Journal Article

NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

LOS, Maarten F, KAVALALI, Ege T, ADACHI, Megumi, NOSYREVA, Elena, AUTRY, Anita E, MONTEGGIA, Lisa M, CHENG, Peng-Fei, NA, Elisa S

2011

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Animals / Antidepressants / Antidepressive Agents - pharmacology / Behavior, Animal - drug effects / Behavior, Animal - physiology / Biological and medical sciences / Brain-derived neurotrophic factor / Brain-Derived Neurotrophic Factor - biosynthesis / Brain-Derived Neurotrophic Factor - deficiency / Brain-Derived Neurotrophic Factor - genetics / Brain-Derived Neurotrophic Factor - pharmacology / Care and treatment / Depression - drug therapy / Depression, Mental / Disease Models, Animal / Dizocilpine Maleate - pharmacology / Elongation Factor 2 Kinase - metabolism / Gene Expression Regulation - drug effects / Health aspects / Ketamine - pharmacology / Kinases / Medical sciences / Methyl aspartate / Mice / Mice, Inbred C57BL / Mice, Knockout / Neuropharmacology / Pharmacology. Drug treatments / Phosphorylation / Phosphorylation - drug effects / Physiological aspects / Piperazines - pharmacology / Protein Biosynthesis - drug effects / Protein synthesis / Proteins / Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer / Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) / Psychology. Psychoanalysis. Psychiatry / Psychopharmacology / Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors / Receptors, N-Methyl-D-Aspartate - metabolism / Rest - physiology / Rodents / Suicide - prevention & control / Synapses - drug effects / Synapses - metabolism / Synaptic Transmission - drug effects / Time Factors