Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression An emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 62: 63-77

Department of Psychiatry, Clinical Neuroscience Research Unit, Yale University School of Medicine, New Haven, CT, USA.
Neuropharmacology (Impact Factor: 5.11). 08/2011; 62(1):63-77. DOI: 10.1016/j.neuropharm.2011.07.036
Source: PubMed


Half a century after the first formulation of the monoamine hypothesis, compelling evidence implies that long-term changes in an array of brain areas and circuits mediating complex cognitive-emotional behaviors represent the biological underpinnings of mood/anxiety disorders. A large number of clinical studies suggest that pathophysiology is associated with dysfunction of the predominant glutamatergic system, malfunction in the mechanisms regulating clearance and metabolism of glutamate, and cytoarchitectural/morphological maladaptive changes in a number of brain areas mediating cognitive-emotional behaviors. Concurrently, a wealth of data from animal models have shown that different types of environmental stress enhance glutamate release/transmission in limbic/cortical areas and exert powerful structural effects, inducing dendritic remodeling, reduction of synapses and possibly volumetric reductions resembling those observed in depressed patients. Because a vast majority of neurons and synapses in these areas and circuits use glutamate as neurotransmitter, it would be limiting to maintain that glutamate is in some way 'involved' in mood/anxiety disorders; rather it should be recognized that the glutamatergic system is a primary mediator of psychiatric pathology and, potentially, also a final common pathway for the therapeutic action of antidepressant agents. A paradigm shift from a monoamine hypothesis of depression to a neuroplasticity hypothesis focused on glutamate may represent a substantial advancement in the working hypothesis that drives research for new drugs and therapies. Importantly, despite the availability of multiple classes of drugs with monoamine-based mechanisms of action, there remains a large percentage of patients who fail to achieve a sustained remission of depressive symptoms. The unmet need for improved pharmacotherapies for treatment-resistant depression means there is a large space for the development of new compounds with novel mechanisms of action such as glutamate transmission and related pathways. This article is part of a Special Issue entitled 'Anxiety and Depression'.

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    • "Among different neurochemical hypotheses explaining mood disorder vulnerability, the glutamate hypothesis has recently gained more attention. For example, the importance of the glutamatergic system in the hippocampus in depression vulnerability has been extensively described (Sanacora et al., 2012). However, an altered glutamate signaling or an imbalance of excitatory and inhibitory neurotransmitters has been proposed as central mechanism for a number of psychiatric disorders, including also schizophrenia (Moghaddam and Javitt, 2012), autism (Tebartz van Elst et al., 2014) or bipolar disorders (Chen et al., 2010). "
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    ABSTRACT: Although mental disorders as major depression are highly prevalent worldwide their underlying causes remain elusive. Despite the high heritability of depression and a clear genetic contribution to the disease, the identification of genetic risk factors for depression has been very difficult. The first published candidate to reach genome-wide significance in depression was SLC6A15, a neuronal amino acid transporter. With a reported 1,42 fold increased risk of suffering from depression associated with a single nucleotide polymorphism (SNP) in a regulatory region of SLC6A15, the polymorphism was also found to affect hippocampal morphology, integrity, and hippocampus-dependent memory. However, the function of SLC6A15 in the brain is so far largely unknown. To address this question, we investigated if alterations in SLC6A15 expression, either using a full knockout or a targeted hippocampal overexpression, affect hippocampal neurochemistry and consequently behavior. We could show that a lack of SLC6A15 reduced hippocampal tissue levels of proline and other neutral amino acids. In parallel, we observed a decreased overall availability of tissue glutamate and glutamine, while at the same time the basal tone of extracellular glutamate in the hippocampus was increased. By contrast, SLC6A15 overexpression increased glutamate/glutamine tissue concentrations. These neurochemical alterations could be linked to behavioral abnormalities in sensorimotor gating, a key translational endophenotype relevant for many psychiatric disorders. Overall, our data supports SLC6A15 as a crucial factor controlling amino acid content in the hippocampus, thereby likely interfering with glutamatergic transmission and behavior. These findings emphasize SLC6A15 as pivotal risk factor for vulnerability to psychiatric diseases. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Psychiatric Research 09/2015; 68:261-269. DOI:10.1016/j.jpsychires.2015.07.012
    • "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
    • "Within the MPFC, task-related activity has been shown to be associated with concentrations of Glx and GABA, as measured using MRS [Duncan et al., 2011, 2013, 2014a, 2014b; Enzi et al., 2012; Hu et al., 2013; Kapogiannis et al., 2013; Northoff et al., 2007]. Interestingly, MRS measures of Glx are altered in schizophrenia and depression, both of which are typified by cognitive defects [Alcaro et al., 2010; Poels et al., 2014; Sanacora et al., 2012; Walter et al., 2009]. Taken together, these prior findings from the MPFC suggest that there will be changes in metabolite concentrations in that region during cognitive tasks, but this remains to be tested. "
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    ABSTRACT: Recent functional magnetic resonance spectroscopy (fMRS) studies have shown changes in glutamate/glutamine (Glx) concentrations between resting-state and active-task conditions. However, the types of task used have been limited to sensory paradigms, and the regions from which Glx concentrations have been measured limited to sensory ones. This leaves open the question as to whether the same effect can be seen in higher-order brain regions during cognitive tasks. Cortical midline structures, especially the medial prefrontal cortex (MPFC), have been suggested to be involved in various such cognitive tasks. We, therefore set out to use fMRS to investigate the dynamics of Glx concentrations in the MPFC between resting-state and mental imagery task conditions. The auditory cortex was used as a control region. In addition, functional magnetic resonance imaging was used to explore task-related neural activity changes. The mental imagery task consisted of imagining swimming and was applied to a large sample of healthy participants (n = 46). The participants were all competitive swimmers, ensuring proficiency in mental-swimming. Glx concentrations in the MPFC increased during the imagery task, as compared to resting-state periods preceding and following the task. These increases mirror BOLD activity changes in the same region during the task. No changes in either Glx concentrations or BOLD activity were seen in the auditory cortex. These findings contribute to our understanding of the biochemical basis of generating or manipulating mental representations and the MPFC's role in this. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Human Brain Mapping 06/2015; 36(8). DOI:10.1002/hbm.22841
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  • Béatrice Marianne Ewalds-Kvist added an answer in Glutamate:
    Can anyone outline steps in how to measure the glutamate levels in cancer cells treated with a drug?


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      ABSTRACT: Recent evidence indicates that glutamate homeostasis and neurotransmission are altered in major depressive disorder, but the nature of the disruption and the mechanisms by which it contributes to the syndrome are unclear. Glutamate can act via AMPA, NMDA, or metabotropic receptors. Using targeted mutagenesis, we demonstrate here that mice with deletion of the main AMPA receptor subunit GluR−A represent a depression model with good face and construct validity, showing behavioral and neurochemical features of depression also postulated for human patients. GluR−A−/− mice display increased learned helplessness, decreased serotonin and norepinephrine levels, and disturbed glutamate homeostasis with increased glutamate levels and increased NMDA receptor expression. These results correspond well with current concepts regarding the role of AMPA and NMDA receptors in depression, postulating that compounds that augment AMPA receptor signaling or decrease NMDA receptor functions have antidepressant effects. GluR−A−/− mice represent a model to investigate the pathophysiology underlying the depressive phenotype and to identify changes in neural plasticity and resilience evoked by the genetic alterations in glutamatergic function. Furthermore, GluR−A−/− mice may be a valuable tool to study biological mechanisms of AMPA receptor modulators and the efficacy of NMDA antagonists in reducing behavioral or biochemical changes that correlate with increased helplessness.−Chourbaji, S., Vogt, M. A., Fumagalli, F., Sohr, R., Frasca, A., Brandwein, C, Hörtnagl, H., Riva, M. A., Sprengel, R., Gass, P. AMPA receptor subunit 1 (GluR−A) knockout mice model the glutamate hypothesis of depression.
      The FASEB Journal 05/2008; 22(9). DOI:10.1096/fj.08-106450

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