Received 4 August 2009; received in revised form 16 January 2010; accepted 19 January 2010.
Glucocorticoid dyshomeostasis is observed in a proportion of depressed individuals. As a result, glucocorticoid receptor (GR) antagonists are currently being tested as potential anti-depressants. The current study was designed to test the efficacy of mifepristone, a GR antagonist, in mitigating behavioral, neuroendocrine and central nervous system (CNS) responses to an acute stressor. Adult male rats were treated for 5 days with mifepristone (10mg/kg) and then exposed to the forced swim test (FST). Treatment with mifepristone decreased immobility and increased swimming (but not climbing) behavior in the FST, consistent with anti-depressant action. In addition, mifepristone dampened the ACTH response to FST exposure. In the CNS, mifepristone increased c-Fos expression in all subdivisions of the medial prefrontal cortex (mPFC) and decreased neuronal activity in some subdivisions of the hippocampus including the CA2, CA3, and hilus region of the dentate gyrus in animals exposed to FST. In contrast, mifepristone increased neuronal activity in the ventral subiculum (output region of the hippocampus) and decreased c-Fos expression in the central amygdala (CeA) in animals exposed to FST. These data suggest that anti-depressant efficacy and perhaps HPA dampening properties of RU486 are related to alterations in key limbic circuits mediating CNS stress responses, resulting in enhanced stress inhibition (via the mPFC and ventral subiculum) as well as decreased stress excitation (central amygdala). Overall the data suggest that drugs targeting the glucocorticoid receptor may ameliorate stress dysfunction associated with depressive illness.
a Department of Psychiatry, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, United States
b Neuroscience Program, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, United States
1 Address: University of Cincinnati, Genome Research Institute, 2170 E. Galbraith Rd. Bldg E. Room 216, Cincinnati, OH 45237-0506, United States. Tel.: +1 513 558 3025; fax: +1 513 558 9104.
2 Address: University of Cincinnati, Genome Research Institute, 2170 E. Galbraith Rd. Bldg A. Room 145, Cincinnati, OH 45237-0506, United States. Tel.: +1 513 558 4813; fax: +1 513 558 9104.
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