Food-motivated Behavior Research Articles

Effect of high-fat diet during gestation, lactation, or postweaning on physiological and behavioral indexes in borderline hypertensive rats

Maternal obesity is becoming more prevalent. We used borderline hypertensive rats (BHR) to investigate whether a high-fat diet at different stages of development has adverse programming consequences on metabolic parameters and blood pressure. Wistar dams were fed a high- or low-fat diet for 6 wk before mating with spontaneously hypertensive males and during the ensuing pregnancy. At birth, litters were fostered to a dam from the same diet group as during gestation or to the alternate diet condition. Female offspring were weaned on either control or "junk food" diets until about 6 mo of age. Rats fed the high-fat junk food diet were hyperphagic relative to their chow-fed controls. The junk food-fed rats were significantly heavier and had greater fat pad mass than those rats maintained on chow alone. Importantly, those rats suckled by high-fat dams had heavier fat pads than those suckled by control diet dams. Fasting serum leptin and insulin levels differed as a function of the gestational, lactational, and postweaning diet histories. Rats gestated in, or suckled by high-fat dams, or maintained on the junk food diet were hyperleptinemic compared with their respective controls. Indirect blood pressure did not differ as a function of postweaning diet, but rats gestated in the high-fat dams had lower mean arterial blood pressures than those gestated in the control diet dams. The postweaning dietary history affected food-motivated behavior; junk food-fed rats earned less food pellets on fixed (FR) and progressive (PR) ratio cost schedules than chow-fed controls. In conclusion, the effects of maternal high-fat diet during gestation or lactation were mostly small and transient. The postweaning effects of junk food diet were evident on the majority of the parameters measured, including body weight, fat pad mass, serum leptin and insulin levels, and operant performance.

Differential effects of a food-based conditioned inhibitor on food- or cocaine-seeking behavior

The present experiment compared the effects of a food-based conditioned inhibitor on food seeking vs. cocaine seeking behavior. In two groups of rats, the A+/AB− Pavlovian conditioned inhibition procedure was used to create a conditioned inhibitor for food. Then, for one group of rats (Food–Food Group), a click stimulus was established as an operant discriminative stimulus (S D) for food-reinforced lever pressing. In the other group (Food–Cocaine Group), the click was established as an S D for cocaine self-administration. In testing, the putative inhibitor for food was simultaneously presented with the click for the first time in both groups. In the Food–Food Group, the food-based inhibitor suppressed responding occasioned by the click significantly more than did a neutral control stimulus. In contrast, in the Food–Cocaine Group, there was no difference in the amount of suppression produced by the food-based inhibitor and the control stimulus. These results suggest that the effects of food-based Pavlovian conditioned inhibitors are specific for food-motivated behavior and do not easily transfer to cocaine-motivated behavior.

Oral bioavailability of the novel cannabinoid CB1 antagonist AM6527: Effects on food-reinforced behavior and comparisons with AM4113

Drugs that interfere with cannabinoid CB1 transmission suppress food-motivated behaviors, and may be clinically useful as appetite suppressants. Several CB1 receptor inverse agonists, such as rimonabant and AM251, as well as the CB1 receptor neutral antagonist, AM4113, have been assessed for their effects on food-motivated behavior. One important criterion for establishing if a drug may be useful clinically is the determination of its oral bioavailability. The present studies compared the effects of AM4113 and a novel CB1 antagonist, AM6527, on the suppression of food-reinforced behavior following intraperitoneal (IP) and oral administration. AM4113 and AM6527 both suppressed lever pressing after IP injections. The ED 50 for the effect on FR5 responding was 0.78 mg/kg for IP AM4113, and 0.5763 mg/kg for IP AM6527. AM6527 also was effective after oral administration (ED 50 = 1.49 mg/kg), however, AM 4113 was ineffective up to oral doses of 32.0 mg/kg. AM 4113 may be very useful as a research tool, but its lack of oral activity suggests that this drug might not be effective if orally administered in humans. In contrast, AM 6527 is an orally active CB1 antagonist, which may be useful for clinical research on the appetite suppressant effects of CB1 antagonists.

Cannabinoid CB1 antagonists and dopamine antagonists produce different effects on a task involving response allocation and effort-related choice in food-seeking behavior

Cannabinoid CB1 antagonists/inverse agonists suppress food-motivated behaviors and are being evaluated as potential appetite suppressants. It has been suggested that the effects of CB1 antagonism on food motivation could be related to actions on mesolimbic dopamine (DA). If this were true, then the effects of interference with cannabinoid CB1 transmission should closely resemble the effects of interference with DA transmission. To directly compare the effects of DA antagonists with those of CB1 antagonists/inverse agonists, the present studies employed a concurrent lever-pressing/chow-intake procedure. With this task, interference with DA transmission shifts choice behavior such that lever pressing for a preferred food is decreased but chow intake is increased. Rats treated with IP injections of the DA D1 antagonist SCH39166 (ecopipam; 0.05-0.2 mg/kg) or the D2 antagonist eticlopride (0.025-0.1 mg/kg) showed substantial decreases in lever pressing and concomitant increases in chow consumption. In contrast, IP administration of the CB1 neutral antagonist AM4113 (4.0-16.0 mg/kg) or the CB1 antagonist/inverse agonist AM251 (2.0-8.0 mg/kg) decreased operant responding for pellets, but there was no corresponding increase in chow intake. These effects of CB1 antagonists/inverse agonists were similar to those produced by the appetite suppressant fenfluramine and by prefeeding. In contrast, low doses of DA antagonists leave primary food motivation intact, but shift behaviors toward food reinforcers that can be obtained with lower response costs. These results suggest that the effects of interference with CB1 transmission are readily distinguishable from those of reduced DA transmission.

Effects of chronic low-dose acrylamide exposure on progressive ratio performance in adolescent rats

Acrylamide (ACR) is a neurotoxicant known to produce peripheral neuropathy in rats and humans, but little is known of its potential for producing cognitive or motivational alterations. Chronic exposure to low doses of ACR as a food contaminant is known to occur widely in humans. This research evaluated the effects of daily ACR exposure on food-motivated behavior, with exposures beginning prenatally on gestation day 6 and continuing through approximately postnatal day (PND) 85. Plug-positive Fischer 344 dams (9–10 per dose) were gavaged daily with 0, 0.1, 0.3, 1.0 or 5.0 mg/kg/day ACR. On PNDs 1–22, pups were gavaged with the same dose their dam had received. On PND 22, pups were weaned and pair-housed with a same-sex littermate and ACR exposure continued at 0, 1, 3, 10 and 50 ppm via drinking water. One male and one female pup per litter were tested in an operant chamber under a progressive ratio (PR) schedule of food reinforcement from approximately 6 to 12 weeks of age. Results over 6 weeks of testing indicated a significant treatment effect of ACR on number of reinforcers earned, with Tukey HSD post hoc tests revealing significantly fewer reinforcers earned in the 5.0 mg/kg/day dose group than in controls. A significant effect of ACR on response rate was also observed, with the Tukey HSD post hoc tests revealing a significantly lower response rate in the 5.0 mg/kg/day group than in controls. No effects of ACR were observed on post-reinforcement pause. These data suggest that daily ACR exposure at 5.0 mg/kg/day can produce measurable decrements on aspects of food-motivated behavior.

Baseline behavior, but not sensitivity to stimulant drugs, differs among Spontaneously Hypertensive, Wistar–Kyoto, and Sprague–Dawley rat strains

Deficits in temporal processing are implicated in Attention Deficit Hyperactivity Disorder (ADHD) for which the most common rodent model is the Spontaneously Hypertensive Rat (SHR). To assess strain differences in temporal processing, males and females of the SHR, Wistar–Kyoto (WKY), and Sprague–Dawley (SD) strains were compared on two timing tasks: one requiring maintenance of a lever press for 10–14 s (TRD, temporal response differentiation) and the other requiring withholding of a lever press for 10–14 s (DRL, differential reinforcement of low rates). Performance of the progressive ratio (PR) task more directly assessed food-motivated behavior. Strains did not differ in task acquisition; however, steady state TRD and DRL performance of the SHR and WKY strains was less accurate which was related to increased burst (non-timing related) responses in those strains relative to the SD. PR performance demonstrated that the SHR and WKY strains exhibited higher response rates and breakpoints than the SD. Subsequently, methylphenidate (1, 3.25, 4.50, 7.50, and 12.0 mg/kg) and d-amphetamine (0.1, 0.25, 0.65, 1.0, and 2.0 mg/kg) were administered intraperitoneally pre-testing. Both drugs disrupted TRD and DRL performances by increasing burst response frequency; however, the strains were not differentially sensitive to either drug. Strain differences were generally maintained throughout the drug and extinction portions of the study. These results indicate increased similarity between the SHR and WKY strains relative to the SD in performance of timing and motivation tasks. Further, the current results do not support continued use of the SHR as a model for ADHD.

The Novel Cannabinoid CB1 Receptor Neutral Antagonist AM4113 Suppresses Food Intake and Food-Reinforced Behavior but Does not Induce Signs of Nausea in Rats

Drugs that interfere with cannabinoid CB1 transmission suppress various food-motivated behaviors, and it has been suggested that such drugs could be useful as appetite suppressants. Biochemical studies indicate that most of these drugs assessed thus far have been CB1 inverse agonists, and although they have been shown to suppress food intake, they also appear to induce nausea and malaise. The present studies were undertaken to characterize the behavioral effects of AM4113, which is a CB1 neutral antagonist, and to examine whether this drug can reduce food-reinforced behaviors and feeding on diets with varying macronutrient compositions. Biochemical data demonstrated that AM4113 binds to CB1 receptors, but does not show inverse agonist properties (ie no effects on cyclic-AMP production). In tests of spontaneous locomotion and analgesia, AM4113 reversed the effects of the CB1 agonist AM411. AM4113 suppressed food-reinforced operant responding with rats responding on fixed ratio (FR) 1 and 5 schedules of reinforcement in a dose-dependent manner, and also suppressed feeding on high-fat, high-carbohydrate, and lab chow diets. However, in the same dose range that suppressed feeding, AM4113 did not induce conditioned gaping, which is a sign of nausea and food-related malaise in rats. These results suggest that AM4113 may decrease appetite by blocking endogenous cannabinoid tone, and that this drug may be less associated with nausea than CB1 inverse agonists.

Cannabinoid CB 1 receptor inverse agonists and neutral antagonists: Effects on food intake, food-reinforced behavior and food aversions

Drugs that interfere with cannabinoid CB1 receptor transmission suppress a number of food-related behaviors, and these compounds are currently being assessed for their potential utility as appetite suppressants. In addition to rimonabant (SR141716A), several other compounds have been evaluated, including AM251 and AM1387. Biochemical studies indicate that most of the drugs assessed thus far have been CB1 inverse agonists, and these drugs all act to suppress food intake and disrupt food-reinforced behavior. Behavioral tests involving intake of different diets (i.e., high fat, high carbohydrate, laboratory chow) indicate that consumption of all three food types is disrupted by CB1 inverse agonists, and that, expressed as a percent of baseline intake, the effect is roughly comparable across different diets. Although CB1 inverse agonists do not appear to produce severe motor impairments that disrupt feeding behavior, there is evidence that they can induce nausea and malaise. Recent studies have been undertaken to characterize the behavioral effects of CB1 receptor neutral antagonists such as AM4113 to determine if these drugs can reduce feeding and food-reinforced behaviors. Across a variety of different tests, AM4113 produces effects on food-motivated behavior that are very similar to those produced by CB1 inverse agonists. Moreover, this drug did not induce conditioned gaping in rats or vomiting in ferrets. These results suggest that CB1 receptor neutral antagonists may decrease appetite by blocking endogenous cannabinoid tone, and that these drugs may be less associated with nausea than is the case for CB1 inverse agonists.

A reciprocal interaction between food-motivated behavior and diet-induced obesity

One of the main causes of obesity is overconsumption of diets high in fat and sugar. We studied the metabolic changes and food-motivated behavior when rats were subjected to a choice diet with chow, lard and a 30% sucrose solution (high fat high sugar (HFHS)-choice diet). Because rats showed considerable variations in the feeding response to HFHS-choice diet and in food-motivated behavior, we investigated whether the motivation to obtain a sucrose reward correlated with the development of obesity when rats were subsequently subjected to HFHS-choice diet. We first studied feeding, locomotor activity and body temperature, fat weights and hormonal concentrations when male Wistar rats were subjected to HFHS-choice diet for 1 week. Second, we studied sucrose-motivated behavior, using a progressive ratio (PR) schedule of reinforcement in rats that were subjected to the HFHS-choice diet for at least 2 weeks, compared to control rats on a chow diet. Third, we measured motivation for sucrose under a PR schedule of reinforcement in rats that were subsequently subjected to HFHS-choice diet or a chow diet for 4 weeks. Fat weights were measured and correlated with the motivation to obtain sucrose pellets. One week on the HFHS-choice diet increased plasma concentrations of glucose and leptin, increased fat stores, but did not alter body temperature or locomotor activity. Moreover, consuming the HFHS-choice diet for several weeks increased the motivation to work for sucrose pellets. Furthermore, the motivation to obtain sucrose pellets correlated positively with abdominal fat stores in rats subsequently subjected to the HFHS-choice diet, whereas this correlation was not found in rats fed on a chow diet. Our data suggest that the motivation to respond for palatable food correlates with obesity due to an obesogenic environment. Conversely, the HFHS-choice diet, which results in obesity, also increased the motivation to work for sucrose. Thus, being motivated to work for sucrose results in obesity, which, in turn, increases food-motivated behavior, resulting in a vicious circle of food motivation and obesity.

Editorial???Behavioural Pharmacology of Cannabinoids

Editorial???Behavioural Pharmacology of Cannabinoids

Dietary Supplementation with n-3 Polyunsaturated Fatty Acids Attenuates the Depression of Food-Motivated Behavior during Zymosan-Induced Peritonitis

Peripheral inflammation is accompanied by neurobehavioral alterations such as depression of feeding, exploratory and sexual behaviors. Our previous investigation reported that dietary enrichment with n-3 polyunsaturated fatty acids (PUFA) attenuated the depression of food-motivated behavior and social exploration, but not endocrinological and metabolic disturbances in the mice with systemic inflammation induced by lipopolysaccharide (LPS). We here demonstrate that dietary n-3 PUFA also attenuate the reduction of food-motivated behavior during zymosan-induced peritonitis in mice without influencing plasma leakage into peritoneum and writhing response. Our results suggest that the common mechanism is involved in the attenuation of behavioral depression during systemic and local inflammation by dietary n-3 PUFA.

Dietary n-3 fatty acids selectively attenuate LPS-induced behavioral depression in mice

Systemic administration of bacterial lipopolysaccharide (LPS) induces a series of physiological and pathological alterations as well as behavioral depression in experimental animals. These alterations induced by LPS administration are known to be mediated by endogenous cytokines and arachidonate metabolites, which may be modulated by dietary n-3 fatty acids. Mice were fed a diet supplemented with n-3 or n-6 fatty acids for 4 weeks prior to LPS administration. Food-motivated behavior after intraperitoneal administration of LPS as compared with that before LPS administration was significantly depressed in the mice fed with the n-6 fatty-acid-rich diet (47% to 85% reduction; P<.05) but not significantly in the mice fed with the n-3 fatty-acid-rich diet. Depression of social exploration by intraperitoneal LPS administration in the n-3 fatty-acid-rich diet group (39% reduction vs. vehicle group) was significantly less in the n-6 fatty-acid-rich diet group (76% reduction vs. vehicle group; P<.05). The behavioral depressions induced by intracerebroventricular LPS injection were not significantly different between the two dietary groups ( P=.60). The elevation of serum corticosterone and the hypoglycemic response following intraperitoneal LPS administration were not significantly different between the two dietary groups ( P=.57 and P=.43, respectively). We demonstrate that dietary n-3 fatty acids attenuate behavioral depression in mice peripherally administered with LPS without affecting the increase in serum corticosterone and the decrease in serum glucose concentration.

How the immune and nervous systems interact during disease-associated anorexia

Anorexia is one of the most common symptoms associated with illness and constitutes an adaptive strategy in fighting acute infectious diseases. However, prolonged reduction in food intake and an increase in metabolic rate, as seen in the anorexia-cachexia syndrome, lead to depletion of body fat and protein reserves, thus worsening the organism’s condition. Because the central nervous system controls many aspects of food intake, soluble factors known as cytokines that are secreted by immune cells might act on the brain to induce anorexia during disease. This review focuses on the communication pathways from the immune system to the brain that might mediate anorexia during disease. The vagus nerve is a rapid route of communication from the immune system to the brain, as subdiaphragmatic vagotomy attenuates the decrease in food-motivated behavior and c-Fos expression in the central nervous system in response to peripheral administration of the proinflammatory cytokine, interleukin-1β, or bacterial lipopolysaccharide. At later time points after peripheral lipopolysaccharide administration, interleukin-1 itself acts in the brain to mediate anorexia and is found in the arcuate nucleus of the hypothalamus. The mechanisms by which interleukin-1β gains access to the brain and the potential role of neuropeptide-Y-containing neurons in the arcuate hypothalamus in mediating anorexia during disease are discussed.

Cholecystokinin receptors do not mediate the suppression of food-motivated behavior by lipopolysaccharide and interleukin-1 beta in mice

During the course of an infection, profound metabolic and behavioral changes are observed. The resulting decrease in food intake can be reproduced by administration of lipopolysaccharide (LPS) or the proinflammatory cytokines (e.g., interleukin-1 [IL-1] and tumor necrosis factor it induces. To test the possibility that cholecystokinin (CCK) mediates anorexia induced by IL-1β and LPS, mice trained to poke their noses in a hole to obtain a food reward according to a fixed ratio (1 reward per 20 actions) were pretreated with the CCK-A receptor antagonist L364,718 (at 1 mg/kg) or with the CCK-B receptor antagonist L365,260 (50 μg/kg) before being injected with LPS (100 μg/kg) or IL-1β (20 μg/kg). All injections were given via the intraperitoneal (i.p.) route. In spite of its ability to block the effects of exogenous CCK-8 on food-motivated behavior in mice, the CCK-A receptor antagonist did not block the depressive actions of LPS and IL-1β on food-motivated behavior. The CCK-B receptor antagonist was not more effective at blocking. These results do not support a role for CCK in the anorexic effect of LPS and IL-1β.

Visual attention task performance in Wistar and Lister Hooded rats: response inhibition deficits after medial prefrontal cortex lesions

The prefrontal cortex has traditionally been implicated in a variety of cognitive processes, including memory, attention and decision making. The detection of effects of prefrontal cortex lesions on attention has been shown to depend on the procedure used to assess the attentional process. We therefore investigated the effects of lesions of the prefrontal cortex in two different visual attention tasks, i.e. a three-choice serial reaction time task involving sustained and divided attention processes and a visual timing task involving sustained attention and response inhibition processes. In two rat strains that are frequently used in behavioural analysis, i.e. albino Wistar rats and pigmented Lister Hooded rats, lesions of the medial prefrontal cortex caused a deterioration of performance in both tasks, although the effect lasted much longer in the visual timing task. This latter task proved to be especially sensitive to detect the consequences of medial prefrontal cortex lesions, consisting of a loss of both attention control and response inhibition. In both attention tasks, Wistar rats performed less accurate and made more anticipatory responses than Listers. Strain differences could not entirely be attributed to possible visual deficits in albinos, which was also evident when locomotor activity in an open field and food-motivated behaviour in a hoarding paradigm were assessed. Due to slower habituation rates, Lister rats were more active and displayed little food hoarding behaviour. In Wistar rats, hoarding was disrupted by medial prefrontal cortex lesions, showing the effectiveness of the lesion. The results indicate that, although different rat strains provide different baseline levels of behaviour for testing lesion- or drug-induced behavioural changes, lesions of the medial prefrontal cortex do not only disrupt sustained attention processes, but also induce a strong impairment in response inhibition in both Wistar and Lister rats.

Immune and endocrine regulation of food intake in sick animals

To understand why sick animals do not eat, investigators have studied how the immune system interacts with the central nervous system (CNS), where motivation to eat is ultimately controlled. The focus has been on the cytokines secreted by activated mononuclear myeloid cells, which include interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Either central or peripheral injection of recombinant IL-1β, IL-6, and TNF-α reduce food-motivated behavior and food intake in rodents. Moreover, these cytokines and their receptors are present in the endocrine system and brain, and antagonism of this system (i.e., the cytokine network) has been shown to block or abrogate anorexia induced by inflammatory stimuli. Recent studies indicate that the same cytokines act on adipocytes and induce secretion of leptin, a protein whose activity has been neuroanatomically mapped to brain areas involved in regulating food intake and energy expenditure. Therefore, many findings converge to suggest that the reduction of food intake in sick animals is mediated by inflammatory cytokines, which convey a message from the immune system to the endocrine system and CNS. The nature of this interaction is the focus of this short review.

Interleukin-1beta-converting enzyme-deficient mice resist central but not systemic endotoxin-induced anorexia.

Interleukin-1beta (IL-1beta) mediates many of the behavioral responses to infection and inflammation, and IL-1beta-converting enzyme (ICE) processes intracellular IL-1beta, leading to its maturation and secretion. Here we demonstrate that intracerebroventricular injections of lipopolysaccharide (LPS) produced a greater reduction in both food intake and food-motivated behavior in wild-type compared with ICE-deficient (ICE -/-) mice. This defect occurred although ICE -/- mice were able to fully respond to intracerebroventricular injections of IL-1beta. In contrast, ICE -/- mice remained fully responsive to intraperitoneal injections of LPS. These results indicate that brain, but not peripheral, IL-1beta plays a critical role in the depression in food intake that occurs during inflammation.

Systemic Capsaicin Pretreatment Fails to Block the Decrease in Food-Motivated Behavior Induced by Lipopolysaccharide and Interleukin-1β

The physiological and behavioral disturbances observed during an infection can be reproduced by systemic administration of proinflammatory cytokines (e.g., interleukin (IL)-1, IL-6, tumor necrosis factor-α) or lipopolysaccharide (LPS), a potent inducer of these cytokines. It is now well established that these molecules induce their effects by acting centrally, however, the mechanisms by which they reach central structures are not clear. We have earlier proposed that the humoral immune message is converted to a central neural activation by the action of cytokines on peripheral terminations of afferent neurons. Subdiaphragmatic vagotomy abolishes several effects of peripherally injected IL-1β and LPS (e.g., decreased food-motivated behavior and social exploration, central expression of cytokines). To further define the nature of the peripheral fibers implicated in this phenomenon, we used a potent sensory neurotoxin, capsaicin, to selectively destroy C-fiber afferents. Adult rats were injected IP with a total dose of 25 mg/kg capsaicin in a series of 10 injections over a 48-h period. Adult mice were injected IP with a total dose of 75 mg/kg in a series of seven injections over a 7-day period. Although capsaicin treatment altered visceral chemosensory function, corneal and pain sensitivity, vagal-mediated anorexic effects of cholecystokinin, and depleted levels of substance P in the thoracic spinal cord, it was completely ineffective in blocking the decrease in food-motivated behavior induced by IL-1β (4 μg/rat IP in rats) and LPS (250 μg/kg IP in rats and 400 μg/kg IP in mice). Thus, other afferents besides capsaicin-sensitive C-fibers appear to be involved in the transduction of cytokine effects during inflammatory and infectious events.

Effects of chronic desipramine on waiting behaviour for a food reward in olfactory bulbectomized rats

The effects of olfactory bulbectomy (OB) on the 'waiting behaviour' of rats for a food reward in a T-maze, as well as the effect of chronic treatment with desipramine (7.5 mg/kg, i.p. x 14 days) prior to and throughout testing was assessed. In the T-maze, the time spent in locating a reward was longer in OB rats during the first phase of the food reward test. However, all groups chose the larger reward in at least 80% of trials by day 5 of test. Upon imposition of a delay in acquisition of the larger reward (phase 2), sham-operated rats chose the larger reward in correspondingly fewer trials until, by day 5, only 13% (control sham group) and 29% (desipramine-treated sham group) of trials were for the larger but delayed reward. By contrast, both OB rat groups continued to choose the larger but delayed reward throughout phase 2 in the majority of trials. The typical behavioural hyperactivity of OB rats in the 'open field' apparatus was attenuated by chronic administration of DMI. The results suggest that the OB rat has a deficit in food-motivated behaviour and appears to have reduced adaptation of this learned response when the conditions of the test are altered. Chronic desipramine treatment did not attenuate this effect.

Mechanisms of sickness-induced decreases in food-motivated behavior

Interleukin-1β (IL-1β) is a cytokine released by activated macrophages and monocytes, which mediates many of the local and systemic responses to inflammation. Interleukin-1β induces anorexia in rats when administered peripherally or centrally. An endogenous antagonist for the IL-1 type I receptor has been characterized and cloned (IL-1ra). We have used this protein to ascertain the site of action for the anorexic effects of IL-1β. Male rats were food restricted and trained on an operant schedule for food reinforcement. Administration of recombinant human IL-1β (4 μg IP or 40 ng ICV) induced profound decreases in operant responding, with maximal effects 1–4 h post-injection. Interleukin-1ra pretreatment (2.4 mg IP or 24 μg ICV) completely blocked these effects when administered by the same route. In contrast, ICV IL-1ra only partially blocked the effects of IP IL-1β, and IP IL-1ra was unable to block the effects of ICV IL-1β. Interleukin-1ra did not affect responding by itself. These results suggest that IL-1β acts at both peripheral and central IL-1 receptors to reduce food-motivated behavior. To determine the central site of action of IL-1β, small quantities of IL-1β (5 and 30 ng) were infused into the ventromedial hypothalamus of male rats. Both doses produced profound decreases in responding; the magnitude and time course of these effects were nearly identical to those observed after ICV administration. These results suggest that the VMH may serve as a central site of action for the depressive effects of IL-1β on food intake. There is much controversy over the pathways of communication from the immune system to the brain. To test the hypothesis that the peripheral immune stimulus is transmitted to the brain via a neural communication pathway, mice were injected with lipopolysaccharide at a behaviorally active dose (10 μg IP). This treatment increased the concentrations of substance P, neurokinin A, and calcitonin gene-related peptide in mouse spinal cord in a prostaglandin-dependent manner. Maximal increases in neuropeptide content were observed 1 h post-injection. Finally, subdiaphragmatic vagotomy was found to attenuate the reduction in food-motivated behavior induced by both IL-1β and lipopolysaccharide in mice.