Physiology & Behavior 69 (2000) 325–331 0031-9384/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved. PII: S0031-9384(00)00212-2 Cholecystokinin receptors do not mediate the suppression of food-motivated behavior by lipopolysaccharide and interleukin-1 beta in mice Jean-Luc Bret-Dibat a , Robert Dantzer b, * a Centre d’Etudes et de Recherches en PsychoPathologie, Université Toulouse II, Toulouse, France b INRA-INSERM U394, Domaine de Carreire, Rue Camille Saint-Saëns 33077 Bordeaux Cedex, France Received 5 August 1999; received in revised form 29 September 1999; accepted 15 December 1999 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 ne- crosis factor it induces. To test the possibility that cholecystokinin (CCK) mediates anorexia induced by IL-1 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 re- ceptor antagonist L364,718 (at 1 mg/kg) or with the CCK-B receptor antagonist L365,260 (50 g/kg) before being injected with LPS (100 g/kg) or IL-1 (20 g/kg). All injections were given via the intraperitoneal (i.p.) route. In spite of its ability to block the effects of exog- enous CCK-8 on food-motivated behavior in mice, the CCK-A receptor antagonist did not block the depressive actions of LPS and IL-1 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. © 2000 Elsevier Science Inc. All rights reserved. Keywords: Lipopolysaccharide; Endotoxin; Interleukin-1; Cholecystokinin; Food-motivated behavior; Mice 1. Introduction Reduced food intake is a common feature of the behav- ioral response to infection. It is mediated by proinflamma- tory 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 secre- tion of cytokines [49] as does live bacteria. Peripheral and central injections of LPS and cytokines induce anorexia [36] and decrease food-motivated behavior [3–5,22]. 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-1 [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 can- didate. 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 ner- vous system to terminate feeding [44,45]. Cholecystokinin can also facilitate memory processing through a vagally mediated mechanism [15]. Cholecystokinin had been im- plicated 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 gas- trin receptor, which is found predominantly in the CNS (in the hypothalamus and area postrema) and in some periph- * Corresponding author. Tel.: 33-5-57-57-37-25, Fax: 33-5-56-98-90-29 E-mail address: robert.dantzer@bordeaux.inserm.fr