NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

Anita E. Autry-Dixon, Megumi Adachi, Elena Nosyreva, Elisa S. Na, Maarten F. Los, Peng Fei Cheng, Ege T. Kavalali, Lisa M. Monteggia

Research output: Contribution to journalArticle

900 Citations (Scopus)

Abstract

Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.

Original languageEnglish (US)
Pages (from-to)91-96
Number of pages6
JournalNature
Volume475
Issue number7354
DOIs
StatePublished - Jul 7 2011
Externally publishedYes

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N-Methyl-D-Aspartate Receptors
Antidepressive Agents
Ketamine
Elongation Factor 2 Kinase
Major Depressive Disorder
Brain-Derived Neurotrophic Factor
Peptide Elongation Factor 2
Aptitude
Serotonin Uptake Inhibitors
Intravenous Infusions
Synaptic Transmission
Suicide
Phosphorylation
Depression
Therapeutics
Proteins

ASJC Scopus subject areas

  • General

Cite this

Autry-Dixon, A. E., Adachi, M., Nosyreva, E., Na, E. S., Los, M. F., Cheng, P. F., ... Monteggia, L. M. (2011). NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature, 475(7354), 91-96. https://doi.org/10.1038/nature10130

NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. / Autry-Dixon, Anita E.; Adachi, Megumi; Nosyreva, Elena; Na, Elisa S.; Los, Maarten F.; Cheng, Peng Fei; Kavalali, Ege T.; Monteggia, Lisa M.

In: Nature, Vol. 475, No. 7354, 07.07.2011, p. 91-96.

Research output: Contribution to journalArticle

Autry-Dixon, AE, Adachi, M, Nosyreva, E, Na, ES, Los, MF, Cheng, PF, Kavalali, ET & Monteggia, LM 2011, 'NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses', Nature, vol. 475, no. 7354, pp. 91-96. https://doi.org/10.1038/nature10130
Autry-Dixon, Anita E. ; Adachi, Megumi ; Nosyreva, Elena ; Na, Elisa S. ; Los, Maarten F. ; Cheng, Peng Fei ; Kavalali, Ege T. ; Monteggia, Lisa M. / NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. In: Nature. 2011 ; Vol. 475, No. 7354. pp. 91-96.
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