Abstract

Introduction

Effects on Serotonin and Noradrenaline

Cytokines and Prostaglandins

Functional Implications

References

Discussion
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Due to extensive research efforts in the field of neuroimmunology, it is now well accepted that the brain, the endocrine system and the immune system form an intricate network directed to maintain the homeostasis of an organism. However, the neuronal networks integrating immune information on the level of the brain still need to be largely characterized. From own experience, most people will recognize that infection and inflammation are accompanied by specific changes in behavior, e.g. lethargy, loss of social interest and appetite, etc. Hence, we were interested in the effects of inflammation on neurotransmission in higher brain structures, such as the hippocampus. Effects on the level of the hippocampus were compared with responses on the level of the preoptic area; a brain structure known to be involved in autonomic and endocrine regulation. Our studies were focussed on serotonin (5-HT) and noradrenaline (NA), because of their primary role in modulation of various responses to stress.

Using an in vivo microdialysis method in freely-moving rats, we have shown that peripheral inflammation, induced by intraperitoneal (i.p.) inoculation of animals with lipopolysaccharide (LPS), caused a profound increase in hippocampal extracellular levels of 5-HT but had no effect on this indoleamine in the preoptic area. In contrast, NA levels rose dramatically in the preoptic area after i.p. administration of LPS, whereas only a moderate effect was observed in the hippocampus. These results clearly demonstrate that peripheral inflammation induces a highly differentiated neurotransmission response in the brain. To investigate the putative role of brain cytokines, experiments were performed in which specific cytokines (i.e. interleukin (IL)-1, IL-2 and tumor necrosis factor-alpha) or antagonists (IL-1 receptor antagonist) were administered intracerebroventricularly. We could demonstrate that IL-1 plays a primary role in the activation of hippocampal serotonergic neurotransmission during peripheral inflammation. Moreover, pretreatment of rats with the cyclo-oxygenase inhibitor indomethacin largely prevented the LPS-induced changes in 5-HT and NA neurotransmission, pointing to a principle role of prostaglandins in these responses.

Next, a series of studies was designed to elucidate the functional implications of inflammation-induced neurotransmission responses. Thereto, in vivo microdialysis was combined with biotelemetry and free corticosterone levels were assessed in dialysates. We have shown that the rise in preoptic noradrenaline levels may be related to the first phase of the fever response and/or the increase in free corticosterone levels. Moreover, based on contemplations elaborated in this chapter, we have postulated that an appropriate activation of hippocampal serotonergic neurotransmission is essential for the full development of sickness behavior.

This study was supported by the Volkswagen Foundation (grant nos I/68 430 and I/70 543).

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Presentation Number SAlinthorst0892
Keywords: serotonin, hippocampus, preoptic area, sickness behavior, fever