Evaluation of the HPA axis' response to pharmacological challenges in experimental and clinical early-life stress-associated depression

Early life stress (ELS) is associated with a higher risk of psychopathologies in adulthood, such as depression, which may be related to persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to evaluate the effects of ELS on the functioning of the HPA axis in clinical and experimental situations. Clinically, patients with current depressive episodes, with and without ELS, and healthy controls, composed the sample. Subjects took a capsule containing placebo, fludrocortisone, prednisolone, dexamethasone or spironolactone followed by an assessment of plasma cortisol the morning after. Experimentally, male Wistar rats were submitted to ELS protocol based on variable, unpredictable stressors from postnatal day (P) 1 to P21. On P65 animals were behaviorally evaluated through the forced swimming test (FST). At P68, pharmacological challenges started, using mifepristone, dexamethasone, spironolactone or fludrocortisone, and corticosterone levels were determined 3 hours after injections. Cortisol response of the patients did not differ significantly from healthy subjects, regardless of their ELS history, and it was lower after fludrocortisone, prednisolone and dexamethasone compared to placebo, indicating the suppression of plasma cortisol by all these treatments. Animals exposed to ELS presented altered phenotype as indicated by an increased immobility time in the FST when compared to control, but no significant long-lasting effects of ELS were observed on the HPA axis response. Limitations on the way the volunteers were sampled may have contributed to the lack of ELS effects on the HPA axis, pointing out the need for further research to understand these complex phenomenaSignificance statement Early life stress (ELS) is associated with a higher risk of psychopathologies in adulthood, including depression, which seems related to persistent changes in the hypothalamic-pituitary-adrenal axis. We evaluated the effects of ELS on the functioning of hypothalamic-pituitary-adrenal axis combining clinical and experimental approaches, challenging GR and MR receptors with agonists and antagonists. Cortisol response of depressive patients did not differ from healthy subjects, regardless of their ELS history. Animals submitted to ELS presented altered behavior, as increased immobility time in the forced-swimming test, but no effects were observed in response to GR and MR challenges. It provides insights into the complexity of HPA axis-related mechanisms involved in the long-lasting consequences of ELS in both experimental animals and humans.