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 hippocampus, 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 microM hIL-1 beta or without hIL-1 beta, usually for 6 h. Time-dependent changes in serotonergic neurotransmission and hypothalamic-pituitary-adrenocortical activity were simultaneously monitored by measuring serotonin [5-hydroxytryptamine (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 hippocampus and behavioral activity. Extracellular 5-HT levels were up to twice as high in behaviorally active rats compared to those in resting or sleeping animals. Intrahippocampal administration of hIL-1 beta markedly increased extracellular 5-HT concentrations in the hippocampus and induced a significant decrease in behavioral activity, thereby uncoupling the parallelism between changes in 5-HT and changes in behavioral activity observed in control rats. Perfusion with 0.1 microM hIL-1 beta, but not with 1 microM hIL-1 beta, produced a decrease in 5-hydroxyindoleacetic acid levels, followed by a return to preinfusion levels. Moreover, intrahippocampal administration of hIL-1 beta increased hypothalamic-pituitary-adrenocortical axis activity, as evidenced by marked increases in both plasma ACTH and plasma and dialysate corticosterone levels. 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 displayed typical characteristics of sickness behavior, such as immobility, piloerection, and a curled-up body posture. Most importantly, no effects 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 play an important role in the coordination of neuroendocrine, autonomic, and behavioral responses after an immune challenge.
Linthorst
A C
AC
Max Planck Institute of Psychiatry, Department of Neuroendocrinology, Munich, Germany.
Flachskamm
C
C
Holsboer
F
F
Reul
J M
JM
D000302:Adrenal Cortex / Q000502:physiology*; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001831:Body Temperature; D002540:Cerebral Cortex / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D003956:Dialysis; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007031:Hypothalamus / Q000502:physiology*; D007375:Interleukin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D010902:Pituitary Gland / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012701:Serotonin / Q000502:physiology*
D007375:Interleukin-1; D011994:Recombinant Proteins; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone