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

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Abstract

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.

Introduction

Reduced food intake is a common feature of the behavioral response to infection. It is mediated by proinflammatory cytokines, such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and interleukin-6 (IL-6), which are released by monocytes and macrophages activated by immune pathogens. Peripheral injection of lipopolysaccharide (LPS), the main active component of the outer cell-wall of Gram-negative bacteria, triggers the same pattern of secretion of cytokines [49] as does live bacteria. Peripheral and central injections of LPS and cytokines induce anorexia [36] and decrease food-motivated behavior 3, 4, 5, 22. These effects are mediated both at the periphery and in the brain because central injection of the specific antagonist of IL-1 receptors (IL-1ra) only partially blocks the decrease in food-motivated behavior induced by intraperitoneal (i.p.) administration of IL-1β [21].

Cytokines can act directly or indirectly on their cellular targets to reduce food intake. Among the diverse mediators of the effects of cytokines, cholecystokinin (CCK, CCK-8, sulfated octapeptide, being the more efficient form), which is the main physiologically active neuropeptide implicated in the regulation of food intake, appears as a primary candidate. After its release by endocrine cells of the intestine, this peptide acts in a nonendocrine manner [40] on specific receptors of the vagus nerve [14], the main nerve implicated in food intake regulation; the peptide signals the central nervous system to terminate feeding 44, 45. Cholecystokinin can also facilitate memory processing through a vagally mediated mechanism [15]. Cholecystokinin had been implicated as an afferent neurotransmitter in the vagus nerve [35], and CCK-binding sites are numerous in the central nervous system, particularly in areas implicated in the central regulation of food intake; namely, the nucleus of the tractus solitarius (NTS), paraventricular nucleus (PVN), and the ventromedial (VMH) and lateral hypothalamus (LHA) [8].

Cholecystokinin mediates its effects through an action on two types of receptors: a type A receptor, which is located essentially in the periphery but also is present in the NTS and area postrema, and a type B receptor, similar to the gastrin receptor, which is found predominantly in the CNS (in the hypothalamus and area postrema) and in some peripheral sites 14, 29, 31. This suggests that CCK released after a meal may not only initiate satiety by acting at peripheral sites but also may intervene to transmit this information and activate the ultimate central targets that regulate food intake in the brain 9, 41, 43.

These mechanisms of effect of CCK show striking similarities to the mode of action of cytokines on food intake. Interleukin-1 increases plasma CCK 10, 24 after a systemic injection and induces in vitro the release of CCK from superfused hypothalamo-neurohypophyseal slices [34]. Interestingly, we found that the effects of LPS and IL-1β on food-motivated behavior are attenuated by vagotomy [3], in spite of the fact that the same surgery is unable to block the depressive effects of these cytokines on spontaneous food intake [42]. Moreover, IL-1β increases firing rate in vivo in the hepatic [33] and gastric [24] branches of the vagus nerve. This effect is partially blocked by the administration of a type A receptor antagonist of CCK, L364,718 [24]. Furthermore, IL-1β potentiates the augmentation of mass afferent vagal nerve activity induced by exogenous CCK [6]. Daun and McCarthy [10] reported an inhibitory effect of L364,718 on the anorexic effect of a low dose of IL-1α but not a two-fold higher one. This same treatment abolishes the decreased emptying of gastric contents induced by the two doses of IL-1α.

In the present study, we used the selective receptor antagonists CCK-A (L364-718) [7] and CCK-B (L365,260) [26] to delineate the implication of CCK in the inhibitory effects of LPS and IL-1β on food-motivated behavior. In spite of the ability of L364,718 to block the depressive effect of exogenous CCK on food-motivated behavior. In spite of the ability of L364-718 to block the depressive effect of exogenous CCK on food-motivated behavior and in spite of the ability of L365,260, at the dose used, to attenuate LPS-induced fever [46], we did not find any effect of these two antagonists on the actions of LPS and IL-1β on food-motivated behavior.

Section snippets

Animals

Six-week-old, male mice of the CD-1 (ICR) BR strain (Charles River, Saint-Aubin-les-Elboeuf, France) weighing 30–40 g were individually housed in polypropylene cages in a room maintained at 23 ± 2°C and on a 12:12-h light:dark cycle (lights on at 21:00 h). Food was restricted to maintain mice at 90% of their free-feeding body weight. All procedures and protocols obeyed the French legislation on animal experimentation and conformed to American Psychological Association ethical standards.

Behavioral observations

Both

IP L364,718 blocks the behavioral effects of IP CCK

We first checked that L364,718 was able to block the anorexic effect of CCK-8 on spontaneous food intake (data not shown), as previously demonstrated (13). The ability of the CCK-A receptor antagonist L-364,718 to block the effect of exogenous CCK-8 on food-motivated behavior was clearly apparent in our protocol (Fig. 1). A two-way ANOVA (two pretreatments × two treatments) revealed significant pretreatment (F(1,22) = 5.40; p < 0.05) and treatment (F(1,22) = 11.10; p < 0.01) effects with an

Discussion

The present report fails to demonstrate any effect of CCK-A and CCK-B receptor antagonists on the decrease in food-motivated behavior induced by LPS and IL-1β in mice, in spite of the ability of L364,718 to abrogate the depressive effect of CCK-8 on food-motivated behavior. These results agree with earlier findings by Bluthé et al [2] that show that intracerebroventricular administration of CCK-A and CCK-B receptor antagonists did not alter the depressing effects of LPS on social exploration in

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