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Effects of a ketamine metabolite on synaptic NMDAR function

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Figure 1: (2R,6R)-HNK blocks NMDAR-mEPSCs and decreases eEF2 phosphorylation in hippocampal neurons.
Figure 2: (2R,6R)-HNK acts as open channel NMDAR blocker.


  1. Berman, R. M. et al. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351–354 (2000)

    Article  CAS  Google Scholar 

  2. Zanos, P. et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533, 481–486 (2016)

    Article  ADS  CAS  Google Scholar 

  3. Autry, A. E. et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475, 91–95 (2011)

    Article  CAS  Google Scholar 

  4. Nosyreva, E. et al. Acute suppression of spontaneous neurotransmission drives synaptic potentiation. J. Neurosci. 33, 6990–7002 (2013)

    Article  CAS  Google Scholar 

  5. Nosyreva, E., Autry, A. E., Kavalali, E. T. & Monteggia, L. M. Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade. Front. Mol. Neurosci. 7, 94 (2014)

    Article  Google Scholar 

  6. Atasoy, D. et al. Spontaneous and evoked glutamate release activates two populations of NMDA receptors with limited overlap. J. Neurosci. 28, 10151–10166 (2008)

    Article  CAS  Google Scholar 

  7. Gideons, E. S., Kavalali, E. T. & Monteggia, L. M. Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. Proc. Natl Acad. Sci. USA 111, 8649–8654 (2014)

    Article  ADS  CAS  Google Scholar 

  8. Lukas, G., Brindle, S. D. & Greengard, P. The route of absorption of intraperitoneally administered compounds. J. Pharmacol. Exp. Ther. 178, 562–564 (1971)

    PubMed  CAS  Google Scholar 

  9. Collingridge, G.L. et al. Antidepressant actions of ketamine versus hydroxynorketamine. Biol. Psychiatry 81, e65–e67 (2016)

    Article  CAS  Google Scholar 

  10. Zanos, P. et al. Reply to: antidepressant actions of ketamine versus hydroxynorketamine. Biol. Psychiatry 81, e69–e71 (2016)

    Article  CAS  Google Scholar 

  11. Singh, J. B. et al. Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biol. Psychiatry 80, 424–431 (2016)

    Article  CAS  Google Scholar 

  12. Moaddel, R. et al. Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors. Eur. J. Pharmacol. 698, 228–234 (2013)

    Article  CAS  Google Scholar 

  13. Kotermanski, S. E., Wood, J. T. & Johnson, J. W. Memantine binding to a superficial site on NMDA receptors contributes to partial trapping. J. Physiol. (Lond.) 587, 4589–4604 (2009)

    Article  CAS  Google Scholar 

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Correspondence to Lisa M. Monteggia.

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Suzuki, K., Nosyreva, E., Hunt, K. et al. Effects of a ketamine metabolite on synaptic NMDAR function. Nature 546, E1–E3 (2017).

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