Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites

Ailin Luo,Chun Yang,Jianjun Yang,Kenji Hashimoto

doi:10.1038/s41398-019-0624-1

Abstract

Although the robust antidepressant effects of the N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine in patients with treatment-resistant depression are beyond doubt, the precise molecular and cellular mechanisms underlying its antidepressant effects remain unknown. NMDAR inhibition and the subsequent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation are suggested to play a role in the antidepressant effects of ketamine. Although (R)-ketamine is a less potent NMDAR antagonist than (S)-ketamine, (R)-ketamine has shown more marked and longer-lasting antidepressant-like effects than (S)-ketamine in several animal models of depression. Furthermore, non-ketamine NMDAR antagonists do not exhibit robust ketamine-like antidepressant effects in patients with depression. These findings suggest that mechanisms other than NMDAR inhibition play a key role in the antidepressant effects of ketamine. Duman’s group demonstrated that the activation of mammalian target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex is reportedly involved in the antidepressant effects of ketamine. However, we reported that mTORC1 serves a role in the antidepressant effects of (S)-ketamine, but not of (R)-ketamine, and that extracellular signal-regulated kinase possibly underlie the antidepressant effects of (R)-ketamine. Several lines of evidence have demonstrated that brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), are crucial in the antidepressant effects of ketamine and its two enantiomers, (R)-ketamine and (S)-ketamine, in rodents. In addition, (2R,6R)-hydroxynormetamine [a metabolite of (R)-ketamine] and (S)-norketamine [a metabolite of (S)-ketamine] have been shown to exhibit antidepressant-like effects on rodents through the BDNF–TrkB cascade. In this review, we discuss recent findings on the molecular and cellular mechanisms underlying the antidepressant effects of enantiomers of ketamine and its metabolites. It may be time to reconsider the hypothesis of NMDAR inhibition and the subsequent AMPAR activation in the antidepressant effects of ketamine.

Highlights

Antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and selective noradrenaline reuptake inhibitors (SNRIs), are widely prescribed for the treatment of depression in patients with major depressive disorder (MDD)
In 2010, Li et al demonstrated that rapamycin, an mechanistic target of rapamycin (mTOR) inhibitor, inhibited the antidepressant-like effects of ketamine in rodents, which acted by increasing the number of synaptic proteins and synaptic spine density by rapidly activating the mammalian target of rapamycin complex 1 (mTORC1)-signaling pathway in the medial prefrontal cortex (PFC)[56]
We reported that, similar to (S)ketamine, brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB) and mTOR signaling might play a role in the antidepressant-like effects of (S)-norketamine in rodents[125]

Summary

Introduction

Antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and selective noradrenaline reuptake inhibitors (SNRIs), are widely prescribed for the treatment of depression in patients with major depressive disorder (MDD). It is known that dissociative symptoms following ketamine infusion are not associated with its clinical benefits[24], suggesting that NMDAR inhibition may not serve a key role in the antidepressant effects of ketamine.

Results

Conclusion