NMDAR inhibition-independent antidepressant actions of ketamine metabolites

Abstract

Major depressive disorder afflicts ~16 percent of the world population at some point in their lives. Despite a number of available monoaminergic-based antidepressants, most patients require many weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), exerts rapid and sustained antidepressant effects following a single dose in depressed patients. Here we show that the metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant actions in vivo. Notably, we demonstrate that these antidepressant actions are NMDAR inhibition-independent but they involve early and sustained α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activation. We also establish that (2R,6R)-HNK lacks ketamine-related side-effects. Our results indicate a novel mechanism underlying ketamine’s unique antidepressant properties, which involves the required activity of a distinct metabolite and is independent of NMDAR inhibition. These findings have relevance for the development of next generation, rapid-acting antidepressants.

On the Eve of Upgrading Antidepressants: (R)-Ketamine and Its Metabolites

“…However, ketamine still has limited clinical application, mainly because of its psychotomimetic side-effects and liability of abuse. A recent paper in Nature [5] showed that the ketamine metabolite enantiomer (2R,6R)-hydroxynorketamine (HNK) has rapid and sustained antidepressant effects without the side-effects associated with ketamine, such as abuse potential. The discovery of (R)-ketamine is a landmark in the field of depression.…”

“…Zanos et al [5] concentrated on ketamine metabolites and investigated the mechanism by which it exerts rapid and sustained antidepressant effects. The authors hypothesized that if ketamine has rapid-onset effects mainly by inhibiting NMDARs, then (S)-ketamine would be predicted to be more potent than (R)-ketamine, and alternative NMDAR inhibitors would also have similar effects.…”

“…Zanos et al [5] showed that (2R,6R)-HNK lacks dissociative and psychotomimetic side-effects in a wide range of tests, even in drug discrimination and self-administration paradigms that evaluate the liability of drug abuse/addiction. In contrast, both ketamine and (2S,6S)-HNK have serious abuse potential and other side-effects.…”

“…1). Zanos et al [5] examined the extent of (2R,6R)-HNK dependence on NMDAR activation. Surprisingly, they found that (2R,6R)-HNK induces robust increases in a variety of a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR)-dependent electrophysiological signatures, without affecting NMDAR-mediated currents in rat hippocampal slices.…”

“…Zanos et al [5] found that both ketamine and its metabolite (2R,6R)-HNK decrease the phosphorylation of eukaryotic translation elongation factor 2 (eEF2) and increase the expression of brain-derived neurotrophic factor (BDNF), GluA1, and GluA2 in hippocampal synaptoneurosomes 24 h after treatment. Combined with the electrophysiological and EEG data, we speculate that AMPAR-mediated maintenance of synaptic potentiation, BDNF release, and protein synthesis through eEF2 dephosphorylation underlies the sustained (24 h) antidepressive effects of ketamine metabolites (Fig.…”