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Journal ArticleDOI

NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

07 Jul 2011-Nature (Nature Publishing Group)-Vol. 475, Iss: 7354, pp 91-95
TL;DR: It is shown 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, suggesting the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast- acting 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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Citations
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Journal ArticleDOI
TL;DR: The effects of subunit composition on NMDAR properties, synaptic plasticity and cellular mechanisms implicated in neuropsychiatric disorders are reviewed and could provide new therapeutic strategies against dysfunctions of glutamatergic transmission.
Abstract: NMDA receptors (NMDARs) are glutamate-gated ion channels and are crucial for neuronal communication. NMDARs form tetrameric complexes that consist of several homologous subunits. The subunit composition of NMDARs is plastic, resulting in a large number of receptor subtypes. As each receptor subtype has distinct biophysical, pharmacological and signalling properties, there is great interest in determining whether individual subtypes carry out specific functions in the CNS in both normal and pathological conditions. Here, we review the effects of subunit composition on NMDAR properties, synaptic plasticity and cellular mechanisms implicated in neuropsychiatric disorders. Understanding the rules and roles of NMDAR diversity could provide new therapeutic strategies against dysfunctions of glutamatergic transmission.

1,918 citations

Journal ArticleDOI
TL;DR: This Review highlights recent advances in the understanding of the complex regulation of the mTOR pathway and discusses its function in the context of physiology, human disease and pharmacological intervention.
Abstract: The mTOR pathway integrates a diverse set of environmental cues, such as growth factor signals and nutritional status, to direct eukaryotic cell growth. Over the past two and a half decades, mapping of the mTOR signalling landscape has revealed that mTOR controls biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Given the pathway's central role in maintaining cellular and physiological homeostasis, dysregulation of mTOR signalling has been implicated in metabolic disorders, neurodegeneration, cancer and ageing. In this Review, we highlight recent advances in our understanding of the complex regulation of the mTOR pathway and discuss its function in the context of physiology, human disease and pharmacological intervention.

1,253 citations

Journal ArticleDOI
26 May 2016-Nature
TL;DR: It is shown that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice.
Abstract: Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-d-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.

1,157 citations

Journal ArticleDOI
TL;DR: Understanding of the mechanisms by which stress and glucocorticoids affect glutamate transmission provides insights into normal brain functioning, as well as the pathophysiology and potential new treatments of stress-related neuropsychiatric disorders.
Abstract: Mounting evidence suggests that acute and chronic stress, especially the stress-induced release of glucocorticoids, induces changes in glutamate neurotransmission in the prefrontal cortex and the hippocampus, thereby influencing some aspects of cognitive processing. In addition, dysfunction of glutamatergic neurotransmission is increasingly considered to be a core feature of stress-related mental illnesses. Recent studies have shed light on the mechanisms by which stress and glucocorticoids affect glutamate transmission, including effects on glutamate release, glutamate receptors and glutamate clearance and metabolism. This new understanding provides insights into normal brain functioning, as well as the pathophysiology and potential new treatments of stress-related neuropsychiatric disorders.

1,121 citations

Journal ArticleDOI
05 Oct 2012-Science
TL;DR: Findings highlight the central importance of homeostatic control of mood circuit connections and form the basis of a synaptogenic hypothesis of depression and treatment response.
Abstract: Basic and clinical studies demonstrate that depression is associated with reduced size of brain regions that regulate mood and cognition, including the prefrontal cortex and the hippocampus, and decreased neuronal synapses in these areas. Antidepressants can block or reverse these neuronal deficits, although typical antidepressants have limited efficacy and delayed response times of weeks to months. A notable recent discovery shows that ketamine, a N -methyl-d-aspartate receptor antagonist, produces rapid (within hours) antidepressant responses in patients who are resistant to typical antidepressants. Basic studies show that ketamine rapidly induces synaptogenesis and reverses the synaptic deficits caused by chronic stress. These findings highlight the central importance of homeostatic control of mood circuit connections and form the basis of a synaptogenic hypothesis of depression and treatment response.

1,089 citations

References
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Journal ArticleDOI
21 Apr 1977-Nature
TL;DR: Results presented below indicate that immobility is reduced by different treatments known to be therapeutic in depression including three drugs, iprindole, mianserin and viloxazine which although clinically active show little or no ‘antidepressant’ activity in the usual animal tests.
Abstract: A MAJOR problem in the search for new antidepressant drugs is the lack of animal models which both resemble depressive illness and are selectively sensitive to clinically effective antidepressant treatments. We have been working on a new behavioural model in the rat which attempts to meet these two requirements. The method is based on the observation that a rat, when forced to swim in a situation from which there is no escape, will, after an initial period of vigorous activity, eventually cease to move altogether making only those movements necessary to keep its head above water. We think that this characteristic and readily identifiable behavioural immobility indicates a state of despair in which the rat has learned that escape is impossible and resigns itself to the experimental conditions. This hypothesis receives support from results presented below which indicate that immobility is reduced by different treatments known to be therapeutic in depression including three drugs, iprindole, mianserin and viloxazine which although clinically active1–3 show little or no ‘antidepressant’ activity in the usual animal tests4–6.

4,172 citations

Journal ArticleDOI
TL;DR: A first placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients with depression suggests a potential role for NMDA receptor-modulating drugs in the treatment of depression.

3,039 citations


"NMDA receptor blockade at rest trig..." refers background or methods in this paper

  • ...Representative field-potential traces (average 2 min) are shown during baseline (1) and at 45 min (2)....

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  • ...average; (2) the timescale in each experiment was converted to the time from the end of ketamine application; and (3) the time-matched, normalized data were...

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  • ...0002 for treatment; ANOVA on dendrites, F(2,23) 5 14....

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Journal ArticleDOI
TL;DR: Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.
Abstract: Context Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. Objective To determine whether a rapid antidepressant effect can be achieved with an antagonist at theN-methyl-D-aspartate receptor in subjects with major depression. Design A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. Setting Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects withDSM-IVmajor depression (treatment resistant). Interventions After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. Results Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. Conclusions Robust and rapid antidepressant effects resulted from a single intravenous dose of anN-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. Trial Registration clinicaltrials.gov Identifier:NCT00088699.

2,965 citations


"NMDA receptor blockade at rest trig..." refers background or methods in this paper

  • ...We examined the time course of behavioural antidepressant effects in wild-type mice after a single, low-dose treatment with ketamine, (5S,10R)-(1)-5-methyl10,11-dihydro -5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK801) or 3-((R)-2-carboxypiperazin-4-yl)-prop-2-enyl-1-phosphonic acid (CPP) (Fig....

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  • ...At 24 h, in a separate cohort, ANOVA F(1,29) 5 3....

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  • ...Representative field-potential traces (average 2 min) are shown during baseline (1) and at 45 min (2)....

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  • ...The group data were analysed as follows: (1) the initial slopes of the field potential were expressed as percentages of the preconditioning baseline...

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Journal ArticleDOI
20 Aug 2010-Science
TL;DR: The results demonstrate that the effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamines.
Abstract: The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.

2,345 citations

Journal ArticleDOI
10 Feb 2006-Science
TL;DR: It is shown that viral-mediated, mesolimbic dopamine pathway–specific knockdown of brain-derived neurotrophic factor is required for the development of experience-dependent social aversion in mice experiencing repeated aggression.
Abstract: Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.

1,873 citations

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