Behavioral and central neurochemical consequences of cytokine challenge: Relationship to stressors

Multidirectional communication likely occurs between the immune, neuroendocrine, autonomicand central nervous systems. In this respect, it has been proposed that signaling molecules (cytokines) released from activated immune cells may serve as messengers (immunotransmitters) stimulating neuroendocrine and central neurotransmitter processes. Further, given that cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), elicit neurochemical changes reminiscent of those provoked by stressors, the view has been expressed that the central nervous system (CNS) interprets immune activation much as if it were a stressor. Among other things, these cytokines stimulate hypothalamic-pituitary-adrenal activity, provoking the release of corticotropin releasing hormone (CRH) from the paraventricular nucleus of the hypothalamus, and hence secretion of pituitary ACTH and adrenal glucocorticoids. As well, like stressors, cytokines provoke increased utilization of norepinephrine, dopamine and serotonin within various brain regions. This includes the hypothalamus, which influences neuroendocrine processes, as well as extrahypothalamic regions, such as the amygdala and prefrontal cortex, which are involved in fear and anxiety. In addition to their independent actions, various cytokines may act synergistically in modulating neuroendocrine functioning. Moreover, paralleling the actions of stressors, acute cytokine exposure may have protracted effects on CNS processes. Having been exposed to a cytokine, subsequent reexposure to the cytokine (or to a stressor) may influence neurochemical functioning, so that even sub-effective cytokine doses have marked effects (sensitization). Interestingly, such effects increase with the passage of time, possibly reflecting diverse processes including such things as phenotypic changes of CRH neurons within the external zone of the median eminence so that the terminals coexpress both CRH and arginine vasopressin. Inasmuch as cytokines induce stressor like effects, efforts have been devoted to the analysisof the behavioral changes exerted by these immunotransmitters. The best known of these effects is the sickness profile induced by proinflammatory cytokines and bacterial endotoxins (e.g., reduced activity, ptosis, piloerection, signs of disturbed blood flow, curled body posture, reduced food consumption, and reduced intake of highly palatable food substances). In part, these effects may reflect the malaise engendered by the challenges, but there is reason to suppose that they also induce anhedonia (diminished reward obtained from otherwise rewarding stimuli), as well as anxiety. Moreover, chronic administration of some cytokines (e.g. IL-2) provoke cognitive disturbances, such that working memory processes are disrupted. It is provisionally suggested that these cytokines may play a role in the provocation or maintenance of depressive disorders, as well as illnesses involving affective components.