The NMDA Receptor as a Therapeutic Target in Major Depressive Disorder

Department of Psychiatry, Yale University, USA.
CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) (Impact Factor: 2.63). 05/2007; 6(2):101-15. DOI: 10.2174/187152707780363267
Source: PubMed


Ample evidence indicates that glutamate homeostasis and neurotransmission are disrupted in major depressive disorder; but the nature of this disruption and the mechanisms by which it contributes to the syndrome are unclear. Likewise, the effect of existing antidepressants on glutamate is unclear, as is the potential of drugs directly targeting glutamatergic neurotransmission to act as novel antidepressant medications. These are areas of active research. Here we review current knowledge of the contribution of the NMDA receptor, one of the several types of glutamate receptor, to depression and its treatment. Several lines of evidence, in humans and in animal models, support the contention that neurotransmission via the NMDA receptor is dysregulated in depression. Drugs that target the NMDA receptor have shown antidepressant properties in both clinical and preclinical studies. Nevertheless, other effects of such medications, including both cognitive side effects and their psychotomimetic properties, complicate such an application and represent a challenge to the development of clinically useful agents.

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    • "Moreover , compelling evidence suggests a key role for the glutamatergic system in mood disorders (Popoli et al., 2012). Tissue glutamate levels are higher in the brain of depressed patients compared with healthy individuals (Sanacora et al., 2012), and evidence indicates that the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors can be successfully targeted for the treatment of MDD (Pittenger et al., 2007). Placebo-controlled trials have demonstrated rapid-acting antidepressant effects, within hours, of subanesthetic doses of the noncompetitive NMDA-receptor antagonist ketamine in treatment-resistant depressed patients [see Duman (2014)]. "
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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
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    • "These receptors are vital for brain function and central to many of the activity-dependent changes in synaptic strength and connectivity thought to underlie the formation of memory and learning (Hardingham and Bading, 2003). Recent studies have suggested that NMDA receptor dysregulation is associated with the pathogenesis of major depression (Beneyto et al., 2007; Pittenger et al., 2007). These include impairment of cortical neuroplasticity associated with NMDA receptor abnormalities (Cotter et al., 2002; Karpova et al., 2013; Nudmamud-Thanoi and Reynolds, 2004; Rajkowska et al., 1999), cognitive impairment due to chronic stress-induced alterations in NMDA receptor subunits (Yuen et al., 2012), and reduced expression of NR2A and NR2B subunits in the prefrontal cortex during major depression (Feyissa et al., 2009). "
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    ABSTRACT: Imipramine, a major antidepressant, is known to inhibit reuptake of serotonin and norepinephrine, which contributes to recovery from major depressive disorder. It has recently been reported that acute imipramine treatment inhibits N-methyl-D-aspartate (NMDA) receptor activity. However, the mechanisms underlying long-term effects of imipramine have not been identified. We tested these distinct effects in mouse cortical neurons and found that acute (30s) imipramine treatment decreased Ca(2+) influx through NMDA receptors, whereas long-term treatment (48h) increased Ca(2+) influx via the same receptors. Furthermore, long-term treatment increased NMDA receptor 2B (NR2B) subunit expression via epigenetic changes, including increased acetylation of histones H3K9 and H3K27 in the NR2B promoter and decreased activity of histone deacetylase 3 (HDAC3) and HDAC4. These results suggest that the long-term effects of imipramine on NMDA receptors are quite different from its acute effects. Furthermore, increased NR2B expression via epigenetic alterations might be a part of the mechanism responsible for this long-term effect. Copyright © 2015 Elsevier B.V. All rights reserved.
    European Journal of Pharmacology 02/2015; 752. DOI:10.1016/j.ejphar.2015.02.010 · 2.53 Impact Factor
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    • "Stress can cause rapid glucocorticoid receptor-mediated alterations in presynaptic glutamate release and slower changes in postsynaptic glutamate receptor expression and function [41] , which can affect LTP and LTD. In addition, stress may induce changes in functional plasticity by shifting the balance between synaptic and extrasynaptic glutamate receptors that are thought to contribute to potentiation and depression, respectively [42] [43] . Learned helplessness in rats is a widely-used behavioral model of depression. "
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    ABSTRACT: Depression is a devastating psychiatric disorder widely attributed to deficient monoaminergic signaling in the central nervous system. However, most clinical antidepressants enhance monoaminergic neurotransmission with little delay but require 4-8 weeks to reach therapeutic efficacy, a paradox suggesting that the monoaminergic hypothesis of depression is an oversimplification. In contrast to the antidepressants targeting the monoaminergic system, a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid (within 2 h) and sustained (over 7 days) antidepressant efficacy in treatment-resistant patients. Glutamatergic transmission mediated by NMDARs is critical for experience-dependent synaptic plasticity and learning, processes that can be modified indirectly by the monoaminergic system. To better understand the mechanisms of action of the new antidepressants like ketamine, we review and compare the monoaminergic and glutamatergic antidepressants, with emphasis on neural plasticity. The pathogenesis of depression may involve maladaptive neural plasticity in glutamatergic circuits that may serve as a new class of targets to produce rapid antidepressant effects.
    Neuroscience Bulletin 02/2015; 31(1):75-86. DOI:10.1007/s12264-014-1484-6 · 2.51 Impact Factor
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