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UBC Theses and Dissertations

The induction of satiety in the rat Ehman, Gerard Kevan 1968

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THE INDUCTION OF SATIETY IN THE RAT by GERARD KEVAN EHMAN B i S c , University of B r i t i s h Columbia, 1966 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Arts i n the Department of Psychology We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA October, 1968 In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of the r e q u i r e m e n t s f o r an advanced degree a t the U n i v e r s i t y of B r i t i s h C olumbia, I a g r e e t h a t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and Study. I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u rposes may be g r a n t e d by the Head o f my Department or by h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g or p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Department The U n i v e r s i t y o f B r i t i s h Columbia Vancouver 8, Canada Date Abstract A number of peripheral changes possibly involved i n the i n i t i a t i o n of satiety were examined by i n j e c t i n g various substances into the duodenum. As neither the presence of food nor the pH was found to be important, i t was concluded that entry of metabolites into the blood, hormone release, and bulk i n the intestine are not s i g n i f i c a n t events i n the induction of satiety. I t was found, however, that the t o n i c i t y of the injected material was important: hypertonic solutions produced a depression i n food intake. The duration of the hypertonic effect was about Ih hours, but this could be shortened considerably by intraperitoneal water injec t i o n s . F i n a l l y , interference with normal digestion by blocking the passage of food and f l u i d s from the stomach to the intestine produced marked and rapid i n h i b i t i o n of intake. These results strongly supported an interpretation for satiety i n i t i a t i o n based upon changes i n blood t o n i c i t y . i i Table of Contents Page Abstract i Table of Contents. . i i L i s t of Figures. i i i Acknowledgement . i v Introduction . . . . . 1 Method 4 Cannulas, Sphincters, and Implantation Techniques . . 4 Injections and Measurement of Food Consumption. . . . 6 Results 7 The Effect of Food i 7 The Effects of pH and Osmotic Pressure. 9 The Duration of the Osmotic Effect; . . . .• .* . . . . 16 The Basis of the Osmotic Effect . . . . . . 16 Gastric Factors i n Satiety 20 Discussion » 26 References 28 L i s t of Figures Cumulative food intake of rats following eight 1.5 cc intraduodenal injections of food or Alphacel at 20 rain i n t e r v a l s . Cumulative food intake of rats following eight 1.5 cc intraduodenal injections of acidic or basic Alphacel at 20 rain i n t e r v a l s . Cumulative food intake of rats following single 3 cc intraduodenal injections of 0.9% or 9.0% saline. Cumulative food intake of rats following single 3 cc intraduodenal injections of 0.9% saline or 45% glucose. Cumulative food intake of experimental rats given single 3 cc intraduodenal injections of isosmotic hypertonic glucose or s a l i n e , compared with intake of control rats given 3 cc of isotonic saline. Cumulative food intake of rats beginning Ih h after receiving 3 cc intraduodenal loads of 0.9% or 9.0% s a l i n e ; water available ad l i b throughout. Cumulative food intake of rats with 6 cc i n t r a -peritoneal water loads administered immediately af t e r 3 cc intraduodenal injections of 0.9% or 9.0% s a l i n e . Cumulative food intake of rats following single 3 cc intraperitoneal injections of 0.9% or 9.0% saline. Cumulative food intake of rats following single 3 cc intraperitoneal injections of 45% glucose or 0.9% saline. Cumulative food intake of rats with and without blockage of the duodenum at the p y l o r i c sphincter. Acknowledgement The author would l i k e to acknowledge a considerable debt to Dr. D. J. Albert of the Department of Psychology. Not only did he support t h i s research, but his c r i t i c i s m s and suggestions during the research and subsequent wr i t i n g were invaluable. 1 Introduction The nature of the peripheral factors influencing satiety i s s t i l l poorly understood, i n spite of extensive experimental work during the past hundred years (reviewed by Grossman, 1967). P o t e n t i a l l y , satiety signals could arise anywhere along the alimentary canal, and be of three types: neural, humoral or metabolite. These could work singly or i n conjunction, be sequentially dependent or not, act d i r e c t l y or i n d i r e c t l y . On the basis of existing evidence, some p o s s i b i l i t i e s may be ruled out. Several types of studies have indicated that the role of oro-pharyngeal factors i n producing satiety i s minor. I t has been shown that o r a l prefeeding does decrease subsequent intake s l i g h t l y more than does gastric preloading of the same amount (5), but the r e l a t i v e i n e f f e c t i v e -ness of o r a l stimulation i n producing satiety i s clear from experiments using sham feeding (14,15). When an animal i s allowed to eat, but the food shunted externally from the esophagus before i t reaches the stomach, food consumption Is far i n excess of a normal meal. Examination of ga s t r i c factors reveals considerable evidence implying these may play a part i n satiety (2,5,10,17). For Instance, sham feeding i 3 inhibited by simultaneous stomach loading (15). In addition, pre-loading g a s t r a l l y with n u t r i t i v e or non-nutritive material i n excess of 20-25% (volume) of normal d a i l y intake shortly before a meal depresses i n -take, but allowing 4 h to elapse following the i n j e c t i o n so the stomach may empty, results i n no depression (15). Although i t Is l i k e l y , as these results suggest, that stomach influences are u t i l i z e d to some extent as signals i n the normal animal, both stomach denervation (4) and stomach removal (18) have no appreciable effect on the regulation of intake. Thus, while stomach signals may be s u f f i c i e n t to induce s a t i e t y , they are not 2 necessary. Since the stomach i s not needed for the normal regulation of intake, a mechanism causing satiety must be capable of acting from the lower gastro - i n t e s t i n a l t r a c t . Unfortunately, there have been few direct investigations of this p o s s i b i l i t y . Tests of several hormones released from the duodenum have given negative results i n terms of intake depression, with the exception of enterogastrone, and results with this hormone are contradictory (16,23). I t i s conceivable that metabolite absorption from the intestine and subsequent c i r c u l a t i o n i n the blood i s involved as a co n t r o l l i n g factor. Although evidence on the o r i g i n of the satiety signals has not c l e a r l y Implicated any single s i t e , there i s some evidence that these peripheral signals consist of blood-borne chemical changes. Hervey (13) found that as the hyperphagic members of pairs of parabiotic rats gained weight, the second members of the pairs reduced their intake and l o s t weight. Davis (9), recently found that blood transfusions from satiated rats to hungry rats resulted i n intake depression i n the hungry r a t s , but that results only held i f the satiated rats had not been fasted before they were fed. Both of these experiments suggest that a chemical agent may be involved i n the regulation of intake, but they do not indicate whether the agent i s normally responsible for the induction of sati e t y . An alternative to a s p e c i f i c blood-borne chemical substance being the agent i n satiety i s that a change i n the t o n i c i t y of the blood i s involved. This was f i r s t expressed by McCleary (19), who found that after preloading g a 3 t r a l l y with equal volumes of several substances, the amount of fructose or glucose solution ingested decreased as the osmotic pressure of the preloaded substance was increased. Subsequently, 3 Shuford (26) found that the drinking of equipreferable but non-isosmotic solutions of glucose and sucrose stopped when the osmotic pressure of stomach contents reached si m i l a r values, and that the volume ingested varied inversely with the t o n i c i t y of the solution. In addition, Schwartzbaum and Ward (24) found that hypertonic preloads tend to depress intake of s o l i d food; hypotonic to increase i t , without respect to the n u t r i t i v e value of the injected material. These and other experiments (27,28,29,30) not only provide a new approach to the regulation of s a t i e t y , but also an alternative explanation f o r many of the other findings. The existing evidence suggests that food i n the stomach normally induces sa t i e t y as a result of the osmotic pressure i t exerts. Bulk may also be involved as the physical l i m i t s of the system are approached. The present experiments are intended to evaluate this conclusion by observing the effect of i n j e c t i n g various substances Into the duodenum. The use of the duodenum rather than the stomach as the i n j e c t i o n s i t e i s possible be-cause the stomach i s not necessary for s a t i e t y , and the technique has the advantage of allowing bulk and osmotic factors to be examined under conditions different from those under which they were o r i g i n a l l y observed. The f i r s t experiments examine the effects of food, pH, and osmotic pressure. The results suggest that osmotic pressure i s the most effec t i v e i n inducing anxiety, and a number of further experiments are done to c l a r i f y the effect. 4 Me thod Twenty-four naive male hooded rats weighing approximately 250 g each were used (National Laboratories, Edmonton, A l t a . , Canada). These were implanted with stainless s t e e l duodenal cannulas, and housed i n separate cages under 24 h illumination during recovery and subsequent testing. With the exception of testing periods, the Ss were maintained ad l i b on water and Purina Lab Chow. Ten Ss were used for each experiment; a l l were food deprived for approximately 17 h. At the end of t h i s time, f i v e of the Ss were injected duodenally with the test substance, and f i v e with the control substance. Following the i n j e c t i o n s , cumulative food intake was recorded every 15 min for 2h h. Five days l a t e r , the Ss were re-run i n the opposite groups i n a standard counterbalanced design. The f i v e day i n t e r v a l was chosen so as to minimize the learning of a deprivation schedule. Cannulas, Sphincters, and Implantation Techniques The cannulas were 4-cra lengths of 15-ga hypodermic tubing. Each cannula required two polyethylene flanges to anchor i t to the muscle w a l l , and a polyethylene t i p for ins e r t i o n into the duodenum. The flanges were made by f l a r i n g the tubing (Intramedic, PE 240) to an 8-mm diameter i n a flame, and then cutting the tubing so as to leave a 6-mm shaft behind the f l a r e . The t i p was prepared by f l a r i n g the sane tubing only s l i g h t l y , and cutting tc \\ cm. To implant the cannulas, the Ss were anaesthetized with sodium pentobarbitol, the abdomen clipped and disinfected, and the i n c i s i o n i n 5 the skin made along the midline. A second i n c i s i o n was then made along the midline through the abdominal w a l l . The duodenum was exposed, a small i n c i s i o n made i n the dorsal surface about 1 cm below the py l o r i c sphincter, and the flare d end of the p l a s t i c t i p inserted. Using a purse s t r i n g s t i t c h , the cut edges of the intestine were sutured around the shaft of the tubing above the f l a r e , thus preventing the duodenum from slipping o f f . At this point, the metal cannula was f i t t e d with one of the f l a r e s , about lh cm from the end. Over the opposite end was f i t t e d a detachable point made of 13-ga hypodermic needle, which enabled the cannula to puncture the dorsal abdominal w a l l . The cannula was thrust through up to the flange. The polyethylene t i p inserted i n the duodenum was forced onto the end of the metal cannula, sulfanilamide sprinkled l i g h t l y over the wounds, and the abdominal wall and skin separately closed with cotton sutures. The second flange was f i t t e d t i g h t l y down over the cannula at the s k i n , and a p l a s t i c cap made by pinching the same polyethylene tubing with hot forceps was f i t t e d over the end of the cannula. L a s t l y , the S was injected with a broad spectrum p e n i c i l l i n ( C r y s t i c i l l i n ) . No cannulas were used i n the f i n a l experiments: instead, the Ss were f i t t e d with a r t i f i c i a l sphincters which could be opened or closed externally to control entry of food materials into the duodenum. A 1-cm piece of cannula tubing was attached l a t e r a l l y at one end of a cannula previously described. This was done by passing 2 i n . of a 5-in. piece of thin stainless s t e e l wire (0.25 mm) through the small tube, winding i t t i g h t l y around both pieces of tubing, and soldering. The wire was then covered with a 3-in. length of polyethylene tubing (Intramedic, PE 50) to prevent damage to the tissues. Sphincters were implanted i n the same way as cannulas, with the 6 following n o d i f i c a t i o n . After the abdominal i n c i s i o n , the f i r s t step was to f i t the sphincter with the in t e r n a l flange and detachable point, and thrust i t through the abdominal w a l l . Only then was the polyethylene-covered wire passed around the duodenum just below the p y l o r i c sphincter, and threaded through the cannula u n t i l i t protruded externally. The loop formed was about 2 cm i n diameter, and a loose suture to the duodenum kept i t from moving. The external flange was applied, the i n c i s i o n s closed, and the C r y s t i c i l l i n injected. For unknown reasons, t h i s operation was not very successful, only a 50% s u r v i v a l rate f i n a l l y being achieved. Injections and Measurement of Food Consumption Duodenal injections were performed with a 5-cc syringe f i t t e d with a 13-ga hypodermic needle, and a 6-in. length of polyethylene tubing which f i t t e d over the duodenal cannula. During i n j e c t i o n s , the plunger of the syringe would be removed, the appropriate volume of well-mixed solution poured In, and the plunger replaced. The cannula cap of the S was removed, the cannula unplugged with a s t i f f piece of wire, and the syringe tubing forced over the end. The syringe was shaken vigorously to prevent s e t t l i n g and compaction, and the contents rapidly injected. The i n j e c t i o n tubing was removed, and the cap replaced. Food consumption was measured cumulatively by presenting the Ss with in d i v i d u a l preweighed food cups containing p a r t i a l l y ground Purina Lab Chow p e l l e t s , prepared by putting the p e l l e t s through a coarse meat grinder. Every 15 min during the 2*g h period, the food cups were removed and replaced with other preweighed cups. Dropped or wasted food was collected underneath the cages on paper during each period, and added to v the cup before weighing. 7 Results The Effect of Food The f i r s t hypothesis tested was that some aspect of food i n the intestine may be capable of inducing satiety. The stomach contents (diluted with two volumes of water) of a rat on ad l i b feeding were injected into each of the experimental Ss i n eight 1.5-cc l o t s , at 20 oin i n t e r v a l s . Introduction of the slurry i n t h i s way not only approximated the normal contents of the duodenum, but also the length of time of stomach emptying. The dry weight of the injected food was approximately 1.5 g. To control for bulk factors, control Ss were injected at the same times with 1.5 cc of Alphacel (a non-nutritive bulk substance) i n physio-l o g i c a l (0.9%) saline. Ten Ss equipped with the duodenal cannulas and food deprived for approximately 17 h were used. Five Ss were injected with food, and f i v e with Alphacel. Fifteen min after the l a s t i n j e c t i o n , food was presented and intake measured cumulatively for 2h h. The Ss were re-run under the opposite conditions f i v e days l a t e r , i n a standard counterbalanced design. The results are shown i n Figure 1. Although the food-injected Ss ate less than the control animals, even the maximum differences at 2 h f a i l e d to achieve significance (p>.05, one-tailed t-test for correlated samples). While these results suggest that the presence of a di g e s t i b l e food i n the duodenum and lower small intestine does not induce s a t i e t y , the amount of food injected was small, and i t i s possible that a depression of intake might occur with i n j e c t i o n of a larger amount. Accordingly, three 10 FOOD N .= 10 ALPHACEL N = 10 Time in hours F i g u r e I. C u m u l a t i v e f o o d . i n t a k e o f r a t s f o l l o w i n g e i g h t I.5 c c i n t r a d u o d e n a I i n j e c t i o n s o f f o o d o r A l p h a c e l a t 20 m i n i n t e r v a l s . 9 17-h food-deprived Ss were injected with 30 cc of Alphacel and saline In ten 3-cc l o t s at 15 min i n t e r v a l s . Three other Ss were injected with 30 cc of a food and water mixture i n the same way. The mixture was prepared by removing the stomach contents of 17-h food-deprived rats 40 n i n after the beginning of ad l i b feeding, and d i l u t i n g these contents with two volumes of water. The dry weight of the food injected was approximately 5 g. Cumulative food intake was measured as before, and counterbalancing was carried out f i v e days l a t e r . Results again showed no s i g n i f i c a n t d i f f e r -ences between the groups. The lack of intake depression with food i n the duodenum would seen to eliminate the importance of absorbed metabolites, as well as hormones released on the presence of food, i n the induction of satiety. This conclusion i s strengthened by the observations made while obtaining the stomach contents of the donor r a t s . The 5 g (dry weight) of food injected exceeded by a factor of three the dry weight of food that normally passes into the duodenum from the stomach during the f i r s t 45 rain of eating. If the s a t i a t i n g factor was dependent on food i n the duodenum, the amount injected experimentally should produce a depression i n intake larger than that produced under normal conditions, due to the excess of injected material. By 45 n i n , the animal has eaten more than 60% of the t o t a l amount of food i t w i l l consume during the 2Jg~h period. Therefore, the intake of the experimental rats should have been less than 40% of normal. Since no differences were observed between the control and experimental animals, the importance of food i n the duodenum may be discounted. The Effects of pH and Osmotic Pressure Two p o s s i b i l i t i e s stand out as explanations for the f a i l u r e of food 10 to i n h i b i t eating. F i r s t , since the pH of the injected food was not as low as that which normally enters the i n t e s t i n e , secretagogic or other action of low pH i s not e n t i r e l y eliminated. Second, the food was diluted into a slurry form, and a test on the. s i m i l a r l y diluted stomach contents of four sample rats showed the s l u r r y to be e s s e n t i a l l y isotonic (freezing-point depression of the supernatant after centrifugation); thus, i t exerted no osmotic pressure. To test the importance of pH, each of ten Ss was injected duodenally with eight 1.5-cc lo t s of acidic (pH 3.0; HC1) or basic (pH 8.5; Na 2C0 3) Alphacel i n saline. To approximate the action of food coming from the stomach, injections were made every 20 min. Food deprivation was 17 h; f i v e Ss were used i n each group. Food intake was measured at 15 min intervals for 2% h, beginning 15 min after the f i n a l i njections. Counter-balanced re-running was carried out f i v e days l a t e r . The effects of pH are shown graphically i n Figure 2. There are no s i g n i f i c a n t differences i n food intake between the two groups (p>.05, one-tailed t e s t ) . The results suggest that pH as w e l l as pH dependent hormones do not contribute to the induction of s a t i e t y . To test the effects of osmotic pressure, food intake was measured after duodenal injections of single 3-cc loads of Alphacel i n either 0.9% (isotonic) or 9.0% saline. Five Ss were used i n each group, following 17 h of food deprivation. The 2^-h period of measurement of food intake began 15 rain after the i n j e c t i o n s . Counterbalancing was carried out after a f i v e day i n t e r v a l . The results are clear (Figure 3). The group injected with the hypertonic saline ate less than did the control group. Differences were s i g n i f i c a n t at the end of the f i r s t 15 min (p<.01, two-tailed t e s t ) , and increased u n t i l the 45-min nark, when they remained constant (aside from 11 a s l i g h t i n i t i a l drop) for another 45 min. Differences then steadily decreased u n t i l the end of the measurement period, although they remained s i g n i f i c a n t . To test whether the effect of hypertonicity i s limited to NaCl solutions, a second experiment was done i n which a solution of 45% glucose was used. (This i s isotonic with the 9% s a l i n e ) . Ten 17-h food deprived Ss were injected with a single 3-cc load of either 0.9% saline or 45% glucose without Alphacel. Cumulative food measurement began 15 min after the i n j e c t i o n s , and counterbalanced re-running was done f i v e days l a t e r . The results are presented i n Figure 4. The i n j e c t i o n of the hyper-tonic glucose produced a clear depression of intake which was s i g n i f i c a n t within 15 min (p<.01, two-tailed t e s t ) . In Figure 5, a comparison of the Intake curves f o r the Ss under both the glucose and hypertonic saline conditions i s given, along with th e i r control groups. Differences i n intake of the control groups were not s i g n i f i c a n t , nor were those of the experimental groups. The results show that the introduction of hypertonic solutions of either n u t r i t i v e or non-nutritive materials into the duodenum w i l l result i n a reduction i n the intake of s o l i d food. The absence of an effect due to the n u t r i t i v e value of the material injected agrees we l l with the lack of depression of intake with food injections. F i n a l l y , the nearly i d e n t i c a l intake of the control groups, only one of which received the Alphacel as w e l l as the s a l i n e , suggests that moderate bulk i s not a potent agent for inducing satiety. ACID N= 10 0=15 0:30 0:45 1:00 1:15 130 1:45 2:00 2;15 2 3 0 ~ ~ Time in hours F i g u r e 2. C u m u l a t i v e f o o d i n t a k e o f r a t s f o l l o w i n g e i g h t I.5 c c i n t r a d u o d e n a l i n j e c t i o n s o f a c i d i c o r b a s i c A l p h a c e l a t 2 0 min i n t e r v a l -Time in hours F i g u r e 3. C u m u l a t i v e food i n t a k e o f r a t s f o l l o w i n g s i n g l e 3 c c i n t r a d u o d e n a l i n j e c t i o n s o f 0.9'/, o r 9.0% s a l i n e . . 4 5 % G L U C O S E N = 10 _ 0 . 9 % S A L ! N E N = 10 0:15 0 :30 0:45 1:00 1 Time M5 1 3 0 1:45 2 : 0 0 2115 2:30 i n hours F i g u r e 4.' C u m u l a t i v e f o o d i n t a k e o f r a t s f o l l o w i n g s i n g l e 3 c c i n t r a d u o d e n a l i n j e c t i o n s o f 0.9% s a l i n e o r g l u c o s e . 1 0 r CONTROLS C u m u l a t i v e 6 food intake (9) N =10 N =10 CONTROLS 4 5 % GLUCOSE N = 10 9.0% SALINE N=10 0:15 0:30 0:45 1:45 2:00 •10 2:30 1:00 1:15 1:30 Time in hours F i g u r e 5 . C u m u l a t i v e food i n t a k e o f e x p e r i m e n t a l r a t s g i v e n s i n g l e 3 c c i n t r a d u o d e n a I i n j e c t i o n s o f i s o s m o t i c h y p e r t o n i c g l u c o s e o r s a l i n e , compared' w i t h i n t a k e of c o n t r o l r a t s g i v e n 3 c c of i s o t o n i c s a l i n e . 16 The Duration of the Osmotic Effect The o r i g i n a l experiment on osmotic pressure i n which the 9% saline was injected duodenally suggests that the effect of the hypertonic solution may be wearing off after about Ih h. This p o s s i b i l i t y was examined by in j e c t i n g the Ss with hypertonic saline and waiting 1% h before presenting the food. Ten Ss were food deprived for 17 h, and then injected with 3 cc of either 9.0% or 0.9% saline i n Alphacel. After the in j e c t i o n s , a 1%-h in t e r v a l was allowed to elapse before presentation of the food for the 2%-h cumulative intake measurements. Water was available ad l i b through-out. Counterbalanced re-running was carried out f i v e days l a t e r . The results (Figure 6) showed a residual depression i n food intake for the Ss receiving the 9% salin e . These Ss i n i t i a l l y ate s l i g h t l y but consistently less than did the control Ss. The difference i n cumulative intake increased to a maximum at 45 min, at which point the difference became s i g n i f i c a n t (p<.05, one-tailed t e s t ) . Thereafter, the depression disappeared, and the differences decreased. During the la s t half hour, the 9% saline-injected rats surpassed the control rats i n amount eaten, although not s i g n i f i c a n t l y . The Basis of the Osmotic Effect An osmotic effect which w i l l depress food intake has been shown as capable of acting from the duodenum. I t seems reasonable that this effect i s due to a systemic dehydration caused by a net flow of water from the blood into the lumen of the int e s t i n e . The following experiment was designed to test t h i s p o s s i b i l i t y . Conditions i n the duodenum were made 0.9%SALINE'N=10 9.0% SALINE N=10 Time in hours F i g u r e 6. C u m u l a t i v e food i n t a k e o f r a t s b e g i n n i n g I j h a f t e r r e c e i v i 3 c c i n t r a d u o d e n a l l o a d s of 0.9?, o f 9 . 0 ? , . s a l i n e ; w a t e r a v a i l a b l e ad I i t h r o u g h o u t . 18 hypertonic by i n j e c t i n g saline solution; immediately afterwards, water was injected into the peritoneal cavity. If the reduction i n food intake i s caused by systemic dehydration, the effect should be reduced or abolished by"intraperitoneal injections of water. Ten Ss f i t t e d with the duodenal cannulas were food deprived for 17 h. Equal numbers of these Ss then received single 3-cc injections of Alphacel i n either 9.0% or 0.9% saline. A l l Ss also simultaneously received 6 cc of water intraperitoneally. Fifteen rain l a t e r , food was presented and the amount eaten recorded cumulatively for 2h h. Counter-balanced re-running occurred f i v e days l a t e r . The results are presented i n Figure 7. The Ss receiving the hyper-tonic saline i n i t i a l l y ate le s s , the maximum difference being achieved at the 30-min mark (p<.01, two-tailed t e s t ) . Subsequently, however, differences between groups decreased rapidly, and by 1% h were no longer s i g n i f i c a n t . These results d i f f e r markedly from those of the i n i t i a l experiment with hypertonic s a l i n e , i n which no water was administered. In the f i r s t experiment, differences remained s i g n i f i c a n t u n t i l the end of testing. Dehydration with i t s consequent change i n blood t o n i c i t y i s thus strongly implicated as a co n t r o l l i n g factor i n the i n i t i a t i o n of sati e t y . Another way of testing the effect of systemic dehydration on satiety i s to simply vary hydration d i r e c t l y , without using the alimentary canal. In the following two experiments, this was done by inj e c t i n g a hypertonic solution intraperitoneally. Ten naive male hooded rats weighing approximately 250 g were food deprived for 17 h. Five animals were intraperitoneally injected with 3 cc of 9.0% s a l i n e , and f i v e control animals with 3 cc of 0.9% saline. Food intake was measured cumulatively, beginning 15 min after the 10r „___9.0°/o SALINE N=10 9- 0.9% SALINE N =10 8r-7h Time in hours F i g u r e 7. C u m u l a t i v e f o o d i n t a k e of r a t s w i t h 6 c c i n t r a p e r i t o n e a l w a t e r l o a d s a d m i n i s t e r e d i m m e d i a t e l y a f t e r 3 c c i n t r a d u o d e n a I i n j e c t i o n s o f 0.9$ o r '9.0? s a l i n e . • * . 20 Injections. Five days l a t e r , the Ss were counterbalanced and re-run. Results of the experiment are presented i n Figure 8. The 9% saline delivered intraperitoneally produced a pronounced depression i n intake, much nore than the sane solution injected duodenally i n an e a r l i e r experi-ment . The experiment was repeated, using a 45% glucose solution instead of 9.0% saline. A graph of these results i s found i n Figure 9. The Ss with the glucose injections ate s i g n i f i c a n t l y less than the control Ss with the 0.9% saline injections (p<.001). In addition, the glucose injected Ss ate s i g n i f i c a n t l y less than the 9% saline injected Ss of the previous experiment (p<.01). The results indicate that systemic dehydration w i l l suppress food intake. The amount of suppression i n the l a s t two experiments exceeds expectations, however, and this nay be due to a confounding variable. Most of the Ss were adversely affected by the hypertonic solutions. Saline-injected Ss almost invariably suffered from spasmatic contractions of t h e i r rear extremities for from. 1 - 2 n i n , and glucose-injected Ss evidenced severe discomfort. However, by the tine food was presented, the Ss appeared normal, and i t i s u n l i k e l y that trauma was completely responsible for the intake depression. The reason for the quantitatively different effects of glucose and saline are not at present clear. Gastric Factors i n Satiety In normal feeding, the osmotic effect which has been demonstrated i n the intestine would not occur, as the chyme entering the intestine i s v i r t u a l l y isotonic (18). Any osmotic e f f e c t s , then, must normally take place i h the stomach, and the role of the intestine may be the resorption 10 9 8 .9.0% SALINE N = 10 Q.9% SALINE N= 10 Cumulative 6j-food intake (9) 0:15 0:30 0:45 1:00 1:15 130 1:45 2:00 2-15 230 Time in hours F i g u r e 8. ' C u m u l a t i v e f o o d i n t a k e o f r a t s f o l l o w i n g s i n g l e . 3 c c i n t r a p e r i t o n e a l i n j e c t i o n s o f 0.9% o r 9.0/) s a l i n e . 10i A5%GLUCOSE N=10 . 0 . 9 % SALINE N=10 C u m u l a t i v e 6f f o o d in take (9) T ime in hours F i g u r e 9. C u m u l a t i v e food i n t a k e of r a t s f o l l o w i n g s i n g l e 3 c c i n t e r a p e r i t o n e a l i n j e c t i o n s o f A5% g l u c o s e o r 0.9% s a l i n e . 23 of the f l u i d so as to at least p a r t i a l l y maintain normal blood t o n i c i t y . If t his reasoning i s v a l i d , then blockage of the intestine so that f l u i d s cannot enter should result i n faster systemic dehydration, and more rapid cessation of eating. This hypothesis was tested by measuring the cumulative food intake of rats f i t t e d with duodenal sphincters, which could prevent gastric f l u i d from entering the duodenum. Six Ss f i t t e d with the sphincters were food deprived for 17 h, t h e i r sphincters l e f t open, and cumulative food intake then measured every 15 min for 2h h. Five days l a t e r , the Ss were again food deprived for 17 h, the i r sphincters closed, and food intake measured beginning 15 min after sphincter closure. Results of this experiment support the hypothesis (Figure 10). Amounts eaten by the Ss with the sphincter open were comparable to the control Ss i n previous experiments. Closure of the sphincter, however, resulted i n a complete cessation of eating after 20 min. In view of the rapid suppression of eating with closed sphincters, i t was f e l t that an estimate of the volume of stomach secretion might indicate the extent of the dehydration occuring with these Ss. In order to arrive at such an estimate, f i v e Ss were food deprived for 17 h, t h e i r sphincters closed, food and water presented 15 min after closure, and intake measured for h h. These Ss were then s a c r i f i c e d , and their stomach contents removed and measured. Since the volume of water drunk and the amount eaten were known, the volume secreted could be calculated. The average food intake of the f i v e Ss was 1.85 g, amount drunk was 4.6 g ( t o t a l intake 6.45 g), and the amount secreted was 6.55 g. I t i s evident that the volume of stomach secretion i s considerable. The average weight of the rats was 300 g, so the Ss secreted 2.2% of t h e i r body weight. Although most of this water normally passes rapidly 24 into the intestine, drinking is initiated with a water loss of only 0.5% (1) of body weight: therefore, i t is evident that considerable dehydration could occur, depending on the rate of intestinal resorption. SPHINCTER OPEN N=6 SPHINCTER CLOSED N= 6 Time in hours F i g u r e 10. C u m u l a t i v e food i n t a k e o f r a t s w i t h and w i t h o u t b l o c k a g e of theduodenum at. t h e p y l o r i c s p h i n c t e r . Discussion 26 The results of these experiments indicate that a change i n the equilibrium of the body f l u i d s i n i t i a t e s s a t i e t y . The s i t e from which this effect arises seems not to be c r i t i c a l , although these findings are consistent with others (19,24,26,27,28,29,30) which suggest that i t i s high osmotic pressure i n the stomach which i s normally important i n producing the effect. Other factors, such as bulk, duodenal hormones, n u t r i t i v e value of the food, and body temperature increase upon digestion ( s p e c i f i c dynamic action) are apparently not involved i n the I n i t i a t i o n of s atiety. The interpretation of the results raises two important questions. The f i r s t i s whether a change i n the body f l u i d equilibrium l a s t s long enough to maintain satiety from meal to meal. Indications are that i t may not. Not only does most of the large amount of stomach secretion pass rapidly into the intestine where i t i s resorbed, the extra water due to drinking i s also passed and absorbed. Thus, while there may be a net i n i t i a l change, the natural process of digestion i s working to restore the equilibrium. Some additional support for a short duration for the effect i s provided by the data from the 9% duodenal saline in j e c t i o n s , i n which the depressant effect was found to be largely over by lh h. I f the phenomenon i s a r e l a t i v e l y short term one, another mechanism must come into play at a l a t e r time. These experiments provide no indication as to what this other mechanism might be, but i t i s possible that i t i s a blood factor (9). The second question i s whether the intake depression observed i n a l l experiments using hypertonic solutions i s merely a function of the animals' being t h i r s t y , rather than satiated, since i t i s known that normal eating produces t h i r s t (7). Certainly, the two are intimately related. I f i t were true that eating was inhibited by the animal being t h i r s t y , i t would be expected that the animal would continue to drink u n t i l I t was no longer t h i r s t y , and then go back to eating. This does not happen; the animal stops both eating and drinking. Furthermore, subjectively we f e e l satiated, but not t h i r s t y at the end of a meal. I t i s possible that dehydration produces t h i r s t only, and that other factors are responsible for producing sat i e t y . However, i n the l i g h t of the negative evidence i n this and other papers (4,18), i t i s hard to imagine what these other factors might be - p a r t i c u l a r l y i n view of the fact that the factor must be capable of acting from the duodenum as w e l l as the stomach. The question then becomes one of how the animal d i f f e r -entiates between being satiated and being t h i r s t y , i f dehydration i s involved i n both conditions. I t i s suggested that future experimental work i n the area be addressed to this question. 28 References 1. Adolph, E. F. Physiological Regulations. Ronald Press: Lancaster, Pa., 1943. 2. Adolph, E. F. Urges to eat and drink i n rats. Amer. J. Physiol., 1947(a), 151, 110 - 125. 3. Adolph, E. F. Water metabolism. Ann. Rev. Physiol., 1947(b), j), 381 - 408. 4. Bash, K. W. An investigation into a possible organic basis for the hunger drive. J. comp. physiol. Psychol. , 1939, 28, 109 - 134. 5. Berkun, M. M., Kessen, M. L., & M i l l e r , N. E. Hunger-reducing effects of food by stomach vrs food by mouth measured by a consummatory response. J . comp.  physiol. Psychol., 1952, 45, 550- - 554. 6. Busch, H. In Cannon, W. B., & Washburn, A. L. An explanation of hunger. Amer. J. Physiol., 1912, ^9, 444 - 454. 7. Calvin, A. D., & Behan, R. H. The effect of hunger on drinking patterns i n the rat. B r i t . J. Psychol., 1954, 45, 294 - 298. 8. Cannon, W. B., & Washburn, A, L. An explanation of hunger. Amer. J. Physiol., 1912, 29, 444 - 454. 9. Davis, J. D., Gallagher, R. L., & Ladove, R. Food intake controlled by a blood factor. Science, 1967, 156, 1247 - 1248. 10. Epstein, A. N., & Teitlebaum, P. Regulation of food intake i n the absence of smell, taste, and other oropharyngeal factors. J. comp. physiol. Psychol., 1962, 55, 753 - 759. 11. Gregory, R. A. Secretory Mechanisms of the Gastro-intestinal Tract. Arnold: London, 1961. 12. Grossman, S. P. A Textbook of Physiological Psychology. John Wiley & Sons: New York, 1967. 13. Hervey, G. R. The effects of lesions i n the hypothalamus i n para-b i o t i c rats. J. Physiol. (London), 1959, 145, 336 - 352. 14. H u l l , C. L. , Livingston, J. R., Rousse, R. 0., & Barker, A. N. True, sham and esophageal feeding as reinforcements. J. comp. physiol. Psychol., 1951, 44, 236 - 245. 29 15. Janowitz, H. D., & Grossman, M. I. Some factors affecting the food intake of normal dogs and dogs with esophagostomy and gastric f i s t u l a e . Amer. J. Physiol., 1949, 159, 143 - 148. 16. Janowitz, H. D. , & Grossman, M. I. Effect of pre-feeding alcohol and b i t t e r s on food intake of dogs. Amer. J. Physiol., 1951, 164, 182. 17. Kohn, M. Satiation of hunger from food injected d i r e c t l y into the stomach vrs. food ingested by mouth. J. comp. physiol. Psychol. , 1951, 44, 412 - 422. 18. MacDonald, R. M. , Ingelfinger, F. J . , & Belding, H. W. Late effects of t o t a l gastrostomy i n man. New Engl. J. Med., 1947, 237, 887. 19. McCleary, R. A. Taste and post-ingestion factors i n s p e c i f i c hunger behaviour. J. comp. physiol. Psychol., 1953, 46, 411 - 421. 20. Pavlov, I. P. The Work of the Digestive Glands. Trans. W. H. Thompson. G r i f f i t h s : London, 1902. 21. Peters, J. P., & Van Slyke, D. D. Quantitative C l i n i c a l Chemistry. Interpretations. Vol. 1 (2nd ed.), Williams & Wilkins: Baltimore, 1946. 22. Richter, C. P. The Harvey Lectures. 1943, _38, 63 - 103. 23. Schally, A. V., Redding, T. W., Lucien, H. W., & Meyer, J. Entero-gastrone i n h i b i t s eating by fasted mice. Science, 1967, 157. 210 - 211. 24. Schwartzbaum, J. S., & Ward, H. P. An osmotic factor i n the regulation of food intake i n the rat. J. comp. physiol. Psychol., 1958, 5J_, 555 - 560. 25. Scott, E. M., & Quint, E. Self selection of d i e t , II - the effect of flav o r . J. N u t r i t . , 1946, 32, 113 - 119. 26. Shuford, E. H., J r . Relative acceptability of sucrose and glucose solutions i n the white rat. 1955. In Young, P. T., Psychologic factors regulating the feeding process. Symposium i n Nutriti o n and Behaviour. The National Vitamin Foundation: New York, 1957. 27. Smith, M. Effects of intravenous injections on eating. J. comp. physiol. Psychol., 1966, 11 - 14. 28. Smith, M., & Duffy, M. The effects of in t r a g a s t r i c i n j e c t i o n of various substances on subsequent bar-pressing. J. comp. physiol. Psychol., 1955, 48, 387 - 391. 30 29. Smith, M., & Duffy, M. Some physiological factors that regulate eating behavior. J. comp. physiol. Psychol., 1957, 50, 601 - 608. 30. Smith, M., Pool, R. , & Weinberg, H. The effect of peripherally -induced shifts in water balance on eating. J. comp. physiol. Psychol. , 1959, 5J2, 289 - 293. 

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