Abstract:
: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.
journal_name
Proc Natl Acad Sci U S Aauthors
Boyle MP,Brewer JA,Funatsu M,Wozniak DF,Tsien JZ,Izumi Y,Muglia LJdoi
10.1073/pnas.0406458102keywords:
subject
Has Abstractpub_date
2005-01-11 00:00:00pages
473-8issue
2eissn
0027-8424issn
1091-6490pii
0406458102journal_volume
102pub_type
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