Responses in the Raphe-Hippocampal Serotonergic System During Peripheral Inflammation: Putative Role in Sickness Behaviour

Summary

It is now well established that challenges to the immune system trigger a number of physiological processes, such as activation of the hypothalamicpituitary- adrenocortical (HPA) axis, fever, and sickness behaviour. The task of these triggered processes is to promote survival and recovery of homeostasis. However, at the level of the brain the neurotransmitter systems underlying these physiological and behavioural responses still need to be fully characterized. By use of an in vivo microdialysis method in rats, we have found that during peripheral inflammation (induced by intraperitoneal (ip) injection of endotoxin (lipopolysaccharide; LPS) marked changes occur in serotonergic neurotransmission in the brain. Hence, a profound increase in extracellular levels of serotonin (5-HT) was observed in the hippocampus after an ip injection of LPS. This endotoxin effect was mainly mediated by interleukin- 1 (IL-1). Based on several studies, it was postulated that the rise in hippocampal 5-HT levels might be associated with the development of sickness behaviour. Moreover, a peripheral inflammatory challenge was shown to evoke a long-term increase in 5-HT_IA receptor density in hippocampal subregions but not in the raphe area.

Disturbances in the functioning of the immune System described in major depression prompted us to study whether disturbed interactions between the central nervous System and the immune System may be implicated in the development of stress-related disorders such as major depression. The Observation that depressed patients show an elevated central drive of corticotropin-releasing hormone (CRH) in conjunction with the fact that this neuropeptide is highly involved in physiological responses to stress lead us to develop an animal model of CRH hyperactivity, i.e., the long-term, intracerebroventricularly (icv) CRH-infused rat. In our experimental design, rats were challenged ip with LPS after seven days of icv CRH or vehicle infusion. The endotoxin evoked a profound fever response in control animals, whereas only a blunted response developed in long-term CRH-treated rats. Moreover, LPS produced an attenuated hippocampal 5-HT response and a delayed onset of HPA axis activation and behavioural inhibition in CRH-treated rats. These attenuated, brain-mediated responses could not have been caused by suppression of the release of plasma cytokines, since CRH-infused animals showed enhanced LPS-induced plasma bioactivities of IL-1 and IL-6 (but not of tumor necrosis factor (TNF)).

These studies indicate that peripheral inflammation elicits vast changes in hippocampal serotonergic neurotransmission, both in terms of Serotonin release and 5-HT_1A receptor density, that might be responsible for the initiation of specific physiological, behavioural and molecular responses in order to cope with the challenge. In addition, chronically elevated CRH drive in the brain, as seen during chronic stress and stress-related disorders results in aberrant brain-mediated responses to an acute inflammatory challenge - a Situation which, in the long run, may present a detrimental threat for health. Thus, these results provide evidence that chronic CRH hypersecretion is an important factor in the etiology of stress-related disorders.