effects of quinine adulterated diets on the food intake and body weight of obese and non-obese...

Physiology & Behavior, Vol. 16, pp. 631-640. Pergamon Press and Brain Research Publ., 1976. Printed in the U.S.A.

Effects of Quinine Adulterated Diets on the Food Intake and Body Weight of Obese and Non-Obese Hypothalamic Hyperphagic Rats'

ANTHONY SCLAFANI, DELERI SPRINGER AND LAWRENCE KLUGE

Department o f Psychology, Brooklyn College o f the City University o f New York Brooklyn N Y 11210

(Received 20 December 1973)

SCLAFANI, A., D. SPRINGER AND L. KLUGE. Effects of quinine adulterated diets on the food intake and body weight of obese and non-obese hypothalamic hyperphagic rats. PHYSIOL. BEHAV. 16(5) 631-640, 1976. - Female rats given knife cuts between the medial and lateral hypothalamus overate and became obese on a high fat diet. When switched to a quinine diet the knife cut rats initially underate and lost weight, but their body weights did not fall significantly below that of controls maintained on the same diet. Knife cut rats also maintained weights at control levels when given a moderately bitter quinine diet immediately after surgery, but displayed subnormal weights when switched to a very bitter diet. Cuts lateral to the fornix produced a greater weight suppression on the quinine diet, but a smaller weight gain on a high fat diet than did cuts medial to the fornix. The results indicate that the hypothalamic knife cuts elevate the upper limit of body weight with little or no change in the lower body weight limit, and that obesity rather than hypothalamic damage per se is the major cause of the hyperphagic rat's finickiness to unpalatable quinine diets. A dual lipostatic model of the hypothalamic hyperphagia syndrome is discussed.

Hypothalamic hyperphagia Medial and lateral perifornical knife cuts Hunger appetite Lipostatic model

Body weight regulation Finickiness

DAMAGE to the ventromedial hypothalamus (VMH) produces hyperphagia and obesity but only when the feeding conditions are favorable, that is when food is good tasting and easily available. When required to work hard for food, or eat unpalatable diets VMH damaged animals fail to overeat and may even undercut relative to intact controls [11, 12, 21, 22]. The motivational deficits displayed by hypothalamic hyperphagic rats have now been found to be primarily the result of their obesity rather than from brain damage per se. That is, several recent studies have demonstrated that hyperphagic rats display normal food motivated behavior when their body weights are restricted to control levels, but subnormal performance when tested at obese weights [ 10, 13, 20].

Based on these findings Sclafani and Kluge [20] proposed that the hyperphagic rat's increased aversion or finickiness to unpalatable diets is also a result of their being overweight rather than being a direct effect of hypothalamic damage. Kennedy [8] had much earlier proposed a similar interpretation and he, as well as Teitelbaum [21] provided some supporting evidence, but this hypothesis has not been rigorously tested until recently [3,4]. Alternative

explanations of hypothalamic finickiness have also been offered. For example, it has been suggested that finickiness results from a lesion-produced deficit in hunger motivation [11], from an increase in affective reactivity [6], or from a neural disorder independent from that responsible for the hyperphagia and obesity [ 5].

The present study further examined the hypothesis that obesity is the major cause of hypothalamic finickiness. Specifically, Experiment 1 tested the prediction of Kennedy [8] and Sclafani and Kluge [20] that obese hyperphagic rats given an unpalatable diet would undereat and lose weight only until their weight reached that of controls fed the same diet, and would then maintain their body weight and food intake at control levels. A second purpose of Experiment 1 was to examine the hyperphagic rat's response to food deprivation. Previous studies have reported that hyperphagic animals do not display the normal increase in food intake produced by periods of food deprivation [ 11,12]. The recent motivational studies cited above suggest, however, that hyperphagic animals should show normal deprivation induced feeding if they are tested at control body weights.

This research was supported by National Institute of Mental Health Grant MH 21563 and by Grants 1743 and 10103 from the Research Foundation of the City University of New York.

631

632 SCLAFANI, SPRINGER AND KLUGE

EXPERIMENT 1

METHOD

Animals

Twenty adult female CFE rats obtained from Carworth (N.Y.) were used. The rats, which weighed 220 -250 g at the beginning of the experiment, were individually housed in wire mesh cages in a colony room under continuous illumination.

Surgery and histology. The rats were anesthetized with Equithesin (2.5 cc/kg BW) and received either hypothalamic knife cuts or sham operations. Bilateral parasagittal knife cuts were made between the ventromedial and lateral hypothalamus (VL Cuts) using the encephalotomy procedure described by Sclafani [ 14]. The guide shaft of the knife was positioned at the de Groot [2] coordinates AP = 8.0, H = 0, L = 1.0, and a 3 mm length of cutting wire was extended posterior to the shaft. The shaft and wire were then lowered to the base of the brain and returned to H = 0 three times before the wire was retracted into the shaft and the knife withdrawn from the brain. Of the initial 20 animals, 8 rats formed the VL Cut group, and 7 rats formed the control group. The remaining rats were dis- carded because of postoperative death (n = 4) or failure to display hyperphagia (n = 1).

At the completion of the study the knife cut rats were perfused intracardially with saline and formol-saline. Frozen sections through the hypothalamus were prepared and stained with cresyl violet. Examination of the brain sections revealed bilateral knife cuts in the perifornical region between the VMH and LH and extending from the anterior to posterior hypothalamus as indicated in Fig. 1. The cuts were located just medial or lateral to the fornix bundle and extended from the level of the fornix to the base of the brain.

Procedure

Part 1. Daily measures of ad lib food and water intake, and body weight were taken for 8 days before and for several weeks following surgery. The animals were maintained on the following diets which were presented in small ceramic dishes: (1)Preoperative and postoperative Days 1-10: high fat diet consisting of 33% Crisco and 67% Purina powder diet; (2)Days 11-20: unadulterated dry Purina powder diet; (3) Days 21-30 : 0.025% quinine diet prepared by mixing one part 0.1% quinine hydrochloride solution with 3 parts of Purina powder; (4) Days 31 -63 : 0.1% quinine diet prepared by mixing one part 0.4% quinine solution with 3 parts of Purina powder. On Days 41 to 43 and 54 to 63 a 0.01% quinine solution replaced tap water as the only drinking fluid available. Although food intake was recorded excessive spillage of the quinine diets made the intake measures unreliable and they are not reported.

Part 2. The animals were switched from the 0.1% quinine diet to the high fat diet and were so maintained for 50 days. They were then returned to the 0.1% quinine diet for 35 days followed by 7 days on a 0.4% quinine diet (one part 1.6% quinine solution to 3 parts Purina powder). Spillage was greatly reduced by presenting the diets in a small (4 oz) jar located within a larger (16 oz) jar fastened to the inside front wall of the cage.

Part 3. The animals were taken off the quinine diet and given unadulterated dry Purina powder. Ten days later they

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FIG. 1. Schematic representation of VL knife cuts and range of variation in their medial-lateral position (shaded area).

were given 3 tests of deprivation induced eating. One hour food intakes were recorded at the same time each day following deprivation periods of 0.5 hr (Day 10), 4 hr (Day 12), and 24 hr (Day 14). One control animal was excluded from this test because of illness.

RESULTS

Part 1. The results of Part 1 are summarized in Fig. 2. Following surgery the VL Cut rats were hyperphagic and gained 46 g (range = 30 to 66 g) in body weight by the end of the 10 day high fat diet period. The control rats gained only 7 g (range = 1 to 11 g) during this period. When switched to the plain powder diet the VL Cut animals stopped overeating and maintained their weights at a stable level which was significantly (p<0.05) higher than that of the controls. On the 0.025% quinine diet, however, the cut rats lost weight to a level only slightly, and not significantly

DIET PALATABILITY AND BODY WEIGHT 633

2 8 0

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.01% QHCL SOLN.

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I I I I 1 10 20 30 40 50 6 0

DAYS

FIG. 2. Body weight of VL-CUT and CON groups maintained on high fat, Purina powder, 0.025% quinine, and 0.1% quinine diets. Operations were performed at time indicated by arrow.

above control weights. Unlike the VL Cut animals, the control animals were not affected by these diet changes and continued gaining weight at the same rate on the high fat, powder, and 0.025% quinine diets. When given the 0.1% quinine diet the VL Cut rats displayed a further body weight loss until their weights became stabilized at the level of the control rats. The 0.1% quinine diet also slightly reduced the weights of the controls.

Prior to the first quinine water test the VL Cut rats consumed less tap water than did the controls (22 vs. 30 ml) on the 0.1% quinine diet, although this difference failed to be significant. When the 0.01% quinine solution was available, however, the VL Cut group consumed significantly (p<0.01) less solution compared to the con- trois (10 vs. 20 ml). Likewise, the VL rats drank less (p<0.05) quinine water solution than did the controls during the last 3 days of the second quinine water test (16 vs. 25 ml). During the quinine solution tests the VL Cut rats lost more body weight than did the controls, but their weights still were not significantly below control levels.

Part 2. The food intake and body weight findings of this part of the experiment are summarized in Table 1 and Fig. 3. When returned to the high fat diet the VL Cut rats were again hyperphagic and rapidly gained weight. The control rats also initially overate until they recovered the weight lost on the quinine diet, but their food intake and body weight remained below (p<0.01) that of the VL Cut group throughout the 50 days on the high fat diet. When switched back to the 0.1% quinine diet both the VL Cut and control groups underate and lost weight. This effect was most profound in the VL Cut group as they ate less (p<0.05) quinine diet and lost much more weight than did the controls. The body weight of the VL Cut group, however, did not fall below that of the controls, and by the end of the 35 day period there was no significant difference between the 0.1% quinine diet intakes of the VL Cut and

control groups. The cut and control rats both displayed similar body weight reductions when offered the 0.4% quinine diet, and although the cut rats consumed less of this diet than did the controls, this difference failed to be significant (Table 1). Part 3. Both the VL Cut and control rats increased their food intake and body weight when switched from the quinine diet to the plain powder diet. By the 10th day on the powder diet the mean body weight of the knife cut group (284 g) was slightly but not significantly above that of the controls (269 g).

The results of the deprivation tests are illustrated in Fig. 4. There were no significant differences between the one hr food intakes of the VL Cut and control groups, F(1,11) = 0.005, and both groups increased their food intake as the deprivation period increased, F(2,2) = 22.7, p<0.05.

DISCUSSION

The results of this experiment confirm the predictions of Kennedy [8] and Sclafani and Kluge [20] that obesity is the major cause of hyperphagic rats' finickiness to unpalatable diets. The obese VL Cut rats initially underate and lost weight when switched from the high fat to the quinine diets, but their body weights did not fall significantly below that of the controls maintained under the same conditions, even when these conditions included a 0.4% quinine diet or a 0.1% quinine diet paired with a 0.01% quinine solution. Also, the cut rats while initially undereating the quinine adulterated foods, did not eat significantly less of these diets compared to controls when their body weights reached control levels. Very similar findings have recently been reported by Franklin and Herberg [4]. In their study VMH lesioned rats fed one hr/day were observed to undereat a quinine diet when they


H I G H FAT . 1 % QHCL

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FIG. 3. Body weight of VL-CUT and CON groups maintained on high fat, 0.1% quinine, and 0.4% quinine diets.

TABLE I

MEAN FOOD INTAKE OF VL-CUT AND CON GROUPS MAINTAINED ON HIGH FAT AND QUININE DIETS

High Fat 0.1% QHCI 0.4% QHCI days 1-5 46-50 51-55 81-85 86-92

VL-CUT kcal 112.4* 82.9* 25.6t 61.4 50.6 grams 20.4* 15.1 * 9.5t 22.7 18.7

CON kcal 90.5 61.2 40.8 60.5 59.6 grams 16.4 I 1.1 15.1 22.4 22.1

*Significantly different from controls, p <0.01. tSignificantly different from controls, p<0.05.

were obese, but not when their weights were reduced to that of controls fed the same diet.

The present results further revealed that nonobese hyperphagic rats display normal increases in their food intake following varying periods of food deprivation. This is consistent with the recent observations that nonobese hyperphagic rats also show normal food motivated performance in a variety of test conditions when they are food deprived and at control body weights [I0, 13, 20]. Earlier studies, however, reported deficient ingestive and operant responses in deprived hyperphagic animals [ 1 1,12 ]. It is possible that these previous results were obtained because the hyperphagic animals were overweight at time of testing, or had received damage extending into the lateral perifornical area (see below).

EXPERIMENT 2

While the results of Experiment 1 demonstrated that hyperphagic rats allowed to become obese maintained their

body weights at control levels when switched to an unpalatable diet, other studies performed in this laboratory (Gale and Sclafani, unpublished) indicate that knife cut animals may display below normal weights if fed quinine diets before and immediately after surgery. Experiment 2 was conducted to examine this possibility further, as well as to replicate the results of the first experiment. Another purpose of this experiment was to compare the effects on body weight of knife cuts placed medial and lateral to the fornix since our previous work [ 17, 18, 19] indicates that the exact parasagittal plane of transection is an important factor determining the hyperphagia and finickiness produced by hypothalamic knife cuts.

METHOD

Anima l s

Forty adult female CFE rats (Carworth, N.Y.) were used. The rats weighed 2 1 0 - 2 7 0 g at the time of surgery


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and were individually housed in a colony room under a 12 hr l ight -dark cycle.

Surgery and histology. Surgery and histology were performed as in Experiment 1. Bilateral parasagittal knife cuts were placed either medial to the fornix at lateral plane L = 0.8 in 16 rats, or lateral to the fornix at L = 1.5 mm in 16 rats, while the remaining 8 animals received sham operations. One sham operated and 6 cut rats died shortly after surgery. The control group, therefore, contained 7 sham operated rats, and the Medial Cut and Lateral Cut groups were reduced to 7 animals each by selecting the 7 rats in each group which gained the greatest weights on the high fat diet.

Examination of the histological material revealed that the L = 0.8 cuts were medial to the fornix bundle, and the L = 1.5 cuts were lateral to the fornix in all cases. As indicated in Fig. 5 both the medial and lateral cuts extended from the anterior to posterior hypothalamus just caudal to the ventromedial nucleus, and from the fornix to the base of the brain.

Procedure

Daily food and water intake, and body weight were recorded for 12 days before and for several weeks following surgery. Preoperatively and for the first 13 postoperative days the animals were given a 0.2% quinine diet. This diet

FIG. 5. Schematic representation of Medial Cuts (solid line) and Lateral Cuts (dashed line).

was prepared by thoroughly mixing with an electric stirrer 2 g of quinine hydrochloride with 998 g of Purina powder. This dry diet was presented in a 4 oz glass jar located within a 16 oz jar attached to the inside front wall of the cage. The animals were next given a 0.4% quinine diet for 8 days, and then a 0.8% quinine diet for another 8 days. Following this, the animals were offered the high fat diet (33% Cricso, 67% Purina) for 40 days. On Days 7 and 8 of the high fat diet a 0.01% quinine solution replaced tap water as the only drinking fluid. Six days later the rats were placed on a restricted feeding schedule (12g high fat diet/day) in order to equate the water intakes of the two cut groups with that of the controls. In successive 2 day tests the animals' intakes of tap water, 0.125% sodium saccharin, tap water, and 0.01% quinine solution were recorded. The rats were then returned to ad lib access to


the high fat diet and tap water. After 40 days on this diet they were switched back to the 0.2% quinine diet for 50 days.

RESULTS

The results of the first part of this experiment are summarized in Fig. 6. Preoperatively there were no significant differences in the food intake and body weight of the three groups, although the Medial Cut rats weighed (230 g) slightly less than did the controls (244 g) and Lateral Cut (245 g) animals. Following surgery the food intake and body weight gain of the Medial Cut rats on the 0.2% quinine diet were very similar to that of the controls (Fig. 6). The Lateral Cut group, on the other hand, was initially hypophagic following surgery and lost weight relative to the control group. They then rapidly recovered their weight loss by increasing their intake of the 0.2% quinine diet to above.control levels (p<0.05).

30 / ] . 2 % QHCL . 4 % QHCL , 8 % QHCL

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FIG. 6. Postoperative food intake and body weight gain of Medial Cut, Lateral Cut and Control groups on quinine diets.

When switched to the 0.4% quinine diet all groups decreased their food intake, although the two cut groups ate significantly less (p<0.05) of this diet than did the controls. The body weight gain of the Medial Cut group on the last day of this diet was slightly, but not significantly less than that of the controls (BW difference = 11 g), while the weight gain of the Lateral Cut group was significantly (p<0.01) below that of the controls (BW difference = 18 g). All rats further reduced their food intake and weight when given 0.8% quinine diet with the knife cut rats again showing the greatest reductions. By the last day on this diet the weight gain of the Medial Cut group was 13 g below that of the controls (p = 0.05), and the weight gain of the Lateral Cut group was 29 g lower than that of the controls

(p<0.01). The difference in the weight gains of the two knife cut groups was not statistically reliable. The knife cut rats initially ate less of the 0.8% quinine diet compared to the controls, but by the last two days on this diet there were no significant differences in the food intakes of the three groups.

Figures 7 and 8 present the food intake and body weight data from the second part of this experiment. When switched to the high fat diet all animals were initially hyperphagic and rapidly gained weight. During the first 3 days on this diet the food intakes of the two cut groups were similar to that of the controls. The cut groups then increased their food intake during the next 9 days and continued to gain weight rapidly, while the control group decreased its intake and rate of weight gain. During the 8 days of restricted feeding the two cut groups stopped gaining weight and then resumed their hyperphagia and elevated weight gain when returned to ad lib feeding. By the 40th day on the high fat diet the Medial Cut animals had gained significantly (p< 0.05) more weight than did the Lateral Cut animals, and the body weight gains of both groups were much greater (p<0.01) than that of the controls (see Fig. 8).

The first quinine solution test was conducted at a time when the water intake and body weight of the control group was only slightly less than that of the two cut groups (see Fig. 8 and Table 2). Quinine adulteration reduced the fluid intake of all 3 groups, but the Medial Cut groups consumed significantly (p<0.01) more of the 0.01% solution than did the controls, while the Lateral Cut group drank only slightly more (p>0.05) than controls (Table 2). The second solution test was conducted when the ad lib food intake, water intake, and body weight of the knife cut rats were significantly above control levels. Food intake was therefore restricted to 12 g/day in order to equate the water intake baselines of the two cut groups with that of controls. When presented with the 0.125% saccharin solution all groups increased their fluid intake, but the Medial Cut and Lateral Cut groups consumed significantly (p<0.05) less of this sweet solution than did the controls. The animals then decreased their fluid intake when offered the 0.01% quinine solution and the two cut groups drank significantly (p<0.05) less quinine solution compared to controls.

After 40 days on the high fat diet, the rats were returned to the 0.2% quinine diet. On the first day of this diet all 3 groups had equally depressed (less than 1 g) intakes. The control group increased its food intake to near normal levels during the next 11 days (Fig. 7) and stabilized its body weight at a level approximately 32 g below its weight on the high fat diet (Fig. 8). The Medial Cut group, in contrast, only slightly increased its quinine intake during this period and it remained significantly (p<0.01) below control levels, while the Lateral Cut group actually decreased its quinine intake and ate less food than did the Medial Cut group (p<0.01). As a result of their reduced intakes the two cut groups rapidly lost weight with the loss for the Lateral Cut group (128 g) during the first 12 days being significantly (p<0.05) greater than that for the Medial Cut group (109 g).

During the second week on the 0.2% quinine diet all of the Lateral Cut and two of the Medial Cut rats did not eat any measurable amounts of the quinine diet, and one of the Lateral Cut animals died on Day 16. Starvation did not appear to be the sole cause of death, however, since the


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FIG. 7. Food intake of Medial Cut, Lateral Cut, and Control groups on high fat diet and 0.2% quinine diet (note different scales on left and right ordinates).

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FIG. 8. Body weight gain of Medial Cut, Lateral Cut, and Control groups on the high fat and 0.2% quinine diet.

rat's body weight (270 g) at time of death was equal to the mean of the control group. Nevertheless, in order to prevent further deaths the remaining aphagic rats were induced to eat by offering them plain Purina powder for 2 days (10 g/day) and then gradually increasing the concen- tration of quinine in the diet during the next 10 days. This change in diet is responsible for the reduction in the rate of weight loss, beginning on Day 53, apparent in Fig. 8. All of the aphagic rats were successfully weaned to the 0.2% quinine diet and by the last 6 days of the experiment the

food intake and body weight of the Medial and Lateral Cut groups did not differ significantly from that of the control group (Figs. 7 and 8).

Correlation coefficients were calculated to assess the relationships between the weight losses and gains displayed by the knife cut animals on the quinine and high fat diets. The weight lost on the 0.8% quinine diet was found not to be correlated with the weight subsequently gained on the high fat diet (Medial Cut r = - . 0 6 ; Lateral Cut, r = - .19) . However, the weight gained on the high fat diet and the


TABLE 2

MEAN FLUID INTAKE (ml) DURING SOLUTION TESTS 1 AND 2

Test 1 Test 2 Food Food Food

Ad Lib Ad Lib Restricted Tap .01% Tap Tap 0.125% Tap

Water QHC 1 Water Water Saccharin Water 0.01% QHCI

CON 39.0 17.3 26.4 23.6 97.5 23.3 17.5 MED-CUT 46.4 34.5* 56.6* 22.7 63.2t 22.1 12.0" LAT-CUT 44.1 22.5 47.6* 25.4 63. I t 24.9 11.9t

*Significantly different from controls, p <0.01. tSignificantly different from controls, p <0.05.

weight then lost on the 0.2% quinine diet were found to be highly correlated, especially for the Medial Cut animals (Medial Cut, r = +.92; Lateral Cut, r = +.67).

DISCUSSION

The findings of Experiment 2 provide additional evidence that obesity greatly increases the hyperphagic rat's aversion to quinine adulterated diets, but at the same time they indicate that quinine finickiness may be a direct result of hypothalamic damage. That is, the knife cut rats, although maintaining normal intakes and body weights on the 0.2% quinine diet, were hypophagic and underweight relative to the control group on the more concentrated diets. In the case of the Medial Cut group this effect was relatively mild and even on the very bitter 0.8% quinine diet their body weight gain was only 13 g less than that of the controls. The Lateral Cut rats showed a greater weight reduction on the more concentrated diets, although their food intake was only slightly less than that of the Medial Cut animals.

The differential effects produced by the medial and lateral cuts suggest that damage to separate, but anatom- ically overlapping neural systems is responsible for the nonobese rats undereating of the quinine diet and overeating of the high fat diet. The Lateral Cut rats, while they lost more weight on the 0.8% quinine diet, gained less weight on the high fat diet compared to the Medial Cut animals, which is consistent with previous observations [ 17, 18,19]. Furthermore, there were no positive correlations in the knife cut groups between the weight lost on the 0.8% diet and the weight subsequently gained on the high fat diet, as would be expected if a common dysfunction was responsible for both effects. Previous studies have also reported that quinine finickiness can occur independently of hyperphagia with the finickiness being related to lateral perifornical and LH damage [ 1,5]. Bevan [ 1 ] observed, for example, that lateral perifornical lesions may produce quinine finickiness associated with normal chow intake and body weight, that more medial lesions may produce hyperphagia and obesity without quinine finickiness, and that combined medial and lateral lesions produce both hyperphagia and finickiness. The lesions which produced enhanced quinine aversion were also found to suppress bar pressing for food rewards which suggests that the finickiness was the result of a motivational disorder rather than a change in taste reactivity per se. That lateral knife cuts interfere with. food motivation is suggested by the

temporary postoperative hypophagia, as well as other symptoms characteristic of the LH lesions, produced by these cuts [ 17 ].

Further evidence that hypothalamic finickiness, defined as the overresponsivity to both good and bad tasting substances [5], does not represent a unitary disorder is provided by the results of the solution tests. In the second solution test the knife cut rats overreacted to the quinine solution by reducing their intake more than controls, but underreacted to the saccharin solution by increasing their intake less than controls. This later result is consistent with other recent findings that hyperphagic rats do not over- respond, ana often underrespond to sweet low calorie solutions [15, 17, 19]. The explanation of this effect remains uncertai~ (see [15,19]), but it is clearly incon- sistent with the view that hypothalamic finickiness represents a general increase in sensory reactivity [6]. The hyperphagic rats underconsumption of quinine solutions also is not necessarily due to altered taste reactivity, but may result from reduced thirst motivation. Hypothalamic knife cuts and the obesity that they produce have been found to interfere with the rat's normal regulation of water balance and thirst drive [17,20]. The failure of the knife cut rats to display enhanced quinine aversion during the first solution test may have resulted because the rats were not yet obese, and their greater than normal food intake may have counteracted any deficits in their thirst motivation.

The present findings, while revealing that obesity may not be essential for the production of enhanced quinine aversion, clearly demonstrate that obesity greatly increases this finickiness. Recall that the knife cut rats displayed normal intakes and body weights on the 0.2% quinine diet following surgery (except for the temporary hypophagia of the Lateral Cut group, which is not specific to quinine diets [17]), but were hypophagic or aphagic and rapidly lost weight when returned to this diet after becoming obese on the high fat diet. That this increased finickiness was related to the animal's obesity is further evidenced by the high positive correlations between the weight gained on the high fat diet and the weight subsequently lost on the 0.2% quinine diet. Nevertheless, the quinine aversion produced by obesity appeared to be potentiated by that produced by the knife cuts directly. This is suggested by the finding that the Lateral Cut animals displayed a greater initial suppression in their food intake and body weight when returned to the 0.2% quinine diet than did the Medial Cut rats, although they were slightly less obese than were the Medial


Cut animals. Thus, the motivational suppressive effects of obesity [20] and lateral perifornical damage [1] appear to interact to produce increased quinine finickiness.

Related to the present experiment are the recent observations of Ferguson and Keesey [3] that hyperphagic rats, in this case VMH lesioned males, maintained body weights significantly below control levels when given a quinine diet postoperatively. It was further observed that castrating the VMH lesioned and control rats at time of brain surgery eliminated the postoperative weight difference between the two groups. Since it is known that castration reduces the body weight of male rats [23] Ferguson and Keesey concluded that a lesion-produced gonadal dysfunction was responsible for the suppressed weights of the VMH lesioned rats. Functional castration cannot explain the present results, however, since parasagittal knife cuts produce little, if any gonadal disruption in comparison to VMH electrolytic lesions [14]. More importantly, females differ from males and respond to castration by increasing their body weights [23], even when they are maintained on quinine diets, and have been given hypothalamic knife cuts (Gale and Sclafani, unpublished findings).

GENERAL DISCUSSION

The results of this study along with other recent findings [3,4] demonstrate that hyperphagic rats defend the same or nearly the same lower body weights as do controls when fed unpalatable diets. In the cases where below normal weights were displayed a dysfunction other than that responsible for the hyperphagia syndrome appears to be involved. Food intake and weight may be suppressed to below normal levels in hyperphagic animals because of damage to the lateral perifornical area ([ 1 ] ; Experiment 2), or because of disruption in testicular function [3]. The well documented finickiness of hyperphagic rats to poor tasting foods, therefore, appears to result primarily from their being overweight. These findings nicely coincide with the recent observations that hyperphagic animals display normal food motivated behavior when tested at percentages of their nonobese weights, but subnormal performance when tested at percentages of their obese weights [ 13,20].

Thus, the hypothalamic hyperphagia syndrome seems to involve an elevation in the animal's upper body weight "limit," "plateau," or "set point" [3, 4, 20], with little or no change in the lower limit of body weight. To explain this effect Sclafani [16] has elaborated on the original lipostatic hypothesis of Kennedy and proposed that two separate lipostatic mechanisms are involved in determining

the upper and lower limits of body weight. VMH damage is thought to impair only the upper lipostatic mechanism which normally functions to limit weight gain by inhibiting the animal's appetite for palatable foods when its weight exceeds a fixed set point level. (This single set point interpretation represents a revision of the earlier two set point model of Sclafani and Kluge [20] .) According to this interpretation the VMH damaged animal overeats and gains weight on palatable diets because its appetite is released from the normal lipostatic inhibition, not because its taste responsivitiy per se is increased. Supporting this view are the findings ([ 15, 17, 19], Experiment 2) that hyperphagic rats fail to overreact and even underreact to palatable solutions of low caloric value. Since the consumption of such solutions does not increase body weight some mechanism other than the postulated appetite inhibitory lipostat must be responsible for limiting the intake of these solutions.

The second lipostatic mechanism proposed by Sclafani [ 16] is thought to defend the lower limit of body weight by stimulating hunger drive when the animal's weight falls below set point. The fact that hyperphagic rats maintain the same or nearly the same weights as do controls on unpalatable diets and bar press at control rates for food when nonobese suggests that VMH damage has little or no effect on the lower lipostatic mechanism nor alters the set point of body weight regulation. Thus, hyperphagic rats show a normal increase in food motivation (i.e., hunger) as their weight falls below set point, but do not show a normal inhibition in their food motivation (i.e., appetite) when their weights increase above set point. This interpretation can explain the findings of Experiment 2 that the control and knife cut rats initially displayed the same degree of hyperphagia when switched from the 0.8% quinine diet to the high fat diet if it is assumed that all rats were equally below set point on the quinine diet. Then, as their weights reached normal levels the hyperphagia and rapid weight gain of the control group were inhibited, according to the model, by the negative feedback from the upper lipostatic mechanisms, while the knife cut animals continued to overeat and gain weight rapidly because of an impairment in this mechanism.

This model, as well as other lipostatic interpretations of the hyperphagia syndrome [3, 7, 8, 9], remains speculative since the exact means by which body weight, that is, body fat stores, is monitored remains largely unknown. Neverthe- less, several lines of behavioral evidence now indicate that both normal and hyperphagic animals can monitor their body weight and that VMH damage reduces the normal inhibition of feeding produced by excessive body weight.

REFERENCES

1. Bevan, T. E. Experimental dissociation of hypothalamic finickiness and motivational deficits from hyperphagia and from hyperemotionality. Unpublished Ph.D. Dissertation, Princeton University, 1973. (University Microfilms No. 74-9665).

2. DeGroot, J. The Rat Forebrain in Stereotaxic Coordinates. Amsterdam: N. V. Noord-Hollandsche Uitgevers, 1967.

3. Ferguson, N. B. L. and R. E. Keesey. Effect of a quinine- adulterated diet upon the level of body weight maintained by male rats with ventromedial hypothalamic lesions. Z comp. physiol. Psychol. 89: 478-488, 1975.

4. Franklin, K. B. J. and L. J. Herberg. Ventromedial syndrome: The rat's "finickiness" results from the obesity, not from the lesions. J. comp. physiol. Psychol. 87: 410-414, 1974.

5. Graft, H. and E. Stellar. Hyperphagia, obesity, and finickiness. J. comp. physiol. Psychol. 55: 418-424, 1962.

6. Grossman, S. P. The VMH: A center for affective reactions, satiety, or both? Physiol. Behav. 1: 1-10, 1966.

7. Hoebel, B. G. and P. Teitelbaum. Weight regulation in normal and hypothalamic hyperphagic rats. J. comp. physiol. Psychol. 61: 189-193, 1966.

8. Kennedy, G. C. The hypothalamic control of food intake in rats. Proc. Royal Soc. B 137: 535-549, 1950.

640 SCLAFANI , S P R I N G E R AND K L U G E

9. Kennedy, G. C. Interactions between feeding behavior and hormones during growth. Ann. N. Y. Acad. Sci. 157: 1049-1061, 1969.

10. Kent, M. A. and R. H. Peters. Effects of ventromedial hypothalamic lesions on hunger-motivated behavior in rats. J. comp. physioL Psychol. 83: 92-97 , 1973.

11. Miller, N. E., C. J. Bailey and J. A. F. Stevenson. Decreased "hunger" but increased food intake resulting from hypothalamic lesions. Science 112: 256-259, 1950.

12. Panksepp, J. and A. Dickinson. On the motivational deficits after medial hypothalamic lesions. Physiol. Behav. 9: 609-614, 1972.

13. Porter, J. H. and J. D. Alien. Food-motivated performance as a function of weight loss in hypothalamic hyperphagic rats. Psychon. Sci. 28: 285-288, 1972.

14. Sclafani, A. Neural pathways involved in the ventromedial hypothalamic lesion syndrome in the rat. J. comp. physiol. Psychol. 77: 70-96 , 1971.

15. Sclafani, A. Deficits in glucose appetite and satiety produced by VMH lesions in the rat. Physiol. Behav. 11: 771-780, 1973.

16. Sclafani, A. Appetite and hunger in experimental obesity syndromes. In: Hunger: Basic Mechanisms and Clinical Implica- tions, edited by D. Novin, W. Wyrwicka and G. A. Bray. New York: Raven Press, 1976, pp. 281-295.

17. Sclafani, A., C. N. Berner and G. Maul. Feeding and drinking pathways between the medial and lateral hypothalamus in the rat. Z comp. physiol. Psyehol. 85: 29-51 , 1973.

18. Sclafani, A., C. N. Berner and G. Maul. Multiple knife cuts between the medial and lateral hypothalamus in the rat: A reevaluation of hypothalamic feeding circuitry. J. comp. physiol. Psychol. 88: 210-217, 1975.

19. Sclafani, A., S. K. Gale and D. Springer. Effects of hypothalamic knife cuts on the ingestive responses to glucose and insulin. Physiol. Behav. 15: 63-70 , 1975.

20. Sclafani, A. and L. Kluge. Food motivation and body weight levels in hypothalamic hyperphagic rats: A dual lipostat model of hunger and appetite. Z comp. physiol. Psychol. 86: 28-46 , 1974.

21. Teitelbaum, P. Sensory control of hypothalamic hyperphagia. J. comp. physiol. Psychol. 48: 158-163, 1955.

22. Teitelbaum, P. Random and food directed activity in hyperphagic and normal rats. J. comp. physiol. Psychol. 50: 486-490, 1957.

23. Wade, G. N. Gonadal hormones and behavioral regulation of body weight. Physiol. Behav. 8: 523-534, 1972.

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