Article

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: 2.7). 05/2007; 6(2):101-15. DOI: 10.2174/187152707780363267
Source: PubMed

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). "
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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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    • "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"
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