Glucocorticoids are involved in the long-term effects of a single immobilization stress on the hypothalamic-pituitary-adrenal axis.

We have previously observed that a single exposure to a severe stressor such as immobilization (IMO) induces long-lasting desensitization of the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to the same stressor that enhances rather than dissipates with time (days). As this desensitization of the HPA axis was not observed in response to a novel stressor, we suggested this might be a particular type of learning linked to severe stressful situations. Taking into account the evidence that glucocorticoids are involved in learning and memory, the present study addresses the role of glucocorticoids in the induction of long-term effects of an acute exposure to IMO. Three different experimental approaches were used: (i) blockade of stress-induced corticosterone release by using adrenalectomized rats supplemented with a low dose of corticosterone in the drinking saline (ADX+B); (ii) blockade of corticosterone synthesis during the first exposure to IMO with the 11-beta-hydroxylase inhibitor metyrapone (200 mg/kg); and (iii) administration of the glucocorticoid receptor antagonist RU486 (100 mg/kg). Previous exposure to IMO resulted in an enhanced post-stress recovery of the HPA response to the same stressor 1 week later. These long-term effects of IMO were blocked in ADX+B rats, were partially reduced in metyrapone-treated rats and only modestly affected by RU486 administration. These data suggest that glucocorticoids play a partial role in the induction of long-term effects of IMO on the HPA responsiveness to the same stressor, although the weak effect of RU486 suggests that non-classical corticosteroid receptors may be involved. The role of glucocorticoids in the expression of the phenomenon is suggested by the full blockade of the phenomenon in ADX+B rats, but further studies are needed. As blockade of corticosterone synthesis only partially blunted the long-term effect of IMO, it appears that full induction of the long-term effects of acute exposure to IMO on the HPA axis is only achieved by the concerted action of several endocrine (or neurochemical) factors.