Pauli S, Linthorst A C, Reul J M
Max Planck Institute of Psychiatry, Department of Neuroendocrinology, Munich, Germany.
Eur J Neurosci. 1998 Mar;10(3):868-78. doi: 10.1046/j.1460-9568.1998.00093.x.
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.
腹腔内注射内毒素以及脑室内注射白细胞介素（IL）-1β可显著激活海马体5-羟色胺能神经传递。本研究旨在运用体内微透析技术，探究另一种内毒素诱导的促炎细胞因子——肿瘤坏死因子-α，以及非炎性细胞因子IL-2对海马体中5-羟色胺细胞外水平的影响。为了比较这些细胞因子对神经传递的影响与对生理参数和行为的影响，还监测了下丘脑-垂体-肾上腺皮质（HPA）轴活性、体温和行为活动。通过测量透析液中的5-羟色胺、其代谢产物5-羟吲哚乙酸和游离皮质酮，确定5-羟色胺能神经传递和HPA轴活性随时间的变化。通过评估大鼠活动的时间来对总的行为活动进行评分。通过生物遥测法测量核心体温。脑室内注射50或100 ng重组鼠肿瘤坏死因子-α对海马体5-羟色胺能神经传递没有影响，也未诱发疾病行为的迹象。然而，这些剂量会使体温和游离皮质酮水平呈剂量依赖性升高。相比之下，脑室内注射500 ng而非50 ng重组人IL-2会使海马体细胞外5-羟色胺和5-羟吲哚乙酸浓度显著升高，同时伴有明显的行为抑制和其他疾病迹象。此外，两种剂量的IL-2都会使体温和游离皮质酮水平呈剂量依赖性升高。有趣的是，脑室内预先注射IL-1受体拮抗剂表明，IL-2对海马体5-羟色胺的影响完全依赖于内源性脑IL-1。然而，IL-1似乎在IL-2诱导的游离皮质酮升高过程中仅起次要作用。综上所述，结果表明细胞因子会产生部分重叠的脑介导反应，但在刺激海马体5-羟色胺能神经传递和诱发疾病行为方面具有选择性作用。此外，我们推测海马体5-羟色胺释放的激活有助于行为抑制的充分发展。
