A single dose of metyrapone caused long-term dysregulation of the hypothalamic-pituitary-adrenal axis in the rat.
There is evidence that metyrapone (MET), apart from its inhibition of 11-beta steroid hydroxylation, may exert some stress-like effects in the brain, including the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the induction of c-fos. Since a single exposure to some stressors has been found to exert long-term effects on the HPA axis, we hypothesized that a single dose of MET (200 mg/kg, s.c.) could exert even stronger effects, due to the combination of its stressful properties with the lack of constrain of the HPA axis by glucocorticoids. Whereas the inhibitory effect of the drug on corticosterone secretion lasted less than 24 h, its stimulatory effect on the HPA axis could be seen for at least 2 days after the injection. Surprisingly, on day 8, an exacerbated HPA response to immobilization stress was observed in MET rats, despite complete normalization of resting levels of HPA hormones. At this time it was also observed, under basal conditions, increased levels of mRNA for CRH and arginin-vasopressin in the parvocellular region of the paraventricular nucleus of the hypothalamus (pPVN), along with reduced mRNA for glucocorticoid receptors in dentate gyrus and hippocampus CA1, but not in pPVN or medial prefrontal cortex. These data suggest that a single MET administration can exert a marked and long-lasting dysregulation of both resting and stress-induced activity of the HPA axis. Thus, attention should be paid to these properties when using the drug to study the functional role of glucocorticoids.
Rotllant
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D
Institut Neurociències and Unitat de Fisiologia Animal, Facultat de Ciències, Departament de Biologia Cellular, de Fisiologia i d'Immunologia, Universitat Autònoma de Barcelona, 08290 Cerdanyola del Vallès, Barcelona, Spain.
Armario
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A
D000818:Animals; D001127:Arginine Vasopressin / Q000235:genetics; D003345:Corticosterone / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000235:genetics; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005938:Glucocorticoids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008797:Metyrapone / Q000494:pharmacology*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000503:physiopathology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000235:genetics; D012149:Restraint, Physical; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism / Q000503:physiopathology*; D013995:Time
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D001127:Arginine Vasopressin; D003346:Corticotropin-Releasing Hormone; D013252:Steroid 11-beta-Hydroxylase; D003345:Corticosterone; D008797:Metyrapone