title: Hypothalamic-pituitary-adrenocortical axis changes in a transgenic mouse with impaired glucocorticoid receptor function.
abstract: Recently, a transgenic mouse with impaired glucocorticoid receptor (GR) function was created to serve as an animal model for the study of neuroendocrine changes occurring in stress-related disorders, such as major depression. Here, we investigated the hypothalamic-pituitary-adrenocortical (HPA) axis changes in these transgenic mice. There were no significant differences between basal early morning plasma ACTH and corticosterone levels in normal and transgenic mice. When animals were exposed to a mild stressor, an enhanced response in plasma ACTH was observed in the transgenic mice, whereas plasma corticosterone responses were not different. In view of these differences in plasma ACTH and corticosterone responses, we directed our studies toward the regulation of ACTH secretion on the hypothalamic-hypophyseal level in vitro. Therefore, an in vitro model, the pituitary-hypothalamic complex (PHc) was developed and its ACTH release profile was compared with that of the pituitary (PI) alone. The basal ACTH release by PHc and PI from normal and transgenic mice was similar. Regardless of the strain under study, the basal ACTH release by PI was significantly lower than the release by PHc. Stimulation of tissues with either high K+ (56 mM) or CRH (10 or 20 nM) produced an enhanced ACTH release from both PHc and PI, whereas the response in PI was larger than that in PHC. Moreover, the responses to these stimuli were markedly enhanced in tissues from transgenic mice. In tissues of normal mice, corticosterone inhibited both basal and CRH-stimulated ACTH release more potently in PHc than in PI. Furthermore, the feedback capacity of corticosterone to restrain both basal and CRH-stimulated ACTH release was highly impaired in tissues of transgenic mice, whereas the feedback in PHc appeared to be more affected than that in the PI of these animals. In conclusion, the in vitro data on PHc and PI revealed intrahypothalamic mechanisms operating 1) to fine-tune stimulus-evoked ACTH responses; and 2) to facilitate the negative feedback action of glucocorticoids. Moreover, in the transgenic tissues, the impaired GR function was found to cause augmented stimulus-evoked ACTH responses and an impaired glucocorticoid feedback efficacy which appeared to be mainly defective at the hypothalamic level. Thus, in the transgenic mice with life-long central GR dysfunction we found impaired negative feedback combined with "normal" (i.e. noncompensated) in vivo plasma corticosterone responses. This is a condition with potentially grave pathophysiological consequences and, therefore, this transgenic animal may be regarded as a valuable model for the study of functional glucocorticoid insufficiency at the central nervous system level.
authors.affiliation: Max Planck Institute of Psychiatry, Clinical Institute, Department of Neuroendocrinology, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Karanth
authors.forename: A C
authors.initials: AC
authors.lastname: Linthorst
authors.forename: G K
authors.initials: GK
authors.lastname: Stalla
authors.forename: N
authors.initials: N
authors.lastname: Barden
authors.forename: F
authors.initials: F
authors.lastname: Holsboer
authors.forename: J M
authors.initials: JM
authors.lastname: Reul
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000032:analysis / Q000378:metabolism / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D003345:Corticosterone / Q000097:blood / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology / Q000502:physiology; D005246:Feedback / Q000502:physiology; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000737:chemistry / Q000502:physiology; D010913:Pituitary-Adrenal System / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000502:physiology*
chemical_list: D011965:Receptors, Glucocorticoid; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone