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Ventromedial hypothalamic syndrome: Finickiness?
Physiology & Behavior, Vol. 20,
pp. 279-285. Pergamon Press and Brain Research Publ., 1978. Printed in the U.S.A.
Ventromedial Hypothalamic Syndrome: Finickiness? RONALD H. PETERS, LARRY L. LUTTMERS, MARK W. GUNION AND PAUL J. WELLMAN
Department o f Psychology, Iowa State University, Ames, IA 50010 (Received 24 October 1977) PETERS, R. H., L. L. LUTTMERS, M. W. GUNION AND P. J. WELLMAN. Ventromedial hypothalamic syndrome: finickiness? PHYSIOL. BEHAV. 20(3) 279-285, 1978. - Female rats with lesions of the ventromedial hypothalamus (VMH) under-ate and lost weight compared to same-diet control rats when fed a 0.2% quinine-adulterated wet-mash maintenance diet, yet overate and gained weight compared to same-diet control rats when fed a 0.4% quinine-adulterated high-fat maintenance diet. Control rats underate and lost comparable amounts of body weight when fed either adulterated diet. These data question the generality of the concept of VMH finickiness and are discussed in terms of an increased hunger hypothesis. VMH
Finickiness
Diet palatability
Hunger
TWO behavioral consequences that generally accompany the hyperphagia and obesity induced by ventromedial hypothalamic (VMH) destruction have served as a springboard for a variety of theoretical interpretations of hypothalamic regulation of feeding behavior [12, 22, 26, 27, 29]. Although VMH lesioned rats overeat, they are typically characterized as finicky eaters with impaired hunger motivation [21, 32, 33]. These animals consume palatable foods in excess of normal nutritional requirements, yet surprisingly display enhanced anorexia when their diets are adulterated with substances such as quinine or cellulose. Additionally, they fail to work as hard as normal rats to obtain food that is not freely available. These two behavioral characteristics, in conjunction with the dramatically large consumption of palatable foods, are in large part responsible for the phrase - the VMH paradox. Numerous recent studies have demonstrated, however, that motivational impairments are not a necessary consequence of VMH destruction, but rather depend on the nature of the testing conditions used to assess such behavior [4, 5, 16, 17, 20]. Under certain circumstances VMH lesioned rats perform at higher levels than control rats and thus appear to be more motivated to work for food [15, 23, 24, 25]. At least some aspects of the behavior of VMH lesioned rats apparently are not as paradoxical as was initially thought. The finickiness of VMH lesioned rats has also been used as additional evidence to support the proposal that VMH lesions impair hunger motivation. Several recent studies have shown, however, that such rats undereat unpalatable foods only when their body weights exceed normal levels [7,8]. Control and VMH lesioned rats maintain similar body weights when fed adulterated maintenance diets. Obesity, rather than VMH damage per se, decreases the ingestion of unpalatable foods.
In further contrast to the VMH finickiness label, the present experiments demonstrate that VMH lesioned rats undereat a wet-mash maintenance diet adulterated with quinine, yet overate and gain substantial amounts of weight when fed a quinine-adulterated high-fat diet. Control rats undereat and lose comparable amounts of body weight when fed either adulterated diet. Finickiness is not a descriptive term that can be used to generally characterize the feeding behavior of VMH lesioned rats. EXPERIMENT 1
Method Animals. The animals were 40 female Long-Evans hooded rats (Blue Spruce Farms, Inc.) approximately 100 days old weighing 2 2 0 - 2 6 0 g at the beginning of the experiment. The rats were housed individually in wire mesh cages in a continuously illuminated, temperature controlled (24 ° C) room. Surgery. The rats were food and water deprived for 24 hr before and after surgery. Anesthesia was induced with sodium secobarbital (Myothesia, 42 mg/kg), and atropine methyl nitrate (10 mg/kg) was used to minimize development of respiratory complications. Bilateral VMH lesions were produced by passing 2.0 mA anodal current for 20 sec between a 30-gauge nichrome steel electrode, insulated except at its conical tip, and a rectal cathode. With the upper incisor bar elevated 5 mm above the interaural line, the electrode was positioned 5.8 mm anterior to the interaural line, 0.7 mm lateral to the midline, and 0.5 mm above the base of the brain. Control rats were also anesthetized and their scalps were incised, but holes were not drilled in their skulls. Diets. Four diets were used. Wet-mash diets consisted of 3 parts ground laboratory chow (Teklad Mouse and Rat
Portions of this report were presented at the Midwestern Psychological Association, Chicago, 1977. 279
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280 Diet) and 7 parts water. High-fat diets consisted of 2 parts ground chow and 1 part melted Crisco vegetable shortening. Parts were by weight for both diets. The adulterated form of the wet-mash diet contained 0.2% quinine sulfate by weight. Based on preliminary data from unoperated rats, a comparably aversive high-fat diet contained 0.4% quinine sulfate by weight. The wet-mash diets were presented fresh each day, while the high-fat diets were presented fresh every 3 days. The diets were contained in glass ointment jars (87 mm high with a 60 mm opening) attached with wire to the front of the cage. Procedure. All rats received the unadulterated wet-mash diet for 6 days before surgery. On the day after surgery, approximately half of the control and VMH lesioned rats continued maintenance on this diet, while the remaining rats in each group began maintenance on the quinine-adulterated wet-mash diet. After 22 days on these diets, the rats were switched to the high-fat diets. Those rats previously fed the unadulterated wet-mash diet received the unadulterated high-fat diet, and rats previously fed the quinine-adulterated wet-mash diet received the quinine-adulterated high-fat diet. Maintenance on these diets was continued for 21 days. VMH lesioned rats on the unadulterated diet and all control rats were then sacrificed, while VMH lesioned rats on the quinine-adulterated diet were switched to the unadulterated high-fat diet for 30 days to identify hyperphagic obese animals. Daily body weight and food intake measures (spillage collected on paper towels) were obtained. No attempt was made to compensate for water evaporation from the wet-mash diets. The high-fat diets were lightly tamped to reduce spillage. Water was freely available throughout the experiment. Histology. Lesioned rats, deeply anesthetized with chloroform, were perfused intracardially with isotonic saline followed by 10% Formalin. Frozen sections were taken at 100 ,, in the coronal plane described by Konig and Klippel [18]. Photographic enlargements of unstained sections were used to assess the extent and location of tissue destruction. Data analysis. Analyses of variance were performed on both food intake and body weight measures. Two-tailed t-tests were used for all statistical comparisons. The conservative Cochran-eox test was used for all comparisons made for individual days.
Results and Discussion Three rats died after surgery and data for four rats were discarded because they failed to overeat and become obese when fed unadulterated diets. Their lesions did not bilaterally destroy the VMH and their weight gains were comparable to those displayed by control rats. The lesions for rats whose data were analyzed generally destroyed large areas medial to the plane of the fornix, ventral to the dorsomedial nuclei, posterior to the anterior hypothalamus, and anterior to the premammillary nuclei. Rats with VMH lesions ate less food (p<0.05, Fig. 1) and weighed less (p<0.001, Fig. 2) than same-diet control rats over 22 days of access to the quinine-adulterated wet-mash diet, while lesioned rats fed the unadulterated diet displayed the hyperphagia and obesity characteristic of the syndrome. Consumption levels at the end o f this portion of the experiment were not statistically different with the obvious exception of VMH lesioned rats fed the
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FIG. 2. Group mean body weights on the wet,mash diets on the day preceding surgery and on the first and every third day thereafter. Each group mean was significantly different from all others (p at least <0.01 for overall means and p at least <0.02 for means on Day 22). unadulterated diet. Each group's mean body weight on Day 22, however, was significantly different from all others (p<0.02). This pattern of feeding behavior following VMH destruction epitomizes the concept of VMH finickiness: VMH lesioned rats overeat palatable yet undereat unpalatable diets. Clearly, foods differ along a palatability dimension. Some foods taste, smell, look, and feet better or worse than others. It is not clear, however, when the terms palatable or unpalatable can be used to appropriately characterize the quality of a particular diet. A diet that is considered palatable for rats, e.g., standard laboratory chow, with respect to one diet, e.g., quinine-adulterated laboratory chow, may be considered unpalatable with respect to another diet, e.g., supermarket foods [30]. Further, a priori procedures can not be used to define diet palatability. The relative palatability of any diet can be indexed only with reference to feeding behavior. Thus rats
VMH FINICKINESS
281
may prefer diet A to diet B in a choice situation, and diet B could therefore be described as less palatable. It is possible, however, that rats would consume and weigh similar amounts when maintained on either diet A or B. A more stringent criterion used here is to describe a diet as either more or less palatable (rather than palatable or unpalatable) only when maintenance consumption and body weight for control animals differ significantly as a function of dietary manipulations. In accord with this criterion, adulteration of t h e wet-mash diet with 0.2% quinine clearly decreased diet palatability because control rats fed this diet decreased both their consumption (p<0.05) and consequently their body weight (p<0.01) relative to control rats fed the unadulterated diet. When all rats were subsequently shifted to the high-fat diets, VMH lesioned rats dramatically increased their body weights by overeating the 0.4% quinine-adulterated diet. Their mean body weight (324 g) after 21 days on this diet significantly exceeded not only that of control rats (259 g) fed the same diet (p<0.01), but also that of control rats (285 g) fed the unadulterated diet (p<0.05). While not typical of all lesioned rats, the intake pattern of one lesioned rat was particularly striking. This rat consumed very little of the adulterated wet-mash diet and decreased its body weight from 237 g on the day preceding surgery to 155 g after 22 days on the diet. When switched to the adulterated high-fat diet, this rat weighed 329 g after 21 days and 559 g after an additional 30 days of access to the unadulterated high-fat diet. Thus lesioned rats that initially underate the quinine-adulterated wet-mash diet overate the quinine-adulterated high-fat diet. Although control rats fed the adulterated high-fat diet maintained their body weights below control rats fed the unadulterated diet throughout the second portion of this experiment, this difference (26 g between means on Day 21), while sizeable, was not significant (p<0.10). Neither was the difference in their food intake levels. Therefore, according to the criterion used here, adulteration of the high-fat diet with 0.4% quinine die not clearly decrease diet palatability. Since the rats fed the adulterated wet-mash diet may have adapted to the aversive properties of quinine prior to the shift to the adulterated high-fat diet, thereby greatly increasing the consumption of thie diet by VMH lesioned rats, a second experiment was run in which VMH lesioned and control rats were maintained on high-fat diets from the outset. EXPERIMENT 2
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Method Animals. The animals were 37 female Long-Evans hooded rats (Blue Spruce Farms, Inc.) approximately 100 days old weighing 2 2 2 - 2 2 7 g at the beginning of the experiment. The high-fat diets, housing conditions, lesion parameters, histological procedures, and data analyses were the same as in the first experiment. Procedure. All rats received the unadulterated high-fat diet for 6 days before surgery. On the day after surgery, approximately half of the control and VMH lesioned rats continued maintenance on this diet, while the remaining rats in each group began maintenance on the 0.4% quinine-adulterated high-fat diet. After 30 days VMH lesioned rats fed the unadulterated high-fat diet and all control rats were sacrificed, while VMH lesioned rats fed the adulterated diet began maintenance on the
Results and Discussion
Four rats died after surgery and five lesioned rats did not overeat and become obese when fed the unadulterated diet. Tissue destruction for lesioned rats that became obese during access to the unadulterated diet was similar to that described in the first experiment. The data from this experiment (Figs. 3 and 4) essentially replicated the results from the high-fat portion of the first experiment. An important exception, however, is that control rats significantly (p<0.05) underate the 0.4% quinine-high-fat diet and maintained their body weights at levels significantly (p
282
PETERS E T AI,
the data presented in the figures of the two experiments is the position of the curves for lesioned rats fed the adulterated diets. Whereas VMH lesioned rats underate an adulterated wet-mash diet, they overate an adulterated high-fat diet. G E N E R A L DISCUSSION
VMH lesioned rats did not respond to dietary adulteration as did control rats in the two experiments described herein. Although control rats decreased their consumption and consequently their body weight when fed either a quinine-adulterated wet-mash or high-fat diet, VMH lesioned rats lost more weight than control rats when fed the adulterated wet-mash diet yet surprisingly overate and gained more weight than control rats when fed the adulterated high-fat diet. How consistent are these observations with the characterization that VMH lesioned rats are finicky eaters? A fundamental difficulty encountered in an attempt to answer this question is the specification of precisely what is meant by the term finickiness. Unfortunately, the term is vague and rather poorly defined [26]. Although there appears to be general agreement among various verbal definitions, e.g., "the exaggerated tendency of animals with VMH lesions to reject unpalatable food while accepting palatable foods to excess (p. 410, [8])", considerable ambiguity is apparent when the actual operations used to define the term are examined. Some investigators have used within-group comparisons and noted that dietary adulterations produced greater changes in consumption in VMH lesioned rats than in control rats [11,32]. Others have used between-group comparisons and noted that the food intake of VMH lesioned rats was often less than that of control rats when diets were adulterated [21,32]. Since body weights for lesioned and control rats often differed substantially in these experiments, still others have concluded that the undereating of certain diets, and therefore finickiness, is a consequence of the animal's obesity rather than an effect of tissue destruction because lesioned rats defend their body weight at essentially the same level as control rats when both are fed adulterated maintenance diets [7,8]. Several recent experiments, however, have demonstrated that rats with knife cuts between the medial and lateral hypothalamus actually do undereat some maintenance diets and lose more weight than control rats fed the same diet [10,31]. Figure 5A presents a model that depicts the relationship between maintenance diet palatability and body weight suggested by these data and also the results from the wet-mash portion of Experiment 1. This model clearly defines VMH finickiness: VMH lesioned rats overeat good tasting food and thereby become obese; VMH lesioned rats do not overeat bad tasting food and fail to become obese. Further, when fed even less palatable diets, they undereat and lose weight relative to control rats fed the same diets. The term finickiness is used here to describe rather than explain this intake pattern. VMH lesioned rats do not overeat or undereat because they are finicky. Those studies which have reported that VMH damage does not alter the lower limits of body weight have not fully explored the low palatability end of the continuum. Franklin and Herberg [8] and Ferguson and Keesey [7] used 0.15% and 0.2% quinine wet-mash diets, respectively. Interestingly, the undereating seen in Experiment 1 was not anticipated because the 0.2% quinine wet-mash diet was
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prepared using the description provided by Ferguson and Keesey. This undereating following VMH damage can not be attributed to gonadal dysfunction [7] since castration induces overeating and weight gain in female rats [34] even when they are maintained on quinine diets [ I 0 ] . This undereating of an adulterated maintenance diet with respect to same-diet controls is also the first time this observation has been reported for female VMH lesioned rats. Undereating, as noted above, has been reported by Sclafani and coworkers in female knife-cut rats with 0.2% and 0.8% quinine powder diets [ 10,31 ]. Several authors [6, 7, 13, 28] have proposed that finickiness and hyperphagia can be dissociated in terms of the specific locus of damage caused by VMH lesions. Finickiness most readily occurs when hypothalamic lesions destroy the subfornical area lateral to the ventromedial nucleus or when parasagittal knife cuts are placed lateral to the plane of the fornix. Lesions in most rats in the present study extended laterally to partially invade this region. If undereating reflects a dysfunction other than that responsible for overeating, the curves shown in Fig. 5B would more appropriately describe the relationship for the brain dysfunction that induces overeating of palatable diets. It is likely that rats with lesions confined to more medial hypothalamic areas or with knife cuts medial to the plane
VMH FINICKINESS of the fornix would maintain their b o d y weights at control levels even when fed very unpalatable diets. Although adulteration of the wet-mash diet with 0.2% quinine and the high-fat diet with 0.4% quinine produced comparable changes in food intake and body weight for control rats, choice data indicate that both control and VMH lesioned rats prefer the quinine-adulterated high-fat diet to the quinine-adulterated wet-mash diet. Control (N = 8) and VMH lesioned rats (N = 6) other than those used in Experiments 1 and 2 were given simultaneous access to both adulterated diets after 24 hr of food deprivation. Contact durations with the 0.4% quinine high-fat diet were longer than those with 0.2% quinine wet-mash diet by ratios of approximately 10:1 for both groups. Rats with VMH lesions may overeat the 0.4% quinine high-fat diet simply because this diet is more palatable than the 0.2% quinine wet-mash diet, as illustrated by the suggested relative locations of the diets along the abscissa of Fig. 5B. This definition of diet palatability in terms of choice behavior is less stringent than the definition used previously in this paper. It is possible, however, that differences in body weight during maintenance on these two adulterated diets would be found only for rats with VMH lesions, even though both VMH lesioned and intact rats prefer the adulterated high-fat diet, because the range of body weights along the palatability continuum is considerably more restricted for intact animals. Although we have not used the term unpalatable to describe either adulterated diet, weight loss at comparable times (Day 22) in Experiments 1 and 2 for control rats fed these diets was approximately 12%. Most readers would probably concur with the statement that the 0.2% quinine wet-mash diet was unpalatable, particularly since VMH lesioned rats underate this diet with respect to same-diet control rats. While diet palatability was defined tautologically for intact rats with reference to intake measures, it is inappropriate to describe a diet as palatable if VMH lesioned rats overeat the diet and conversely as unpalatable if they undereat the diet. If the 0.2% quinine wet-mash diet were labeled unpalatable, then the same label appears appropriate for the 0.4% quinine high-fat diet with reference in both instances to the feeding behavior of intact rats. Rats with VMH lesions underate one quinine-adulterated diet that was demonstrably less palatable (unpalatable) for control rats yet overate another quinine-adulterated diet that was also demonstrably less palatable (unpalatable) for control rats. In this respect our data are inconsistent with traditional conceptions of VMH finickiness. Although some writers (e.g., [26], page 91] use the term finickiness to describe the feeding behavior of rats with VMH damage because they do not overeat all diets, we suggest that this term would more meaningfully characterize the feeding behavior of such rats if the relationship depicted in Fig. 5A held for all hypothalamic brain manipulations that induce overeating of some diets, i.e., if undereating and overeating are not dissociable in terms of locus of hypothalamic damage. If, on the other hand, overeating and undereating are dissociable phenomena and Fig. 5B approximates the relationship between maintenance diet palatability and body weight for certain types of hypothalamic damage, then the term finickiness has historical surplus meaning regarding the nature of the feeding disturbances that may be misleading. The first author, for example, has previously suggested that VMH lesions nonadditively increase hunger motivation
283
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FIG. 6. Behavioral indices of hunger for control rats typically increase and become asymptotic as hunger, def'med operationally as percentage of ad lib body weight, increases. Although there are no asymptotic differences in hunger, the increased hunger hypothesis suggests that VMH destruction elevates hunger motivation above control levels as deprivation conditions become more moderate. [1 ~, 23, 24, 25]. The increment is described as nonadditive because the lesion does not increase hunger motivation above asymptotic levels of hunger inferred from the behavior of intact animals (Fig. 6). Thus VMH lesioned rats may overeat certain foods that are freely available simply because they are more hungry than control rats. If their diet is made less palatable, they will decrease their consumption of the diet but perhaps still consume more than control rats fed the same diet. As diets are made progressively less palatable, VMH lesioned rats will maintain their b o d y weights at comparable levels since there are no asymptotic differences in hunger motivation. In this explanation of the effects of diet palatability on feeding behavior in VMH lesioned rats, the term finickiness has little utility. Recent theoretical analyses of the feeding disturbances induced by VMH destruction [9, 14, 26] p r o m p t further clarification of the increased hunger hypothesis. Basically, this proposal argues that rats with VMH lesions behave in a manner similar to intact rats that have been made hungrier by any of the variety of operations. While it is possible that these behavior changes reflect the disruption of central nervous system mechanisms directly controlling feeding behavior [14], Friedman and Stricker [9] suggest that VMH destruction induces a primary dysfunction in fat metabolism that promotes lipogenesis. Secondary hyperphagia is caused by increased hunger because more metabolic fuels than normal are removed from circulation to be deposited as fat. Although Friedman and Stricker argue that rats with VMH lesions do not always behave like hungry rats because changes in sensory reactivity and emotionality depress food-directed activity in certain situations, we feel that the behaviors of VMH lesioned rats are like those of hungry rats in more situations than previously suggested, and the two positions are therefore congruent. Powley [26] has recently suggested that the cephalic reflexes of digestion, cued by oropharyngeal contact with food stimuli, are exaggerated by VMH damage and thereby generate the hyperphagia and paradoxes of the VMH syndrome. Although Powley's proposal is seemingly anti-
P[ I'ERS t:'T ell.
284 thetical to the position described here since we argue that aspects of the feeding behavior of VMH lesioned rats are not remarkably paradoxical, there is considerable agreement on certain points. Powley uses an example to illustrate that hyperphagia could occur because "the heightened cephalic salivary reflex would inform the VMH animal that it was still hungry (italic ours, p. 103)." Further, we concur that increased hunger may be induced by and is therefore secondary to phasic metabolic dysfunctions triggered by palatable diets. However, unless diet palatability is defined tautologically with respect to the feeding behavior of VMH lesioned rather than control rats, neither Powley's cephalic phase hypothesis, Grossman's affective hypothesis [12], nor Sclafani's dual lipostat hypothesis [28] can account for the fact that VMH lesioned rats in the present study overate one adulterated diet and underate another while control rats lost comparable amounts of body weight when fed either diet.
Finally, Ahlskog and Hoebel [2] have demonstrated a hyperphagia syndrome in rats following damage to the ventral noradrenergic bundle (VNB). Since such rats did not significantly decrease their intake below that of same-diet control rats when their high-fat diet was adulterated with 0.125% quinine, it was suggested that hyperphagia in the VNB syndrome is not accompanied by finickiness 1 1 , 2 ] Preliminary work in this laboratory indicated that the intake of VMH lesioned rats was not substantially depressed when their high-fat diet was adulterated at this concentration and therefore was obviously above the intake of control rats. The VMH syndrome may be dissimilar to that produced by destruction of the VNB because the present data indicate that VMH lesions induce overeating of even a 0.4% quinine-adulterated high-fat diet. Other dissimilarities between the two syndromes have been noted [3,19].
REFERENCES
1. Ahlskog, J. E. Feeding response to regulatory challenges after 6-hydroxydopamine injection into the brain noradrenergic pathways. Physiol. Behav. 17:407-411, 1976: 2. Ahlskog, J. E. and B. G. Hoebel. Overeating and obesity from damage to a nora&energic system in the brain. Science 182: 166-169, 1973. 3. Ahlskog, J. E., P. K. Randall and B. G. Hoebel. Hypothalamic hyperphagia: dissociation from hyperphagia following destruction of noradrenergic neurons. Science 190: 399-401, 1975. 4. Beatty, W. W. Influence of type of reinforcement on operant responding by rats with ventromedial lesions. Physiol. Behav. 10: 841-846, 1973. 5. Beatty, W. W., T. R. Vilberg, T. S. Shirk and W. A. Siders. Pretraining: effects on operant responding for food, frustration, and reactiveness to food-related cues in rats with VMH lesions. Physiol. Behav. 15: 577-584, 1975. 6. Bevan, T. E. Experimental dissociation of hypothatamic finickiness and motivational deficits from hyperphagia and from hyperemotionality. Unpublished doctoral dissertation. Princeton University, 1973. 7. Ferguson, N. B. L. and R. E. Keesey. Effect of a quinineadulterated diet upon body weight maintenance in male rats with ventromedial hypothalamic lesions. J. comp. physiol. Psychol. 89: 478-488, 1975. 8. 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. 9. Friedman, M. I. and E. Stricker. The physiological psychology of hunger: A physiological perspective. Psychol. Rev. 83: 409-431, 1976. 10. Gale, S. K. and A. Sclafani. Comparisons of ovarian and hypothalamic obesity syndromes in the female rat: effects of diet palatability on food intake and body weight. J. comp. physiol. PsychoL 91: 381-392, 1977. 11. Graft, H. and E. Stellar, Hyperphagia, obesity, and finickiness. J. comp. physiol. Psychol. 55: 418-424, 1962. 12. Grosslnan, S. P. The VMH: a center for affective reactions, satiety, or both? Physiol. Behav. 1: 1-13, 1966. 13. Hoebel, B. G. Brain reward and aversion systems in the control of feeding and sexual behavior. In: Nebraska Symposium on Motivation, edited by J. K. Cole and T. B. Sonderegger. Lincoln: University of Nebraska Press, 1975, pp. 49 - 112. 14. Keesey, R. E. and T. L. Powley. Hypothalamic regulation of body weight. Am. Scient. 63: 558-565, 1975.
15. 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. 16. King, M. B. and M. G. Gaston. The effects of pretraining on the bar-pressing performance of VMH-lesioned rats. Physiol. Behav. 11: 161-166, 1973. 17. King, B. M. and M. G. Gaston. Factors influencing the hunger and thirst motivated behavior of hypothalamic hyperphagic rats. Physiol. Behav. 16: 33-41, 1976. 18. Konig, J. F. R. and R. A. Klippel. The Rat Brain. Baltimore: Williams and Wilkins, 1963. 19. Lorden, J., G. A. Oltmans and D. L. Margules. Ventral noradrenergic neurons: differential effects on body weight and electrolytic and 6-hydroxydopamine lesions in rats. J. comp. physiol. Psychol. 90: 144-155, 1976. 20. Marks, H. E. and N. R. Remley. The effects of type of lesion and percentage body weight loss on measures of motivated behavior in rats with hypothalarnic lesions. Behav. Biol. 7: 95-111, 1972. 21. 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. 22. Panksepp, J. A re-examination of the role of the ventromedlal hypoth_alamus in feeding behavior. PhysioL Behav. 7: 385-394, 1971. 23. Peters, R. H. Effects of ventromedial hypothalamic lesions on restricted feeding behavior in the rat. Physiol. 8ehav. 12: 761-766, 1974. 24. Peters, R. H. and M. J. Reich. Effects of ventromedial hypothalamic lesions on conditioned sucrose aversions in rats. J. comp. physiol. Psychol. 84: 502-506, 1973. 25. Peters, R. H., L. D. Sensenig and M. J. Reich. Fixed-ratio performance following ventromedial hypothalamic lesions in rats. PhyMo/. Psychol. 1: 136-138, 1973. 26. Powiey, T. L. The ventxomeMial hypothalamic syndrome, satiety, and a cephalic phase hypothesis. Psychol. Rev. 84: 89-126, 1977. 27. Schaehter, S. and J. Rodin. Obese Humans and Rats. Potomac: Erlhaum, 1974. 28. Sclafani, A. Appetite and hunger in experimental obesity syndromes. In: Hunger: Mechanisms and Clinical Implications, edited by D. Novin, W. Wyrwicka and G. A. Bray. New York: Raven Press, 1976, pp. 281-295.
VMH FINICKINESS 29. Sclafani, A. and L. Kluge. Food motivation and body weight levels in hypothalamic hyperphagic rats. J. comp. physiol. Psychol. 86: 28-46, 1974. 30. Sclafani, A. and D. Springer. Dietary obesity in adult rats: similarities to hypothalamic and human obesity syndromes. Physiol. Behav. 17: 461-471, 1976. 31. Sclafani, A., D. Springer and L. Kluge. Effects of genuine adulterated diets on the food intake and body weight of obese and non-obese hypothalamic hyperphagic rats. Physiol. Behav. 16: 631-640, 1976.
285 32. Teitelbaum, P. Sensory control of hypothalamic hyperphagia. Y. comp. physiol. Psychol. 48: 156-163, 1955. 33. Teitelbaum, P. Random and food-directed activity in hyperphagic and normal rats. Y. comp. physiol. Psychol. 50: 486-490, 1957. 34. Wade, G. N. Gonadal hormones and behavioral regulation of body weight. Physiol. 8ehav. 8: 523-534, 1972.
pp. 279-285. Pergamon Press and Brain Research Publ., 1978. Printed in the U.S.A.
Ventromedial Hypothalamic Syndrome: Finickiness? RONALD H. PETERS, LARRY L. LUTTMERS, MARK W. GUNION AND PAUL J. WELLMAN
Department o f Psychology, Iowa State University, Ames, IA 50010 (Received 24 October 1977) PETERS, R. H., L. L. LUTTMERS, M. W. GUNION AND P. J. WELLMAN. Ventromedial hypothalamic syndrome: finickiness? PHYSIOL. BEHAV. 20(3) 279-285, 1978. - Female rats with lesions of the ventromedial hypothalamus (VMH) under-ate and lost weight compared to same-diet control rats when fed a 0.2% quinine-adulterated wet-mash maintenance diet, yet overate and gained weight compared to same-diet control rats when fed a 0.4% quinine-adulterated high-fat maintenance diet. Control rats underate and lost comparable amounts of body weight when fed either adulterated diet. These data question the generality of the concept of VMH finickiness and are discussed in terms of an increased hunger hypothesis. VMH
Finickiness
Diet palatability
Hunger
TWO behavioral consequences that generally accompany the hyperphagia and obesity induced by ventromedial hypothalamic (VMH) destruction have served as a springboard for a variety of theoretical interpretations of hypothalamic regulation of feeding behavior [12, 22, 26, 27, 29]. Although VMH lesioned rats overeat, they are typically characterized as finicky eaters with impaired hunger motivation [21, 32, 33]. These animals consume palatable foods in excess of normal nutritional requirements, yet surprisingly display enhanced anorexia when their diets are adulterated with substances such as quinine or cellulose. Additionally, they fail to work as hard as normal rats to obtain food that is not freely available. These two behavioral characteristics, in conjunction with the dramatically large consumption of palatable foods, are in large part responsible for the phrase - the VMH paradox. Numerous recent studies have demonstrated, however, that motivational impairments are not a necessary consequence of VMH destruction, but rather depend on the nature of the testing conditions used to assess such behavior [4, 5, 16, 17, 20]. Under certain circumstances VMH lesioned rats perform at higher levels than control rats and thus appear to be more motivated to work for food [15, 23, 24, 25]. At least some aspects of the behavior of VMH lesioned rats apparently are not as paradoxical as was initially thought. The finickiness of VMH lesioned rats has also been used as additional evidence to support the proposal that VMH lesions impair hunger motivation. Several recent studies have shown, however, that such rats undereat unpalatable foods only when their body weights exceed normal levels [7,8]. Control and VMH lesioned rats maintain similar body weights when fed adulterated maintenance diets. Obesity, rather than VMH damage per se, decreases the ingestion of unpalatable foods.
In further contrast to the VMH finickiness label, the present experiments demonstrate that VMH lesioned rats undereat a wet-mash maintenance diet adulterated with quinine, yet overate and gain substantial amounts of weight when fed a quinine-adulterated high-fat diet. Control rats undereat and lose comparable amounts of body weight when fed either adulterated diet. Finickiness is not a descriptive term that can be used to generally characterize the feeding behavior of VMH lesioned rats. EXPERIMENT 1
Method Animals. The animals were 40 female Long-Evans hooded rats (Blue Spruce Farms, Inc.) approximately 100 days old weighing 2 2 0 - 2 6 0 g at the beginning of the experiment. The rats were housed individually in wire mesh cages in a continuously illuminated, temperature controlled (24 ° C) room. Surgery. The rats were food and water deprived for 24 hr before and after surgery. Anesthesia was induced with sodium secobarbital (Myothesia, 42 mg/kg), and atropine methyl nitrate (10 mg/kg) was used to minimize development of respiratory complications. Bilateral VMH lesions were produced by passing 2.0 mA anodal current for 20 sec between a 30-gauge nichrome steel electrode, insulated except at its conical tip, and a rectal cathode. With the upper incisor bar elevated 5 mm above the interaural line, the electrode was positioned 5.8 mm anterior to the interaural line, 0.7 mm lateral to the midline, and 0.5 mm above the base of the brain. Control rats were also anesthetized and their scalps were incised, but holes were not drilled in their skulls. Diets. Four diets were used. Wet-mash diets consisted of 3 parts ground laboratory chow (Teklad Mouse and Rat
Portions of this report were presented at the Midwestern Psychological Association, Chicago, 1977. 279
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280 Diet) and 7 parts water. High-fat diets consisted of 2 parts ground chow and 1 part melted Crisco vegetable shortening. Parts were by weight for both diets. The adulterated form of the wet-mash diet contained 0.2% quinine sulfate by weight. Based on preliminary data from unoperated rats, a comparably aversive high-fat diet contained 0.4% quinine sulfate by weight. The wet-mash diets were presented fresh each day, while the high-fat diets were presented fresh every 3 days. The diets were contained in glass ointment jars (87 mm high with a 60 mm opening) attached with wire to the front of the cage. Procedure. All rats received the unadulterated wet-mash diet for 6 days before surgery. On the day after surgery, approximately half of the control and VMH lesioned rats continued maintenance on this diet, while the remaining rats in each group began maintenance on the quinine-adulterated wet-mash diet. After 22 days on these diets, the rats were switched to the high-fat diets. Those rats previously fed the unadulterated wet-mash diet received the unadulterated high-fat diet, and rats previously fed the quinine-adulterated wet-mash diet received the quinine-adulterated high-fat diet. Maintenance on these diets was continued for 21 days. VMH lesioned rats on the unadulterated diet and all control rats were then sacrificed, while VMH lesioned rats on the quinine-adulterated diet were switched to the unadulterated high-fat diet for 30 days to identify hyperphagic obese animals. Daily body weight and food intake measures (spillage collected on paper towels) were obtained. No attempt was made to compensate for water evaporation from the wet-mash diets. The high-fat diets were lightly tamped to reduce spillage. Water was freely available throughout the experiment. Histology. Lesioned rats, deeply anesthetized with chloroform, were perfused intracardially with isotonic saline followed by 10% Formalin. Frozen sections were taken at 100 ,, in the coronal plane described by Konig and Klippel [18]. Photographic enlargements of unstained sections were used to assess the extent and location of tissue destruction. Data analysis. Analyses of variance were performed on both food intake and body weight measures. Two-tailed t-tests were used for all statistical comparisons. The conservative Cochran-eox test was used for all comparisons made for individual days.
Results and Discussion Three rats died after surgery and data for four rats were discarded because they failed to overeat and become obese when fed unadulterated diets. Their lesions did not bilaterally destroy the VMH and their weight gains were comparable to those displayed by control rats. The lesions for rats whose data were analyzed generally destroyed large areas medial to the plane of the fornix, ventral to the dorsomedial nuclei, posterior to the anterior hypothalamus, and anterior to the premammillary nuclei. Rats with VMH lesions ate less food (p<0.05, Fig. 1) and weighed less (p<0.001, Fig. 2) than same-diet control rats over 22 days of access to the quinine-adulterated wet-mash diet, while lesioned rats fed the unadulterated diet displayed the hyperphagia and obesity characteristic of the syndrome. Consumption levels at the end o f this portion of the experiment were not statistically different with the obvious exception of VMH lesioned rats fed the
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FIG. 2. Group mean body weights on the wet,mash diets on the day preceding surgery and on the first and every third day thereafter. Each group mean was significantly different from all others (p at least <0.01 for overall means and p at least <0.02 for means on Day 22). unadulterated diet. Each group's mean body weight on Day 22, however, was significantly different from all others (p<0.02). This pattern of feeding behavior following VMH destruction epitomizes the concept of VMH finickiness: VMH lesioned rats overeat palatable yet undereat unpalatable diets. Clearly, foods differ along a palatability dimension. Some foods taste, smell, look, and feet better or worse than others. It is not clear, however, when the terms palatable or unpalatable can be used to appropriately characterize the quality of a particular diet. A diet that is considered palatable for rats, e.g., standard laboratory chow, with respect to one diet, e.g., quinine-adulterated laboratory chow, may be considered unpalatable with respect to another diet, e.g., supermarket foods [30]. Further, a priori procedures can not be used to define diet palatability. The relative palatability of any diet can be indexed only with reference to feeding behavior. Thus rats
VMH FINICKINESS
281
may prefer diet A to diet B in a choice situation, and diet B could therefore be described as less palatable. It is possible, however, that rats would consume and weigh similar amounts when maintained on either diet A or B. A more stringent criterion used here is to describe a diet as either more or less palatable (rather than palatable or unpalatable) only when maintenance consumption and body weight for control animals differ significantly as a function of dietary manipulations. In accord with this criterion, adulteration of t h e wet-mash diet with 0.2% quinine clearly decreased diet palatability because control rats fed this diet decreased both their consumption (p<0.05) and consequently their body weight (p<0.01) relative to control rats fed the unadulterated diet. When all rats were subsequently shifted to the high-fat diets, VMH lesioned rats dramatically increased their body weights by overeating the 0.4% quinine-adulterated diet. Their mean body weight (324 g) after 21 days on this diet significantly exceeded not only that of control rats (259 g) fed the same diet (p<0.01), but also that of control rats (285 g) fed the unadulterated diet (p<0.05). While not typical of all lesioned rats, the intake pattern of one lesioned rat was particularly striking. This rat consumed very little of the adulterated wet-mash diet and decreased its body weight from 237 g on the day preceding surgery to 155 g after 22 days on the diet. When switched to the adulterated high-fat diet, this rat weighed 329 g after 21 days and 559 g after an additional 30 days of access to the unadulterated high-fat diet. Thus lesioned rats that initially underate the quinine-adulterated wet-mash diet overate the quinine-adulterated high-fat diet. Although control rats fed the adulterated high-fat diet maintained their body weights below control rats fed the unadulterated diet throughout the second portion of this experiment, this difference (26 g between means on Day 21), while sizeable, was not significant (p<0.10). Neither was the difference in their food intake levels. Therefore, according to the criterion used here, adulteration of the high-fat diet with 0.4% quinine die not clearly decrease diet palatability. Since the rats fed the adulterated wet-mash diet may have adapted to the aversive properties of quinine prior to the shift to the adulterated high-fat diet, thereby greatly increasing the consumption of thie diet by VMH lesioned rats, a second experiment was run in which VMH lesioned and control rats were maintained on high-fat diets from the outset. EXPERIMENT 2
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Method Animals. The animals were 37 female Long-Evans hooded rats (Blue Spruce Farms, Inc.) approximately 100 days old weighing 2 2 2 - 2 2 7 g at the beginning of the experiment. The high-fat diets, housing conditions, lesion parameters, histological procedures, and data analyses were the same as in the first experiment. Procedure. All rats received the unadulterated high-fat diet for 6 days before surgery. On the day after surgery, approximately half of the control and VMH lesioned rats continued maintenance on this diet, while the remaining rats in each group began maintenance on the 0.4% quinine-adulterated high-fat diet. After 30 days VMH lesioned rats fed the unadulterated high-fat diet and all control rats were sacrificed, while VMH lesioned rats fed the adulterated diet began maintenance on the
Results and Discussion
Four rats died after surgery and five lesioned rats did not overeat and become obese when fed the unadulterated diet. Tissue destruction for lesioned rats that became obese during access to the unadulterated diet was similar to that described in the first experiment. The data from this experiment (Figs. 3 and 4) essentially replicated the results from the high-fat portion of the first experiment. An important exception, however, is that control rats significantly (p<0.05) underate the 0.4% quinine-high-fat diet and maintained their body weights at levels significantly (p
282
PETERS E T AI,
the data presented in the figures of the two experiments is the position of the curves for lesioned rats fed the adulterated diets. Whereas VMH lesioned rats underate an adulterated wet-mash diet, they overate an adulterated high-fat diet. G E N E R A L DISCUSSION
VMH lesioned rats did not respond to dietary adulteration as did control rats in the two experiments described herein. Although control rats decreased their consumption and consequently their body weight when fed either a quinine-adulterated wet-mash or high-fat diet, VMH lesioned rats lost more weight than control rats when fed the adulterated wet-mash diet yet surprisingly overate and gained more weight than control rats when fed the adulterated high-fat diet. How consistent are these observations with the characterization that VMH lesioned rats are finicky eaters? A fundamental difficulty encountered in an attempt to answer this question is the specification of precisely what is meant by the term finickiness. Unfortunately, the term is vague and rather poorly defined [26]. Although there appears to be general agreement among various verbal definitions, e.g., "the exaggerated tendency of animals with VMH lesions to reject unpalatable food while accepting palatable foods to excess (p. 410, [8])", considerable ambiguity is apparent when the actual operations used to define the term are examined. Some investigators have used within-group comparisons and noted that dietary adulterations produced greater changes in consumption in VMH lesioned rats than in control rats [11,32]. Others have used between-group comparisons and noted that the food intake of VMH lesioned rats was often less than that of control rats when diets were adulterated [21,32]. Since body weights for lesioned and control rats often differed substantially in these experiments, still others have concluded that the undereating of certain diets, and therefore finickiness, is a consequence of the animal's obesity rather than an effect of tissue destruction because lesioned rats defend their body weight at essentially the same level as control rats when both are fed adulterated maintenance diets [7,8]. Several recent experiments, however, have demonstrated that rats with knife cuts between the medial and lateral hypothalamus actually do undereat some maintenance diets and lose more weight than control rats fed the same diet [10,31]. Figure 5A presents a model that depicts the relationship between maintenance diet palatability and body weight suggested by these data and also the results from the wet-mash portion of Experiment 1. This model clearly defines VMH finickiness: VMH lesioned rats overeat good tasting food and thereby become obese; VMH lesioned rats do not overeat bad tasting food and fail to become obese. Further, when fed even less palatable diets, they undereat and lose weight relative to control rats fed the same diets. The term finickiness is used here to describe rather than explain this intake pattern. VMH lesioned rats do not overeat or undereat because they are finicky. Those studies which have reported that VMH damage does not alter the lower limits of body weight have not fully explored the low palatability end of the continuum. Franklin and Herberg [8] and Ferguson and Keesey [7] used 0.15% and 0.2% quinine wet-mash diets, respectively. Interestingly, the undereating seen in Experiment 1 was not anticipated because the 0.2% quinine wet-mash diet was
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prepared using the description provided by Ferguson and Keesey. This undereating following VMH damage can not be attributed to gonadal dysfunction [7] since castration induces overeating and weight gain in female rats [34] even when they are maintained on quinine diets [ I 0 ] . This undereating of an adulterated maintenance diet with respect to same-diet controls is also the first time this observation has been reported for female VMH lesioned rats. Undereating, as noted above, has been reported by Sclafani and coworkers in female knife-cut rats with 0.2% and 0.8% quinine powder diets [ 10,31 ]. Several authors [6, 7, 13, 28] have proposed that finickiness and hyperphagia can be dissociated in terms of the specific locus of damage caused by VMH lesions. Finickiness most readily occurs when hypothalamic lesions destroy the subfornical area lateral to the ventromedial nucleus or when parasagittal knife cuts are placed lateral to the plane of the fornix. Lesions in most rats in the present study extended laterally to partially invade this region. If undereating reflects a dysfunction other than that responsible for overeating, the curves shown in Fig. 5B would more appropriately describe the relationship for the brain dysfunction that induces overeating of palatable diets. It is likely that rats with lesions confined to more medial hypothalamic areas or with knife cuts medial to the plane
VMH FINICKINESS of the fornix would maintain their b o d y weights at control levels even when fed very unpalatable diets. Although adulteration of the wet-mash diet with 0.2% quinine and the high-fat diet with 0.4% quinine produced comparable changes in food intake and body weight for control rats, choice data indicate that both control and VMH lesioned rats prefer the quinine-adulterated high-fat diet to the quinine-adulterated wet-mash diet. Control (N = 8) and VMH lesioned rats (N = 6) other than those used in Experiments 1 and 2 were given simultaneous access to both adulterated diets after 24 hr of food deprivation. Contact durations with the 0.4% quinine high-fat diet were longer than those with 0.2% quinine wet-mash diet by ratios of approximately 10:1 for both groups. Rats with VMH lesions may overeat the 0.4% quinine high-fat diet simply because this diet is more palatable than the 0.2% quinine wet-mash diet, as illustrated by the suggested relative locations of the diets along the abscissa of Fig. 5B. This definition of diet palatability in terms of choice behavior is less stringent than the definition used previously in this paper. It is possible, however, that differences in body weight during maintenance on these two adulterated diets would be found only for rats with VMH lesions, even though both VMH lesioned and intact rats prefer the adulterated high-fat diet, because the range of body weights along the palatability continuum is considerably more restricted for intact animals. Although we have not used the term unpalatable to describe either adulterated diet, weight loss at comparable times (Day 22) in Experiments 1 and 2 for control rats fed these diets was approximately 12%. Most readers would probably concur with the statement that the 0.2% quinine wet-mash diet was unpalatable, particularly since VMH lesioned rats underate this diet with respect to same-diet control rats. While diet palatability was defined tautologically for intact rats with reference to intake measures, it is inappropriate to describe a diet as palatable if VMH lesioned rats overeat the diet and conversely as unpalatable if they undereat the diet. If the 0.2% quinine wet-mash diet were labeled unpalatable, then the same label appears appropriate for the 0.4% quinine high-fat diet with reference in both instances to the feeding behavior of intact rats. Rats with VMH lesions underate one quinine-adulterated diet that was demonstrably less palatable (unpalatable) for control rats yet overate another quinine-adulterated diet that was also demonstrably less palatable (unpalatable) for control rats. In this respect our data are inconsistent with traditional conceptions of VMH finickiness. Although some writers (e.g., [26], page 91] use the term finickiness to describe the feeding behavior of rats with VMH damage because they do not overeat all diets, we suggest that this term would more meaningfully characterize the feeding behavior of such rats if the relationship depicted in Fig. 5A held for all hypothalamic brain manipulations that induce overeating of some diets, i.e., if undereating and overeating are not dissociable in terms of locus of hypothalamic damage. If, on the other hand, overeating and undereating are dissociable phenomena and Fig. 5B approximates the relationship between maintenance diet palatability and body weight for certain types of hypothalamic damage, then the term finickiness has historical surplus meaning regarding the nature of the feeding disturbances that may be misleading. The first author, for example, has previously suggested that VMH lesions nonadditively increase hunger motivation
283
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FIG. 6. Behavioral indices of hunger for control rats typically increase and become asymptotic as hunger, def'med operationally as percentage of ad lib body weight, increases. Although there are no asymptotic differences in hunger, the increased hunger hypothesis suggests that VMH destruction elevates hunger motivation above control levels as deprivation conditions become more moderate. [1 ~, 23, 24, 25]. The increment is described as nonadditive because the lesion does not increase hunger motivation above asymptotic levels of hunger inferred from the behavior of intact animals (Fig. 6). Thus VMH lesioned rats may overeat certain foods that are freely available simply because they are more hungry than control rats. If their diet is made less palatable, they will decrease their consumption of the diet but perhaps still consume more than control rats fed the same diet. As diets are made progressively less palatable, VMH lesioned rats will maintain their b o d y weights at comparable levels since there are no asymptotic differences in hunger motivation. In this explanation of the effects of diet palatability on feeding behavior in VMH lesioned rats, the term finickiness has little utility. Recent theoretical analyses of the feeding disturbances induced by VMH destruction [9, 14, 26] p r o m p t further clarification of the increased hunger hypothesis. Basically, this proposal argues that rats with VMH lesions behave in a manner similar to intact rats that have been made hungrier by any of the variety of operations. While it is possible that these behavior changes reflect the disruption of central nervous system mechanisms directly controlling feeding behavior [14], Friedman and Stricker [9] suggest that VMH destruction induces a primary dysfunction in fat metabolism that promotes lipogenesis. Secondary hyperphagia is caused by increased hunger because more metabolic fuels than normal are removed from circulation to be deposited as fat. Although Friedman and Stricker argue that rats with VMH lesions do not always behave like hungry rats because changes in sensory reactivity and emotionality depress food-directed activity in certain situations, we feel that the behaviors of VMH lesioned rats are like those of hungry rats in more situations than previously suggested, and the two positions are therefore congruent. Powley [26] has recently suggested that the cephalic reflexes of digestion, cued by oropharyngeal contact with food stimuli, are exaggerated by VMH damage and thereby generate the hyperphagia and paradoxes of the VMH syndrome. Although Powley's proposal is seemingly anti-
P[ I'ERS t:'T ell.
284 thetical to the position described here since we argue that aspects of the feeding behavior of VMH lesioned rats are not remarkably paradoxical, there is considerable agreement on certain points. Powley uses an example to illustrate that hyperphagia could occur because "the heightened cephalic salivary reflex would inform the VMH animal that it was still hungry (italic ours, p. 103)." Further, we concur that increased hunger may be induced by and is therefore secondary to phasic metabolic dysfunctions triggered by palatable diets. However, unless diet palatability is defined tautologically with respect to the feeding behavior of VMH lesioned rather than control rats, neither Powley's cephalic phase hypothesis, Grossman's affective hypothesis [12], nor Sclafani's dual lipostat hypothesis [28] can account for the fact that VMH lesioned rats in the present study overate one adulterated diet and underate another while control rats lost comparable amounts of body weight when fed either diet.
Finally, Ahlskog and Hoebel [2] have demonstrated a hyperphagia syndrome in rats following damage to the ventral noradrenergic bundle (VNB). Since such rats did not significantly decrease their intake below that of same-diet control rats when their high-fat diet was adulterated with 0.125% quinine, it was suggested that hyperphagia in the VNB syndrome is not accompanied by finickiness 1 1 , 2 ] Preliminary work in this laboratory indicated that the intake of VMH lesioned rats was not substantially depressed when their high-fat diet was adulterated at this concentration and therefore was obviously above the intake of control rats. The VMH syndrome may be dissimilar to that produced by destruction of the VNB because the present data indicate that VMH lesions induce overeating of even a 0.4% quinine-adulterated high-fat diet. Other dissimilarities between the two syndromes have been noted [3,19].
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