Impact of previous acute and chronic stress on negative glucocorticoid feedback in laboratory animal: theoretical background and methodological concerns

AI Summary

Chronic stress shows weak evidence for impaired negative glucocorticoid feedback (nGF), mainly for HPA activity under resting conditions.
Evidence that single severe stress exposure enhances feedback under stress conditions is controversial and studies have major limitations.
Key methodological problems include missing plasma ACTH, use of stressors animals previously experienced, and dexamethasone doses acting mainly at the anterior pituitary.

Neurosci Biobehav Rev. 2026 Oct 18:107055. doi: 10.1016/j.neubiorev.2026.107055. Online ahead of print.

ABSTRACT

Chronic stress or acute severe stressors have been extensively used as putative animal models of psychiatric diseases, particularly depression and post-traumatic stress disorder (PTSD), respectively. The hypothalamus-pituitary-adrenal (HPA) axis not only represents a prototypical stress response system, but also mediates or modulates a wide range of the behavioral and physiological consequences of stress exposure. Therefore, particular attention has been paid to the parallelisms between stress-induced alterations of the HPA axis in animal models and the alterations observed in PTSD and depression. The canonical views suggest that PTSD patients are characterized by hypocortisolemia and an enhanced negative glucocorticoid feedback (nGF), whereas major depression patients typically show hypercortisolemia and impaired nGF. Here, we critically review studies on the effects of different stress models on nGF, distinguishing between nGF under resting and stress conditions. The evidence that chronic stress exposure is associated with impaired nGF is weak, except for HPA activity under resting conditions. The evidence that a single exposure to severe stressors leads to enhanced nGF under stress conditions is controversial, and the studies supporting this present important limitations. In general, the major limitations of nGF studies are the lack of plasma ACTH data, the assessment of nGF using exposure to a stressor with which animals have prior experience, and the predominant use of dexamethasone instead of natural glucocorticoids. At the dexamethasone doses typically used, this drug acts mainly at the anterior pituitary rather than at the brain level, making it difficult to relate altered nGF with changes in brain corticosteroid receptors.

PMID:42893748 | DOI:10.1016/j.neubiorev.2026.107055

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