In a recent issue of Nature, Zanos et al. (
1
) show that metabolites of ketamine have rapid antidepressant-like actions in mice
and that these are independent of the N-methyl-D-aspartate receptor (NMDAR). They report that a racemic mixture of R- and S-ketamine is metabolized to (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), and that this metabolism is essential for the sustained
antidepressant action of ketamine. They also show that (2R,6R)-HNK is the enantiomer of HNK that exerts behavioral, electroencephalographic, and
cellular antidepressant-like effects in mice. Significantly, the effects of (2R,6R)-HNK are independent of NMDARs but somehow involve the activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid (AMPA) receptors. These findings challenge the widely held view that
the rapid and sustained antidepressant actions of single ketamine administration are
caused by its ability to inhibit the NMDAR (
2
) and consequently NMDAR-dependent synaptic plasticity (
3
).To read this article in full you will need to make a payment
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References
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Article info
Publication history
Published online: September 28, 2016
Accepted:
June 23,
2016
Received in revised form:
June 23,
2016
Received:
June 21,
2016
Identification
Copyright
© 2016 Published by Elsevier Inc. All rights reserved.
ScienceDirect
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- Reply to: Antidepressant Actions of Ketamine Versus HydroxynorketamineBiological PsychiatryVol. 81Issue 8
- PreviewWe recently published a report in Nature describing the antidepressant actions of (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), which are metabolites of S- and R-ketamine, respectively (1). In humans, S- and R-ketamine are rapidly metabolized and cleared, with more sustained levels of HNKs (2). We provided evidence that the metabolic breakdown of (R,S)-ketamine is essential for its antidepressant effects in mice, and that (2S,6S)- and (2R,6R)-HNK independently exert antidepressant actions that do not require N-methyl-D-aspartate receptor (NMDAR) inhibition (1).
- Full-Text
- Preview
- What’s the Buzz About Hydroxynorketamine? Is It the History, the Story, the Debate, or the Promise?Biological PsychiatryVol. 81Issue 8
- PreviewThe History: Early in the 1990s, a set of animal studies presented N-methyl-D-aspartate receptor (NMDAR) modulation as a common pathway to traditional antidepressants (1). Later in the 1990s, a group of Yale University scientists set out to demonstrate the role of NMDAR modulation in clinical depression using subanesthetic doses of the NMDAR antagonist ketamine. Surprisingly, they discovered that a single ketamine infusion exerted rapid acting antidepressant (RAAD) effects that were sustained for 3 days, well beyond the short half-life of the ketamine compound (2).
- Full-Text
- Preview
