NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

AE Autry, M Adachi, E Nosyreva, ES Na, MF Los… - Nature, 2011 - nature.com
AE Autry, M Adachi, E Nosyreva, ES Na, MF Los, P Cheng, ET Kavalali, LM Monteggia
Nature, 2011nature.com
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 …
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.
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