Environmental context differentially affects behavioral, leukocyte, cortisol, and interleukin-6 responses to low doses of endotoxin in the rhesus monkey

Bacterial infections and proinflammatory cytokines induce behavioral and physiological responses associated with withdrawal and sickness behavior. These effects in rodents are often exacerbated by stressful environmental contexts. To model this synergistic effect of arousal and stress, low doses of lipopolysaccharide (LPS), 4 or 40 ng/kg, were administered to rhesus monkeys in different environmental contexts. Activity, emotional and social behaviors, cortisol, interleukin-6 (IL-6), and peripheral leukocyte trafficking were assessed in 4 experiments: an initial 3 h time-course in a novel cage (Experiment 1); an extended 24 h time-course (Experiment 2); a highly arousing context in which an animal was engaged in the Human Intruder Paradigm (HIP, Experiment 3); and finally in an undisturbed context in their Home Cage (Experiment 4). The moderately arousing novel cage potentiated leukocyte, neutrophilic, IL-6, and cortisol changes as compared to the Home Cage. Unlike the social withdrawal seen in rodents, monkeys engaged in a marked increase in social behavior. IL-6 levels were positively correlated with Proximal Contact, which was induced to a greater degree by the higher dose of LPS. In contrast, the high arousal HIP condition appeared to obviate the effects of LPS. Thus, the rhesus monkey provides an excellent animal model for investigating the behavioral and physiological actions of endotoxemia, which are profoundly influenced by the situational context in which the individual is evaluated.