Influenza virus infection of mice induces anorexia: comparison with endotoxin and interleukin-1 and the effects of indomethacin

The effects of infection of mice with influenza virus on ingestive behavior were assessed by both 22-h intake of food pellets, and intake of sweetened milk in a 30-minute access period. Infection with a lethal dose of virus resulted in losses in body weight as well as a reduction in food pellet intake. By contrast, infection with a sublethal dose of virus decreased body weight and food pellet intake to a lesser extent, but did not alter milk intake. Acute intraperitoneal injection of endotoxin (LPS, 0.3-5 micrograms), interleukin-1 alpha (IL-1 alpha, 50-100 ng) or IL-1 beta (100 ng) reduced milk intake, suggesting that the reduction of ingestive behavior may be associated with immune activation in general, and IL-1 in particular Pretreatment of the mice with the cyclooxygenase inhibitor, indomethacin (10 mg/kg SC) substantially attenuated, but did not completely reverse, the reduction in milk intake by LPS and IL-1. However, chronic treatment with indomethacin failed to alter the body weight or the intake of sweetened milk in influenza-infected mice, although there was some attenuation of the reduction in food intake. These results suggest that although IL-1 may play a role in the anorexia caused by influenza virus infection, it is not the only factor involved.     

Stress-induced increase in urinary isatin excretion in rats: reversal by both dexamethasone and alpha-methyl-P-tyrosine

The effects of acute food deprivation and acute cold exposure on 24-hr urinary isatin excretion in rats and a mechanism responsible for changes in urinary isatin excretion during stress were investigated. This is the first study to demonstrate by HPLC that urinary isatin excretion is increased by stress. Both types of stress induced a marked increase in urinary isatin excretion during the 24 hr following the initiation of stress. Dexamethasone administration prevented the increase in urinary isatin excretion induced by both of the different types of stress. Furthermore, administration of either the benzodiazepine receptor agonist diazepam or the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine prevented the increase in urinary isatin excretion induced by acute food deprivation, whereas the dopamine-beta-hydroxylase inhibitor diethyldithiocarbamate proved ineffective. These observations suggest that during stress, activated catecholamine-synthesizing cells and corticotropin-releasing factor cells, both of which play central roles in stress responses, may be involved in total isatin production. Isatin may serve as an endogenously generated marker for some types of stress.     

Changes in the regulation by endothelium of norepinephrine response in isolated, perfused mesenteric vascular bed of rats at different ages

Unlesioned rats exploring a black-white two compartment box spent most of the time in the covered, black half of the box and only little time in the uncovered, white half (67 s/5 min). Large radio-frequency lesions of the amygdala or hippocampus did not alter this pattern of exploration, but rats with hippocampus lesions were more active than the other two groups of rats. Treatment with the 5-HT1A receptor agonist buspirone (0.1 mg/kg, s.c.) increased the time that unlesioned rats spent in the uncovered compartment (103 s), an effect that was less pronounced in hippocampus-lesioned rats and completely abolished by amygdala lesions. In a food transport test, unlesioned rats that traveled from a home cage to an exposed food source consumed small and medium-sized pellets immediately at the food source. Larger pellets, however, were carried back to the home cage for consumption. Rats with amygdala lesions ate fewer pellets at the food source and tended to carry more pellets back to the home cage for consumption than unlesioned rats. Rats with hippocampus lesions carried fewer pellets back to the home cage and ate more pellets at the food source. Buspirone (0.5-1.5 mg/kg, s.c.) reduced the carrying of large food items to the home cage and increased consumption of these pellets at the food source in all groups of rats. These results suggest that neither the amygdala nor the hippocampus play an important role in controlling exploratory behavior in a black-white compartment box, but that the amygdala may have some role in mediating the effect of buspirone to increase exploration of the white/open compartment. Further, the amygdala and hippocampus have opposing influences on the transport of food items to a shelter, the amygdala suppressing food carrying, and the hippocampus enhancing it. Neither structure is essential for the effect of buspirone to reduce food carrying. The hypothesis that limbic structures mediate 'fear/anxiety' responses is discussed critically.     

Male/female comparison of morphine effect on food intake--relation to anorexia nervosa

We have proposed that endogenous opioids play a critical role in the etiology of anorexia nervosa by mediating an auto-addiction. A biological predisposition may result from an atypical endogenous opioid system. Morphine activation of the system increases food intake in most species, including normal humans and rats, but decreases food intake in mice. The atypical opioid system in mice may be representative of that in anorexia nervosa patients, causing the biological predisposition. Anorexia nervosa is 10 times more prevalent in females than males. In the context of this auto-addiction opioid model, it was interesting to determine if the effects of morphine on food intake were markedly different between the two sexes. Full dose-response curves were done of the effects of morphine on food intake in males and females in both rats and mice, representing the typical and atypical responses, respectively. Differences between the sexes were not found to explain the marked prevalence of anorexia nervosa for females. The marked preference is probably at some other step.     

Position of operant costs affects visits to resources by laboratory mice, Mus musculus

A recently recognized problem in consumer demand studies has been whether subjects should be allowed free exit from a resource cage that they have paid to enter. If decisions related to switches in behaviour are affected by the position of operant costs, then demand studies that offer free return routes from resources may result in different behavioural organization from those that split the same payment between entry to and exit from resources. We aimed to assess the extent of any such differences by comparing results from four operant treatments. The closed economy treatments differed in the position of the operant costs required to allow a mouse to enter a food cage and then return to the home cage. Three of the treatments carried the same overall cost: a full cost to enter the food cage; a full cost to leave the food cage; or with the cost split equally between entering and leaving the food cage. The fourth treatment imposed a half cost to enter the food cage but allowed free exit. The mice spent longer in whichever cage carried an exit cost. The most even distribution of their time was with the split cost. The number of visits undertaken depended on the magnitude of the cost, and on the resource cage for which the mice were paying. Significantly more visits were made when payment was required to enter the home cage. The mice responded to the immediate costs of entry to the cages, rather than the overall costs of a round trip. The lower number of visits made under higher costs was compensated for by the greater duration of those visits. Copyright 1998 The Association for the Study of Animal Behaviour. Copyright 1998 The Association for the Study of Animal Behaviour.     

Incidence and outcome of schizophrenia in whites, African-Caribbeans and Asians in London

The endogenous, meal-contingent release of bombesin (BN)-like peptides is thought to contribute to the termination of a meal. In the following experiments the potency of BN receptor antagonists to attenuate the ability of nutrients to suppress food intake was tested. First, the effectiveness of BN receptor subtype antagonists was verified by testing their ability to block the effects of exogenous BN on food intake. Rats were administered intraperitoneal (i.p.) injections of either saline or 0.1 mg/kg [D-Phe12,Leu14]BN (binds both GRP and NMB receptors), [D-Phe6]BN(6-13) ethyl amide (binds GRP > NMB), and cyclo-SS-octa (BIM-23042; binds NMB > GRP). Five minutes later rats were administered 8 micrograms/kg BN (i.p.) and milk intake was measured. Injections of [D-Phe12,Leu14]BN and [D-Phe6]BN(6-13) ethyl amide reliably attenuated the ability of BN to suppress milk intake whereas BIM-23042 was ineffective. The results show that the antagonists were behaviorally effective and that exogenous BN may exert its effects on food intake primarily through the GRP receptor subtype. Next, the antagonists were administered either 5 min prior to or 5 min after an intragastric nutrient load or no load in both overnight-deprived and nondeprived rats, and milk intake was then measured. Stomach loads reduced intake and this effect was not attenuated by BN receptor antagonists. Finally, rats were allowed to prefeed and the milk was then removed. Rats were then administered a BN receptor antagonist (0.1 and 1.0 mg/kg) or saline either immediately after the prefeed, 10 min later, or 20 min later. Milk diet was then returned and intake was measured. Peripheral injections of the BN receptor antagonist had no effect compared to saline on milk intake. Collectively, the results indicate that the blockade of peripheral Bn peptide receptors is not sufficient to attenuate the safety signals generated by stomach loads or prefeeding.     

Regulation of melanogenesis in B16 mouse melanoma cells by protein kinase C

Serotonergic neuronal networks are important for food intake and body weight regulation. Dexfenfluramine (dF), a serotonin releaser and reuptake inhibitor, was used to investigate changes in food intake, body weight development, energy expenditure, respiratory quotient, and substrate oxidation rates for 12 days. Rats, which had been made obese by early postnatal overfeeding, received an energy-controlled mash diet and water ad lib and were intraperitoneally injected daily with either saline, 5 or 10 mg dF/kg. Compared to controls, food intake, body weight development, and energy expenditure were decreased in a dose-dependent manner, especially during the first 6 days. Lipid oxidation was increased while oxidation of carbohydrates was decreased. Pair-feeding experiments over 2 days revealed that this was not solely a result of diminished food intake but also an additional metabolic effect of dF, different from its anorectic effect. At the end of these experiments, plasma glucose and liver glycogen were unchanged after dF, but plasma free fatty acids were significantly decreased. Insulin-sensitivity was probably improved, indicated by decreased insulin levels and increases in muscle glycogen contents and activities of muscle pyruvate kinase. Liver-glutamine and contents of valine, leucine, and isoleucine in the muscle were significantly decreased after dF-treatment, the latter indicating a diminished proteolysis. The plasma tryptophan/large neutral amino acids ratio of the dF-rats was unchanged but that of the paired-fed rats was changed, despite similar changes in food intake. It is concluded that both increased oxidation of endogenous fat and reduced food intake could mediate the body weight reducing effect of dF.     

Olfactory mechanisms in the control of maternal aggression, appetite, and fearfulness: Effects of lesions to olfactory receptors, mediodorsal thalamic nucleus, and insular prefrontal cortex.

During lactation the female rat is hyperphagic, aggressive toward adult conspecifics, and less fearful than usual. In the first experiment the importance of olfactory receptors was investigated by surgically removing the olfactory epithelium of the nasal cavity. Mother rats subjected to this treatment consumed significantly less food and weighed less than sham-operated females. Moreover, experimental subjects displayed a dramatic decrease in maternal aggression. Fear behavior (sound-elicited freezing), on the other hand, was not affected by the lesions. The mediodorsal thalamic nucleus and the prefrontal insular cortex form part of the central olfactory system. The second experiment assessed the involvement of this olfactory-related thalamocortical system on the behavioral profile of mother rats. It was found that whereas the thalamic and cortical lesions left food intake and fear behavior unaffected, they significantly decreased the frequency with which the mother would attack an intruder male placed into her home cage. The sense of smell appears, according to the present experimenters, to play a crucial role in maternal aggression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Anticipation of future food: Suppression and facilitation of saccharin intake depending on the delay and type of future food.

A series of studies examined the (Sprague-Dawley) rat's tendency to suppress intake of .15% saccharin when it was followed by a second food after 4-, 16-, or 32-min delays. The second foods examined were 32% sucrose, 64% sucrose, lab chow, a Nutrasweet solution, skim milk, and chocolate milk. Saccharin intake was influenced by both the delay and the specific food available. Subsequent analysis showed that saccharin intake before the 4-min delay was an inverse function of the caloric value of the second food. However, saccharin intake before the 16-min delay was better predicted as an inverse function of the hedonic value of the second food. The results suggest that the caloric and hedonic values of a food may influence food selection across different time courses, and that the effective time horizon for the sequential comparison of foods depends on the specific foods that are compared. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Greater behavioral effects of stress in immature as compared to mature male mice

The effect of sexual maturity on behavioral effects of stress was examined in male mice. Immature (4-week-old) or mature (8-week-old) animals were subjected to either social stress (exposure to an isolated adult male) or restraint stress for 5 days and examined for body weight, food intake, or plus-maze behavior. Social stress reduced food intake, body weight, and open-arm entries in 4-week-old but not 8-week-old mice. Restraint reduced body weight in 4-week-old but not 8-week-old mice. It is concluded that immature male mice show greater behavioral disturbances after stress than their mature counterparts. The findings are in agreement with much anecdotal evidence that children are more vulnerable to stress than adults.     

Differential effect of lipopolysaccharide on food hoarding behavior and food consumption in rats

Experimental studies assessing the suppressing effect of lipopolysaccharide (LPS) on feeding behavior have focused exclusively on the ingestive component of this behaviour without taking into account its appetitive component. The appetitive sequence of feeding behavior regroups activities animals engage in to gain access to food without necessarily eating it. The objective of the present study was to compare the effects of LPS on food intake and food hoarding. Rats were given the possibility to access food during a 30-min daily session in an apparatus consisting of a cage connected to an alley with free food at its end. Subjects were tested under different motivational levels for food hoarding: a first group (FS) received a food supplement to maintain stable body weight while a second group (noFS) did not receive such a supplement. LPS (250 micrograms/kg i.p.) dramatically decreased total food intake in rats from both groups whereas food hoarding was much less affected in LPS-treated rats from the noFS group. This expression of a still salient secondary motivation in LPS-treated rats which did not receive any food supplement can be interpreted to suggest the expression of an anticipatory feeding behavior along with a reduced immediate appetite. In addition, LPS had no effect, in rats from the noFS group, on the amount of food eaten after transport to the refuge. LPS-treated animals still appear to be able to adjust their defensive behavioral strategies with regard to their needs and capacities. These findings support the adaptive value of the behavioral changes displayed by LPS-treated animals.     

Some determinants of milk ingestion in suckling rats.

Eight experiments were conducted to examine several possible determinants and controls of milk intake in 10-day-old preweanling Sprague-Dawley rats. Results indicate that while the amount of milk the mother provides is a major determinant of milk consumption, pups will individually adjust their intake in response to certain treatments. Deprived pups ingested more milk than nondeprived littermate controls if given access to enough milk. Intragastric intubations of skimmed milk or distilled water reduced milk intake; heavy cream or isotonic saline did not. Injections of polyethylene glycol or formalin, which produced hypovolemia, increased milk consumption, and hypertonic saline decreased it. Results indicate that preweanling rats are behaviorally responsive to certain changes in body fluids and suggest that milk intake involves more than an invariant reflex. (30 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Glycated cholecystokinin-8 has an enhanced satiating activity and is protected against enzymatic degradation

Monoglycated cholecystokinin octapeptide (CCK-8) (glucitol-Asp1 adduct) modified at the NH2-terminus was prepared under hyperglycemic conditions, purified by high-performance liquid chromatography, and characterized by mass spectrometry (Mr 1228.4 Da) and peptide sequencing. CCK-8 (100 nmol/kg, i.p.) significantly (P < 0.001) reduced voluntary food intake of fasted mice for up to 30 min after its administration, compared with saline-administered controls. Glycated CCK-8 reduced food intake at 30-120 min (P < 0.01 to P < 0.001) and significantly reduced feeding compared with CCK-8 from 60 to 120 min (P < 0.01). In vitro plasma degradation studies indicated that glycated CCK-8 was resistant to the normal rapid enzymatic conversion to CCK fragments. This study demonstrated that CCK-8 is a potent short-term inhibitor of food intake, and that structural modification of this peptide by amino-terminal glycation leads to enhanced satiating activity, partially due to increased resistance to serum aminopeptidase degradation.     

Leptin is not necessary for gestation and parturition but regulates maternal nutrition via a leptin resistance state

Leptin levels are significantly elevated in pregnant mice, rats and humans suggesting a critical role for leptin during gestation. To address whether leptin plays a putative role in the physiology of pregnancy, we asked whether a mouse pregnancy would be affected by the complete absence of leptin from both the mother and fetuses. Thus, leptin-deficient ob/ob females were first treated with exogenous leptin and then mated to similarly treated ob/ob males. All resulting fetuses have an ob/ob genotype and lack like their mothers any endogenous leptin production. Withdrawal of leptin treatment at 0.5, 6.5, 10.5 and 19.5 days p.c. did not affect any stage of the pregnancy despite a gradual return of the mothers to an obese state. However, some mice had delayed gestation periods of 21-23 days which were associated with prolonged parturition. The pups were normally delivered with no obvious signs of deformities although none survived beyond a day after delivery due to failure of lactation. Monitoring daily food intake of pregnant ob/ob females treated throughout gestation with leptin revealed significantly elevated levels of food intake from day 10 p.c. and onward demonstrating an attenuation of a leptin response during pregnancy and a leptin resistance effect. These studies demonstrate that in the mouse, leptin is not a critical molecule for implantation, gestation, fetal growth and parturition but that the leptin resistance effect at mid-gestation aims to stimulate food intake thus providing sustained energy resources for pregnancy.     

Gastrodin and p-hydroxybenzyl alcohol facilitate memory consolidation and retrieval, but not acquisition, on the passive avoidance task in rats

This study evaluated synthetic trehalose dicorynomycolate (S-TDCM), an immunomodulator, for its survival enhancing capacity and behavioral toxicity in B6D2F1 female mice. In survival experiments, mice were administered S-TDCM (25-400 micrograms/mouse i.p.) 20-24 hr before 5.6 Gy mixed-field fission-neutron irradiation (n) and gamma-photon irradiation. The 30-day survival rates for mice treated with 100-400 micrograms/mouse S-TDCM were significantly enhanced compared to controls. Toxicity of S-TDCM was measured in nonirradiated mice by locomotor activity, food intake, water consumption, and alterations in body weight. A dose-dependent decrease was noted in all behavioral measures in mice treated with S-TDCM. Doses of 100 and 200 micrograms/mouse S-TDCM significantly reduced motor activity beginning 12 hr postinjection with recovery by 24 hr. A dose of 400 micrograms/mouse significantly decreased activity within the first 4 hr after administration and returned to control levels by 32 hr following injection. Food and water intake were significantly depressed at doses of 200 and 400 micrograms/mouse on the day following drug administration, and were recovered in 24 hr. Body weight was significantly decreased in the 200 micrograms/mouse group for 2 days and in the 400 micrograms/mouse group for 4 days following injection. A dose of 100 micrograms/mouse effectively enhanced survival after fission-neutron irradiation with no adverse effect on food consumption, water intake, or body weight and a minimal, short-term effect on locomotor activity.     

Induction of uncoupling protein expression in brown and white adipose tissue by leptin

Deposition of excess body fat occurs when energy intake chronically exceeds energy expenditure. In ob/ob mice, the absence of leptin affects both components of the energy balance equation, and the mice become morbidly obese after weaning. Treatment of ob/ob mice with exogenous leptin reduces body weight by decreasing food intake and stimulating energy utilization, but even when saline- and leptin-injected ob/ob mice are pair-fed, mice receiving leptin lose significantly more weight. Therefore, the purpose of the present study was to test the hypotheses that uncoupling protein-1 (UCP1) expression is reduced in adipose tissue from ob/ob mice and is restored by treatment with exogenous leptin. Lean and ob/ob mice (5-6 weeks old) were housed at 23 C and treated with leptin (20 microg/g BW x day) for 3 days before they were killed. Compared with levels in lean littermates, UCP1 messenger RNA (mRNA) and protein levels were lower in brown adipose tissue (BAT) and retroperitoneal white adipose tissue (WAT) from ob/ob mice. Treatment of ob/ob mice with leptin reduced body weight and produced a 4- to 5-fold increase in UCP1 mRNA levels in both interscapular BAT and retroperitoneal WAT. The increases in UCP1 mRNA were accompanied by comparable increases in UCP1 protein in mitochondrial preparations from each tissue. Given that the sole known function of UCP1 is to uncouple oxidative phosphorylation, the present results are consistent with the conclusion that leptin stimulates energy utilization in ob/ob mice by increasing thermogenic activity and capacity (UCP1). In addition, the present results suggest that decreased UCP1 expression in BAT and WAT of ob/ob mice is in part responsible for their increased metabolic efficiency and propensity to become obese.     

On the reduction of dodging in mice: A comparison of food wrenching and dodging in rats (Rattus norvegicus) and mice (Mus musculus).

Rats attempt to steal food from conspecifics by approaching them from the side to wrench the food from the victims' paws, but victims dodge laterally away to protect their food. Given the pervasive necessity of obtaining food, it might be expected that the behaviors of food wrenching and dodging would be common to many animals, but this idea has not been examined. In the present study, food wrenching and dodging were compared in Long-Evans and Sprague-Dawley rats (Rattus norvegicus) and out-crossed CDF1 and inbred C57b mice (Mus musculus). Mice stole food using a strategy very similar to that of rats, but they did not dodge in an open field test and dodged less in a home cage test and ran away or fought more than rats. There were no strain differences in rats, but C57b mice dodged less than CDF1 mice. Given that dodging is a component not only of food defensive behavior but also of play, sexual, and aggressive behavior, the species and strain difference may be a marker (or a key element) of changes in social behaviors that have occurred since the evolutionary separation of rats and mice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Endogenous nitric oxide modulates morphine-induced changes in locomotion and food intake in mice

Opioids increase the dopaminergic turnover in nucleus striatum and nucleus accumbens of mice, causing behavioural changes such as increased locomotion and food intake. We have now shown that L-arginine administration increases morphine-induced locomotion and changes in food intake in mice. D-Arginine had no effect, suggesting a stereospecific mechanism. Furthermore NG-nitro-L-arginine methyl ester, a specific inhibitor of nitric oxide synthase, reduced the morphine-induced effects. These results suggest that endogenous nitric oxide could play a role in the modulation of dopaminergic effects elicited by morphine.     

Angiomyolipomatous hamartoma of the tongue

To examine the role of the liver in lipopolysaccharide (LPS)-induced hypophagia, we investigated the effect of hepatic portal and vena cava infusions (1 mL/30 min) of LPS (100 microg/kg of body weight) on feeding in rats. LPS infusion significantly reduced food intake when administered via either the hepatic portal vein or the vena cava. Both the magnitude and time course of this hypophagia were similar regardless of the infusion route. As in previous experiments of ours in which LPS was administered by intraperitoneal (i.p.) injection, LPS reduced food intake by decreasing meal frequency, without affecting meal size or duration. The results suggest that peripherally administered LPS does not act primarily in the liver to reduce food intake.     

Inhibition of hepatocellular carcinoma development in hepatitis B virus transfected mice by low dietary casein

In a comprehensive human ecological study, primary liver cancer has been shown to be highly significantly associated with 1) the prevalence of persistent infection with hepatitis B virus (HBV) and 2) plasma cholesterol concentrations that are, in turn, associated with the consumption of animal based foods. In rat studies, aflatoxin-induced hepatocellular carcinoma is substantially prevented by decreasing the intake of animal based protein (casein), a hypercholesterolemic nutrient. Thus the development of primary liver cancer associated with persistent HBV infection or with aflatoxin exposure may be controlled by reduced intake of animal-based proteins. Transgenic mice transfected with an HBV gene fragment containing the viral transactivator of hepatis B virus, HBx, which induces the formation of hepatocellular carcinoma, were used to examine the ability of dietary casein to modify tumor formation. Reducing the concentration of dietary casein to 6% from the traditional level of 22% markedly inhibited (by 75%) hepatic tumor formation in these transgenic mice. Tumor development also was substantially altered by interchanging dietary casein concentration well after tumor development had begun (at 8 months), increasing by 173% from the expected yield when casein intake was increased and decreasing by 99% when casein was reduced. These findings suggest that the development of liver tumor formation among individuals persistently infected with HBV may be controlled by minimizing or eliminating the intake of animal protein-based foods.