Summary

Sickness is a common if not trivial experience that occurs during the course of an infectious process (Dantzer, 2001). At the behavioral level, sick individuals typically display depressed activity and little or no interest in the environment. Body care activities are usually absent, and food intake is profoundly depressed despite the increased metabolism that is necessary for the fever response. At the subjective level, a sick person experiences malaise, fatigue and apathy, and sometimes mental confusion. Hyperalgesia, or enhanced sense of pain, is another Important component of sickness (Watkins and Maier, 2000). The symptoms of sickness can be elicited in healthy subjects and experimental animals by systemic injection of the cytokine inducer lipopolysaccharide (LPS) or the pro-inflammatory cytokines that are released by activated monocytes and macrophages during the host response to infection (Dantzer and Kelley, 1989). Similar symptoms can be induced by direct administration of LPS or pro-inflammatory cytokines into the brain of experimental animals. During the last 15 years, the mechanisms of cytokine-induced sickness behavior have been the subject of intense research, carried out at several levels of analysis, from the molecular to the behavioral and clinical levels. The purpose of the present chapter is to review the results that have been obtained in this fi eld. At the behavioral level, cytokine-induced sickness behavior has been demonstrated to be the expression of a central motivational state that reorganizes the organism's priorities in order to cope with infectious microorganisms. At the organ level, this motivational aspect of sickness behavior is mediated by the action of endogenous signals of sickness that are represented by pro-infl ammatory cytokines on neuronal networks integrating the subjective, behavioral, and physiological components of sickness. Cytokine receptors are present in the brain, and they are activated in most cases not by peripheral cytokines that enter the brain, but by cytokines that are produced locally in the brain in response to peripheral cytokines. At the cellular level, brain cytokines are produced by macrophage-like cells in the meninges and around the blood vessels and by microglial cells in the brain parenchyma. These locally produced cytokines act on other glial cells and ultimately on neurons. At the molecular level, the brain effects of cytokines are mediated by receptors that are similar to those characterized at the periphery.