Changes in Sleep Wake Behavior Following Endotoxin

It is known from many animal studies that a prominent increase in inflammatory cytokine levels increases non-REM sleep (Krueger, Obal, and Fang 1999). In human beings most experiments have not injected cytokines themselves but administered bacterial endotoxin to healthy people. Mostly, a highly purified preparation derived from salmonella abortus equi was used, an endotoxin stripped of protein, prepared specifically for use in humans. In order to facilitate the comparison of results between the different studies using different dosages and/or different times of the day, we have focused on the consecutive increases in inflammatory cytokines and the neuroendocrine activation in parallel. Very low amounts of bacterial endotoxin (0.2 ng/kg) administered to healthy volunteers at 23:00 h induced neither neuroendocrine activation nor an increase in body temperature, but an increase in TNF-a and IL-6 levels to about 200% of baseline. The administration of intermediate dosages of 0.4 ng/kg body weight in the evening or of 0.8 ng/kg in the morning were followed by more robust increases in cytokine plasma levels and by a slight, but significant activation of the HPA-system in parallel to increases of body temperature of about 0.5 to 1.0°. Finally, injections of 0.8 ng/kg bodyweight in the evening led to even higher fever and increased the levels of cytokines and hormones even stronger (Mullington et al. 2000).

Following different stimulation conditions, sleep is changed with respect to both rapid eye movement (REM) sleep and non-REM sleep: Non-REM sleep was influenced by the acute phase response in a bimodal manner: when slight increases in inflammatory cytokines occur without concomitant neuroendocrine activation, non-REM sleep is slightly increased. When immune parameters are more strongly increased and fever is induced, sleep continuity and non-REM sleep amount are reduced. REM-sleep changes are less complex, the amount of REM-sleep suppression is directly related to the induction of temperature increased (Schuld, Haack, Hinze-Selch, Mullington, and Pollmacher 2001). Thus, one can conclude that proinflammatory cytokines, which also increase non-REM sleep in animals, also tend to increase non-REM sleep in humans. When the immunological changes are more prominent, other mechanisms like, for example, the activation in HPA-system may lead to a disturbance in sleep continuity and reduce non-REM amount. This view is also supported by the fact that in humans experimental enhancement of the circulating amounts of cytokine antagonists (IL-1 receptor antagonist and soluble TNF receptors) transiently suppressed non-REM sleep (Schuld et al. 1999). Additionally, there is some evidence from psychopharmacological research that all psychotropic drugs which tend to slightly increase circulating TNF-a levels are sedating or increase non-REM sleep amount (Pollmacher, Haack, Schuld, Kraus, and Hinze-Selch 2000).

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