(2S,6S)- and (2R,6R)- hydroxynorketamine inhibit the induction of NMDA receptor-dependent LTP at hippocampal CA1 synapses in mice

The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has been proposed to have rapid and persistent antidepressant actions in rodents, but its mechanism of action is controversial. We have compared the ability of (R,S)-ketamine with the (2S,6S)- and (2R,6R)- isomers of HNK to affect the induction of NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) in the mouse hippocampus. Following pre-incubation of these compounds we observed a concentration-dependent (1 -10 µM) inhibition of LTP by ketamine and a similar effect of (2S,6S)-HNK. At a concentration of 10 µM (2R,6R)-HNK also inhibited the induction of LTP. These findings raise the possibility that inhibition of NMDAR-mediated synaptic plasticity is a site of action of the HNK metabolites with respect to their rapid and long-lasting antidepressant-like effects.