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

Pharmacol Rep. 2022 Apr;74(2):340-352. doi: 10.1007/s43440-021-00342-z. Epub 2021 Nov 30.


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.

Keywords: AMPK; BDNF; Ketamine; Metformin; Scopolamine; mTOR.

MeSH terms

  • Animals
  • Antidepressive Agents / metabolism
  • Antidepressive Agents / pharmacology
  • Brain-Derived Neurotrophic Factor / metabolism
  • Diabetes Mellitus, Type 2* / metabolism
  • Humans
  • Ketamine* / pharmacology
  • Male
  • Metformin* / pharmacology
  • Prefrontal Cortex / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Scopolamine / metabolism
  • Scopolamine / pharmacology


  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Ketamine
  • Metformin
  • Scopolamine