Merazin Hydrate Produces Rapid Antidepressant Effects Depending on Activating mTOR Signaling by Upregulating Downstream Synaptic Proteins in the Hippocampus

Major depressive disorder has become an increasingly serious disease in the world. However, convenient antidepressants have low efficacy and slow onset defects, which is dangerous for suicidal tendency patients. Nowadays, rapid antidepressant research has become the focus. Merazin hydrate (MH), a component of the natural herb Fructus Aurantii, has been shown to produce rapid antidepressant-like effects in animal models. However, the mechanism of its rapid antidepressant-like effects was still elusive like that of ketamine. The study aimed to reveal the relationship between the rapid antidepressant-like effects of MH and mTOR signaling, which is closely related to rapid antidepressants. The results showed that a single administration of MH was capable of reversing the behavioral defects at 2 h in two classic depressive models including learned helplessness (LH) and chronic mild stress (CMS). Moreover, the phosphorylated expression of mTOR, reduced by LH or CMS, was upregulated after a single administration of MH, and the expressions of BDNF and synaptic proteins in the hippocampus were also reversed 2 h later, similar to ketamine. Moreover, LH increased the expressions of eNOS, IL-10, and TNF-α in serum, which were all reversed by a single dose of MH at 2 h, similar to ketamine. Furthermore, we used rapamycin, an antagonist of mTOR, to confirm whether the rapid antidepressant-like effects of MH depend on mTOR or not. We found that inhibiting the activation of mTOR blocked the rapid antidepressant-like effects of MH, which also inhibited the upregulation of expressions of BDNF and PSD95. To sum up, the rapid antidepressant effect of MH depended on the activation of mTOR to regulate downstream BNDF and synaptic protein expressions.