Intraperitoneal endotoxin injection and central administration of interleukin (IL)-1beta profoundly activate hippocampal serotonergic neurotransmission. This study was designed to investigate, using in vivo microdialysis, the effects of another endotoxin-induced proinflammatory cytokine, tumour necrosis factor-alpha, and the effects of the non-inflammatory cytokine, IL-2, on hippocampal extracellular levels of serotonin. To compare the effects of these cytokines on neurotransmission with the effects on physiological parameters and behaviour, hypothalamic-pituitary-adrenocortical (HPA) axis activity, body temperature and behavioural activity were monitored as well. Time-dependent changes in serotonergic neurotransmission and HPA axis activity were determined by measuring serotonin, its metabolite 5-hydroxyindoleacetic acid and free corticosterone in dialysates. Total behavioural activity was scored by assessing the time during which rats were active. Core body temperature was measured by biotelemetry. Intracerebroventricular injection of 50 or 100 ng recombinant murine tumour necrosis factor-alpha exerted no effect on hippocampal serotonergic neurotransmission, and induced 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 not of 50 ng, recombinant human IL-2 produced a marked increase in hippocampal extracellular concentrations of serotonin and 5-hydroxyindoleacetic acid, accompanied by a pronounced behavioural inhibition and other signs of sickness. Moreover, both doses of IL-2 caused a dose-dependent increase in body temperature and free corticosterone levels. Interestingly, intracerebroventricular pretreatment with the IL-1 receptor antagonist showed that the effects of IL-2 on hippocampal serotonin were completely dependent on endogenous brain IL-1. However, IL-1 seemed to play only a minor role in the IL-2-induced increase in free corticosterone. Taken together, the results show that cytokines produce partially overlapping brain-mediated responses, but are selectively effective in stimulating hippocampal serotonergic neurotransmission and inducing sickness behaviour. Moreover, we postulate that activation of hippocampal serotonin release is instrumental in the full development of behavioural inhibition.