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Dietary salt and doca-salt treatments modify ethanol self-selection in rats
BEHAVIORAL AND NEURALBIOLOGY 40, 239--250 f1984)
Dietary Salt and Doca-Salt Treatments Modify Ethanol Self-Selection in Rats LARRY A . GRUPP, EDWARD PERLANSKI, AND ROBERT B. STEWART I
Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 1A8, and Canada and Addiction Research Foundation of Ontario, Toronto, Ontario M5S 2S1, Canada The effect of a salt supplemented diet on the voluntary intake of ethanol in male Wistar rats was examined in two experiments. In Experiment 1, the addition of 3% sodium chloride to the diet selectively increased the intake of moderately concentrated ethanol solutions (3 and 6%) while leaving the choice of a 12% solution unaffected. The choice and intake of water in the two former groups declined. In a second experiment four different groups of rats were offered the 3% salt supplemented diet in combination with daily injections of the synthetic salt-retaining mmeralocorticoid desoxycorticosterone acetate (0.5, 1.5, and 6.0 rag/day). Ethanol intake again tended to increase in the 3 and 6% groups but in contrast to the results of Experiment 1 water intake also increased significantly. When desoxycorticosterone was administered without the salt supplemented diet. ethanol intake was significantly depressed while water intake increased. These findings indicate that a salt supplemented diet can significantly and selectively enhance the intake of moderately concentrated ethanol solutions and that while the addition of desoxycorticosterone injections to this diet has its effect primarily on water intake, these rejections alone can also suppress ethanol intake indirectly by shifting the ammals choice toward water and away from ethanol.
The need for sodium or sodium appetite is a well-documented phenomenon in neurobiology (Denton, 1967, 1982). But, over the past 30 years, investigators have recognized the role of excess sodium in the etiology of hypertension and a number of extensive reviews covering this subject have been written (e.g., Beyer & Peuler, 1983; Dahl, 1977; Tobian, 1978). Interestingly, hypertension and heart disease have also been the focus of many investigations in the field of alcoholism since both these maladies have been found to frequently accompany alcohol The authors gratefully acknowledge the assistance of Dr. Hau kei and Mr. Henzel Jupiter of Computer Services, Addiction Research Foundation, for the statistical analyses and of Mrs. June Shepperd and Mrs. Val Cabral for typing the manuscript. DOCA was generously provided by Dr. E. Vos, CIBA-Geigy Canada, Ltd. Send requests for reprints to Dr. Larry A. Grupp. Department of Pharmacology, University of Toronto, Toronto. Ontario M5S 1A8, Canada. M5S 1A8. 239 0163-1047/84 $3.00 Copyright © 1984by AcademicPress, Inc All rightsof teproductlonm any form reserved.
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GRUPP, PERLANSKI, AND STEWART
abuse (e.g., Friedman, Klatsky, & Siegelaub, 1982; Kannel & Sorlie, 1975; Klatsky, Friedman, Siegelaub, & Gerard, 1977; Wallace, Lynch, Pomrehn, Criqui, & Heis, 1981). Putting these observations together we investigated the possible relationship between sodium intake and alcohol intake and in a recent paper (Grupp, Stewart, & Perlanski, manuscript submitted for publication) reported that indeed a low salt diet in combination with a brief series of injections of the salt-losing diuretic furosemide produced a significant decrease in the voluntary intake and choice of ethanol solutions. Other investigators have shown that manipulations which alter some parameter related to sodium balance also modify ethanol intake. For example, Iida (1957) showed that the availability of ethanol in a 1% saline solution, or daily ip injections of a 1% saline solution or daily injections of the sodium retaining mineralocorticoid desoxycorticosterone acetate (Doca) all led to increases in intake of a 15% ethanol solution. Similarly, Linkola (1982) has shown that the alcohol preferring AA strain of rats has both a higher level of sodium retention and a higher level of the endogenous mineralocorticoid, aldosterone, than the control ANA strain which does not readily drink ethanol. The present study examines the relationship between salt and ethanol consumption further by describing the changes in the voluntary intake and choice of ethanol that accompany the ingestion of a salt supplemented diet by itself or in combination with injections of DOCA. EXPERIMENT 1 Methods
Subjects The subjects were 24 naive male Wistar rats weighing 300-340 g at the beginning of the experiment. All animals were housed individually in cages equipped with a glass feeder cup and two Richter tubes spaced 5 cm apart. A 12-hr/12-hr light/dark cycle was in effect throughout with lights on at 7 AM.
Procedure The animals were distributed equally according to weight into four groups of six animals, each allowed continuous access to either distilled water, 3, 6, or 12% ethanol (v/v) prepared in distilled water. To facilitate comparisons with Experiment 2 where drug was given, the present experiment was divided into seven phases each comprising 7-15 3-day cycles and injections of a drug vehicle were administered as described below. Each cycle consisted of two consecutive 24-hr periods during which each animal was offered only its respective ethanol solution to drink (forced days) followed by a third 24-hr period during which both ethanol and distilled water were available (choice day). The positions of
SALT-INDUCED ETHANOL DRINKING
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the water and ethanol tubes were alternated regularly. Progression from one phase to the next was done only after consumption had stabilized. Phase 1. All animals were fed standard Purina Rat Chow in powdered form for seven cycles (21 days). This diet contains 0.5% sodium. Phases 2, 3, and 4. All animals were switched to a salt supplemented diet which consisted of the standard rat chow powder with 3% added salt. During phases 2 and 3 daily subcutaneous injections of 0.2 ml/rat sesame seed oil (Sigma Chemical Co.) were administered while 0.3 ml/ rat of the oil was given during phase 4. Each phase lasted seven cycles (21 days). Phase 5. Injections were suspended and the animals continued to receive the salt supplemented diet. This phase lasted 12 cycles (36 days). Phases 6 and 7. During these final phases (13 and 15 cycles, respectively) all animals were returned to the nonsupplemented powdered rat chow. Vehicle (0.3 ml/rat) was administered only during phase 6.
Data Analysis Both Experiments 1 and 2 employed a within subject (ABA) design so that each subject acted as its own control. Thus phases 1 and 7 were control conditions (AA) and were identical, while the experimental manipulations (B) took place during the intervening phases. Such a design allows for the partialing of the effect due to the manipulations per se from any other effects related to time or exposure to ethanol. The results of Experiments 1 and 2 were analyzed in the same way. For each animal, daily fluid consumption was converted to milliliters of ethanol solution or water per kilogram body weight. Statistical analyses on this measure were done by means of two-way analyses of variance, while post hoc tests comparing eacl~ phase to the immediately preceding phase were done using paired t tests. Results and Discussion
Effect of Sodium Supplemented Diet on Ethanol and Water Intake Figure 1 illustrates the mean ethanol and water intake for the choice days in each phase. During control phase 1 ethanol intake for both the 3 and 6% groups was modest (1.0-1.2 g/kg/day) and below that of the water consumption. The period of sodium supplementation (phases 25) produced an immediate (phase 2), significant t(5) = 4.2, p < .008-3%; t(5) = 3.0, p < .03--6%) and sustained increase in ethanol intake and a significant (t(5) = 4.3, p < .008--3%; t(5) = 5.1, p < .004--6%) but delayed (phase 3) decrease in water intake. Ethanol intake doubled during this period reaching a maximum of 2.2-2.4 g/kg/day. When these animals were returned to the control diet in phases 6 and 7 ethanol intake decreased significantly (t(5) = 5.0, p < .004 3%; t(5) = 3.1, p < .03--
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6%) returning to levels very close to those of phase 1. Water intake on the other hand continued to fall and did not return to the presupplement levels of phase 1. The introduction of the sodium supplement during phases 2-5 or its removal (phases 6-7) failed to produce any significant change in ethanol intake for the 12% group. Water intake, however, increased immediately (phase 2) and significantly (t(5) = 3.6, p < .02) and remained elevated until phases 6-7 when the removal of the sodium supplement led to a
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significant decline in water intake (t(5) = 32.9, p < .0001) to a level below that of phase 1. Animals in the water group'and never offered ethanol responded to the sodium supplementation and removal in a similar fashion to the 12% group, i.e., with an immediate, significant (t(5) = 4.6, p < .006), and sustained increase in intake, followed by a significant decline in a level below that of phase 1 (t(5) = 18.1, p < .0001).
Effect o f Sodium Supplemented Diet on Forced Ethanol Intake Figure 2A gives the mean intake for the 2 days intervening between choice days when only ethanol was offered. Animals drinking the 3 and 6% solutions showed similar changes in consumption which paralleled those during the choice days. Thus during the period of sodium supplementation (phase 2-5) ethanol intake increased significantly (t(5) = 4.2, p < .009--3%; t(5) = 3.1, p < .03--6%) and then decreased significantly (t(5) = 9.5, p < .0002--3%; t(5) = 7.8, p < .006---6%) and below
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presupplement values when the sodium supplement was removed (phases 6 and 7). The group of animals drinking the 12% solution did not alter their intake significantly following the sodium supplementation but did show a significant decrease in intake (phase 6, t(5) = 7.9, p < .0005) once the supplement was removed. Taken together these findings indicate that a 3% sodium supplemented diet can produce a significant increase in general fluid intake. This is evident in the enhanced water intake of the water as well as in the enhanced ethanol intake during forced days. Furthermore, the significant decrease in intake that occurred in phases 6 and 7, where the control (nonsupplemented) diet was reintroduced, to similar levels of intake achieved during phase I, indicates that the increase in ethanol consumption during phases 2-5 was for the most part related to the introduction of the salt supplemented diet and not to a change in consumption over time. Most important, however, is the finding that the salt supplement has a primary effect on ethanol intake so that when offered a choice between moderately concentrated ethanol solutions (3, 6%) and water this general increase in fluid intake translates into a specific increase in ethanol intake and a decrease in water intake. EXPERIMENT 2
Doca is a synthetic mineralocorticoid which promotes sodium retention. Previous studies (Iida, 1957; Linkola, 1982) have reported a positive relationship between enhanced mineralocorticoid activity and ethanol intake. In light of these findings we decided to investigate the effect of combining Doca injections with the sodium supplemented diet on the voluntary intake of ethanol. Methods
Subjects The subjects were 24 naive male Wistar rats weighing 300-340 g at the beginning of the experiment. These animals were housed and treated identically to those of Experiment 1.
Procedure As per Experiment 1 except that Doca (Percorten, Ciba-Geigy) suspended in sesame seed oil was administered in three different doses: 0.5, 1.5, and 6.0 mg/animal/day. The respective concentrations were 2.5, 7.5, and 20 mg/ml. Phase 1. All animals were fed Purina Rat Chow in powdered form for seven cycles. Phase 2. Animals were switched to the 3% salt supplemented diet and given daily injections of 0.5 mg Doca (seven cycles).
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Phase 3. Same as phase 2 except the dose of Doca was raised to 1.5 mg/day (seven cycles). Phase 4. Same as phase 2 except that Doca was administered in a dose of 6 mg/day (seven cycles). Phase 5. Doca injections were suspended while the salt supplemented diet continued (12 cycles). Phase 6. Doca injections (6 mg/day) were reinstated and the animals were returned to the nonsupplemented powdered rat chow (13 cycles). Phase 7. During the final phase (15 cycles) Doca injections were suspended and the animals continued on the nonsupplemented diet. During the course of this experiment one animal from the 3% and one animal from the 6% group died. Their data is not included in the analysis. Results and Discussion
Effect of Doca-Salt on Choice Day Intake of Ethanol and Water Figure 3 shows that during the first Doca-salt phases (2-4) the 3 and 6% groups showed an increase in ethanol intake which was not dose dependent but more marked and significant in the 3% group (t(5) = 3.7, p < .04) than in the 6% group (t(4) = 2.1, n.s.). Across these same phases water intake also increased dramatically and in a dose-dependent manner so that by the end of phase 4 these two groups had at least doubled their water intake. The suspension of the Doca injections during phase 5 did not reduce ethanol intake significantly (t(4) = 1.35, n . s . - 3%; t(4) = 1.21, n . s . - - 6 % ) but produced a significant decrease toward control levels in water intake (t(4) = 3.1, p < .05--3%; t(4) = 12.3, p < .0002--6%). The results of phase 5 replicate the findings of experiment 1 where the salt supplemented diet alone was found to produce a bias toward the intake of ethanol and away from the intake of water. These findings when c o m p a r e d to those of Experiment 1 suggest that the Doca injections w h e n combined with the sodium supplement exert their effect primarily on water intake while having no apparent effect on ethanol intake. With the change back to control diet and the reintroduction of Doca in phase 6 came a significant decrease in ethanol intake (t(4) = 6.1, p < .004. 3%; t(4) = 3.6, p < .02--6%) to a level below that of control. This decrease reflects an actual suppression in intake since suspension of the D o c a injections in phase 7 representing a return to the control conditions of phase 1, resulted in a significant increase (t(4) = 3.7, p < .02--3%): t(4) = 3.6, p < 0.02--6%) in levels of intake. These levels were statistically equivalent to those seen in phase 1 (t(4) = 0.6, n . s . - 3%; t(4) = 0.5, n.s.--6%). Water consumption on the other hand was significantly increased during phase 6 (t(4) = 4.4, p < .01--3%; t(4) = 3.2, p < .03--6%) and returned to control levels with the return to control diet in phase 7.
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FIG. 3. Mean ethanol and water intake on choice days for the groups drinking ethanol (3, 6, or 12%) or water across the seven phases of Experiment 2. Doca indicates desoxycorticosterone acetate suspended in sesame seed oil and administered at the indicated doses. All other conventions as per Fig. 1. The D o c a - s a l t manipulation did not appear to be able to increase the low ethanol intake of the 12% group throughout this experiment. However, the previously observed suppressive effect of the change to control diet plus D o c a injections in phase 6 can also be seen in this group (Fig. 3) except that the tendency was not significant (t(5) = 3.0, p < .07). The main effect of this manipulation in this group was to cause a dosedependent increase in water intake. In the group offered only water, intake again increased in a dosedependent manner. The effect of the D o c a was clearly seen in phase 5 where the suspension of injections led to a significant decrease in intake (t(5) -- 13.8, p < .0001). The lack of reduction in intake in phase 6 where the only manipulation was D o c a injections (no salt supplement)
SALT-INDUCED ETHANOL DRINKING
247
and the decrease in intake following suspension of Doca injectons in phase 7 indicate that Doca injections can by themselves maintain an elevated water intake. Taken together these findings indicate that Doca injections can increase general fluid intake independently of the salt supplemented diet and that when a choice between ethanol and water is offered, this translates into a specific increase in water intake and no apparent effect on ethanol intake. Thus the suppressive effect on ethanol intake of the Doca injections alone (phase 6) may be an indirect result of the enhance water intake. The equivalent levels of ethanol intake during the first and final control phases (phases 1 and 7) indicate that the change in ethanol consumption during the intervening phases were indeed related to the manipulations performed and not to other influences on consumption.
Effect of DOCA-Salt Manipulation on Forced Ethanol Intake Figure 2B indicates that when ethanol was the only available fluid, the 3, 6, and 12% groups showed statistically significant increases in intake as a result of this manipulation (t(4) = 6.6, p < .007--3%; t(4) = 5.3, p < .006--6%; t(5) = 3.6, p < .02--12%). For both the 3% and the 6% groups this increase in intake tended to be dose dependent. Removal of the Doca injections in phase 5 led to a corresponding decrease in intake with no further change occurring until the control diet was restored in phase 7 at which point intake decreased further and approximated the original levels of phase 1. These findings are further confirmation of a Doca induced enhancement of fluid intake. The dose-related increase in intake (phases 2-4) and the absence of suppression in intake during the control-Doca diet phase (phase 6) appear to be consequences of this increased fluid intake requirement. This latter finding also indicates that the integrity of the animals" fluid balance retains priority and that when a greater fluid intake is required and water is not present, attention will be directed to the other available fluid regardless of any suppressive influences accruing to that fluid. GENERAL DISCUSSION The results of both experiments clearly show that a salt supplemented diet can significantly and selectively augment the voluntary intake and choice of moderately concentrated ethanol solutions. These findings are in agreement with Iida (1957) who found that either saline injections or the availability of ethanol in a saline solution, increased the voluntary intake of ethanol. They further extend those findings by indicating that low doses of the salt-retaining mineralocorticoid, Doca, do not appear to be additive with a salt-induced enhancement of ethanol intake. The present findings, together with our previous work showing a decrease in
248
GRUPP, PERLANSKI, AND STEWART
ethanol intake following a low sodium diet/diuretic-natriuretic manipulation (Grupp et al., manuscript submitted for publication) clearly indicate that ethanol intake can vary with and be modulated by the availability of sodium in the diet. One of the most striking findings of this study is that 6 mg Doca/day administered in conjunction with a nonsupplemented diet resulted in a suppression of ethanol intake. It is known that high daily doses of mineralocorticoid (i.e., in excess of 2 mg) can lead to a robust sodium appetite (Braun-Menedez, 1952; Rice & Richter, 1943). In a former experiment (Grupp et al., manuscript submitted for publication) we found that animals will also decrease their ethanol consumption if treated with a salt-losing diuretic and maintained on a low sodium diet. This latter condition is also known to produce a sodium appetite (Jalowiec, 1974; Schulkin, 1978; Wolf, McGovern, & DiCara 1974). Taken together these findings suggest that those conditions which lead to the development of a salt appetite can be antagonistic to the consumption of ethanol. The results of the present study can be summarized in terms of a change in two parameters of fluid intake: (a) overall amount, and (b) specific choice. Both experiments involved a sodium supplement to the diet and both produced an overall increase in the amount of fluid consumed on both choice and forced days. In addition, the injections of Doca in Experiment 2 enhanced the already increased level of fluid intake on both choice and forced days. The difference between the two experiments resides in the nature of the increase. In Experiment 1 the sodium supplemented diet alone resulted in a specific increase in ethanol intake and decrease in water intake. In Experiment 2 the sodium supplement again increased ethanol intake but the addition of Doca injections to this diet appeared to specifically increase water intake without any additional effect on ethanol intake. Doca injections in combination with a control • diet significantly suppressed ethanol intake, but this effect appeared to be due to a redistribution of the animals' choice of fluid favoring water at the expense of ethanol. Thus in these experiments the sodium supplement appeared to enhance overall fluid intake in general and ethanol intake specifically while the Doca injections enhanced overall fluid intake in general and water intake specifically. At present it is not clear how a salt supplemented diet enhances ethanol intake. The notion that the animals are attempting to meet the challenge of the diet and regulate their sodium balance by ingesting more ethanol requires the assumption that ethanol intake lead to an enhanced sodium loss. This assumption, however, is not born out by the literature which shows that ethanol leads to a net retention, not loss of sodium (Sargent, Simpson, & Beard, 1974, 1980, 1981). An enhanced ethanol intake could result if the salty diet were to enhance the palatibility of the ethanol solutions. The literature, however,
SALT-INDUCED ETHANOL DRINKING
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indicates that altering the sodium concentration of a diet changes the sensitivity only to salty substances and not to sweet, sour, or bitter substances (Pfaffmann, 1957; Yensen, 1958). The failure of the 12% group to increae its level of ethanol intake is also not consistent with this explanation. From a homeostatic point of view, a chronically administered sodium supplemented diet represents a challenge of some proportion, for without corrective measures sodium concentration may continue to increase and plasma volume expand to a point where the integrity of the organism is in jeopardy. Renin, angiotensin, and aldosterone play a role both centrally and peripherally in the regulation of salt and water excretion and it is known their activity is decreased when a salt supplemented diet is imposed (FUgita, Delea, & Bartter, 1982; Reid & Ganong 1977; Williams & Dluhy, 1977). In the present study, the salt supplemented diet led to a selective increase in ethanol intake and in a previous paper (Grupp et al., manuscript submitted for publication) we reported that conditions congruent with increased renin, angiotensin, and aldosterone activity (low sodium diet/ furosemide injections) led to a decrease in ethanol intake. It would thus be of some interest to determine whether the activity of these endogenous substances merely correlates with changes in ethanol intake or is more intimately and causally related to these changes. REFERENCES Beyer, K. H., Jr., & Peuler, J. D. (1983). Hypertension: Perspectives. Pharmacological Reviews, 34, 287-313. Braun-Menedez, E. (1952). Aumento del apetito especifico para la sal provocado por la desoxicorticosterona. I. Caracteristicas. II. Sustancias que potencian o inhiben esta accion. Revista de la Sociedad Argentina de Biologia, 28, 15-32. Daht, L. K. (1977). Salt intake in hypertension. In J. Genest, E. Koiw, & O. Kuchel (Eds.), Hypertension (pp, 548-558). New York: McGraw-Hill. Denton, D. A. (1967). Salt appetite. In Handbook of Experimental Physiology. The Alimentary Canal: Control of Food and Water Intake. (Vol. 2, pp. 443-459). American Physiological Society. Denton, D. A. (1982). The Hnngerfor Salt (pp. 10-44, 188-217). New York: SpringerVerlag. Friedman, G, D., Klatsky, A. L.. & Siegelaub, A. B. (1982). Alcohol, tobacco and hypertension. Perspectives in Hypertension, 4(Suppl. lII), 143-150. Fugita, T., Delea, C. S., & Bartter, F. C. (1982). The role of the renin-angiotensin and prostaglandin systems in salt-sensitive and non-salt-sensitive hypertension in man. In M. J. Fregly & M. R. Kare (Eds.), The Role of Salt in Cardiovascular Hypertension (pp. 207-219). New York: Academic Press. Grupp, L. A., Stewart, R. B., & Perlanski. E. (1983). Salt restriction and the voluntary intake of ethanol in rats. Manuscript submitted for publication. Iida, S. (1957). Experimental studies on the craving for alcohol. I. Alcohol drive in mice following administration of saline. Japanese Journal of Pharmacology, 6, 87-93. Jalowiec, J. E. (1974). Sodium appeUte ehcited by furosemide: Effects of differential dietary maintenance. Behavioral and Neural Biology, 10, 313-327. Kannel, W. B., & Sorlie. P. (1975). Hypertension in Framingham. In O. Paul (Ed.), Epidemiology and Control of Hypertension (pp. 553-590). New York: Stratton.
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Klatsky, A. L., Friedman, G. D., Siegelaub, A. B., & Gerard, M. J. (1977). Alcohol consumption and blood pressure. New England Journal of Medicine, 296, 1194-1200. Linkola, J. (1982). Strain differences in water and electrolyte metabolism between alcohol preferring (AA) and alcohol avoiding (ANA) rats. Minerva Foundation for Medical Research, Helsinki. Pfaffmann, C. (1957). Taste mechanisms in preference behavior. American Journal of Clinical Natrition, 5, 142-147. Reid, I. A., & Ganong, W. F. (1977). Control of aldosterone secretion. In. J. Genest, E. Koiw, & O. Kuchel (Eds.), Hypertension (pp. 265-292. New York: McGraw-Hill. Rice, K. K., & Richter, C. P. (1943). Increased sodium chloride and water intake of normal rats treated with desoxycorticosterone acetate. Endocrinology, 33, 106-115. Sargent, W. Q., Simpson, J. R., & Beard, J. D. (1974). Effect of acute and chronic alcohol administration on renal hemodynamics and monovalent ion excretion. Journal of Pharmacology and Experimental Therapeutics, 188, 461-471. Sargent, W. Q., Simpson, J. R., & Beard, J. D. (1980). Twenty-four-hour fluid intake and renal handling of electrolytes after various doses of ethanol. Alcoholism: Clinical and Experimental Research, 4, 74-88. Sargent, W. Q., Simpson, J. R., & Beard, J. D. (1981). Water metabolism and monovalent ion excretion during one day of multiple ethanol doses. Substance and Alcohol Actions/ Misuse, 2, 301-310. Schulkin, J. (1978). Mineralocorticoids, dietary conditions and sodium appetite. Behavioral and Neural Biology, 23, 197-205. Tobian, L. (1978). Salt and hypertension, Annals of the New York Academy of Science, 304, 178-202. Wallace, R. D., Lynch, C. F., Pomrehn, P. R., Criqui, M. H., & Heiss, G. (1981). Alcohol and hypertension: Epidemiologic and experimental considerations. Circulation, fi4(Suppl. III), 41-47. Williams, G. H., & Dluhy, R. G. (1977). Regulation of the renin-angiotensin-aldosterone axis in hypertension. In J. Genest, E. Koiw, & O. Kuchel (Eds.), Hypertension (pp. 292-312). New York: McGraw-Hill. Wolf, G., McGovern, J. F., & DiCara, L. V. (1974). Sodium appetite: Some conceptual and methodologic aspects of a model drive system. Behavioral and Neltral Biology, 10, 27-42. Yensen, R. (1958). Influence of salt deficiency on taste sensitivity in human subjects. Nature (London), 181, 1472-1474.
Dietary Salt and Doca-Salt Treatments Modify Ethanol Self-Selection in Rats LARRY A . GRUPP, EDWARD PERLANSKI, AND ROBERT B. STEWART I
Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 1A8, and Canada and Addiction Research Foundation of Ontario, Toronto, Ontario M5S 2S1, Canada The effect of a salt supplemented diet on the voluntary intake of ethanol in male Wistar rats was examined in two experiments. In Experiment 1, the addition of 3% sodium chloride to the diet selectively increased the intake of moderately concentrated ethanol solutions (3 and 6%) while leaving the choice of a 12% solution unaffected. The choice and intake of water in the two former groups declined. In a second experiment four different groups of rats were offered the 3% salt supplemented diet in combination with daily injections of the synthetic salt-retaining mmeralocorticoid desoxycorticosterone acetate (0.5, 1.5, and 6.0 rag/day). Ethanol intake again tended to increase in the 3 and 6% groups but in contrast to the results of Experiment 1 water intake also increased significantly. When desoxycorticosterone was administered without the salt supplemented diet. ethanol intake was significantly depressed while water intake increased. These findings indicate that a salt supplemented diet can significantly and selectively enhance the intake of moderately concentrated ethanol solutions and that while the addition of desoxycorticosterone injections to this diet has its effect primarily on water intake, these rejections alone can also suppress ethanol intake indirectly by shifting the ammals choice toward water and away from ethanol.
The need for sodium or sodium appetite is a well-documented phenomenon in neurobiology (Denton, 1967, 1982). But, over the past 30 years, investigators have recognized the role of excess sodium in the etiology of hypertension and a number of extensive reviews covering this subject have been written (e.g., Beyer & Peuler, 1983; Dahl, 1977; Tobian, 1978). Interestingly, hypertension and heart disease have also been the focus of many investigations in the field of alcoholism since both these maladies have been found to frequently accompany alcohol The authors gratefully acknowledge the assistance of Dr. Hau kei and Mr. Henzel Jupiter of Computer Services, Addiction Research Foundation, for the statistical analyses and of Mrs. June Shepperd and Mrs. Val Cabral for typing the manuscript. DOCA was generously provided by Dr. E. Vos, CIBA-Geigy Canada, Ltd. Send requests for reprints to Dr. Larry A. Grupp. Department of Pharmacology, University of Toronto, Toronto. Ontario M5S 1A8, Canada. M5S 1A8. 239 0163-1047/84 $3.00 Copyright © 1984by AcademicPress, Inc All rightsof teproductlonm any form reserved.
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abuse (e.g., Friedman, Klatsky, & Siegelaub, 1982; Kannel & Sorlie, 1975; Klatsky, Friedman, Siegelaub, & Gerard, 1977; Wallace, Lynch, Pomrehn, Criqui, & Heis, 1981). Putting these observations together we investigated the possible relationship between sodium intake and alcohol intake and in a recent paper (Grupp, Stewart, & Perlanski, manuscript submitted for publication) reported that indeed a low salt diet in combination with a brief series of injections of the salt-losing diuretic furosemide produced a significant decrease in the voluntary intake and choice of ethanol solutions. Other investigators have shown that manipulations which alter some parameter related to sodium balance also modify ethanol intake. For example, Iida (1957) showed that the availability of ethanol in a 1% saline solution, or daily ip injections of a 1% saline solution or daily injections of the sodium retaining mineralocorticoid desoxycorticosterone acetate (Doca) all led to increases in intake of a 15% ethanol solution. Similarly, Linkola (1982) has shown that the alcohol preferring AA strain of rats has both a higher level of sodium retention and a higher level of the endogenous mineralocorticoid, aldosterone, than the control ANA strain which does not readily drink ethanol. The present study examines the relationship between salt and ethanol consumption further by describing the changes in the voluntary intake and choice of ethanol that accompany the ingestion of a salt supplemented diet by itself or in combination with injections of DOCA. EXPERIMENT 1 Methods
Subjects The subjects were 24 naive male Wistar rats weighing 300-340 g at the beginning of the experiment. All animals were housed individually in cages equipped with a glass feeder cup and two Richter tubes spaced 5 cm apart. A 12-hr/12-hr light/dark cycle was in effect throughout with lights on at 7 AM.
Procedure The animals were distributed equally according to weight into four groups of six animals, each allowed continuous access to either distilled water, 3, 6, or 12% ethanol (v/v) prepared in distilled water. To facilitate comparisons with Experiment 2 where drug was given, the present experiment was divided into seven phases each comprising 7-15 3-day cycles and injections of a drug vehicle were administered as described below. Each cycle consisted of two consecutive 24-hr periods during which each animal was offered only its respective ethanol solution to drink (forced days) followed by a third 24-hr period during which both ethanol and distilled water were available (choice day). The positions of
SALT-INDUCED ETHANOL DRINKING
241
the water and ethanol tubes were alternated regularly. Progression from one phase to the next was done only after consumption had stabilized. Phase 1. All animals were fed standard Purina Rat Chow in powdered form for seven cycles (21 days). This diet contains 0.5% sodium. Phases 2, 3, and 4. All animals were switched to a salt supplemented diet which consisted of the standard rat chow powder with 3% added salt. During phases 2 and 3 daily subcutaneous injections of 0.2 ml/rat sesame seed oil (Sigma Chemical Co.) were administered while 0.3 ml/ rat of the oil was given during phase 4. Each phase lasted seven cycles (21 days). Phase 5. Injections were suspended and the animals continued to receive the salt supplemented diet. This phase lasted 12 cycles (36 days). Phases 6 and 7. During these final phases (13 and 15 cycles, respectively) all animals were returned to the nonsupplemented powdered rat chow. Vehicle (0.3 ml/rat) was administered only during phase 6.
Data Analysis Both Experiments 1 and 2 employed a within subject (ABA) design so that each subject acted as its own control. Thus phases 1 and 7 were control conditions (AA) and were identical, while the experimental manipulations (B) took place during the intervening phases. Such a design allows for the partialing of the effect due to the manipulations per se from any other effects related to time or exposure to ethanol. The results of Experiments 1 and 2 were analyzed in the same way. For each animal, daily fluid consumption was converted to milliliters of ethanol solution or water per kilogram body weight. Statistical analyses on this measure were done by means of two-way analyses of variance, while post hoc tests comparing eacl~ phase to the immediately preceding phase were done using paired t tests. Results and Discussion
Effect of Sodium Supplemented Diet on Ethanol and Water Intake Figure 1 illustrates the mean ethanol and water intake for the choice days in each phase. During control phase 1 ethanol intake for both the 3 and 6% groups was modest (1.0-1.2 g/kg/day) and below that of the water consumption. The period of sodium supplementation (phases 25) produced an immediate (phase 2), significant t(5) = 4.2, p < .008-3%; t(5) = 3.0, p < .03--6%) and sustained increase in ethanol intake and a significant (t(5) = 4.3, p < .008--3%; t(5) = 5.1, p < .004--6%) but delayed (phase 3) decrease in water intake. Ethanol intake doubled during this period reaching a maximum of 2.2-2.4 g/kg/day. When these animals were returned to the control diet in phases 6 and 7 ethanol intake decreased significantly (t(5) = 5.0, p < .004 3%; t(5) = 3.1, p < .03--
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6%) returning to levels very close to those of phase 1. Water intake on the other hand continued to fall and did not return to the presupplement levels of phase 1. The introduction of the sodium supplement during phases 2-5 or its removal (phases 6-7) failed to produce any significant change in ethanol intake for the 12% group. Water intake, however, increased immediately (phase 2) and significantly (t(5) = 3.6, p < .02) and remained elevated until phases 6-7 when the removal of the sodium supplement led to a
243
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significant decline in water intake (t(5) = 32.9, p < .0001) to a level below that of phase 1. Animals in the water group'and never offered ethanol responded to the sodium supplementation and removal in a similar fashion to the 12% group, i.e., with an immediate, significant (t(5) = 4.6, p < .006), and sustained increase in intake, followed by a significant decline in a level below that of phase 1 (t(5) = 18.1, p < .0001).
Effect o f Sodium Supplemented Diet on Forced Ethanol Intake Figure 2A gives the mean intake for the 2 days intervening between choice days when only ethanol was offered. Animals drinking the 3 and 6% solutions showed similar changes in consumption which paralleled those during the choice days. Thus during the period of sodium supplementation (phase 2-5) ethanol intake increased significantly (t(5) = 4.2, p < .009--3%; t(5) = 3.1, p < .03--6%) and then decreased significantly (t(5) = 9.5, p < .0002--3%; t(5) = 7.8, p < .006---6%) and below
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244
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presupplement values when the sodium supplement was removed (phases 6 and 7). The group of animals drinking the 12% solution did not alter their intake significantly following the sodium supplementation but did show a significant decrease in intake (phase 6, t(5) = 7.9, p < .0005) once the supplement was removed. Taken together these findings indicate that a 3% sodium supplemented diet can produce a significant increase in general fluid intake. This is evident in the enhanced water intake of the water as well as in the enhanced ethanol intake during forced days. Furthermore, the significant decrease in intake that occurred in phases 6 and 7, where the control (nonsupplemented) diet was reintroduced, to similar levels of intake achieved during phase I, indicates that the increase in ethanol consumption during phases 2-5 was for the most part related to the introduction of the salt supplemented diet and not to a change in consumption over time. Most important, however, is the finding that the salt supplement has a primary effect on ethanol intake so that when offered a choice between moderately concentrated ethanol solutions (3, 6%) and water this general increase in fluid intake translates into a specific increase in ethanol intake and a decrease in water intake. EXPERIMENT 2
Doca is a synthetic mineralocorticoid which promotes sodium retention. Previous studies (Iida, 1957; Linkola, 1982) have reported a positive relationship between enhanced mineralocorticoid activity and ethanol intake. In light of these findings we decided to investigate the effect of combining Doca injections with the sodium supplemented diet on the voluntary intake of ethanol. Methods
Subjects The subjects were 24 naive male Wistar rats weighing 300-340 g at the beginning of the experiment. These animals were housed and treated identically to those of Experiment 1.
Procedure As per Experiment 1 except that Doca (Percorten, Ciba-Geigy) suspended in sesame seed oil was administered in three different doses: 0.5, 1.5, and 6.0 mg/animal/day. The respective concentrations were 2.5, 7.5, and 20 mg/ml. Phase 1. All animals were fed Purina Rat Chow in powdered form for seven cycles. Phase 2. Animals were switched to the 3% salt supplemented diet and given daily injections of 0.5 mg Doca (seven cycles).
SALT-INDUCED ETHANOL DRINKING
245
Phase 3. Same as phase 2 except the dose of Doca was raised to 1.5 mg/day (seven cycles). Phase 4. Same as phase 2 except that Doca was administered in a dose of 6 mg/day (seven cycles). Phase 5. Doca injections were suspended while the salt supplemented diet continued (12 cycles). Phase 6. Doca injections (6 mg/day) were reinstated and the animals were returned to the nonsupplemented powdered rat chow (13 cycles). Phase 7. During the final phase (15 cycles) Doca injections were suspended and the animals continued on the nonsupplemented diet. During the course of this experiment one animal from the 3% and one animal from the 6% group died. Their data is not included in the analysis. Results and Discussion
Effect of Doca-Salt on Choice Day Intake of Ethanol and Water Figure 3 shows that during the first Doca-salt phases (2-4) the 3 and 6% groups showed an increase in ethanol intake which was not dose dependent but more marked and significant in the 3% group (t(5) = 3.7, p < .04) than in the 6% group (t(4) = 2.1, n.s.). Across these same phases water intake also increased dramatically and in a dose-dependent manner so that by the end of phase 4 these two groups had at least doubled their water intake. The suspension of the Doca injections during phase 5 did not reduce ethanol intake significantly (t(4) = 1.35, n . s . - 3%; t(4) = 1.21, n . s . - - 6 % ) but produced a significant decrease toward control levels in water intake (t(4) = 3.1, p < .05--3%; t(4) = 12.3, p < .0002--6%). The results of phase 5 replicate the findings of experiment 1 where the salt supplemented diet alone was found to produce a bias toward the intake of ethanol and away from the intake of water. These findings when c o m p a r e d to those of Experiment 1 suggest that the Doca injections w h e n combined with the sodium supplement exert their effect primarily on water intake while having no apparent effect on ethanol intake. With the change back to control diet and the reintroduction of Doca in phase 6 came a significant decrease in ethanol intake (t(4) = 6.1, p < .004. 3%; t(4) = 3.6, p < .02--6%) to a level below that of control. This decrease reflects an actual suppression in intake since suspension of the D o c a injections in phase 7 representing a return to the control conditions of phase 1, resulted in a significant increase (t(4) = 3.7, p < .02--3%): t(4) = 3.6, p < 0.02--6%) in levels of intake. These levels were statistically equivalent to those seen in phase 1 (t(4) = 0.6, n . s . - 3%; t(4) = 0.5, n.s.--6%). Water consumption on the other hand was significantly increased during phase 6 (t(4) = 4.4, p < .01--3%; t(4) = 3.2, p < .03--6%) and returned to control levels with the return to control diet in phase 7.
246
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FIG. 3. Mean ethanol and water intake on choice days for the groups drinking ethanol (3, 6, or 12%) or water across the seven phases of Experiment 2. Doca indicates desoxycorticosterone acetate suspended in sesame seed oil and administered at the indicated doses. All other conventions as per Fig. 1. The D o c a - s a l t manipulation did not appear to be able to increase the low ethanol intake of the 12% group throughout this experiment. However, the previously observed suppressive effect of the change to control diet plus D o c a injections in phase 6 can also be seen in this group (Fig. 3) except that the tendency was not significant (t(5) = 3.0, p < .07). The main effect of this manipulation in this group was to cause a dosedependent increase in water intake. In the group offered only water, intake again increased in a dosedependent manner. The effect of the D o c a was clearly seen in phase 5 where the suspension of injections led to a significant decrease in intake (t(5) -- 13.8, p < .0001). The lack of reduction in intake in phase 6 where the only manipulation was D o c a injections (no salt supplement)
SALT-INDUCED ETHANOL DRINKING
247
and the decrease in intake following suspension of Doca injectons in phase 7 indicate that Doca injections can by themselves maintain an elevated water intake. Taken together these findings indicate that Doca injections can increase general fluid intake independently of the salt supplemented diet and that when a choice between ethanol and water is offered, this translates into a specific increase in water intake and no apparent effect on ethanol intake. Thus the suppressive effect on ethanol intake of the Doca injections alone (phase 6) may be an indirect result of the enhance water intake. The equivalent levels of ethanol intake during the first and final control phases (phases 1 and 7) indicate that the change in ethanol consumption during the intervening phases were indeed related to the manipulations performed and not to other influences on consumption.
Effect of DOCA-Salt Manipulation on Forced Ethanol Intake Figure 2B indicates that when ethanol was the only available fluid, the 3, 6, and 12% groups showed statistically significant increases in intake as a result of this manipulation (t(4) = 6.6, p < .007--3%; t(4) = 5.3, p < .006--6%; t(5) = 3.6, p < .02--12%). For both the 3% and the 6% groups this increase in intake tended to be dose dependent. Removal of the Doca injections in phase 5 led to a corresponding decrease in intake with no further change occurring until the control diet was restored in phase 7 at which point intake decreased further and approximated the original levels of phase 1. These findings are further confirmation of a Doca induced enhancement of fluid intake. The dose-related increase in intake (phases 2-4) and the absence of suppression in intake during the control-Doca diet phase (phase 6) appear to be consequences of this increased fluid intake requirement. This latter finding also indicates that the integrity of the animals" fluid balance retains priority and that when a greater fluid intake is required and water is not present, attention will be directed to the other available fluid regardless of any suppressive influences accruing to that fluid. GENERAL DISCUSSION The results of both experiments clearly show that a salt supplemented diet can significantly and selectively augment the voluntary intake and choice of moderately concentrated ethanol solutions. These findings are in agreement with Iida (1957) who found that either saline injections or the availability of ethanol in a saline solution, increased the voluntary intake of ethanol. They further extend those findings by indicating that low doses of the salt-retaining mineralocorticoid, Doca, do not appear to be additive with a salt-induced enhancement of ethanol intake. The present findings, together with our previous work showing a decrease in
248
GRUPP, PERLANSKI, AND STEWART
ethanol intake following a low sodium diet/diuretic-natriuretic manipulation (Grupp et al., manuscript submitted for publication) clearly indicate that ethanol intake can vary with and be modulated by the availability of sodium in the diet. One of the most striking findings of this study is that 6 mg Doca/day administered in conjunction with a nonsupplemented diet resulted in a suppression of ethanol intake. It is known that high daily doses of mineralocorticoid (i.e., in excess of 2 mg) can lead to a robust sodium appetite (Braun-Menedez, 1952; Rice & Richter, 1943). In a former experiment (Grupp et al., manuscript submitted for publication) we found that animals will also decrease their ethanol consumption if treated with a salt-losing diuretic and maintained on a low sodium diet. This latter condition is also known to produce a sodium appetite (Jalowiec, 1974; Schulkin, 1978; Wolf, McGovern, & DiCara 1974). Taken together these findings suggest that those conditions which lead to the development of a salt appetite can be antagonistic to the consumption of ethanol. The results of the present study can be summarized in terms of a change in two parameters of fluid intake: (a) overall amount, and (b) specific choice. Both experiments involved a sodium supplement to the diet and both produced an overall increase in the amount of fluid consumed on both choice and forced days. In addition, the injections of Doca in Experiment 2 enhanced the already increased level of fluid intake on both choice and forced days. The difference between the two experiments resides in the nature of the increase. In Experiment 1 the sodium supplemented diet alone resulted in a specific increase in ethanol intake and decrease in water intake. In Experiment 2 the sodium supplement again increased ethanol intake but the addition of Doca injections to this diet appeared to specifically increase water intake without any additional effect on ethanol intake. Doca injections in combination with a control • diet significantly suppressed ethanol intake, but this effect appeared to be due to a redistribution of the animals' choice of fluid favoring water at the expense of ethanol. Thus in these experiments the sodium supplement appeared to enhance overall fluid intake in general and ethanol intake specifically while the Doca injections enhanced overall fluid intake in general and water intake specifically. At present it is not clear how a salt supplemented diet enhances ethanol intake. The notion that the animals are attempting to meet the challenge of the diet and regulate their sodium balance by ingesting more ethanol requires the assumption that ethanol intake lead to an enhanced sodium loss. This assumption, however, is not born out by the literature which shows that ethanol leads to a net retention, not loss of sodium (Sargent, Simpson, & Beard, 1974, 1980, 1981). An enhanced ethanol intake could result if the salty diet were to enhance the palatibility of the ethanol solutions. The literature, however,
SALT-INDUCED ETHANOL DRINKING
249
indicates that altering the sodium concentration of a diet changes the sensitivity only to salty substances and not to sweet, sour, or bitter substances (Pfaffmann, 1957; Yensen, 1958). The failure of the 12% group to increae its level of ethanol intake is also not consistent with this explanation. From a homeostatic point of view, a chronically administered sodium supplemented diet represents a challenge of some proportion, for without corrective measures sodium concentration may continue to increase and plasma volume expand to a point where the integrity of the organism is in jeopardy. Renin, angiotensin, and aldosterone play a role both centrally and peripherally in the regulation of salt and water excretion and it is known their activity is decreased when a salt supplemented diet is imposed (FUgita, Delea, & Bartter, 1982; Reid & Ganong 1977; Williams & Dluhy, 1977). In the present study, the salt supplemented diet led to a selective increase in ethanol intake and in a previous paper (Grupp et al., manuscript submitted for publication) we reported that conditions congruent with increased renin, angiotensin, and aldosterone activity (low sodium diet/ furosemide injections) led to a decrease in ethanol intake. It would thus be of some interest to determine whether the activity of these endogenous substances merely correlates with changes in ethanol intake or is more intimately and causally related to these changes. REFERENCES Beyer, K. H., Jr., & Peuler, J. D. (1983). Hypertension: Perspectives. Pharmacological Reviews, 34, 287-313. Braun-Menedez, E. (1952). Aumento del apetito especifico para la sal provocado por la desoxicorticosterona. I. Caracteristicas. II. Sustancias que potencian o inhiben esta accion. Revista de la Sociedad Argentina de Biologia, 28, 15-32. Daht, L. K. (1977). Salt intake in hypertension. In J. Genest, E. Koiw, & O. Kuchel (Eds.), Hypertension (pp, 548-558). New York: McGraw-Hill. Denton, D. A. (1967). Salt appetite. In Handbook of Experimental Physiology. The Alimentary Canal: Control of Food and Water Intake. (Vol. 2, pp. 443-459). American Physiological Society. Denton, D. A. (1982). The Hnngerfor Salt (pp. 10-44, 188-217). New York: SpringerVerlag. Friedman, G, D., Klatsky, A. L.. & Siegelaub, A. B. (1982). Alcohol, tobacco and hypertension. Perspectives in Hypertension, 4(Suppl. lII), 143-150. Fugita, T., Delea, C. S., & Bartter, F. C. (1982). The role of the renin-angiotensin and prostaglandin systems in salt-sensitive and non-salt-sensitive hypertension in man. In M. J. Fregly & M. R. Kare (Eds.), The Role of Salt in Cardiovascular Hypertension (pp. 207-219). New York: Academic Press. Grupp, L. A., Stewart, R. B., & Perlanski. E. (1983). Salt restriction and the voluntary intake of ethanol in rats. Manuscript submitted for publication. Iida, S. (1957). Experimental studies on the craving for alcohol. I. Alcohol drive in mice following administration of saline. Japanese Journal of Pharmacology, 6, 87-93. Jalowiec, J. E. (1974). Sodium appeUte ehcited by furosemide: Effects of differential dietary maintenance. Behavioral and Neural Biology, 10, 313-327. Kannel, W. B., & Sorlie. P. (1975). Hypertension in Framingham. In O. Paul (Ed.), Epidemiology and Control of Hypertension (pp. 553-590). New York: Stratton.
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Klatsky, A. L., Friedman, G. D., Siegelaub, A. B., & Gerard, M. J. (1977). Alcohol consumption and blood pressure. New England Journal of Medicine, 296, 1194-1200. Linkola, J. (1982). Strain differences in water and electrolyte metabolism between alcohol preferring (AA) and alcohol avoiding (ANA) rats. Minerva Foundation for Medical Research, Helsinki. Pfaffmann, C. (1957). Taste mechanisms in preference behavior. American Journal of Clinical Natrition, 5, 142-147. Reid, I. A., & Ganong, W. F. (1977). Control of aldosterone secretion. In. J. Genest, E. Koiw, & O. Kuchel (Eds.), Hypertension (pp. 265-292. New York: McGraw-Hill. Rice, K. K., & Richter, C. P. (1943). Increased sodium chloride and water intake of normal rats treated with desoxycorticosterone acetate. Endocrinology, 33, 106-115. Sargent, W. Q., Simpson, J. R., & Beard, J. D. (1974). Effect of acute and chronic alcohol administration on renal hemodynamics and monovalent ion excretion. Journal of Pharmacology and Experimental Therapeutics, 188, 461-471. Sargent, W. Q., Simpson, J. R., & Beard, J. D. (1980). Twenty-four-hour fluid intake and renal handling of electrolytes after various doses of ethanol. Alcoholism: Clinical and Experimental Research, 4, 74-88. Sargent, W. Q., Simpson, J. R., & Beard, J. D. (1981). Water metabolism and monovalent ion excretion during one day of multiple ethanol doses. Substance and Alcohol Actions/ Misuse, 2, 301-310. Schulkin, J. (1978). Mineralocorticoids, dietary conditions and sodium appetite. Behavioral and Neural Biology, 23, 197-205. Tobian, L. (1978). Salt and hypertension, Annals of the New York Academy of Science, 304, 178-202. Wallace, R. D., Lynch, C. F., Pomrehn, P. R., Criqui, M. H., & Heiss, G. (1981). Alcohol and hypertension: Epidemiologic and experimental considerations. Circulation, fi4(Suppl. III), 41-47. Williams, G. H., & Dluhy, R. G. (1977). Regulation of the renin-angiotensin-aldosterone axis in hypertension. In J. Genest, E. Koiw, & O. Kuchel (Eds.), Hypertension (pp. 292-312). New York: McGraw-Hill. Wolf, G., McGovern, J. F., & DiCara, L. V. (1974). Sodium appetite: Some conceptual and methodologic aspects of a model drive system. Behavioral and Neltral Biology, 10, 27-42. Yensen, R. (1958). Influence of salt deficiency on taste sensitivity in human subjects. Nature (London), 181, 1472-1474.