We 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
). The antidepressant actions of the (2R,6R)-HNK stereoisomer involve early and sustained activation of α-amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid receptors (AMPARs) (
1
).To read this article in full you will need to make a payment
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Article info
Publication history
Published online: September 30, 2016
Accepted:
August 25,
2016
Received in revised form:
August 24,
2016
Received:
August 23,
2016
Identification
Copyright
© 2016 Published by Elsevier Inc. All rights reserved.
ScienceDirect
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- Antidepressant Actions of Ketamine Versus HydroxynorketamineBiological PsychiatryVol. 81Issue 8
- PreviewIn 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.
- 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
