The NMDA Receptor as a therapeutic target in major depressive disorder
ABSTRACT 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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- "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). "
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 · 2.68 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  , 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   . Learned helplessness in rats is a widely-used behavioral model of depression. "
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 · 1.83 Impact Factor
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- "cal GR expression . Membrane - bound corticosteroid receptors might also be differentially regulated in High and Low LG offspring . Glutamate receptors are gaining increased attention as therapeutic targets in depression research . The glutamater - gic hypothesis of depression implicates NMDAR hyperfunction in the pathophysiology of the disorder ( Pittenger et al . , 2007 ; Skolnick et al . , 2009 ) . Expression of NMDARs is bidirectionally regulated by antidepressants and chronic - stress . Clinically , the NMDAR - antagonist ketamine alleviates symptoms of treatment - resistant depression after a single acute treat - ment ( Berman et al . , 2000 ; Zarate et al . , 2006 ) . NMDAR - antagonists also prod"
ABSTRACT: Stressful experiences during early-life can modulate the genetic programming of specific brain circuits underlying emotional and cognitive aspects of behavioral adaptation to stressful experiences later in life. Although this programming effect exerted by experience-related factors is an important determinant of mental health, its outcome depends on cognitive inputs and hence the valence an individual assigns to a given environmental context. From this perspective we will highlight, with studies in rodents, non-human primates and humans, the three-hit concept of vulnerability and resilience to stress-related mental disorders, which is based on gene-environment interactions during critical phases of perinatal and juvenile brain development. The three-hit (i.e., hit-1: genetic predisposition, hit-2: early-life environment, and hit-3: later-life environment) concept accommodates the cumulative stress hypothesis stating that in a given context vulnerability is enhanced when failure to cope with adversity accumulates. Alternatively, the concept also points to the individual's predictive adaptive capacity, which underlies the stress inoculation and match/mismatch hypotheses. The latter hypotheses propose that the experience of relatively mild early-life adversity prepares for the future and promotes resilience to similar challenges in later-life; when a mismatch occurs between early and later-life experience, coping is compromised and vulnerability is enhanced. The three-hit concept is fundamental for understanding how individuals can either be prepared for coping with life to come and remain resilient or are unable to do so and succumb to a stress-related mental disorder, under seemingly identical circumstances.Psychoneuroendocrinology 07/2013; 38(9). DOI:10.1016/j.psyneuen.2013.06.008 · 5.59 Impact Factor