Interleukin-1-induced long-lasting changes in hypothalamic corticotropin-releasing hormone (CRH)—neurons and hyperresponsiveness of the hypothalamus-pituitary-adrenal axis

E D Schmidt, A W Janszen, F G Wouterlood, F J Tilders
Journal of Neuroscience 1995, 15 (11): 7417-26
Hypothalamic CRH neurons that control ACTH secretion from the pituitary gland have secretory terminals in the external zone of the median eminence (ZEME). These neurons can coproduce vasopressin (AVP), a neuropeptide that potentiates the ACTH releasing effects of CRH. Recently, we found increased AVP production in adult rats weeks after single exposure to a stressor, which may play a role in event-induced stress disorders. Here, we describe the long-term changes in the HPA axis of adult male rats following a single exposure to a stressor, the cytokine interleukin-1 beta (IL-1 beta). The effects on storage and release of AVP and CRH were established by quantitative immunocytochemistry, the effects on ACTH and corticosterone responses by radioimmunoassay. Single administration of IL-1 beta (5 micrograms/kg i.p.) induces a delayed (at least 4 d) and a long-lasting (at least 3 weeks) increase of vasopressin (AVP) stores in CRH terminals of the ZEME without affecting the CRH stores, and a marked increase of the fraction of CRH terminals that costore AVP. Eleven days after IL-1 beta administration, a second IL-1 beta challenge causes a marked depletion of the AVP stores in the ZEME within 2 hr, which is not seen in rats treated with vehicle 11 d earlier. This is accompanied by twofold higher ACTH and corticosterone responses, as compared to those in vehicle pretreated rats. IL-1 beta-pretreated rats also showed increased ACTH and corticosterone responses to electric footshocks. We conclude that transient activation of the HPA axis by a single administration of IL-1 beta induces a delayed and long-lasting hyperproduction, hyperstorage, and hypersecretion of AVP from hypothalamic CRH neurons that results in hyperresponsiveness of the HPA axis to subsequent stimuli.

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