NMDA Receptor Blockade at Rest Triggers Rapid Behavioural Antidepressant Responses

Nature. 2011 Jun 15;475(7354):91-5. doi: 10.1038/nature10130.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Brain-Derived Neurotrophic Factor / biosynthesis
  • Brain-Derived Neurotrophic Factor / deficiency
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / pharmacology
  • Depression / drug therapy
  • Disease Models, Animal
  • Dizocilpine Maleate / pharmacology
  • Elongation Factor 2 Kinase / metabolism
  • Gene Expression Regulation / drug effects
  • Ketamine / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphorylation / drug effects
  • Piperazines / pharmacology
  • Protein Biosynthesis / drug effects
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Rest / physiology*
  • Suicide / prevention & control
  • Synapses / drug effects
  • Synapses / metabolism
  • Synaptic Transmission / drug effects
  • Time Factors

Substances

  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Piperazines
  • Receptors, N-Methyl-D-Aspartate
  • Ketamine
  • Dizocilpine Maleate
  • 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid
  • Elongation Factor 2 Kinase