lithium-chloride and Anorexia

Infections frequently accompany with non-specific symptoms such as anorexia and hyperthermia. In addition, there may be unpleasant sensations such as visceral discomfort during infection. Lipopolysaccharide (LPS), a Gram-negative bacteria cell wall component, is known to induce the unpleasant sensation of conditioned taste aversion in mammals. However, the relationship between unpleasant sensations and changes in behavior and physiological conditions has not been investigated extensively in birds. Lithium chloride (LiCl) is a compound that induces unpleasant sensations, including visceral discomfort, although its effects on behavior and physiological conditions have also not been investigated extensively in birds. Thus, the present study was aimed to investigate the effect of an intraperitoneal (IP) injection of LiCl on conditioned visual aversion, food intake, cloacal temperature, voluntary activity, crop-emptying rate, and blood constituents in chicks (Gallus gallus). We also examined the effect of IP injections of LPS and zymosan, a cell wall component of fungus, on conditioned visual aversion formation. First, IP injection of LiCl was confirmed to induce conditioned visual aversion in chicks. An IP injection of LiCl significantly decreased food intake, voluntary activity, and crop-emptying rate but did not affect the temperature. In addition, the injection of LiCl significantly increased plasma corticosterone concentration, indicating that LiCl serves as a stressor in chicks. Finally, IP injections of LPS and zymosan were found to induce conditioned visual aversion in chicks. Collectively, these results suggest that LiCl induces conditioned aversion, anorexia, hypoactivity, and inhibition of crop-emptying in chicks. In addition, LPS and zymosan would induce unpleasant sensations in chicks.

Topics: Animals; Anorexia; Chickens; Eating; Lipopolysaccharides; Lithium; Lithium Chloride; Mammals; Taste; Temperature; Zymosan

The overlap in neurobiological circuitry mediating the physiological and behavioral response to satiation and noxious/stressful stimuli are not well understood. The interaction between serotonin (5-HT) and glucagon-like peptide-1 (GLP-1) could play a role as upstream effectors involved in mediating associations between anorectic and noxious/stressful stimuli. We hypothesize that 5-HT acts as an endogenous modulator of the central GLP-1 system to mediate satiation and malaise in rats. Here, we investigate whether interactions between central 5-HT and GLP-1 signaling are behaviorally and physiologically relevant for the control of food intake and pica (i.e., behavioral measure of malaise). Results show that the anorexia and body weight changes induced by administration of exogenous hindbrain 5-HT are dependent on central GLP-1 receptor signaling. Furthermore, anatomical evidence shows mRNA expression of 5-HT2C and 5-HT3 receptors on GLP-1-producing preproglucagon (PPG) neurons in the medial nucleus tractus solitarius by fluorescent in situ hybridization, suggesting that PPG neurons are likely to express both of these receptors. Behaviorally, the hypophagia induced by the pharmacological activation of both of these receptors is also dependent on GLP-1 signaling. Finally, 5-HT3, but not 5-HT2C receptors, are required for the anorectic effects of the interoceptive stressor LiCl, suggesting the hypophagia induced by these 5-HT receptors may be driven by different mechanisms. Our findings highlight 5-HT as a novel endogenous modulator of the central GLP-1 system and suggest that the central interaction between 5-HT and GLP-1 is involved in the control of food intake in rats.

Topics: Animals; Anorexia; Feeding Behavior; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Lithium Chloride; Male; Neurons; Ondansetron; Peptide Fragments; Pica; Proglucagon; Rats; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin, 5-HT3; Rhombencephalon; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT3 Receptor Agonists; Serotonin 5-HT3 Receptor Antagonists; Signal Transduction; Solitary Nucleus; Stress, Psychological; Weight Loss

Diphtheria toxin-mediated, acute ablation of hypothalamic neurons expressing agouti-related protein (AgRP) in adult mice leads to anorexia and starvation within 7 d that is caused by hyperactivity of neurons within the parabrachial nucleus (PBN). Because NMDA glutamate receptors are involved in various synaptic plasticity-based behavioral modifications, we hypothesized that modulation of the NR2A and NR2B subunits of the NMDA receptor in PBN neurons could contribute to the anorexia phenotype. We observed by Western blot analyses that ablation of AgRP neurons results in enhanced expression of NR2B along with a modest suppression of NR2A. Interestingly, systemic administration of LiCl in a critical time window before AgRP neuron ablation abolished the anorectic response. LiCl treatment suppressed NR2B levels in the PBN and ameliorated the local Fos induction that is associated with anorexia. This protective role of LiCl on feeding was blunted in vagotomized mice. Chronic infusion of RO25-6981, a selective NR2B inhibitor, into the PBN recapitulated the role of LiCl in maintaining feeding after AgRP neuron ablation. We suggest that the accumulation of NR2B subunits in the PBN contributes to aphagia in response to AgRP neuron ablation and may be involved in other forms of anorexia.

Topics: Adjuvants, Immunologic; Agouti-Related Protein; Animals; Anorexia; Appetite; Blotting, Western; Body Weight; Deglutition Disorders; Eating; Lithium Chloride; Male; Mice; Mice, Knockout; Neurons; Phenols; Piperidines; Pons; Receptors, N-Methyl-D-Aspartate; Rhombencephalon; Time Factors; Vagotomy

In rats, central administration of glucagon-like peptide-1 (GLP-1) elicits symptoms of visceral illness like those caused by the toxin lithium chloride (LiCl), including anorexia, conditioned taste aversion (CTA) formation, and neural activation in the hypothalamus and hindbrain including activation of brainstem preproglucagon cells. Most compellingly, pharmacological antagonists of the GLP-1 receptor (GLP-1R) block several effects of LiCl in rat. The major goal of these experiments was to further test the hypothesis that the central nervous system GLP-1 system is critical to the visceral illness actions of LiCl by using mice with a targeted disruption of the only described GLP-1R. First, we observed that, like the rat, LiCl activates preproglucagon neurons in wild-type mice. Second, GLP-1R -/- mice demonstrated normal anorexic and CTA responses to LiCl. To test the possibility that alternate GLP-1Rs mediate aversive effects, we examined the ability of GLP-1 to produce a CTA in GLP1R -/- mice. Although lateral ventricular GLP-1 produced a CTA in wild-type mice, it did not produce a CTA in GLP-1R -/- mice. Furthermore, the same GLP-1R antagonist that can block the aversive effects of LiCl in the rat failed to do so in the mouse. These results support the conclusion that in mouse, unlike in rat, GLP-1R signaling is not required for the visceral illness response to LiCl. Such species differences are an important consideration when comparing results from rat and mouse studies.

Topics: Animals; Anorexia; Avoidance Learning; Brain Diseases; Glucagon; Glucagon-Like Peptide 1; Lithium Chloride; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Neurons; Peptide Fragments; Proglucagon; Protein Precursors; Rats; Species Specificity; Taste

Intracerebroventricular administration of glucagon-like peptide-1 (7-36) amide (GLP-1) reduces food intake and produces symptoms of visceral illness, such as a conditioned taste aversion (CTA). The central hypothesis of the present work is that separate populations of GLP-1 receptors mediate the anorexia and taste aversion associated with GLP-1 administration. To test this hypothesis, we first compared the ability of various doses of GLP-1 to induce anorexia or CTA when administered into either the lateral or fourth ventricle. Lateral and fourth ventricular GLP-1 resulted in reduction of food intake at similar doses, whereas only lateral ventricular GLP-1 resulted in a CTA. Such data indicate that both hypothalamic and caudal brainstem GLP-1 receptors are likely to participate in the ability of GLP-1 to reduce food intake. We also hypothesized that the site that must mediate the ability of GLP-1 to induce visceral illness is in the central nucleus of the amygdala (CeA). Administration of 0.2 or 1.0 microg of GLP-1 (7-36) but not the inactive GLP-1 (9-36) resulted in a strong CTA with no accompanying anorexia. In addition, bilateral CeA administration of 2.5 microg of a GLP-1 receptor antagonist before intraperitoneal administration of the toxin lithium chloride resulted in a diminished CTA. Together, these data indicate that separate GLP-1 receptor populations mediate the multiple responses to GLP-1. These results indicate that GLP-1 is a flexible system that can be activated under various circumstances to alter the ingestion of nutrients and/or produce other visceral illness responses, depending on the ascending pathways of the GLP-1 system that are recruited.

Topics: Amygdala; Animals; Anorexia; Appetite Regulation; Behavior, Animal; Catheterization; Conditioning, Psychological; Dose-Response Relationship, Drug; Eating; Fourth Ventricle; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Injections, Intraperitoneal; Injections, Intraventricular; Lateral Ventricles; Lithium Chloride; Male; Paraventricular Hypothalamic Nucleus; Peptide Fragments; Rats; Rats, Long-Evans; Receptors, Glucagon; Signal Transduction; Taste; Visceral Afferents

The present study sought to determine whether central glucagon-like peptide-1 (GLP-1)-receptor signalling contributes to the anorexigenic effects of systemically administered lithium chloride (LiCl). Male Sprague-Dawley rats with chronic intracerebroventricular (ICV) cannulas were acclimated to a feeding schedule that included daily 30-min access to palatable mash. In the first experiment, ICV infusion of a GLP-1-receptor antagonist [exendin-4-(3-39)] significantly attenuated (10 microgram dose) or completely blocked (20 microgram dose) the inhibition of food intake produced by subsequent ICV infusion of GLP-1-(7-36) amide (5 microgram). In the second experiment, rats were infused with 0, 10, or 20 microgram of the GLP-1-receptor antagonist ICV, followed by injection of 0.15 M LiCl (50 mg/kg ip) or the same volume of 0.15 M NaCl. The ability of LiCl treatment to suppress food intake was significantly attenuated in rats that were pretreated with the GLP-1-receptor antagonist. These results support the view that central mechanisms underlying LiCl-induced anorexia include a prominent role for endogenous GLP-1 neural pathways.

Topics: Animals; Anorexia; Brain; Dose-Response Relationship, Drug; Eating; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Injections, Intraventricular; Lithium Chloride; Male; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Glucagon

Area postrema (AP) lesions were produced by vacuum aspiration in adult male Sprague-Dawley rats. Consistent with previous findings, when water-deprived rats were allowed to drink novel flavored fluids immediately before treatment with LiCl (3 mEq/kg, i.p.), sham-operated and non-operated control rats demonstrated a pronounced aversion to the fluids whereas rats with AP lesions did not decrease fluid consumption significantly. However, in a 30-min test period after overnight food deprivation, rats with AP lesions reduced food intake significantly and to an equivalent degree as control animals when pretreated with LiCl (3 mEq/kg, i.p. or i.v.). These and other results are consistent with the traditional view that AP mediates the sensation of nausea produced by LiCl treatment (hence the loss of conditioned taste aversions after AP lesions), but suggest that neither nausea nor AP is necessary for the marked disinclination to eat that is induced in rats by acute administration of LiCl.

Topics: Analysis of Variance; Animals; Anorexia; Conditioning, Psychological; Feeding Behavior; Food Deprivation; Lithium Chloride; Male; Oxytocin; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Reference Values; Taste; Time Factors

Ob/ob mice (OB) with B16 melanoma become anorectic, but lean mice (LN) do not. Present studies suggest that this difference reflects a greater bent for OB to form conditioned taste aversions (CTA). In Exp 1, healthy OB formed stronger CTAs than LN to a saccharin taste paired with lithium chloride (LiCl, 3 mEq/kg ip). In Exp 2, the OB-LN difference of Exp 1 was decreased by giving naltrexone (10 mg/kg sc) before LiCl, which suggested opiate involvement. Exp 3 showed that OB tumor anorexia vanishes if foods dissociated from tumor growth are given: OB fed a constant diet became anorectic 16 days after B16 inoculation; giving a new diet on Day 16 delayed anorexia onset for 8 days; a second new diet on Day 32 abolished anorexia for 24 hr. LN with tumors ate all diets at nontumor control levels. OB survived melanoma longer than LN regardless of diet, but OB fed a varied diet died first; thus, anorexia may enhance OB survival.

Topics: Animals; Anorexia; Avoidance Learning; Body Weight; Conditioning, Classical; Extinction, Psychological; Lithium Chloride; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Obese; Neoplasm Metastasis; Neoplasm Transplantation; Saccharin; Species Specificity; Taste

Interferon-alpha treatment induces anorexia in cancer patients and in mice. The ability of interferon-alpha to induce a conditioned taste aversion (CTA) in mice was explored. Mice were injected with doses of interferon-alpha that had been shown to induce anorexia (M. A. Segall & L. S. Crnic, Behav. Neurosci., 1990; 1600 or 800 U/g of mouse) after being given a novel solution (chocolate milk). Neither dose of interferon resulted in a decrease of milk intake on the test day. To determine whether the known cognitive effects of interferon interfere with the ability of a mouse to learn CTA, a combined injection of interferon-alpha and LiCl (an illness-inducing agent) was given. The combination of interferon-alpha with LiCl did not interfere with the LiCl-induced CTA. Thus, any possible cognitive effects of interferon did not interfere with conditioned taste aversion. To test the possibility that repeated trials might establish a conditioned taste aversion to interferon, mice were given three conditioning trials spaced 3 days apart. No aversion developed. Doses of interferon-alpha that produce anorexia do not produce a conditioned taste aversion, indicating that separate mechanisms are activated in these two behaviors.

Topics: Animals; Anorexia; Avoidance Learning; Cacao; Chlorides; Conditioning, Classical; Drinking Behavior; Interferon Type I; Lithium; Lithium Chloride; Male; Mice; Mice, Inbred DBA; Taste

In these experiments we examined the effects on gastric motility of cholecystokinin, LiCl, hypertonic NaCl solution, gastric distension, and intraduodenal glucose loads, five dissimilar treatments known to reduce food intake in rats. In addition, we investigated whether any observed effects were dependent on the afferent vagus nerve by pretreating subjects with the neurotoxin capsaicin. Each of the five treatments virtually eliminated the gastric contractions seen after rats had consumed a large meal of chow; these effects were rapid in onset and continued for up to 30 min. The inhibitory effects of cholecystokinin and gastric distension were eliminated by pretreatment with capsaicin, whereas the effects of the other treatments were attenuated only slightly or not at all. Because most of these treatments have been shown to stimulate pituitary oxytocin secretion in rats as well as to inhibit food intake and gastric motility, these results are consistent with the hypothesis that the hypothalamic paraventricular nucleus is a site at which information is integrated in the coordinated control of food intake, gastric function, and neuroendocrine secretion.

Topics: Animals; Anorexia; Capsaicin; Chlorides; Cholecystokinin; Eating; Feeding and Eating Disorders; Gastrointestinal Motility; Glucose; Lithium; Lithium Chloride; Male; Oxytocin; Paraventricular Hypothalamic Nucleus; Rats; Rats, Inbred Strains; Saline Solution, Hypertonic

The study of experimentally induced anorexia poses a problem for investigations of the processes controlling food intake. Inhibition of food consumption may arise from a specific intervention in a physiological system controlling nutritional requirements or from non-specific changes leading to the suppression or contamination of behaviour. The present experiment used the analysis of the structure of behaviour to distinguish between normal anorexia (natural development of satiation) and pathological anorexia brought about by intestinal discomfort (injection of lithium chloride) or adulteration of food (quinine added to diet). The treatments produced marked changes in parameters of feeding and in the frequencies of behaviours associated with eating. Both lithium chloride and quinine treatments gave rise to a slow rate of eating accompanied by a disordered temporal sequence of eating, grooming and resting. This behavioural calibration of anorexia can contribute to the behavioural pharmacology of feeding by helping to diagnose drugs which facilitate normal processes of satiation and those which act via a non-specific disruption of behaviour.

Topics: Animals; Anorexia; Behavior, Animal; Chlorides; Feeding and Eating Disorders; Feeding Behavior; Lithium; Lithium Chloride; Male; Quinine; Rats; Satiation; Satiety Response