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

In a mouse model of depression, (R)-ketamine altered mGlu5 receptor availability in several brain regions, reversing stress-induced changes in the hippocampus. Adding a partial mGlu5 receptor negative allosteric modulator (M-5MPEP) boosted the effectiveness of a subeffective dose of (R)-ketamine, reducing apathy- and anhedonia-like behaviors. These behavioral improvements were accompanied by changes in hippocampal eEF2 and TrkB protein levels. The findings suggest that weakening mGlu5 receptor function in the hippocampus may contribute to (R)-ketamine's antidepressant-like effects, and combining it with M-5MPEP could enhance its antidepressant activity.

Study at a glance

Abstract

(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). 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. 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. (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. 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.