Effect of bacterial endotoxin and interleukin-1β on hippocampal serotonergic neurotransmission, behavioral activity, and free corticosterone levels: An in vivo microdialysis study

Abstract

In this study the effect of immune system stimulation and intracerebroventricular (i.c.v.) administration of interleukin-1β (IL-1β) on hippocampal serotonergic neurotransmission, behavioral activity, and the hypothalamic-pituitary-adrenocortical (HPA) axis is described. An in vivo microdialysis method was used to measure hippocampal extracellular concentrations of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in conscious, freely moving rats. In addition, we established a method to continuously monitor free corticosterone levels in dialysates. Behavioral activity was scored by measuring the time during which rats were active (locomotion, grooming, eating, drinking). We found a significant, positive relationship between behavioral activity and hippocampal extracellular concentrations of 5-HT. Intraperitoneal (i.p.) administration of the bacterial endotoxin lipopolysaccharide (LPS; 30, 100, and 300 μg/kg body weight) produced an increase in the extracellular concentrations of 5- HT and 5-HIAA in the hippocampus, which was paralleled by a significant decline in behavioral activity and a marked increase in extracellular corticosterone levels. Thus, the close correlation between hippocampal extracellular 5-HT levels and behavioral activity observed in control rats was disrupted in the LPS-treated animals. The effects of i.p. LPS could be mimicked by i.c.v. application of recombinant human IL-1β (hIL-1β; 100 ng). I.c.v. pretreatment with the IL-1 receptor antagonist (IL-1ra; 10 μg) antagonized the hlL-1β-induced effects. IL-1ra showed no intrinsic effects. Furthermore, it was found that i.c.v. pretreatment with IL-1ra (10 μg) significantly attenuated the i.p. LPS-induced (100 μg/kg body weight) rise in hippocampal extracellular 5-HT levels. No significant effect of IL-1ra was found on LPS-induced changes in extracellular levels of 5-HIAA and corticosterone, and behavioral activity. Taken together, these results suggest that the hippocampus, and more specifically the raphe-hippocampal serotonergic system, participates in the CNS responses to an immune stimulus. Moreover, the present study supports the notion that centrally acting IL-1 substantially contributes to the hippocampal serotonergic neurotransmission changes observed following a peripheral immune challenge.