Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior

Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):473-8. doi: 10.1073/pnas.0406458102. Epub 2004 Dec 27.


Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of major depressive disorder. A number of studies have shown that this dysregulation is correlated with impaired forebrain glucocorticoid receptor (GR) function. To determine whether a primary, acquired deficit in forebrain GR signaling is an etiologic factor in the pathogenesis of depression, we generated a line of mice with time-dependent, forebrain-specific disruption of GR (FBGRKO). These mice develop a number of both physiological and behavioral abnormalities that mimic major depressive disorder in humans, including hyperactivity of the HPA axis, impaired negative feedback regulation of the HPA axis and, increased depression-like behavior. Importantly, a number of these abnormalities are normalized by chronic treatment with the tricyclic antidepressant, imipramine. Our findings suggest that imipramine's proposed activities on forebrain GR function are not essential for its antidepressant effects, and that alteration in GR expression may play a causative role in disease onset of major depressive disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corticotropin-Releasing Hormone / genetics
  • Depression / drug therapy
  • Depression / etiology*
  • Hippocampus / physiology
  • Hypothalamo-Hypophyseal System / physiology*
  • Imipramine / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Knockout
  • Pituitary-Adrenal System / physiology*
  • Prosencephalon / physiology*
  • RNA, Messenger / analysis
  • Receptors, Glucocorticoid / deficiency
  • Receptors, Glucocorticoid / physiology*
  • Time Factors


  • RNA, Messenger
  • Receptors, Glucocorticoid
  • Corticotropin-Releasing Hormone
  • Imipramine