EFFECT OF BACTERIAL-ENDOTOXIN AND INTERLEUKIN-1-BETA ON HIPPOCAMPAL SEROTONERGIC NEUROTRANSMISSION, BEHAVIORAL ACTIVITY, AND FREE CORTICOSTERONE LEVELS - AN IN-VIVO MICRODIALYSIS STUDY

In this study the effect of immune system stimulation and intracerebro ventricular (i.c.v.) administration of interleukin-1 beta (IL-1 beta) on hippocampal serotonergic neurotransmission, behavioral activity, an d the hypothalamic-pituitary-adrenocortical (HPA) axis is described. A n in vivo microdialysis method was used to measure hippocampal extrace llular concentrations of serotonin (5-HT) and its metabolite 5-hydroxy indoleacetic acid (5-HIAA) in conscious, freely moving rats. In additi on, we established a method to continuously monitor free corticosteron e levels in dialysates. Behavioral activity was scored by measuring th e time during which rats were active (locomotion, grooming, eating, dr inking). We found a significant, positive relationship between behavio ral activity and hippocampal extracellular concentrations of 5-HT. Int raperitoneal (i.p.) administration of the bacterial endotoxin lipopoly saccharide (LPS; 30, 100, and 300 mu g/kg body weight) produced an inc rease in the extracellular concentrations of 5-HT and 5-HIAA in the hi ppocampus, 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 l evels and behavioral activity observed in control rats was disrupted i n the LPS-treated animals. The effects of i.p. LPS could be mimicked b y i.c.v. application of recombinant human IL-1 beta (hIL-1 beta; 100 n g). I.c.v, pretreatment with the IL-1 receptor antagonist (IL-1ra; 10 mu g) antagonized the hIL-1 beta-induced effects. IL-1ra showed no int rinsic effects. Furthermore, it was found that i.c.v. pretreatment wit h IL-1ra (10 mu g) significantly attenuated the i.p. LPS-induced (100 mu g/kg body weight) rise in hippocampal extracellular 5-HT levels. No significant effect of IL-1ra was found on LPS-induced changes in extr acellular 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 stud y supports the notion that centrally acting IL-1 substantially contrib utes to the hippocampal serotonergic neurotransmission changes observe d following a peripheral immune challenge.