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

(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.