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Rationale <p><i>(S)</i>-Ketamine, which is used to treat depression, has significant undesirable effects and has potential for abuse. A safe alternative to <i>(S)</i>-ketamine is <i>(R)</i>-ketamine. The relationship between <i>(R)</i>-ketamine and the mGlu<sub>5</sub> receptor is unknown, although screening tests indicate the possibility of potentiation of the antidepressant effect of <i>(R)</i>-ketamine by the mGlu<sub>5</sub> receptor negative allosteric modulator (NAM).</p> Objectives <p>We aimed to investigate whether the antidepressant-like effect of <i>(R)</i>-ketamine is mGlu<sub>5</sub> receptor-dependent. Specifically, we investigated the possibility of enhancing <i>(R)</i>-ketamine antidepressant-like effects using the partial mGlu<sub>5</sub> receptor NAM, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), in a chronic unpredictable mild stress (CUMS) model of depression in mice.</p> Methods <p>The effect of <i>(R)</i>-ketamine on mGlu<sub>5</sub> receptor availability in the mouse brain was investigated using an autoradiographic method. Animal behaviors reflecting anhedonia, apathy, and helplessness were analyzed to study the rapid and sustained antidepressant-like effects of the combined administration of <i>(R)</i>-ketamine and M-5MPEP. Hippocampal protein levels were measured via Western blotting.</p> Results <p><i>(R)</i>-Ketamine altered mGlu<sub>5</sub> receptor availability in several mouse brain regions. Importantly, in the hippocampus, <i>(R)</i>-ketamine reversed CUMS-induced effects. Behavioral studies revealed that M-5MPEP enhanced the effectiveness of a subeffective dose of <i>(R)</i>-ketamine. This drug combination effectively reduced CUMS-induced apathy- and anhedonia-like behavior symptoms. Changes in hippocampal eukaryotic elongation factor2 (eEF2) and tropomyosin receptor kinase B (TrkB) levels accompanied these effects.</p> Conclusions <p>The weakening of mGlu<sub>5</sub> receptor function in the hippocampus appears to be related to the <i>(R)</i>-ketamine antidepressant-like effect, and coadministration of the partial mGlu<sub>5</sub> receptor NAM, M-5MPEP, might increase its antidepressant activity.</p>

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(R)-ketamine induces mGlu5 receptor-dependent antidepressant-like effects in the chronic unpredictable mild stress model of depression in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月8日

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  • Agnieszka Pałucha-Poniewiera,
  • Anna Rafało-Ulińska,
  • Agata Faron-Górecka,
  • Paulina Pabian,
  • Katarzyna Kaczorowska

摘要

Rationale

(S)-Ketamine, which is used to treat depression, has significant undesirable effects and has potential for abuse. A safe alternative to (S)-ketamine is (R)-ketamine. The relationship between (R)-ketamine and the mGlu5 receptor is unknown, although screening tests indicate the possibility of potentiation of the antidepressant effect of (R)-ketamine by the mGlu5 receptor negative allosteric modulator (NAM).

Objectives

We aimed to investigate whether the antidepressant-like effect of (R)-ketamine is mGlu5 receptor-dependent. Specifically, we investigated the possibility of enhancing (R)-ketamine antidepressant-like effects using the partial mGlu5 receptor NAM, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), in a chronic unpredictable mild stress (CUMS) model of depression in mice.

Methods

The effect of (R)-ketamine on mGlu5 receptor availability in the mouse brain was investigated using an autoradiographic method. Animal behaviors reflecting anhedonia, apathy, and helplessness were analyzed to study the rapid and sustained antidepressant-like effects of the combined administration of (R)-ketamine and M-5MPEP. Hippocampal protein levels were measured via Western blotting.

Results

(R)-Ketamine altered mGlu5 receptor availability in several mouse brain regions. Importantly, in the hippocampus, (R)-ketamine reversed CUMS-induced effects. Behavioral studies revealed that M-5MPEP enhanced the effectiveness of a subeffective dose of (R)-ketamine. This drug combination effectively reduced CUMS-induced apathy- and anhedonia-like behavior symptoms. Changes in hippocampal eukaryotic elongation factor2 (eEF2) and tropomyosin receptor kinase B (TrkB) levels accompanied these effects.

Conclusions

The weakening of mGlu5 receptor function in the hippocampus appears to be related to the (R)-ketamine antidepressant-like effect, and coadministration of the partial mGlu5 receptor NAM, M-5MPEP, might increase its antidepressant activity.