Sodium depletion and maternal separation in the suckling rat increase its salt intake when adult

Physiology & Behavior, Vol. 59, No. 1, 199-204, 1996 Copyright © 1995 Elsevier Science Inc. Printed in the USA. All rights reserved 0031-9384/96 $15.00 + .00

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Sodium Depletion and Maternal Separation in the Suckling Rat Increase Its Salt Intake When Adult M I C A H LESHEM, 1 M O U N A M A R O U N A N D S O N I A D E L C A N H O

Psychology Department, Haifa University, Haifa, Israel 31905 Received 23 January 1995 LESHEM, M., M. MAROUN AND S. DEL CANHO. Sodium depletion and maternal separation in the suckling rat increase its salt intake when adult. PHYSIOL BEHAV 59(1) 199-204, 1996.--To establish whether neonatal sodium depletion increases the adult's avidity for NaCI, 12-day-old suckling pups were injected with the natriuretic-diuretic furosemide (1 mg) while with their dams. The injections surged plasma aldosterone, and when the rats were adult (70 days), their spontaneous intake of 3% NaCI was increased. Additional experiments investigated whether maternal separation has a similar effect and could thus be a source of individual variation in salt intake of the adult. Fifteen-day-old pups were separated from their dams for 24 h in an incubator. When adult, their intake of 3% NaCI was increased. Availability of saline during maternal separation obviated the effect. The increase in adult intake of 3% NaC1 was specific insofar as drinking of water was not increased similarly. The results show that the adult rat's avidity for sodium can be increased by postnatal natriuresis and possibly stress. The implications of the findings are discussed. Aldosterone

Development

Maternal separation

Rats

Salt appetite

Sodium intake

does not reduce intake in adult male rats (17,29) but does in females (17). More extended sodium restriction, including gestation and lactation until weaning, reduces sodium intake at weaning (2), but has no specific long-term influence even when continued until 30 days of age (6). Similarly, continuous familiarity with different NaC1 concentrations from weaning into adulthood does not alter sodium preference (28). Finally, in the wake of the suggestion that gestational dehydration might enhance sodium intake (31), recent findings in humans show that adult offspring of mothers who vomited excessively during pregnancy have an enhanced avidity for salt (8). Thus, early sodium restriction can increase adult intake (8,31), reduce it depending on gender and strain (17,30), or have no effect (2,6,29), so that variation in perinatal sodium availability does not explain variation in adult salt preference. It remains possible that acute, severe, sodium deficit will have an enduring effect, as it does in the adult (36). Indeed, Epstein has proposed that an episode of sodium deficit engenders permanent changes in predisposed neural substrates that increase the avidity for salt as a behavioral adaptation to an ecology of proven sodium scarcity. He has asked: "can the enhancement of need-free (salt) intake be produced in adult animals that have had sodium depletions in infancy?" (12). The first experiments reported here address this question.

THE study of sodium appetite should include the search for determinants of individual differences in sodium preference. One source of the variation may be genetic, insofar as differences in sodium appetite across rat strains are known (1,7,10,35), and are also likely to occur between individuals. Another source of variation might be experiential, because an episode of sodium deficit, or activation of the neurohormonal substrates of sodium hunger even in the absence of sodium deficit, cause long-term increases in sodium intake (36). Both genetic and experiential factors may interact during early development (10), or when routine biological challenges to sodium homeostasis such as gestation and lactation permanently increase the avidity for salt (14). Early development is a crucial period for the determinants of individuality in behavior and may be similarly important for establishment of individual differences in sodium preference. However, despite attempts to relate perinatal sodium availability to long-term changes in sodium intake in the rat, no coherent relationship has emerged. Three episodes of dehydration during gestation increase spontaneous 3% NaC1 intake in adult offspring (31), and high levels of dietary NaC1 during gestation decrease sodium preference in adult Munich Wistar, but not SpragueDawley, rats (30). In apparent contradiction, continuous sodium dietary restriction from preconception until day 12 of lactation

1 To w h o m requests for reprints should be addressed.

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Nevertheless, acute, severe natriuresis is unlikely to be a common enough occurrence in infancy to account for all the variation in sodium intake in a population. On the other hand, stress is both a likely and graded occurrence during development and could increase sodium intake via a number of hormonal mechanisms such as by increasing levels of CRF, ACTH, corticosterone, and glucocorticoids, and reducing levels of androgens (50), all of which have been associated with increased sodium appetite (5,9,26,37,39,44-47). Moreover, experimental stressors, and even transient increases in blood pressure, increase the release of aldosterone, renin, and angiotensin (16,19,32,33,38,49), which are known to regulate sodium appetite (9,12,13,21,36,37,48). Activation of these neurohormonal substrates of sodium hunger, even in the absence of sodium deficit, causes long-term enhancement of the adult rat's spontaneous sodium intake (12,36). During development, some degree of maternal separation is a likely occurrence, and the stress response to postnatal maternal separation in the rat is well documented (18,25,41-43). For these reasons, in a second set of experiments, we investigated postnatal maternal separation as a possible determinant of the adult rat's avidity for sodium.

burets in addition to ad lib chow and water. After 10 days of habituation fluid intakes were monitored daily for 7 days.

Measurement of Intake Fluid intake was measured daily at 1100 h. Water was available in 500-ml bottles that were weighed to the nearest 0.1 g. NaCI (3%, w / v ) was available in 25-ml Richter tubes, with 0.2-ml gradations.

Design and Statistics All treatments were within litters. One-way or mixed (between-within) analysis of variance (ANOVA) was employed as required, with the Newman-Keuls serving for post hoc comparisons. Data were also analyzed for interactions between treatments and litter differences. These data are not reported because no significant interactions were found. This permits the use of individual rats rather than litters as subjects in the analyses. Probability values over 0.05 were not considered significant and are not reported. SEMs are presented throughout. EXPERIMENT 1

GENERALMETHOD

Method Subjects Charles River-derived rats bred in the lab were used in all the experiments. Pregnant dams and litters were maintained in large cages [600 x 300 × 180 (h) mm], with wood-flake bedding in a quiet room dedicated to the experiment. Temperature was maintained at 22 5: 2°C, and lights were on between 0700 and 1900 h. Pups born before 1700 h were considered 0 days old. Litters were culled to 10 pups within 48 h of birth, where possible five males and five females. The sexes were equally distributed across experimental conditions. Pups were toe or ear clipped for identification together with the experimental treatments. Food pellets (containing 0.55-0.65% NaCI) and water were available ad lib in the nesting cages.

Sodium Depletion Pups 12 days old were removed individually from the dam and litter, injected, and immediately returned to the nest. Half of each litter was injected SC with saline vehicle (0.1 ml) and half with 1 mg lasix (furosemide).

At 12 days of age (which is the earliest age at which sodium depletion arouses sodium appetite) (23), pups were sodium depleted, and then reared and tested as described. Ten litters were tested.

Results and Discussion Mean daily intake of 3% NaC1 solution in adult experimental rats was increased, F(1, 91)= 5.4, p = 0.02) (Fig. 1), with depleted rats ingesting about 50% more salt solution. Drinking of water was not significantly different in the two groups, but an interaction of gender and treatment, F(1, 86) = 3.9, p = 0.05, reflects a lasix-induced decrease of drinking in males (45.4 + 2.4 vs. 41.2 + 2.0 ml), and an increase in drinking in females (35.6 + 2.0 vs. 40.4 + 2.8 ml), a pattern of results that confirms the dissociation of the effects of lasix injection on salt and water intakes. Adult body weight did not differ between experimental and control rats. These results show that the transient loss of sodium engendered by the diuretic in the suckling increased the adult rats'

Maternal Separation Maternally separated pups were taken from their dam for 24 h at 15 days of age and placed in an incubator maintained humidified and warm at 32°C. Each pup was in an individual metal compartment [40 x 100 x 100 (h) ram] with a slatted floor over water-saturated towels, so that it could lick fluid yet remain dry.

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Rearing Because we were also assessing the effects of stress on sodium appetite, rearing conditions were designed to minimize stressful events that might mask the long-term effects of natriuresis or maternal deprivation. The pups were reared in the same dedicated room in the large nesting cages and, except for the treatments on day 15 (or as described below), were left undisturbed with their dam until day 35. They were then separated into groups of two to three same-sex siblings in smaller cages [350 x 250 x 200 (h) ram], and separated into individual cages at 60 days of age, when they were first provided with 3% NaC1 in

20

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FIG. 1. Effect of 1 mg lasix injection at 12 days of age on intake of 3% NaC1 (bars on left) and water (on right) in adults. Each bar is the mean of 36-38 rats. * p < 0.05 differentfrom vehicle controls.

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FIG. 2. Effect of 1 mg lasix injection at 12 days of age on plasma aldosterone. Experimentals differed from controls at each time interval, p < 0.01. Each column is the mean of 8-10 sucklings. avidity for salt. Such an enhancement results from sodium depletion and the synergistic action of brain angiotensin II (AII) and peripheral aldosterone in adult rats (12,36). Although the hormonal synergy does not influence sodium appetite at 12 days of age (48), the two hormones (All and aldosterone) could act additively to establish the long-term change. Because the brain AII substrates of sodium appetite are functional in the neonate (21,24), the following experiment tested whether aldosterone is activated by sodium depletion at this age. EXPERIMENT2

FIG. 3. Effect of 24-h maternal separation at 15 days of age on daily intake (3-day running means) of 3% NaCI (scale on left) and water (scale on right) from weaning into adulthood. *p < 0.01 greater intakes in maternally deprived rats, days 62-80. h (five maternally separated pups) as described. Rearing and testing differed in this experiment in that 3% NaC1 was made available in burets from day 35 and daily (group) intakes of NaCI and water were monitored. This change was introduced to reveal when the hypothesized increase in salt intake emerges. Measurements continued after 60 days (when the rats were put in individual cages) until 80 days of age. Ten litters were used in the experiment. Results and Discussion

Method Twelve-day-old pups were injected with lasix and returned to their dams as described. At 2, 6, and 24 h after injection the pups of two litters were decapitated and trunk blood was collected for analysis. Plasma aldosterone was measured as described elsewhere (36). Results and Discussion Lasix injection caused a surge in plasma aldosterone, F(1, 33) = 26.8, p < 0.001, that was still evident 24 h after injection (Fig. 2). Lasix also caused a transient (6 h) loss of body weight [controls gained 0.44 + 0.3 g, experimentals lost 1.52 + 0.17 g, F(1, 9) = 60.0, p < 0.001], confirming the diuretic effect. These findings indicate that despite the fact all the pups were with their dams (and observation did not reveal differences in attachment duration), diuresis was sufficiently severe to cause a substantial weight loss and evoke a powerful hormonal response, even at this early age. Taken together, these two experiments demonstrate that the enhanced intake in the adults could be due to the neurohormonal sequelae of sodium deficit postnatally, as occurs in adults (36). Having established that the hormones arousing sodium appetite are functional at this age, in the following experiment we investigated whether maternal separation (which we have argued above can activate these hormones) causes similar effects on the long-term avidity for salt.

In the weanlings, NaC1 and water intakes were not significantly influenced by maternal separation (Fig. 3, days 36-55). In adult rats, intake of 3% NaC1 was increased following maternal separation, F(1, 91)---10.6, p < 0.01 (Figs. 3 and 4). Water intake in the adults was also increased 11% by separation, F(1, 91) = 14.9, p < 0.001 (Figs. 3 and 4). Adult body weight was reduced by maternal separation, F(1, 91) = 5.8, p < 0.05, but an interaction of gender and separation condition, F(1, 205) = 9.4, p < 0.01, was due to a separation-induced decrease in male weight (375.9 ___4.8 vs. 352.9 + 4.2 g) and increase in female body weight (235.0 + 3.2 vs. 240.6 + 3.4 g) so that the increase in fluid intake cannot be ascribed to the changes in body weight.

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EXPERIMENT3 0 Method In this experiment 15-day-old pups were either left in the nest with the dam (five control pups) or placed in the incubator for 24

0

FIG. 4. Mean increase in adult fluid intake (days 62-80) consequent on 24-h maternal separation at 15 days of age. NaC1 on left, water on right. * p < 0.01 different from controls.

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Thus, neonatal maternal separation increases spontaneous intake of fluid in adult, but not weanling, rats. It therefore appears to be a maturationally delayed change, as occurs with sex hormones (5,20). In this respect, the increase in NaCI intake differs from the long-term enhancement of sodium intake found after sodium depletion in adults, which occurs without a delay (36). In this experiment drinking of water was also increased, but the temporal patterns of the increases in salt and water intakes differed: inspection of Fig. 3 reveals that the enhancement in salt intake persists during the 18 days of testing and appears to increase, whereas for water it is transient and dissipates before measurement ceased (as planned a priori). These differences dissociate the increases in sodium intake and drinking, so that the increase in NaC1 intake is not merely due to a global increase in fluid intake. To test this conclusion, and to compare maternal separation directly with the lasix-induced increase in adult salt intake, the experiment was replicated with the rearing and testing protocol used in Experiment 1. The experiment also included a sodium-supplemented group of separated pups to show whether the separation-enhanced appetite could be due to sodium deficit, rather than stress, incurred during the 24-h separation. EXPERIMENT 4 Method Pups were maternally separated as described in the General Method section. In each litter of 10 pups, three to four were left with the dam and six to seven were placed in the incub0tor for 24 h. Of these, three to four sucklings were maintained on a towel saturated with water and three to four on a towel saturated with 0.9% ( w / v ) NaC1. The pups were reared and tested as described in the General Method section. Ten litters were tested. Results and Discussion Average adult dally intake of 3% NaCI was significantly influenced by the treatments, F(2, 92) = 3.2, p < 0.05. Figure 5 shows that adults that had water available in the incubator doubled their intake of 3% NaCI in comparison to nonseparated controls ( p < 0.05). (When intakes were analyzed as percent body weight, they differed from both control groups, all p < 0.05.) The treatments also influenced body weight loss during the 24-h separation, F(2, 91) = 212.3, p < 0.001: nonseparated pups increased weight by 5.0 _+ 0.26 g, those maternally separated in

6

water (ml)

3% NaCI (ml)

IL~ Z _

60

-50 40

l

no maternal separation separation *saline

l

separation *water

30 20 10 0

FIG. 5. Effect of availability of 0.9% saline or water during 24-h maternal separation at 15 days of age on intake of 3% NaC1 (left) and water (fight) in adult rats. Each column is the mean daily intake of 8-23 rats. * p < 0.05 different from both other groups.

the incubator with saline available lost 0.7 _+ 0.28 g, and those with water lost 2.17 _+ 0.18 g ( p < 0.01 for all comparisons). Deprivation condition did not influence gender differences in NaCl intake (females took more than males, p < 0.05), drinking (of water), or adult body weight. Thus, the enhancement of adult salt appetite in maternally deprived sucklings is specific insofar as drinking was not increased, and it is prevented by availability of 0.9% NaC1 during the deprivation.

GENERALDISCUSSION Our results show that 12- or 15-day-old sucklings that are sodium depleted or separated from their dam for 24 h have a higher spontaneous intake of an aversive 3% NaCl solution when they are adults. The increase in adult intake of NaCl was replicated in three independent experiments. Adult rats acutely deprived of sodium or dam postnatally averaged 17-100% greater NaC1 intakes than their siblings. The effect is specific to NaCl insofar as there was no consistent influence on water intake or body weight, and it occurred in both sexes. There are no previous reports of acute postnatal manipulations exerting a robust longterm influence on sodium intake, but our findings are in line with the increase in adult salt-liking consequent on repeated prenatal dehydration (which causes sodium deficit) in rats (31) and humans (8). It is remarkable that a single circumscribed event in the suckling period can increase the adult's avidity for sodium. The search for long-term effects on behavior has generally employed repeated treatments or extended regimens for much of the period between preconception and weaning (2,6,17,29,31,50), so that the avidity for salt appears to be particularly labile in infancy and given to long-term increase. The enhancement may also involve maturation, because it is delayed, emerging in adults but not weanlings (Experiment 3) as does the the gender difference in spontaneous NaCl intake (5). In this it may differ from the long-term enhancement that occurs without a delay after sodium depletion in adults (12,36). The enhancement in adult NaC1 intake may be due to sodium deficiency incurred during maternal separation rather than to the stress of separation because sodium depletion without maternal separation enhances adult salt intake (Experiment 1), whereas maternal separation without sodium depletion does not (Experiment 4). Nevertheless, the possibility that postnatal stress might contribute to the adult's avidity for NaCl cannot be dismissed at present. Availability of saline during maternal separation could prevent the enhancement by alleviating the stress of maternal separation as does feeding (34) and sucrose because, like sucrose (3), we find that 5% NaCl applied to the tongue of 10-day-old pups increases hot plate paw-lift latency (22). Moreover, individual differences in sodium liking in a population might more appropriately be related to small differences in recurring or persistent early stress (which has not been modeled experimentally) rather than to a single episode of 24 h of maternal separation. The experiments do not establish the duration of the enhancement or its permanence, nor do they reveal whether there is a sensitive postnatal period for influencing adult salt liking because the manipulations were limited to 12-15 days of age. Future studies should address these issues. Because enhancement of the adult's avidity for salt as a consequence of perinatal events can apparently occur in humans (8), there are important implications to our findings. Sodium deficit in infancy can result from relatively common ailments such as dietary deficiency, diuresis, diarrhea, or vomiting. More-

EARLY DETERMINANTS OF A D U L T NaCI INTAKE

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over, furosemide is the most widely prescribed drug in pediatrics (4,15,51). Many human neonates are prescribed furosemide repeatedly and continuously (not merely a single injection as we gave rats) but the possible influence on their subsequent intake of salt is unknown. These questions are clinically relevant because of the link between sodium intake and hypertension (11,40). In conclusion, we find that if the suckling rat is subjected to acute sodium deficit, or 24-h maternal separation without sodium, its adult intake of NaC1 is substantially enhanced. It is unlikely that such severe separation accounts for individual differences in NaC1 intake in a normal population, but there are circumstances in which human infants are subjected to sodium deficit, and

which may increase their subsequent sodium intake, as occurs in rats. ACKNOWLEDGEMENTS Some of these data were reported at the meeting of the Society for the Study of Ingestive Behavior, Princeton, June 1992. We thank Gidi Poyas and Dror Oren for carrying out Experiment 1, and Randall Sakal for the aldosterone assays. This research was supported by USA-Israel Binational Foundation grant #89-00261 to Micah Leshem, Alan Epstein, and Eliot Stellar. Most of all, we are grateful for Alan's inspiration and Eliot's encouragement. We are fortunate to have had the opportunity to collaborate with these memorable scientists.

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