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NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.

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.

SUBMITTER: Autry AE

PROVIDER: S-EPMC3172695 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.

Autry Anita E AE Adachi Megumi M Nosyreva Elena E Na Elisa S ES Los Maarten F MF Cheng Peng-fei PF Kavalali Ege T ET Monteggia Lisa M LM

Nature 20110615 7354

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 ...[more]

PMID: 21677641

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Project description:BackgroundCovid-status certification - certificates for those who test negative for the SARS-CoV-2 virus, test positive for antibodies, or who have been vaccinated against SARS-CoV-2 - has been proposed to enable safer access to a range of activities. Realising these benefits will depend in part upon the behavioural and social impacts of certification. The aim of this rapid review was to describe public attitudes towards certification, and its possible impact on uptake of testing and vaccination, protective behaviours, and crime.MethodA search was undertaken in peer-reviewed databases, pre-print databases, and the grey literature, from 2000 to December 2020. Studies were included if they measured attitudes towards or behavioural consequences of health certificates based on one of three indices of Covid-19 status: test-negative result for current infectiousness, test-positive for antibodies conferring natural immunity, or vaccination(s) conferring immunity.ResultsThirty-three papers met the inclusion criteria, only three of which were rated as low risk of bias. Public attitudes were generally favourable towards the use of immunity certificates for international travel, but unfavourable towards their use for access to work and other activities. A significant minority was strongly opposed to the use of certificates of immunity for any purpose. The limited evidence suggested that intention to get vaccinated varied with the activity enabled by certification or vaccination (e.g., international travel). Where vaccination is seen as compulsory this could lead to unwillingness to accept a subsequent vaccination. There was some evidence that restricting access to settings and activities to those with antibody test certificates may lead to deliberate exposure to infection in a minority. Behaviours that reduce transmission may decrease upon health certificates based on any of the three indices of Covid-19 status, including physical distancing and handwashing.ConclusionsThe limited evidence suggests that health certification in relation to COVID-19 - outside of the context of international travel - has the potential for harm as well as benefit. Realising the benefits while minimising the harms will require real-time evaluations allowing modifications to maximise the potential contribution of certification to enable safer access to a range of activities.

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NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.

Publications

NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.

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