Treatment with Shuyu capsule increases 5-HT1AR level and activation of cAMP-PKA-CREB pathway in hippocampal neurons treated with serum from a rat model of depression

Depressive disorder (DD) is one of the typical affective disorders with a high morbidity, high suicide rate and high recurrence rate. Dysfunction of the 5-hydroxytryptamine 1A receptor (5-HT1AR) in the brain may serve an important role in the pathogenesis of DD. Currently, selective serotonin reuptake inhibitors are the first line antidepressants with 60–70% efficacy and severe adverse effects. Previous studies have demonstrated that Chinese herbal medicines, including the Shuyu capsule (SYC), are effective antidepressants with few side effects. However, the mechanism remains unclear. In the present study, the effects of the SYC on the 5-HT1AR level and the activation of adenylyl cyclase-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element-binding (CREB) signaling pathway that 5-HT1AR mediates in the cells of hippocampal neurons were investigated in vitro. The SYC demonstrated an antidepressant effect similar to that of fluoxetine in a rat depression model. Treatment of hippocampal neurons with the serum of depressive rats resulted in a decrease in the 5-HT1AR protein level and the activation of the cAMP-PKA-CREB signaling pathway in hippocampal neurons. Exposure to the serum of rats that received chronic mild stress plus SYC treatment led to no alterations in the 5-HT1AR level or the activation of the cAMP-PKA-CREB signaling pathway compared with those of cells exposed to normal rat serum. This effect is similar to the effects of 5-HT1AR antagonist WAY-100635. In addition, the 5-HT1A agonist 8-hydroxy-(dipropylamino) tetralin did not antagonize the effects of the SYC. Furthermore, the SYC exhibited an increased effect compared with fluoxetine on 5-HT1AR levels and CREB activation. The present study suggested that the SYC functions by increasing 5-HT1AR protein levels and the activation of the 5-HT1AR-mediated cAMP-PKA-CREB signaling pathway in hippocampal neurons.