Low doses of dexamethasone can produce a hypocorticosteroid state in the brain.
The synthetic glucocorticoid dexamethasone (dex) blocks stress-induced hypothalamic-pituitary-adrenal (HPA) activation primarily at the level of the anterior pituitary because multidrug resistance P-glycoprotein hampers its penetration in the brain. Here, we tested the hypothesis that central components of the HPA axis would escape dex suppression under conditions of potent peripheral glucocorticoid action. We subchronically treated rats with low or high doses of dex. The animals were subjected on the last day of treatment for 30 min to a restraint stressor after which central and peripheral markers of HPA axis activity were measured. Basal and stress-induced corticosterone secretion, body weight gain, adrenal and thymus weight, as well as proopiomelanocortin mRNA in the anterior pituitary were reduced in a dose-dependent manner by dex administered either 5 d sc or 3 wk orally. In the brain, the highest dose dex suppressed CRH mRNA and CRH heteronuclear RNA in the paraventricular nucleus (PVN). However, in the peripherally active low-dose range of dex CRH mRNA and heteronuclear RNA showed resistance to suppression, and CRH mRNA expression in the PVN was in fact enhanced under the long-term treatment condition. In the PVN, c-fos mRNA was suppressed by the highest dose of dex, but this effect showed a degree of resistance after long-term oral treatment. c-fos mRNA responses in the anterior pituitary followed those in PVN and reflect central drive of the HPA axis even if corticosterone responses are strongly reduced. The results support the concept that low doses of dex can create a hypocorticoid state in the brain.
Karssen
A M
AM
Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, The Netherlands.
Meijer
O C
OC
Berry
A
A
Sanjuan Piñol
R
R
de Kloet
E R
ER
D000284:Administration, Oral; D000305:Adrenal Cortex Hormones / Q000172:deficiency*; D000315:Adrenalectomy; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D003345:Corticosterone / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000235:genetics; D003907:Dexamethasone / Q000008:administration & dosage* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007279:Injections, Subcutaneous; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D010903:Pituitary Gland, Anterior / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012332:RNA, Heterogeneous Nuclear / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012149:Restraint, Physical; D013312:Stress, Physiological / Q000209:etiology / Q000378:metabolism
D000305:Adrenal Cortex Hormones; D016760:Proto-Oncogene Proteins c-fos; D012332:RNA, Heterogeneous Nuclear; D012333:RNA, Messenger; D011333:Pro-Opiomelanocortin; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone