An animal model for the behavioral effects of interferon

Interferon, which is produced during viral infections, has cognitive and neurological effects in humans. A dose of 1600 U/g of mouse interferon-alpha significantly depressed horizontal activity, head pokes into a food chamber, and food intake in mice 10 hr and 24 hr after injection. An 800 U/g dose had only slight effects on horizontal activity and food intake, whereas a 400 U/g dose had no effect. There was no evidence of sensitization to interferon when a second 400 U/g dose was given after the 1600 U/g dose. The results imply that mouse interferon-alpha can be used in mice as a model for studying the fatigue and anorexia produced by interferon.     

Food intake inhibition elicited by intraportal glucose and adrenaline in dogs on a 22 hour-fasting/2 hour feeding schedule

The intraportal injections of saline or 1.2 g/kg glucose had no effect on the food intake of dogs being fed for 2 hr daily in their home cages with a mixture of Purina chow and canned meat. However, intraportal injections of 2 to 3.6 g/kg produced a complete supression of feeding lasting more than 2 hr, or at least a substantial reduction of food intake. The same doses injected intrajugularly had no effect. Adrenaline injected intraperitoneally (100–200 μg/kg) or intraportally (100 μg/kg) elicited a complete inhibition of feeding lasting more than two hours, or a substantial reduction, while the same doses injected intramuscularly or intrajugularly had no effect. All these results indicate that glucose and adrenaline produce food intake inhibition via receptors located in the portohepatic region.     

Cholecystokinin octapeptide and lithium produce different effects on feeding and taste aversion learning

The strengths of taste aversion induced by sulphated cholecystokinin 26-33 (CCK-8; 1,2,4 and 8 micrograms/kg IP) and lithium chloride (LiCl; 7.5, 15, 30 and 60 mg/kg IP) were determined in order to assess the relative aversiveness of the two compounds. All doses of LiCl induced strong aversion, but only the highest dose of CCK-8 induced aversion, which was mild. Effects of CCK-8 and LiCl on food intake were then compared in the hour (hr) following 8 hr of food deprivation; rats were on this food deprivation schedule for a relatively long time (78 days) throughout testing. All doses of CCK-8 reduced food intake significantly. Most doses of LiCl either did not affect or significantly increased food intake. Although 60 mg/kg LiCl did not affect food intake when administered 15 or 30 min before food presentation, it significantly increased food intake when administered 1, 2 or 3 hr before food presentation. Overeating of solid food may be an illness-induced behavior. Although a very high dose of LiCl (120 mg/kg) decreased food intake markedly, the rats were obviously distressed, not satiated. Failure of CCK-8 to affect feeding behavior like LiCl is indirect evidence that the reduction of food intake by CCK-8 is not merely the result of aversiveness, but is an extremely potent and specific behavioral effect.     

Variety in the diet enhances intake in a meal and contributes to the development of obesity in the rat

Male and female rats were given three palatable, high energy foods either simultaneously or in succession during three 40 min courses. Both simultaneous and successive variety enhanced energy intake compared to the intake of single palatable foods, which was itself enhanced compared to the intake of chow. Rats deprived of food for 24 hr showed a compensatory increase in chow intake (84%) but only a 20% increase in intake in the single palatable food conditions, and no increase in the variety conditions. Male and female rats showed a similar response to variety and deprivation. The effect of variety on body weight was also examined in rats offered either chow, or chow and one palatable food, or chow and three palatable foods in succession (changed every 12 hr) or simultaneously, for seven weeks. All rats offered the palatable foods were hyperphagic compared to chow-fed controls. Rats given the simultaneous but not the successive variety diet were more hyperphagic than the other palatable food groups and showed significantly greater body weight and fat gains. The availability of a variety of foods is an important factor in the amount eaten in the meal and in the etiology of obesity.     

Sham feeding is inhibited by dietary-induced obesity in rats

A group of six female, albino rats were maintained on a cafeteria diet of cookies, milk, and elevated-fat (shortening), rat-chow mixture and rat chow while a similar group received only rat chow ad lib for 17 weeks. When the groups differed significantly in mean body weight (obese-387.5 g, controls-287.2 g; p less than 0.001), gastric fistulas were implanted in each animal. After recovery, the rats were adapted to a liquid diet and assessed for sham feeding. Control-fed, normal-body-weight subjects showed substantial sham feeding when ingesting the Vivonex with the fistulas open compared to fistula-closed intake; meal frequency, meal size (apart from the initial meal) and total food intake were significantly increased while the satiety ratios following each meal were significantly decreased. Obese animals showed no significant increased feeding and satiety ratios were unreliably altered; while normal-body-weight controls increased 4-hr food intakes by 93% and halved their mean satiety ratios the obese animals showed an 8% increase in 4-hr food intake and only a 22% decrease in mean satiety ratios. We offer the hypothesis that, when animals are induced to become obese by palatable and varied diets which are then terminated, the anorexia produced is independent of gastrointestinal interactions inasmuch as that anorexia extends to sham feeding.     

Food intake of rats administered with glycerol

The effect of glycerol on rats food intake was determined when it was administered either via bolus gastric intubation, or by a continuous 24 hr infusion into the aorta. Both of these treatments resulted in a suppression of the 24 hr food consumption to an extent which was greater than that accounted for by the caloric value of the administered metabolite. Gastric loading with urea solutions equiosmotic to glycerol or with glucose solutions equicaloric to glycerol were less effective than glycerol in reducing the 24 hr food intake. The time course effect on food intake varied between gastric loading with glycerol and with equicaloric glucose solutions, with the former usually exerting a more delayed and longer lasting effect. Continuous intraaortal infusions of glycerol were more effective than glucose solutions in suppressing 24 hr food intake even though the latter had twice the caloric value of the former. Our data suggest that the action of glycerol on food intake is not mediated through its conversion to glucose. The possibility that glycerol may participate in a lipostatic control mechanism of food intake is discussed.     

Failure of portal glucose and adrenaline infusions or liver denervation to affect food intake in dogs

Total liver denervations were attempted on 5 mongrel dogs. At the same time, the hepatic portal vein was cannulated with a polyethylene cannula which was exteriorized. Five sham operated, cannulated dogs served as controls. Both denervated and sham operated dogs returned to preoperative food intake within 8 days post surgery. After recovery, intraportal infusions of 6 to 25 g of glucose prior to food presentation in 23 hr fasted sham or denervated dogs resulted in no anorexia. The portal vein and jugular vein were cannulated in an additional 4 dogs. Jugular blood samples were taken prior to and after portal infusion of 20 g of glucose in 23 hr fasted dogs. Both jugular blood glucose and insulin concentration increased significantly 1 to 2 min after portal infusion. The dogs were presented with food 3 to 5 min after the cessation of infusion, yet they showed no anorexia. These same 4 dogs were given portal infusions of either 0.5 μg/kg, 1.0 μg/kg or 1.5 μg/kg of adrenaline after a 23 hr fast. When food was presented 10 min after the infusions were stopped, the dogs ate immediately showing no signs of anorexia. These results question the role or the existence of hepatic glucoreceptors in the control of food intake in the dog.     

Comparison of the interoceptive sensory consequences of CCK, LiCl, and satiety in rats

In three experiments we assessed the degree to which ad lib feeding, injection of cholecystokinin (CCK), and injection of lithium chloride (LiCl) produce states with similar sensory consequences. In each experiment, two groups of rats were trained to use cues arising from food deprivation and satiation as discriminative signals for shock. One group was shocked when deprived but not when nondeprived. The other group received the reversed discrimination. Testing began when incidence of freezing was greater under the shocked deprivation than under the nonshocked deprivation condition. In Experiment 1, the rats were tested under 24-hr food deprivation after injections of CCK, LiCl, and saline (in counterbalanced order). We reasoned that if either CCK or LiCl induce satiety-like states, they should promote patterns of responding different from those produced by saline but similar to those produced by ad lib feeding. The effects of CCK on freezing did not differ from those of saline, whereas both CCK and LiCl had effects that were different from ad lib feeding. This pattern of results was also obtained when deprivation level during training and testing was reduced to 8 hr (Experiment 1A) and also when rats received small amounts of food in conjunction with CCK (Experiment 2). The intubation of a high-calorie stomach load (Experiment 1A) produced a response profile like that observed after free feeding. Freezing after LiCl treatment differed from that observed after free feeding and from that found after injection of CCK. The results indicate that rats can differentiate between the sensory consequences of the states produced by CCK, by LiCl, and by ad lib feeding.     

Effects of gustation and gastric loading on rapid calorie metering in rats

On gustation/intubation of nutritive sucrose or glucose solution, both ad lib and meal-time rats reduced their subsequent 1 hr calorie intake via stock diet. But gustation/intubation of calorically-inert water had no effect on 1 hr calorie intake of either group of rats. In contrast, on tasting calorically-inert but sweet saccharin, the 1 hr intake of meal-time rats was reduced, though not the intake of ad lib rats. However, on intubation of saccharin solution no reduction in 1 hr intake was shown by either meal-time or ad lib rats. Quinine also showed differential effects on calorie intake. On intubation, but not on gustation of quinine, both ad lib and meal-time rats evidenced increase in their 1 hr calorie intake. Daily (24 hr) calorie intake via stock diet of ad lib rats, in contrast to 1 hr intake was unaffected by gustation/intubation of any test solution, including nutritive sucrose and glucose. Meal-time rats daily (3 hr) intake, on the other hand, was similar to 1 hr calorie intake following test solution treatment. It was reduced on gustation/intubation of calorically-rich solution as well as on tasting the sweet, but calorically-inert saccharin. Taste/intubation of quinine did not cause any change in daily calorie intake of either ad lib or meal-time rats.     

Differential effects of quinine and sucrose octa acetate on food intake in the rat

Twenty-seven adult female rats were fed chow diets containing quinine sulfate, sucrose octa acetate, or alphacel. Quinine produced a greater, more prolonged depression of food intake than did SOA. Quinine also resulted in loss of body weight.     

The effects of 2-deoxy-D-glucose given via the jugular or hepatic-portal vein on food intake and plasma glucose levels in pigs

Intracellular glucose metabolism is reduced in the presence of its analogue 2-deoxy-D-glucose (2-DG). In the present experiments, 2-DG has been administered to pigs to see if it affects appetite and to test the hypothesis that pigs will respond to intracellular glucoprivation by increasing food intake. During the experiments, the pigs were fed on either a one meal per day or an ad lib regime. 2-DG was either given as a rapid injection or by slow infusion over 2 hr. The site of 2-DG administration was either via the jugular or the hepaticportal vein. Injections of 2.5, 3.75 or 7.5 g 2-DG into the jugular vein of hungry pigs 15 min before a meal produced no effect on food intake. With food available ad lib, there was a reduction in the rate of responding for food shortly after the injection of 2-DG. Later, after a 4–5 hr latent period, there was a significant increase in food intake. In hungry pigs 7.5 g 2-DG intraportally produced no effect on meal size, whereas similar treatment with food available ad lib produced a total suppression of responding for the 2–5 hr period post-injection. A lower dose (3.75 g) intraportally in ad lib fed pigs produced no effect. Injections of 2-DG via either route produced a marked hyperglycaemia.     

The effect of naloxone on feeding and spontaneous locomotion in the wolf

The effect of naloxone on food intake and activity levels was studied in the wolf (Canis lupus). Naloxone decreased food intake at both the 1 mg/kg and 5 mg/kg dose. There was no quantitative difference in the magnitude of the decrease in food intake produced by naloxone in winter or summer. Wolves ate significantly greater amounts of deer meat than dog chow after naloxone when expressed on a mass basis but there was no difference when the amounts of food ingested were expressed in calories. This suggests a role for endogenous opiates in the regulation of energy intake. The putative satiety factor, cholecystokinin-octapeptide, had no effect on food intake in wolves. Naloxone decreased spontaneous locomotion and increased time spent resting in wolves. The effects of naloxone on activity were significantly more marked in winter compared to summer.     

Preoptic-hypothalamic periventricular lesions: impairment of thirst-motivated behavior

To assess the effect of anteroventral third ventricle (AV3V) lesions on thirst-motivated behavior in the rat, the intake of quinine hydrochloride (QHCl) solutions and of QHCl-adulterated food was evaluated. Two-bottle choice tests were also administered to determine if lesions altered the rejection threshold for QHCl solutions. AV3V ablation significantly reduced QHCl solution intake in a one-bottle test, but did not alter the two-bottle preference relationships. Ingestion of QHCl-adulterated food was slightly reduced only if the animals had no prior experience with the taste of QHCl. These findings suggest that AV3V ablation produces deficits in thirst-motivated behavior, and that AV3V periventricular tissue contains elements necessary for the elaboration of normal thirst.     

Differential effects of the selective orexin-1 receptor antagonist SB-334867 and lithium chloride on the behavioural satiety sequence in rats

Recent studies have shown that acute systemic administration of the selective orexin-1 receptor antagonist SB-334867 significantly reduces food intake in rats. Although this anorectic action of orexin-1 receptor blockade is associated with an acceleration in the transition from eating to resting, it is widely recognised that the behavioural indices of satiety are not dissimilar to those of illness. In this context, Experiment 1 confirmed a significant anorectic effect of 90 (but not 60) mg/kg lithium chloride (LiCl) in male rats presented with palatable mash in the home-cage environment. Experiment 2 employed a continuous monitoring technique to contrast the effects of LiCl (90 mg/kg) and SB-334867 (10 and 30 mg/kg) on food intake and behaviour during a 1-h test with palatable mash. SB-334867 dose-dependently inhibited food intake, with the higher dose producing a comparable degree of appetite suppression (approximately 40%) to that seen with LiCl. Despite equivalent anorectic action, the two compounds produced very different effects on behaviour. LiCl reduced active behaviours (locomotion, rearing, grooming and sniffing), slowed the rate of eating and disrupted the behavioural satiety sequence (BSS). In contrast, SB-334867 (30 mg/kg) decreased the duration of feeding and grooming, and modestly accelerated the transition between eating and resting. Furthermore, whereas LiCl failed to alter posttreatment bodyweight gain, SB-334867 (30 mg/kg) produced a significant weight loss in the 24-h period immediately following injection. Overall, the divergent profiles obtained with equianorectic doses of LiCl and SB-334867 provide convincing evidence for the behavioural selectivity of SB-334867-induced anorexia.     

Water intake regulation in rats after intestinal bypass surgery

Jejunoileal bypass surgery in normal-weight female rats produced a temporary reduction in food intake, and small but more long lasting reductions in water intake and the water to food intake ratio. The bypass rats, however, did not differ from controls in their drinking response in a variety of thirst tests. That is, the bypass rats displayed normal increases in water intake following 24 hr water deprivation, hypertonic saline injection, or injection of polyethylene glycol; and normal decreases in water intake when food deprived or when given quinine-adulterated water. On the other hand, the bypass rats did not drink as much as did the controls when offered isotonic saline, or a saccharin solution for 24 hr/day, or when tested for schedule-induced-polydipsia 3 hr/day. The results indicate that bypassing a large segment of the jejunum and ileum does not disrupt regulatory drinking in the rat, but it does limit their ability to consume large volumes of fluid.     

Effects of thirst-inducing stimuli on consumption of ethanol solutions by golden hamsters

Two experiments were performed to examine the acute effects of thirst-inducing stimuli upon the intake of tap water and ethanol solutions by golden hamsters, a species which avidly consumes ethanol solutions. In Experiment 1, three groups of adult male hamsters (n = 6/group) were maintained on Purina chow and tap water; hamsters in two of the groups also had access to one of two ethanol solutions (15% or 30%, v/v). Animals were deprived at various times of either one or both fluids for 24 hr, and then either one or both fluids were presented during a 2-hr drinking test. Total water intake increased substantially following both selective water deprivation and total fluid deprivation whenever tap water was available during the drinking test, but no significant changes occurred when only the ethanol solution was available. Both total fluid deprivation and selective ethanol deprivation produced similar increases in ethanol consumption, but selective water deprivation did not, suggesting that the temporary removal of tap water has little direct effect upon ethanol intake in hamsters, at least at the ethanol concentration levels studied here. In Experiment 2, thirst was induced by a subcutaneous injection of 10% saline (1 ml/100 g). This procedure produced large increases in total water intake whenever tap water was available during the drinking test, but ethanol intake did not change under any circumstances. These results suggest that factors that acutely enhance water intake have little or no effect upon the ethanol consumption of golden hamsters.     

Hyperactivity and obesity: The interaction of social isolation and cafeteria feeding

Rats were reared in social isolation or in social groups of 4 or 5 rats per cage from weaning and were fed either a lab chow diet or a diet of 4 palatable foods (cafeteria diet), in addition to the lab chow. The hyperactivity of isolation-reared rats appears to be a reactivity to novel environmental stimuli, since it was seen only in the 0.5 hr tests and not in the near 24 hr test. It was found that hyperactivity and increased body weight can develop within as few as 7 to 10 days in rats reared in isolation from weaning. Cafeteria feeding enhanced activity in isolation-reared rats, but suppressed it in group-reared rats. Isolation-reared rats fed a cafeteria diet had strong, stable preferences for their most preferred food over the 25 days of measurement. Rats reared in isolation had significantly different food preferences, as compared with rats reared in groups. Cafeteria fed rats had a significantly greater calorie intake and body weight than rats fed lab chow. On analysis, cafeteria fed rats had significantly greater carcass energy and an increased amount of parametrial white adipose tissue as compared with rats fed only lab chow. The interscapular brown adipose tissue (IBAT) weights of cafeteria fed rats were also greater. However, as there was no difference between the cafeteria and chow fed rats in the total amount of protein in the IBAT, it was concluded that the increased weight of the IBAT did not reflect a genuine hypertrophy of the tissue.     

The anorectic action of peripherally administered 5-HT is enhanced by vagotomy

Peripherally administered 5-HT produced a greater suppression of food intake in rats with subdiaphragmatic vagotomy than in sham-operated controls. The enhanced anorexia to 5-HT in vagotomised rats and the anorexia in sham-operated controls were reversed by methysergide, indicating the involvement of 5-HT receptors in the observed anorexia in both groups of animals. Thus the increased suppression of food intake in vagotomised rats cannot be explained in terms of non-specific effects of 5-HT. Both vagotomised and sham-operated rats showed an equivalent degree of anorexia when treated with fenfluramine suggesting that the receptor mechanism responsible for the anorectic action of 5-HT plays little or no part in the action of fenfluramine. Systemic administration of 5-HT was found to slow the rate of gastric clearance. Unlike the anorexia induced by 5-HT this effect was not reversed by methysergide. Thus it appears that peripherally administered 5-HT interacts with the vagus nerve but the mechanism responsible for 5-HT anorexia is independent of any action on gastric clearance.     

Olfactory contributions to dehydration-induced anorexia in weanling rats

By 20 days of age, dehydration produces a clear anorexia, even though weanling rats have had only limited feeding and drinking experience. Their lack of ingestive experience makes weanlings good subjects for studying the physiological mechanisms subserving anorexic phenomena because learned contributions are unlikely to add significant complications. Twenty-day-old rats dehydrated by hypertonic saline injection were anorexic when offered milk or solid food (rat chow), but not when offered sucrose solutions (Experiment I). However, when the scent of almond was associated with sucrose solutions, or with water, intake of these solutions was depressed by dehydration (Experiment II). Thus for dehydrated rats, olfactory stimulation may help produce dehydrationinduced anorexia. Making rats anosmic by intransal lavage with ZnSO₄ (Experiment III) eliminated the anorexia to almond-scented water and partially eliminated that to milk. For these fluids, an odor cue seems a requirement for the occurrence of dehydration-anorexia. In Experiment IV, we found that dehydration-anorexia did not occur when milk was infused directly into pups' mouths. This finding suggests that the inhibitory process mediating dehydration-anorexia influences the approach to food and not the actual consumatory response that occurs once food is in the mouth. The inhibition of feeding produced by dehydration, therefore, may depend largely on olfactory cues, and seems to operate at a distance, as rats locate and approach food.     

Hypothalamic hyperphagic rats overeat bitter sucrose octa acetate diets but not quinine diets.

Female rats were made hyperphagic with knife cuts or lesions in the ventromedial hypothalamus (VMH) and their aversion to food made bitter by adulteration with quinine or sucrose octa acetate (SOA) was examined. In short-term choice tests VMH obese rats, as well as controls, strongly preferred a 0.1% quinine diet to a 1.0% SOA diet. Yet, in 24 hr intake tests VMH obese rats overate, relative to controls, the 1% SOA diet, but underate the 0.1% quinine diet. VMH rats in both dynamic and static stages also overate SOA diets in concentrations up to 16%. However, VMH obese rats underate a 1% SOA diet when previously fed a 0.1% quinine diet. The results indicate that the VMH rat's finickiness to quinine diets may not be due to bitter taste alone, but may result from toxic postingestive effects of quinine and the development of a conditioned taste aversion.