Decreased efficacy of the ketamine and scopolamine-induced sustained antidepressant-like effects in rats receiving metformin.

BACKGROUND: Metformin is the most widely used drug for treating type 2 diabetes mellitus (DM), which frequently co-occurs with depressive disorders. Thus, patients with depression are likely to receive metformin. Metformin activates AMP-activated kinase (AMPK), which inhibits mechanistic target of rapamycin complex 1 (mTORC1) signaling. mTORC1 activation is essential for the antidepressant effects of ketamine and scopolamine. Thus, we hypothesized that metformin may attenuate ketamine- or scopolamine-induced antidepressant efficacies by blocking their mTORC1 activation. METHODS: We assessed the acute and sustained antidepressant-like actions of ketamine and scopolamine in male Sprague-Dawley rats subjected to the forced swim test with or without metformin pretreatment. The expressions of AMPK, mTORC1, and brain-derived neurotrophic factor (BDNF) in their prefrontal cortex were assessed. RESULTS: Metformin (50 mg/kg) attenuated the sustained, but not acute, antidepressant-like effects of ketamine (10 mg/kg) and scopolamine (25 µg/kg). Although metformin reduced mTORC1 downstream activated P70S6K, it did not significantly alter mTORser2448 activation and even increased BDNF expression. Notably, ketamine, scopolamine, and metformin all exerted significant antidepressant-like actions, as evidenced by increased AMPK phosphorylation and BDNF expression. CONCLUSIONS: Metformin-induced attenuation of sustained antidepressant-like effects are not directly dependent on AMPK-deactivated mTORC1. Our results indicate the complexity of interactions between AMPK, BDNF, and mTORC1. Further research, including mechanistic studies, is warranted to comprehensively evaluate the application of metformin in patients receiving mTORC1-based antidepressants.

Roles of Akt and ERK in mTOR-Dependent Antidepressant Effects of Vanillic Acid.

Vanillic acid, an oxidized form of vanilla, is a flavoring agent with a creamy odor. Several studies have reported the neuroprotective effects of vanillic acid, which are predominantly associated with anti-inflammatory and antioxidative properties. The anti-inflammatory and antioxidative properties may result from Akt or ERK signaling activation. The activation of the mammalian target of rapamycin (mTOR), a key downstream target of Akt and ERK signaling, is a crucial therapeutic target for treating depression. However, the antidepressant effects of vanillic acid remain unknown. The present study applied the forced swim test (FST) to investigate the antidepressant effects of vanillic acid and its association with Akt, ERK, and mTOR signaling and upstream α-amino-3-hydroxy-5-methyl-4-isoxazolepropionaic acid receptor (AMPAR) in the prefrontal cortex (PFC) of mice. Vanillic acid demonstrated antidepressant effects by significantly reducing behavioral despair in the FST. None of the treatments changed locomotor activity. Additionally, vanillic acid increased AMPAR throughput, Akt, and mTOR signaling but not ERK signaling in the PFC. NBQX (an AMPAR blocker), MK 2206 (an Akt blocker), and rapamycin (an mTOR blocker) used in pretreatment attenuated the antidepressant effects of vanillic acid, but SL327 (an ERK inhibitor) did not. The immunochemical results indicated that the antidepressant effects of vanillic acid depend on the AMPAR-Akt-mTOR signaling transduction pathway. Our findings reveal an Akt-dependent, but ERK-independent, the mechanism underlying the antidepressant effects of vanillic acid, which may be beneficial for some patients with depression.