TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-2 DIFFERENTIALLY AFFECT HIPPOCAMPAL SEROTONERGIC NEUROTRANSMISSION, BEHAVIORAL ACTIVITY, BODY-TEMPERATURE AND HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL AXIS ACTIVITY IN THE RAT

Intraperitoneal endotoxin injection and central administration of inte rleukin (IL)-1 beta profoundly activate hippocampal serotonergic neuro transmission. This study was designed to investigate, using in vivo mi crodialysis, the effects of another endotoxin-induced proinflammatory cytokine, tumour necrosis factor-alpha, and the effects of the non-inf lammatory cytokine, IL-2, on hippocampal extracellular levels of serot onin, To compare the effects of these cytokines on neurotransmission w ith the effects on physiological parameters and behaviour, hypothalami c-pituitary-adrenocortical (HPA) axis activity, body temperature and b ehavioural activity were monitored as well, Time-dependent changes in serotonergic neurotransmission and HPA axis activity were determined b y measuring serotonin, its metabolite 5-hydroxyindoleacetic acid and f ree corticosterone in dialysates, Total behavioural activity was score d by assessing the time during which rats were active. Core body tempe rature was measured by biotelemetry. Intracerebroventricular injection of 50 or 100 ng recombinant murine tumour necrosis factor-alpha exert ed no effect on hippocampal serotonergic neurotransmission, and induce d no signs of sickness behaviour. However, these doses produced a dose -dependent increase in body temperature and free corticosterone levels . In contrast, intracerebroventricular administration of 500 ng, but n ot of 50 ng, recombinant human IL-2 produced a marked increase in hipp ocampal extracellular concentrations of serotonin and 5-hydroxyindolea cetic acid, accompanied by a pronounced behavioural inhibition and oth er signs of sickness. Moreover, both doses of IL-2 caused a dose-depen dent increase in body temperature and free corticosterone levels. Inte restingly, intracerebroventricular pretreatment with the IL-1 receptor antagonist showed that the effects of IL-2 on hippocampal serotonin w ere completely dependent on endogenous brain IL-1. However, IL-1 seeme d to play only a minor role in the IL-2-induced increase in free corti costerone. Taken together, the results show that cytokines produce par tially overlapping brain-mediated responses, but are selectively effec tive in stimulating hippocampal serotonergic neurotransmission and ind ucing sickness behaviour, Moreover, we postulate that activation of hi ppocampal serotonin release is instrumental in the full development of behavioural inhibition.