sodium intake and renal excretion in rats. Physiol Behav. 1997;62: 1391e1396. 15. Bertino M, Tordoff MG. Sodium depletion increases rat’s preferences for salted food. Behav Neurosci. 1988; 102:565e573. 16. McKinley MJ. Adaptive appetites for salted and unsalted food in rats: differential effects of sodium depletion, DOCA and dehydration. Am J Physiol. 2013; 304:R1149eR1160. 17. Weisinger RS, Denton DA, McKinley MJ, Nelson JF. Dehydration-induced sodium appetite in rats. Physiol Behav. 1985;34:45e50. 18. DeLuca LA, Pereira-derderian DT, Vendramani RC, David RB, Menani JV. Water deprivation-induced sodium appetite. Physiol Behav. 2010;100:535e544. 19. Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci. 2009;10:397e409.
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42. Prior AM, Grimley Evans J, Harvey HPB, Davidson F. Lindsey M. Sodium intake and blood pressure in two Polynesian populations. New Eng J Med. 1968;279: 515e520. 43. Torres SJ, Turner AI, Nowson CA. Does stress induce salt intake? Brit J Nutrit. 2010;103:1562e1568. 44. Miller SB, Friese M, Dolgoy L, Sita A, Lavoie K, Campbell T. Hostility, sodium consumption, and cardiovascular response to interpersonal stress. Psychosom Med. 1998;60:71e77. 45. Goldstein P, Lesham M. Dietary sodium, added salt, and serum sodium associations with growth and depression in the U.S. general population. Appetite. 2014;79:83e90. 46. Leshem M. The human penchant for deranged salt balance. In: De Luca LA, Menani JV, Johnson AK, eds. Neurobiology of Body Fluid Homeostasis: Transduction and Integration. Boca Raton: CRC Press/Taylor Francis; 2014:1e22.