Targeting Protein Synthesis for Fast Antidepressant Action

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RESEARCH HIGHLIGHTS MOOD DISORDERS Targeting protein synthesis for fast antidepressant action Ketamine, an injectable drug that tricyclic antidepressant imipramine) is used to induce anaesthesia in did not produce these antidepressant- surgery, also has a rapid and sustained like responses. antidepressant effect. However, its Ketamine blocks NMDARs at psychotomimetic and cognitive the phencyclidine site within the effects preclude its long-term use. As ionotropic channel, but little is known currently available antidepressants about the downstream signalling commonly take weeks to reach events that lead to its antidepressant efficacy, understanding the fast effects. In this study, the authors mechanism of action of ketamine investigated whether BDNF, which could aid the development of much- is involved in the pathophysiology needed treatment options for patients of mood-related disorders, could be with major depressive disorders. Now, mediating the antidepressant effects Monteggia and colleagues show that of ketamine. Interestingly, ketamine the rapid synthesis of brain-derived did not have an antidepressant effect neurotrophic factor (BDNF) that in BDNF-knockout mice or in mice with EEF2 kinase (EEF2K) results from the ketamine-mediated mice in which the BDNF receptor inhibitors also led to a decrease blockade of N-methyl-D-aspartate TRKB had been conditionally in EEF2 phosphorylation and an receptors (NMDARs) is responsible knocked out. Furthermore, they increase in levels of BDNF protein in for the fast-acting antidepressant found that ketamine triggers a the hippocampus. Importantly, these effects of the drug in mice. rapid but transient increase in inhibitors exerted antidepressant-like First, the authors determined BDNF protein translation in the effects in the FST after 30 minutes, the time course of behavioural hippocampus, which is required a timescale that is comparable to antidepressant effects in wild-type for the fast-acting and long-lasting ketamine. No such responses were mice, by carrying out antidepressant- antidepressant response. observed in the BDNF-knockout predictive tasks such as the forced NMDAR blockade in the absence mice, which indicates that BDNF swim test (FST), and in a mouse of neuronal activity has been shown expression following EEF2K model of depression, following to trigger protein synthesis by inhibition is required for producing the administration of a single low dephosphorylating and activating antidepressant-like responses. This dose (3 mg per kg) of ketamine. In eukaryotic elongation factor 2 study suggests that EEF2K might be agreement with previous findings, (EEF2), which is a key mediator a novel target for the development of an antidepressant-like response was of ribosomal translocation. Here, fast-acting antidepressants. observed after 30 minutes and lasted the authors show that in ketamine- Monica Hoyos Flight for 1 week. Similarly, acute treatment treated neurons there is a decrease ORIGINAL RESEARCH PAPER Autry, A. E. et al. with conventional antidepressants in EEF2 phosphorylation, which NMDA receptor blockade at rest triggers rapid (such as the selective serotonin allows for an increase in BDNF behavioural antidepressant responses. 15 June 2011 Nature 475, 91–95 (2011). reuptake inhibitor fluoxetine or the translation. Treatment of wild-type NATURE REVIEWS | DRUG DISCOVERY VOLUME 10 | AUGUST 2011 © 2011 Macmillan Publishers Limited. All rights reserved.

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