Exploring the influence of reward mechanisms on the interaction between sickness and immunity: Reasons to 'press-on'

Abstract

The clinical use of cytokines such as interleukin (IL)-2 and interferon (IFN)-alpha has been accompanied by reports of central nervous system disruptions, tempering their effectiveness as front line treatments of defense against cancer and hepatitis C. Along with the potential to change the course of disease, these cytokines often elicit an array of generalized non-specific side effects, known as sickness behaviours; these include disrupted febrile changes, lethargy, hypersomnia, anorexia, decreased mobility, and depression, all of which impact patient compliance in treatment plans. As of yet, an animal model has not been well developed to study the mechanisms underlying the sickness-inducing effects of these cytokines. In the first three experiments, we evaluated the short- and long-term effects of a single systemic injection of either rat recombinant IL-2 (study 1) or IFN-alpha (studies 2 and 3) on a variety of physiological and behavioural indices. In the first experiment, a single IL-2 challenge increased thresholds for rewarding brain stimulation of the ventral tegmental area (VTA) in a progressive manner over the month long test period. The next two studies were designed to investigate the sickness-inducing effects of IFN-alpha on temperature, body weight, food intake, sickness behaviours, and locomotor activity in both male and female rats. In the latter, thresholds for brain stimulation reward (BSR) were also chronicled. Unlike the first study, BSR thresholds were not compromised by the systemic cytokine challenge. Significant physiological disruptions such as elevated temperature and piloerection scores were observed; locomotor activity was only disrupted in male rats. Most of the behavioural and physiological effects of IFN-alpha were observed at the lowest dose level (10 units) suggesting that this cytokine can induce long-term somatic changes without altering hedonic status. In the third study, we observed that animals obtaining rewarding brain stimulation had attenuated signs of sickness consistent with previous work suggesting that BSR stimulates immunological processes, such as natural killer cell activity. Thus, in the fourth study, we further exploited this phenomenon and included, in addition to a BSR group, animals exposed to an environmentally enriched condition. In this study, the immune challenge consisted of 150 microg/kg i.p. of lipopolysaccharide (LPS). Both BSR and environmental enrichment diminished the sickness behaviours typically evoked by LPS. Real-time RT-PCR and a multiplex bead assay revealed that the mRNA and protein levels for several peripheral cytokines and their receptors varied according to environmental context. For example, BSR significantly influenced the cytokine profiles for IL-10 and natural killer cell receptor gene, whereas a trend of reduced IL-6 levels and a significantly elevated profile of IFN-gamma was observed in the environmentally enriched group. The effect of LPS challenge on brain cytokine levels in the VTA was modest at best. Only IL-6 was significantly elevated in LPS control versus saline-treated animals while the environmentally enriched animals demonstrated a trend toward lower levels of this cytokine in the VTA. Together, these data suggest that environmental context may influence the physical demonstrations of sickness through redistributions of immunological parameters and status.