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

The ketamine metabolite (2,6)-hydroxynorketamine 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 ()-ketamine with the (2,6)- and (2,6)-isomers of hydroxynorketamine to affect the induction of -methyl-d-aspartate receptor-dependent long-term potentiation in the mouse hippocampus. Following pre-incubation of these compounds, we observed a concentration-dependent (1-10 μM) inhibition of long-term potentiation by ketamine and a similar effect of (2,6)-hydroxynorketamine. At a concentration of 10 μM, (2,6)-hydroxynorketamine also inhibited the induction of long-term potentiation. These findings raise the possibility that inhibition of -methyl-d-aspartate receptor-mediated synaptic plasticity is a site of action of the hydroxynorketamine metabolites with respect to their rapid and long-lasting antidepressant-like effects.