Antidepressant-Like Effects of Paroxetine via Regulation of HPA Axis Function and Activation of the cAMP/PKA/CREB/BDNF Pathway in Mice Subjected to CUMS (Chronic Unpredictable Mild Stress)
YANG Liu1*, ZHANG Xinyu2, ZHANG Huiming1
This study aimed to investigate the mechanisms underlying the antidepressant-like effects of paroxetine in a mouse model of CUMS (chronic unpredictable mild stress), focusing on its regulation of HPA (hypothalamic-pituitary-adrenal) axis function and activation of the cAMP/PKA/CREB/BDNF pathway. Mice were randomly divided into five groups (n=12 per group): Control, CUMS, L-PX (administered by gavage with 2.5 mg/kg paroxetine), H-PX (administered by gavage with 10 mg/kg paroxetine), and H-PX+H-89 (administered 10 mg/kg paroxetine by gavage and 5 mg/kg H-89 via intraperitoneal injection). A mouse depression model was established using the CUMS procedure. Depression-like behaviors were assessed using behavioral tests (sucrose preference test, tail suspension test, and forced swim test). HE (hematoxylin-eosin) and Nissl staining were used to detect neuronal damage in the mouse hippocampus. The levels of 5-HT, DA, NE, CRH, ACTH, CORT, and cAMP were measured using commercial assay kits. Dendritic spine density was quantified via Golgi staining. The protein expression levels of PKA, p-CREB/CREB, and BDNF were detected by Western blot. Compared with the Control group, the CUMS group showed significantly decreased sucrose preference rate, the levels of 5-HT, DA, NE, cAMP, dendritic spine density, as well as the protein expression levels of PKA, p-CREB/CREB, and BDNF (P<0.05), while immobility time in the tail suspension and forced swim tests, and the contents of CRH, ACTH, and CORT were significantly increased (P<0.05). Compared with the CUMS group, both the L-PX and H-PX groups exhibited significantly increased sucrose preference rate, the levels of 5-HT, DA, NE, cAMP, dendritic spine density, as well as the protein expression levels of PKA, p-CREB/CREB, and BDNF (P<0.05), along with significantly decreased immobility time in the tail suspension and forced swim tests, and the contents of CRH, ACTH, and CORT (P<0.05). Compared with the L-PX group, the H-PX group showed significantly greater increases in the sucrose preference rate, the levels of 5-HT, DA, NE, cAMP, dendritic spine density, as well as the protein expression levels of PKA, p-CREB/CREB, and BDNF (P<0.05), and significantly greater decreases in immobility time and the contents of CRH, ACTH, and CORT (P<0.05). Compared with the H-PX group, the H-PX+H-89 group showed significantly reduced sucrose preference rate, the levels of 5-HT, DA, NE, cAMP, dendritic spine density, as well as the protein expression levels of PKA, p-CREB/CREB, and BDNF (P<0.05), and significantly increased immobility time and the contents of CRH, ACTH, and CORT (P<0.05). Paroxetine exerts antidepressant-like effects, potentially by regulating HPA axis function and activating the cAMP/PKA/CREB/BDNF signaling pathway.
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