mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

Yale University, New Haven, Connecticut, United States
Science (Impact Factor: 33.61). 08/2010; 329(5994):959-64. DOI: 10.1126/science.1190287
Source: PubMed

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.

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Available from: Rong-Jian Liu, Sep 28, 2015
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    • "Interestingly, higher baseline levels of glutamate within the cerebrospinal fluid is associated with higher levels of suicidal thinking in patients with MDD (Garakani et al. 2013). NMDA receptor-regulated neuroplasticity (Dwivedi et al. 2005; Li et al. 2010; Duman & Aghajanian, 2012; Kang et al. 2013) and neuroinflammatory processes (Lindqvist et al. 2009; Erhardt et al. 2013) may also represent important mechanisms by which NMDA receptor antagonists bring about anti-suicidal effects. Future research using molecular and brain-imaging tools will be required to further explicate the mechanisms of suicidal behavior and those of putative treatments. "
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    ABSTRACT: Suicide is a devastating public health problem and very few biological treatments have been found to be effective for quickly reducing the intensity of suicidal ideation (SI). We have previously shown that a single dose of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, is associated with a rapid reduction in depressive symptom severity and SI in patients with treatment-resistant depression. We conducted a randomized, controlled trial of ketamine in patients with mood and anxiety spectrum disorders who presented with clinically significant SI (n = 24). Patients received a single infusion of ketamine or midazolam (as an active placebo) in addition to standard of care. SI measured using the Beck Scale for Suicidal Ideation (BSI) 24 h post-treatment represented the primary outcome. Secondary outcomes included the Montgomery-Asberg Depression Rating Scale - Suicidal Ideation (MADRS-SI) score at 24 h and additional measures beyond the 24-h time-point. The intervention was well tolerated and no dropouts occurred during the primary 7-day assessment period. BSI score was not different between the treatment groups at 24 h (p = 0.32); however, a significant difference emerged at 48 h (p = 0.047). MADRS-SI score was lower in the ketamine group compared to midazolam group at 24 h (p = 0.05). The treatment effect was no longer significant at the end of the 7-day assessment period. The current findings provide initial support for the safety and tolerability of ketamine as an intervention for SI in patients who are at elevated risk for suicidal behavior. Larger, well-powered studies are warranted.
    Psychological Medicine 08/2015; DOI:10.1017/S0033291715001506 · 5.94 Impact Factor
    • "A major drawback of monoamine-based antidepressant medications that are currently in clinical use is that they require sustained treatment of several weeks or longer before therapeutic benefits are achieved (Rush et al., 2006). The ineffectiveness of acute FLX administration in the 24-hour FST and LH paradigms markedly contrasts with the actions of ketamine, which have been documented in recent animal studies (Maeng et al., 2008; Li et al., 2010; Autry et al., 2011; Browne and Lucki, 2013). "
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    ABSTRACT: Currently approved antidepressant drug treatment typically takes several weeks to be effective. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown efficacy as a rapid-acting treatment for depression, but its use is associated with significant side effects. We assessed effects following blockade of the glycineB co-agonist site of the NMDA receptor by the selective full antagonist 7-Cl-kynurenic acid (7-Cl-KYNA), delivered by systemic administration of its brain-penetrant prodrug 4-Cl-kynurenine (4-Cl-KYN) in mice. Following administration of 4-Cl-KYN, 7-Cl-KYNA was promptly recovered extracellularly in hippocampal microdialysate of freely-moving animals. The behavioral responses of the animals were assessed using measures of ketamine-sensitive antidepressant efficacy (including the 24-hour forced swim test, learned helplessness test, and novelty-suppressed feeding test). In these tests, distinct from fluoxetine, and similar to ketamine, 4-Cl-KYN administration resulted in rapid, dose-dependent and persistent antidepressant-like effects following a single treatment. The antidepressant effects of 4-Cl-KYN were prevented by pre-treatment with glycine or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX). 4-Cl-KYN administration was not associated with the rewarding and psychotomimetic effects of ketamine, and did not induce locomotor sensitization or stereotypic behaviors. Our results provide further support for antagonism of the glycineB site for the rapid treatment of treatment-resistant depression and indicate that the prodrug approach using 4-Cl-KYN holds promise for use in humans, without the negative side effects seen with ketamine or other channel blocking NMDA receptor antagonists. The American Society for Pharmacology and Experimental Therapeutics.
    Journal of Pharmacology and Experimental Therapeutics 08/2015; 355(1). DOI:10.1124/jpet.115.225664 · 3.97 Impact Factor
    • "Because the rapid and long-lasting effects of ketamine contrast with the effects of clinically used antidepressants, which require several weeks of administration to relieve depressive symptoms (Skolnick, 1999), a number of hypotheses have been proposed to explain ketamine's uniqueness. These include the activation of the mammalian target of rapamycin (mTOR) signaling cascade in the prefrontal cortex (Li et al., 2010; Paul et al., 2014), the activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors and brain-derived neurotrophic factor (BDNF) (Zhou et al., 2014), the involvement of Shank3, a postsynaptic density protein contributing to NMDA receptor tethering and dendritic spine rearrangement (Ortiz et al., 2015), and a "
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    ABSTRACT: Ketamine produces rapid and long-lasting antidepressant effects in patients. The involvement of ketamine metabolites in these actions has been proposed. The effects of ketamine and its metabolites norketamine and dehydronorketamine on ligand binding to 80 receptors, ion channels and transporters was investigated at a single concentration of 10 μM. The affinities of all three compounds were then assessed at NMDA receptors using [(3)H]MK-801 binding. The dose-response relationships of all 3 compounds in the forced swim test were also investigated in mice 30 minutes after IP administration. The effects of ketamine and norketamine (both 50 mg/kg) were then examined at 30 minutes, 3 days and 7 days post administration. Among the 80 potential targets examined, only NMDA receptors were affected with a magnitude of > 50% by ketamine and norketamine at the concentration of 10 μM. The Ki values of ketamine, norketamine and dehydronorketamine at NMDA receptors were 0.119 ± 0.01, 0.97 ± 0.1 and 3.21 ± 0.3 μM, respectively. Ketamine and norketamine reduced immobility with minimum effective doses (MEDs) of 10 and 50 mg/kg, respectively; dehydronorketamine did not affect immobility at doses of up to 50 mg/kg. Neither ketamine nor norketamine reduced immobility in the forced swim test 3 and 7 days following administration. Further, oral administration of ketamine (5-50 mg/kg) did not affect immobility. We demonstrate that ketamine and norketamine but not dehydronorketamine given acutely at subanesthetic doses reduced immobility in the forced swim test. These antidepressant-like effects appear attributable to NMDA receptor inhibition. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 08/2015; 99. DOI:10.1016/j.neuropharm.2015.07.037 · 5.11 Impact Factor
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