Central and peripheral glucocorticoid receptors are involved in the plasma cortisol response to an acute stressor in rainbow trout

Cortisol, the primary circulating corticosteroid in teleosts, is elevated during stress following activation of the hypothalamus–pituitary–interrenal (HPI) axis. Cortisol exerts genomic effects on target tissues in part by activating glucocorticoid receptors (GR). Despite a well-established negative feedback loop involved in plasma cortisol regulation, the role of GR in the functioning of the HPI axis during stress in fish is still unclear. We used mifepristone (a GR antagonist) to suppress GR signaling in rainbow trout (Oncorhynchus mykiss) and assessed the resultant changes to HPI axis activity. We show for the first time that mifepristone caused a functional knockdown of GR by depleting protein expression 40–75%. The lower GR protein expression corresponded with a compensatory up-regulation of GR mRNA levels across tissues. Mifepristone treatment completely abolished the stressor-induced elevation in plasma cortisol and glucose levels seen in the control fish. A reduction in corticotropin-releasing factor (CRF) mRNA abundance in the hypothalamic preoptic area was also observed, suggesting that GR signaling is involved in maintaining basal CRF levels. We further characterized the effect of mifepristone treatment on the steroidogenic capacity of interrenal tissue in vitro. A marked reduction in cortisol production following adrenocorticotropic hormone stimulation of head kidney pieces was observed from mifepristone treated fish. This coincided with the suppression of steroidogenic acute regulatory protein, but not P450 side chain cleavage mRNA abundances. Overall, our results underscore a critical role for central and peripheral GR signaling in the regulation of plasma cortisol levels during stress in fish.

► Mifepristone downregulated trout GR protein expression in trout.
► Mifepristone blocked the stressor-induced elevation in plasma cortisol levels in trout.
► Mifepristone reduced ACTH-stimulated cortisol production in trout head kidney pieces.
► Mifepristone suppressed brain CRF and head kidney StAR mRNA abundances.
► Overall, central and peripheral GR signaling is involved in the stressor-mediated HPI axis functioning in trout.