Loss of the sustained antidepressant-like effect of (2R,6R)-hydroxynorketamine in NMDA receptor GluN2D subunit knockout mice.

The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) produces both immediate and lasting antidepressant-like effects in mice, while its stereoisomer (2S,6S)-HNK does not. The sustained effects depend on the GluN2D subunit of the NMDA receptor: they disappear in mice lacking this subunit, although the acute effects remain. In stressed wildtype mice, GluN2B protein expression decreases in the nucleus accumbens, but this decrease does not occur in GluN2D-knockout mice. These findings suggest that the GluN2D subunit, and possibly GluN2B, mediate the long-lasting antidepressant-like action of (2R,6R)-HNK.

Study at a glance

Abstract

Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has attracted attention for its acute and sustained antidepressant effects in patients with depression. Hydroxynorketamine (HNK), a metabolite of ketamine, exerts antidepressant effects without exerting ketamine's side effects and has attracted much attention in recent years. However, the detailed pharmacological mechanism of action of HNK remains unclear. We previously showed that the GluN2D NMDA receptor subunit is important for sustained antidepressant-like effects of (R)-ketamine. Therefore, we investigated whether the GluN2D subunit is involved in antidepressant-like effects of (2R,6R)-HNK and (2S,6S)-HNK. Treatment with (2R,6R)-HNK but not (2S,6S)-HNK exerted acute and sustained antidepressant-like effects in the tail-suspension test in wildtype mice. Interestingly, sustained antidepressant-like effects of (2R,6R)-HNK were abolished in GluN2D-knockout mice, whereas acute antidepressant-like effects were maintained in GluN2D-knockout mice. When expression levels of GluN2A and GluN2B subunits were evaluated, a decrease in GluN2B protein expression in the nucleus accumbens was found in stressed wildtype mice but not in stressed GluN2D-knockout mice. These results suggest that the GluN2D subunit and possibly the GluN2B subunit are involved in the sustained antidepressant-like effect of (2R,6R)-HNK.