Combined Administration of (R)-Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Induces Rapid and Sustained Effects in the CUMS Model of Depression via a TrkB/BDNF-Dependent Mechanism.

Anna Rafało-Ulińska,Piotr Brański,Agnieszka Pałucha-Poniewiera

doi:10.3390/ph15020125

Abstract

Ketamine is an effective, rapid-acting antidepressant drug (RAAD), but it induces side effects. To overcome these challenges, attempts have been made to use safer enantiomer ((R)-ketamine) or mGlu2/3 receptor antagonists, which induce ketamine-like effects and enhance its action. Here, we propose combining these two strategies to investigate the antidepressant-like effects of low doses of two ketamine enantiomers in combination with a low dose of the mGlu2/3 receptor antagonist LY341495. Rapid and sustained antidepressant-like effects were assessed in C57BL/6J mice using the tail suspension test (TST) and the chronic unpredictable mild stress (CUMS) model of depression in stress-naïve mice. ELISA was used to measure BDNF levels. In the TST, low doses of both (S)-ketamine and (R)-ketamine were potentiated by a subeffective dose of LY341495. However, in the CUMS model, only (R)-ketamine was able to induce long-lasting anti-apathetic and anti-anhedonic effects when coadministered with low-dose LY341495. The mechanism of this drug combination was dependent on BDNF and AMPA receptor activity. ELISA results suggest that the hippocampus might be the site of this action. MGlu2/3 receptor antagonists, in combination with (R)-ketamine, may serve as potential RAADs, with a high efficiency and low risk of side effects.

Highlights

Ketamine, a new rapid-acting antidepressant drug (RAAD) that induces fast and long-lasting therapeutic action [1] and has been introduced for treatment of resistant major depressive disorder [2], produces serious side effects that can be dangerous, especially in psychiatric patients [3,4]
We found that LY341495 potentiated subeffective doses of ketamine in screening tests that assess the antidepressant effects of drugs in rats both 40 min and 24 h after administration [13,14] and produced a rapid antidepressant-like effect in a depression model based on chronic unpredictable mild stress in mice when coadministered with a subeffective dose of ketamine [15]
The results of the present study indicate that the antidepressant-like effects of (R)ketamine, but not (S)-ketamine, in C57BL/6J mice may be potentiated by the mGlu2/3 receptor antagonist LY341495 in the chronic unpredictable mild stress (CUMS) model of depression

Summary

Introduction

A new rapid-acting antidepressant drug (RAAD) that induces fast and long-lasting therapeutic action [1] and has been introduced for treatment of resistant major depressive disorder [2], produces serious side effects that can be dangerous, especially in psychiatric patients (e.g., psychostimulant effects, dissociation, short-term memory impairments and abuse potential) [3,4]. Several studies show that the use of (R)-ketamine instead of (S)-ketamine, which is currently an approved psychiatric drug [2], might have beneficial therapeutic effects while reducing side effects, especially those related to psychostimulatory action [5,6,7]. Animal studies have shown that mGlu receptor ligands, especially mGlu2/3 receptor antagonists, may meet these requirements. These compounds induce rapid antidepressant-like effects in animal models of depression and share many mechanisms of antidepressant activity with ketamine, including involvement of the BDNF and mTOR pathways and dependence on AMPA receptor activation and serotonergic system activity [8,9,10,11]. An important role of the mGlu receptor in the mechanism of the antidepressant action of ketamine in mice was found by Zanos et al [12], who showed that the antidepressant-like effects of ketamine and its metabolite, (2R,6R)-HNK, were absent in Grm−/− mice and were blocked by the mGlu2/3 receptor agonist LY379268

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Conclusion