Abstract
BackgroundChronic stress or prolonged administration of glucocorticoids suppresses proliferation and/or survival of newborn cells in adult rat dentate gyrus. Earlier we showed that administration of the glucocorticoid receptor antagonist mifepristone during the final 4 days of a 21 days period of corticosterone treatment fully normalized the number of newborn cells. Here we aimed to better understand how mifepristone achieves this effect and questioned whether an even shorter (single day) mifepristone treatment (instead of 4 days) also suffices to normalize neurogenesis.MethodsWe investigated various steps of the neurogenic process, using the immunohistochemical markers BrdU, doublecortin, proliferating cell nuclear antigen as well as glial fibrillary acidic protein, after 17 or 21 days of corticosterone (versus vehicle) treatment.ResultsCorticosterone primarily attenuates the proliferation of cells which subsequently develop into neurons; this is fully reversed by mifepristone. Surprisingly, the corticosteroid effects on neurogenesis can even be fully re-set by a single-day treatment with mifepristone (on day 18), despite the continued corticosterone exposure on subsequent days.ConclusionsOur results emphasize that studies into the therapeutical efficacy of new antidepressants, especially those targeting HPA-activity or the glucocorticoid receptor, should explore the possibility to reduce treatment duration.
Highlights
Exposure to stress leads to activation of hypothalamo-pituitaryadrenal axis (HPA), eventually resulting in enhanced release of glucocorticoid hormones from the adrenal
HPA dysfunction is partly normalized upon treatment and the degree of normalization inversely correlates with relapse probability [10]
BrdU+ cells prevailed in the subgranular zone (SGZ; see Figure 2A for typical example) but were found in the hilus and -in considerably lower numbers- the granule cell layer (GCL)
Summary
Exposure to stress leads to activation of hypothalamo-pituitaryadrenal axis (HPA), eventually resulting in enhanced release of glucocorticoid hormones from the adrenal. These hormones enter the brain and bind to intracellular receptors [1]. Chronic stress and HPA dysfunction are generally considered risk factors for the development of psychiatric disorders, including major depression [3,4,5,6]. Chronic stress or prolonged administration of glucocorticoids suppresses proliferation and/or survival of newborn cells in adult rat dentate gyrus. Earlier we showed that administration of the glucocorticoid receptor antagonist mifepristone during the final 4 days of a 21 days period of corticosterone treatment fully normalized the number of newborn cells. We aimed to better understand how mifepristone achieves this effect and questioned whether an even shorter (single day) mifepristone treatment (instead of 4 days) suffices to normalize neurogenesis
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