MECHANISMS OF SICKNESS-INDUCED DECREASES IN FOOD-MOTIVATED BEHAVIOR

Interleukin-1 beta (IL-1 beta) is a cytokine released by activated mac rophages and monocytes, which mediates many of the local and systemic responses to inflammation. Interleukin-la induces anorexia in rats whe n 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 anor exic effects of IL-1 beta. Male rats were food restricted and trained on an operant schedule for food reinforcement. Administration of recom binant human IL-1 beta (4 mu g IP or 40 ng ICV) induced profound decre ases in operant responding, with maximal effects 1-4 h post-injection. Interleukin-1ra pretreatment (2.4 mg IP or 24 mu g ICV) completely bl ocked these effects when administered by the same route. In contrast, ICV IL-1ra only partially blocked the effects of IP IL-1 beta, and IP IL-1ra was unable to block the effects of ICV IL-1 beta. Interleukin-1 ra did not affect responding by itself. These results suggest that IL- 1 beta acts at both peripheral and central IL-1 receptors to reduce fo od-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 t he ventromedial hypothalamus of male rats. Both doses produced profoun d decreases in responding; the magnitude and time course of these effe cts were nearly identical to those observed after ICV administration. These results suggest that the VMH may serve as a central site of acti on for the depressive effects of IL-1 beta on food intake. There is mu ch controversy over the pathways of communication from the immune syst em to the brain. To test the hypothesis that the peripheral immune sti mulus is transmitted to the brain via a neural communication pathway, mice were injected with lipopolysaccharide at a behaviorally active do se (10 mu g IP). This treatment increased the concentrations of substa nce P, neurokinin A, and calcitonin gene-related peptide in mouse spin al cord in a prostaglandin-dependent manner. Maximal increases in neur opeptide content were observed 1 h post-injection. Finally, subdiaphra gmatic vagotomy was found to attenuate the reduction in food-motivated behavior induced by both IL-1 beta and lipopolysaccharide in mice.