Venlafaxine exerts antidepressant effects possibly by activating MAPK-ERK1/2 and P13K-AKT pathways in the hippocampus

•Venlafaxine causes differential expression of 27 mouse hippocampal metabolites.•These metabolites are highly related to MAPK-ERK1/2 and P13K-AKT signaling pathways.•Six key proteins were verified by western blotting.•This study sheds light on the possible biological mechanisms of venlafaxine.

Serotonin noradrenaline reuptake inhibitors are effective antidepressant drugs, which include venlafaxine and duloxetine. Venlafaxine is commonly used in a clinical context, but the molecular biological mechanisms behind its effects have not been fully determined. Here, we explored the potential biological effects of venlafaxine on mouse hippocampus. Mice were randomly divided into two groups and injected daily with 0.9% NaCl solution or venlafaxine. A GC-MS-based metabolomic approach was used to identify possible metabolic differences between these groups, and the key proteins involved in the relevant pathways were validated by western blotting. In our experiments, 27 hippocampal metabolites that distinguished the venlafaxine group from the control group were identified. These differential metabolites were subjected to Ingenuity Pathway Analysis, which revealed that they were strongly related to two metabolic pathways (MAPK-ERK1/2 and P13K-AKT signaling pathways). Six key proteins, BDNF, p-c-Raf, p-MAPK, p-MEK, p-AKT, and CREB, were verified by western blotting and the results were consistent with the differential metabolites identified by GC-MS. This study sheds light on the biological mechanisms underlying the effects of venlafaxine.