LOCAL-ADMINISTRATION OF RECOMBINANT HUMAN INTERLEUKIN-1-BETA IN THE RAT HIPPOCAMPUS INCREASES SEROTONERGIC NEUROTRANSMISSION, HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL AXIS ACTIVITY, AND BODY-TEMPERATURE

In this study, we equipped rats with a microdialysis probe in the hipp ocampus, which enabled stress-free intrahippocampal administration of recombinant human IL-1 beta (hIL-1 beta). Perfusion of the probes was conducted with a Ringer's solution containing 0.1 or 1.0 mu M hIL-1 be ta or without hIL-1 beta, usually for 6 h. Time-dependent changes in s erotonergic neurotransmission and hypothalamic-pituitaly-adrenocortica l activity were simultaneously monitored by measuring serotonin [5-hyd roxytryptamine (5-HT)], 5-hydroxyindoleacetic acid, and corticosterone concentrations in the dialysates. In control rats, there was a clear relationship between extracellular 5-HT concentrations in the hippocam pus and behavioral activity. Extracellular 5-HT levels were up to twic e as high in behaviorally active rats compared to those in resting or sleeping animals. Intrahippocampal administration of hIL-1 beta marked ly increased extracellular 5-HT concentrations in the hippocampus and induced a significant decrease in behavioral activity, thereby uncoupl ing the parallelism between changes in 5-HT and changes in behavioral activity observed in control rats. Perfusion with 0.1 mu M hIL-1 beta, but not with 1 mu M hIL-1 beta, produced a decrease in 5-hydroxyindol eacetic acid levels, followed by a return to preinfusion levels. Moreo ver, intrahippocampal administration of hIL-1 beta increased hypothala mic-pituitary-adrenocortical axis activity, as evidenced by marked inc reases in both plasma ACTH and plasma and dialysate corticosterone lev els. In addition, a rise in body temperature by approximately 2 C was observed at time points at which the effects of hIL-1 beta on 5-HT and corticosterone levels were (near-)maximal. hIL-1 beta-treated rats di splayed typical characteristics of sickness behavior, such as immobili ty, piloerection, and a curled-up body posture, Most importantly, no e ffects were found either with heat-inactivated hIL-1 beta or when hIL- 1 beta was administered via a probe implanted in the neocortex. Based on these results, we postulate that the hippocampal IL-1 system may pl ay an important role in the coordination of neuroendocrine, autonomic, and behavioral responses after an immune challenge.