Reul J M, Labeur M S, Wiegers G J, Linthorst A C
Max Planck Institute of Psychiatry, Department of Neuroendocrinology, Munich, Germany.
Ann N Y Acad Sci. 1998 May 1;840:444-55. doi: 10.1111/j.1749-6632.1998.tb09583.x.
Presently, it is clear that the brain, immune system, and endocrine system build a complex network of interactions at various levels. Inflammation, which may be regarded as a stressful challenge, initiates apart from immunological, autonomic, and neuroendocrine responses also profound behavioral (e.g., immobility, social disinterest) changes. Key mediators herein are corticotropin-releasing hormone (CRH) and cytokines, such as interleukin-1 beta (IL-1 beta). Currently, the behavioral changes, collectively termed sickness behavior, are thought to be adaptive responses to support the body's efforts to fight the infection. Using in vivo microdialysis and biotelemetry in freely moving animals, we have studied the monoaminergic circuits in the brain implicated in the regulation of physiological and behavioral responses to a peripheral inflammatory challenge (see also chapter of Linthorst and Reul in this volume). To expand our insight into the relationship between hypersecretion of CRH and physiological and behavioral abnormalities associated with stress-related disorders, a series of experiments was conducted with long-term centrally CRH-infused rats. These rats showed reduced body weight gain, decreased food intake, elevated plasma ACTH and corticosterone levels, thymus involution and immunosuppression, but, paradoxically, enhanced IL-1 beta mRNA expression in spleen macrophages. After a peripheral endotoxic challenge on the seventh day of treatment, the CRH-infused rats produced aberrant (i.e., blunted and/or delayed) HPA axis, fever, behavioral, and hippocampal serotonergic responses. However, endotoxin-induced plasma IL-1 and IL-6 bioactivities were significantly enhanced in these animals. The data show that chronically elevated central CRH levels as occurring during chronic stress result in defective central nervous system and immune system responses to an acute (inflammatory) challenge. These observations provide evidence that chronic CRH hypersecretion is an important factor in the etiology of stress-related disorders.
目前，很明显大脑、免疫系统和内分泌系统在各个层面构建了一个复杂的相互作用网络。炎症可被视为一种应激挑战，除了引发免疫、自主神经和神经内分泌反应外，还会引起深刻的行为变化（如不动、对社交不感兴趣）。其中的关键介质是促肾上腺皮质激素释放激素（CRH）和细胞因子，如白细胞介素-1β（IL-1β）。目前，这些统称为疾病行为的行为变化被认为是适应性反应，以支持身体对抗感染的努力。我们利用在自由活动动物体内的微透析和生物遥测技术，研究了大脑中与对外周炎症挑战的生理和行为反应调节有关的单胺能回路（另见本卷中林托斯特和勒尔的章节）。为了深入了解CRH分泌过多与应激相关障碍所伴发的生理和行为异常之间的关系，我们对长期经中枢注射CRH的大鼠进行了一系列实验。这些大鼠体重增加减少、食物摄入量减少、血浆促肾上腺皮质激素（ACTH）和皮质酮水平升高、胸腺萎缩和免疫抑制，但矛盾的是，脾脏巨噬细胞中IL-1β mRNA表达增强。在治疗第7天进行外周内毒素攻击后，注射CRH的大鼠出现异常（即迟钝和/或延迟）的下丘脑-垂体-肾上腺（HPA）轴、发热、行为和海马5-羟色胺能反应。然而，内毒素诱导的血浆IL-1和IL-6生物活性在这些动物中显著增强。数据表明，慢性应激期间出现的中枢CRH水平长期升高会导致中枢神经系统和免疫系统对急性（炎症）挑战的反应出现缺陷。这些观察结果提供了证据，表明慢性CRH分泌过多是应激相关障碍病因中的一个重要因素。
