Anti-stress effects of combined glucocorticoid and mineralocorticoid
receptor blockade in the paraventricular nucleus of the hypothalamus
Abstract
Background and Purpose: Mineralocorticoid receptors (MRs),
glucocorticoid receptors (GRs) and corticotropin-releasing factor (CRF)
in the paraventricular nucleus of the hypothalamus (PVN) are implicated
in the stress response. The present study investigated the role of GRs
and MRs in the PVN in regulating depressive and anxiety-like behaviors.
Experimental Approach: To model chronic stress, rats were exposed to
chronic corticosterone treatment via drinking water for 21 days, and the
GR antagonist RU486 and MR antagonist spironolactone, alone and
combined, were directly injected in the PVN daily for 7 days before the
behavioral tests. Depressive- and anxiety-like behaviors were evaluated
in forced swim test, sucrose preference test, novelty-suppressed feeding
test and social interaction test. The expression of GRs, MRs and CRF
were detected by Western-Blot. Key Results: The rats exposed to
corticosterone exhibited depressive- and anxiety-like behaviors. The
expression of GRs and MRs decreased, and CRF levels increased in the
PVN. The intra-PVN administration of RU486 increased the levels of GRs
and CRF without influencing depressive- or anxiety-like behaviors. The
spironolactone-treated group exhibited an increase in MRs without
influencing GRs and CRF in the PVN, and improved anxiety-like behaviors.
Interestingly, the intra-PVN administration of RU486 and spironolactone
combined restored the expression of GRs, MRs, and CRF and improved
depressive- and anxiety-like behaviors. Conclusion and Implications:
These results suggest that the simultaneous restoration of GRs, MRs, and
CRF in the PVN in this rat model of stress might play an important role
in the treatment of depression and anxiety.