Decreased in vitro sensitivity to dexamethasone in corticotropes from middle-age rats S. Revskoy*, E. Redei The Asher Center, Department of Psychiatry and Behavioral Sciences, Northwestern University Medical School, 303 E. Chicago Ave., Chicago IL, 60611, USA Received 13 December 1999; received in revised form 10 January 1999; accepted 11 January 1999 Abstract A disregulation of the hypothalamic-pituitary-adrenal (HPA) axis due to a decline of negative feedback regulation is a consistent feature of the aging process. Hippocampus has been proposed to be a primary site responsible for this alteration in the HPA axis in aging in rat. In this study an alternative hypothesis that the decreased sensitivity of the HPA axis to glucocorticoids in aging occurs directly in pituitary corticotropes has been tested. The sensitivity of corticotropes isolated from 2- and 13-month old male Sprague–Dawley rats to dexamethasone (DEX) in vitro was examined using a modification of the combined DEX/CRH challenge test that was originally designed for investigation of relative glucocorticoid resistance in vivo. No significant difference in basal ACTH production by corticotropes from the two age groups was detected. Corticotropes from middle-aged rats showed a diminished response of ACTH to CRH stimulation. DEX treatment did not cause a significant inhibition of either basal or CRH-stimulated ACTH release in corticotropes from middle-aged rats. These findings demonstrate an age-related decrease in the sensitivity of corticotropes to glucocorticoids in vitro suggesting that there is a direct, pituitary-mediated dys- regulation of the HPA axis in rat starting as early as middle age. © 2000 Elsevier Science Inc. All rights reserved. Keywords: Anterior pituitary; Dexamethasone; ACTH; CRH; Aging; Sprague–Dawley rats; In vitro 1. Introduction Altered regulation of the hypothalamic-pituitary-adrenal (HPA) axis is typical in aged vertebrates ranging from fish to humans (Wexler, 1976). One of these alterations, a decline in negative feedback regulation has been implicated in the acceleration of various age- related diseases and diminished cognitive function with age (Dilman et al. 1986, Lupien * Corresponding author. Tel.: +1-312-908-1771; fax: +1-312-503-0466. E-mail address: s-revskoy@nwu.edu (S. Revskoy). Experimental Gerontology 35 (2000) 237–242 0531-5565/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved. PII: S0531-5565(00)00078-4