Fig. 2.

Mechanisms of rapid and sustained antidepressant actions of ketamine metabolites in the hippocampus. Racemic ketamine is metabolized into a wide range of components. (2S,6S)-HNK and (2R,6R)-HNK are the major HNK metabolites in both plasma and the brain in mice. (2R,6R)-HNK elicits rapid (A) and sustained (B) antidepressant effects, whereas (2S,6S)-HNK has no such beneficial effects and induces ketamine-like side-effects. (A) Ketamine and its metabolites may both contribute to the rapid antidepressant effects. Ketamine blocks NMDARs in GABAergic interneurons, and (2R,6R)-HNK induces glutamate release and activates AMPARs through an unknown mechanism, both of which lead to eukaryotic translation elongation factor 2 (eEF2) dephosphorylation and rapid antidepressant effects. (B) Glutamate bursts are induced by (2R,6R)-HNK through an unknown mechanism to stimulate AMPARs, resulting in BDNF release and protein synthesis through eEF2 dephosphorylation, which may be responsible for the sustained antidepressant effects of (2R,6R)-HNK.