Biomedical subjects

J L Bret-Dibat

Publications and source records attributed to J L Bret-Dibat.

7 recordsLinked to original sources

PubMed2000

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-1 beta 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 microg/kg) before being injected with LPS (100 microg/kg) or IL-1 beta (20 microg/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-1 beta 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-1 beta.

Animals↗

PubMed1998

Cytokines and sickness behavior.

Peripheral and central injections of interleukin-1 (IL-1) and lipopolysaccharide (LPS) induce the expression of proinflammatory cytokines in the brain and have profound depressing effects on spontaneous and learned behaviors. These effects are mediated by vagal afferents, because they are abrogated by section of the vagus nerves at the subdiaphragmatic level in rats and mice. Vagotomy does not interfere with the synthesis and release of proinflammatory cytokines at the periphery, because plasma and tissue levels of interleukin-1 of vagotomized animals are similar to those of sham-operated animals. Furthermore, the consequences of vagotomy on the host behavioral response to peripheral cytokines are specific to the intraperitoneal route of administration of cytokines because vagotomized animals are still able to respond to IL-1 injected intravenously, subcutaneously, and into the lateral ventricle of the brain. Finally, substance P and cholecystokinin do not appear to play a key role in the transmission of the immune message to the brain because pretreatment by capsaicin or by specific antagonists of CCKA and CCKB receptors does not alter the behavioral effects of LPS and IL-1. All these findings point to the role of neural afferents for transmitting the immune message from the periphery to the brain.

Animals↗

PubMed1997

Systemic capsaicin pretreatment fails to block the decrease in food-motivated behavior induced by lipopolysaccharide and interleukin-1beta.

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-alpha) 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-1beta 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 I.P. with a total dose of 25 mg/kg capsaicin in a series of 10 injections over a 48-h period. Adult mice were injected I.P. 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-1beta (4 microg/rat I.P. in rats) and LPS (250 microg/kg I.P. in rats and 400 microg/kg I.P. 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.

Animals↗

PubMed1996

Mechanisms of sickness-induced decreases in food-motivated behavior.

Interleukin-1 beta (IL-1 beta) is a cytokine released by activated macrophages and monocytes, which mediates many of the local and systemic responses to inflammation. Interleukin-1 beta 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-1 beta. Male rats were food restricted and trained on an operant schedule for food reinforcement. Administration of recombinant human IL-1 beta (4 micrograms i.p. or 40 ng i.c.v.) induced profound decreases in operant responding, with maximal effects 1-4 h post-injection. Interleukin-1ra pretreatment (2.4 mg i.p. or 24 micrograms i.c.v.) completely blocked these effects when administered by the same route. In contrast, i.c.v. Il-1ra only partially blocked the effects of i.p. IL-1 beta, and i.p. IL-1ra was unable to block the effects of i.c.v. IL-1 beta. Interleukin-1ra did not affect responding by itself. These results suggest that IL-1 beta acts as both peripheral and central IL-1 receptors to reduce food motivated behavior. To determine the central site of action of IL-1 beta, small quantities of IL-1 beta (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 i.c.v. administration. These results suggest that the VMH may serve as a central site of action for the depressive effects of IL-1 beta 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 neutral communication pathway, mice were injected with lipopolysaccharide at a behaviorally active dose (10 micrograms i.p.). 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-1 beta and lipopolysaccharide in mice.

Animals↗

PubMed1995

Lipopolysaccharide and interleukin-1 depress food-motivated behavior in mice by a vagal-mediated mechanism.

In order to assess the role of vagal nerve afferents in the decrease in food-motivated behavior induced by proinflammatory cytokines, the effects of lipopolysaccharide (LPS, 400 micrograms/kg ip) and recombinant human interleukin-1 beta (IL-1, 750-1500 ng/mouse ip) were tested on nose poke for food in vagotomized and sham-operated mice. Subdiaphragmatic vagotomy attenuated the decrease in response rate induced by IL-1 and LPS. These results suggest that the peripheral immune message is transmitted to the brain via a neural rather than a humoral pathway.

Animals↗

PubMed1994

A behaviorally active dose of lipopolysaccharide increases sensory neuropeptides levels in mouse spinal cord.

To assess whether peripheral immune stimuli activate sensory afferents at behaviorally active doses, we measured the effects of lipopolysaccharide (LPS) on the levels of sensory neuropeptides in the spinal cord. LPS (10 micrograms/mouse i.p.) increased the levels of substance P, neurokinin A, and calcitonin gene-related peptide in the spinal cord, the maximum being observed 1 hr post-injection. Pretreatment with indomethacin at a dose (5 mg/kg i.p.) which completely blocked the decrease in food-motivated behavior induced by LPS abrogated this effect.

Animals↗

PubMed1994

Antipeptide polyclonal antibodies that recognize a substance P-binding site in mammalian tissues: a biochemical and immunocytochemical study.

We used complementary peptide methodology to obtain antibodies against the receptor for the neuropeptide substance P, specifically directed at the ligand-binding domain. Rabbits were immunized with two distinct peptides derived from the sequence of the RNA complementary to the mRNA for substance P. Binding experiments revealed that antipeptide polyclonal antibodies were able to recognize, through their paratope, a specific binding site on the rat parotid cell membranes. Substance P and antibodies competed for this binding site, because preincubation of membranes in the presence of substance P significantly reduced antibody binding, and conversely, preincubation of membranes in the presence of antibodies partly inhibited the binding of radioiodinated substance P. Immunocytochemical experiments performed on the rat cervical spinal cord show that the distribution of labeling by antibodies is similar to that observed by conventional autoradiography using 125I-substance P. Here again, control experiments demonstrated that antibodies and substance P were competing for the same binding site on the spinal cord. These biochemical and immunocytochemical data indicate that antipeptide antibodies recognize a substance P membrane binding site in nervous and nonnervous mammalian tissues. This site is likely to correspond to the NK1 specific receptor for substance P.

Amino Acid Sequence↗