Norepinephrine and glucocorticoids modulate chronic unpredictable stress-induced increase in the type 2 CRF and glucocorticoid receptors in brain structures related to the HPA axis activation.

The stress response is multifactorial and enrolls circuitries to build a coordinated reaction, leading to behavioral, endocrine, and autonomic changes. These changes are mainly related to the hypothalamus-pituitary-adrenal (HPA) axis activation and the organisms integrity. However, when self-regulation is ineffective, stress becomes harmful and predisposes the organism to pathologies. The chronic unpredictable stress (CUS) is a widely used experimental model since it induces physiological and behavioral changes and better mimics the stressors variability encountered in daily life. Corticotropin-releasing factor (CRF) and glucocorticoid (GCs) are deeply implicated in the CUS-induced physiological and behavioral changes. Nonetheless, the CUS modulation of CRF receptors and GR and the norepinephrine role in extra-hypothalamic brain areas were not well explored. Here, we show that 14-days of CUS induced a long-lasting HPA axis hyperactivity evidenced by plasmatic corticosterone increase and adrenal gland hypertrophy, which was dependent on both GCs and NE release induced by each stress session. CUS also increased CRF2 mRNA expression and GR protein levels in fundamental brain structures related to HPA regulation and behavior, such as the lateral septal nucleus intermedia part (LSI), ventromedial hypothalamic nucleus (VMH), and central nucleus of the amygdala (CeA). We also showed that NE participates in the CUS-induced increase in CRF2 and GR levels in the LSI, reinforcing the locus coeruleus (LC) involvement in the HPA axis modulation. Despite the CUS-induced molecular changes in essential areas related to anxiety-like behavior, this phenotype was not observed in CUS animals 24 h after the last stress session. HighlightsO_LICUS persistently increased plasma CORT levels via GCs and NE signaling. C_LIO_LICUS persistently increased CRF2 mRNA in extra-hypothalamic brain areas. C_LIO_LICUS increased GR protein levels in brain regions related to GCs release control. C_LIO_LINE and GCs participate in the CUS-induced increase in CRF2 and GR levels. C_LIO_LILSI could be the brain nucleus that dictates the fine-tuned response of CUS. C_LIO_LICUS animals did not present anxiety-like behavior. C_LI