Disturbance of the Glutamatergic System in Mood Disorders

Experimental neurobiology 03/2014; 23(1):28-35. DOI: 10.5607/en.2014.23.1.28
Source: PubMed


The role of glutamatergic system in the neurobiology of mood disorders draws increasing attention, as disturbance of this system is consistently implicated in mood disorders including major depressive disorder and bipolar disorder. Thus, the glutamate hypothesis of mood disorders is expected to complement and improve the prevailing monoamine hypothesis, and may indicate novel therapeutic targets. Since the contribution of astrocytes is found to be crucial not only in the modulation of the glutamatergic system but also in the maintenance of brain energy metabolism, alterations in the astrocytic function and neuroenergetic environment are suggested as the potential neurobiological underpinnings of mood disorders. In the present review, the evidence of glutamatergic abnormalities in mood disorders based on postmortem and magnetic resonance spectroscopy (MRS) studies is presented, and disrupted energy metabolism involving astrocytic dysfunction is proposed as the underlying mechanism linking altered energy metabolism, perturbations in the glutamatergic system, and pathogenesis of mood disorders.

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    • "In bipolar patients, glutamate and glutamine levels have been found elevated in the grey matter areas of the anterior cingulate cortex, medial prefrontal cortex, dorsolateral prefrontal cortex, parieto-occipital cortex , occipital cortex, insula and hippocampus (Jun et al., 2007). "
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    ABSTRACT: Major depression is a common, recurrent mental illness that affects millions of people worldwide. Recently, a unique fast neuroprotective and antidepressant treatment effect has been observed by ketamine, which acts via the glutamatergic system. Hence, a steady accumulation of evidence supporting a role for the excitatory amino acid neurotransmitter (EAA) glutamate in the treatment of depression has been observed in the last years. Emerging evidence indicates that N-methyl-D-aspartate (NMDA), group 1 metabotropic glutamate receptor antagonists and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) agonists have antidepressant properties. Indeed, treatment with NMDA receptor antagonists has shown the ability to sprout new synaptic connections and reverse stress-induced neuronal changes. Based on glutamatergic signaling, a number of therapeutic drugs might gain interest in the future. Several compounds such as ketamine, memantine, amantadine, tianeptine, pioglitazone, riluzole, lamotrigine, AZD6765, magnesium, zinc, guanosine, adenosine aniracetam, traxoprodil (CP-101,606), MK-0657, GLYX-13, NRX-1047, Ro25-6981, LY392098, LY341495, D-cycloserine, D-serine, dextromethorphan, sarcosine, scopolamine, pomaglumetad methionil, LY2140023, LY404039, MGS0039, MPEP, 1-Aminocyclopropanecarboxylic acid all of which target this system have already been brought up, some of them recently. Drugs targeting the glutamatergic system might open up a promising new territory for the development of drugs to meet the needs of patients with major depression. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Mar 2015 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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    • "In the last two decades, a considerable number of studies have shown a central role of the glutamatergic system in mood disorders, including MDD (Jun et al., 2014; Soeiro-de-Souza et al., 2013; Reus et al., 2011a; 2014a). In fact, Hashimoto et al. (2007) showed an increase in glutamate levels in the brain of patients with depression and bipolar disorder. "
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    ABSTRACT: Ketamine, an antagonist of NMDA receptors, has produced rapid antidepressant effects in patients with depression, as well as in animal models. However, the extent and duration of the antidepressant effect over longer periods of time has not been considered. This study evaluated the effects of single dose of ketamine on behavior and oxidative stress, which is related to depression, in the brains of adult rats subjected to maternal deprivation. Deprived and non-deprived Wistar rats were divided into 4 groups: non-deprived+saline; non-deprived+S-ketamine (15 mg/kg); deprived+saline; deprived+S-ketamine (15 mg/kg). A single dose of ketamine or saline was administrated during the adult phase,and 14 days later depressive-like behavior was assessed. In addition, lipid damage, protein damage, and antioxidant enzyme activities were evaluated inthe rat brain. Maternal deprivation induces a depressive-like behavior, as verified by an increase in immobility and anhedonic behavior. However, a single dose of ketamine was able to reverse these alterations, showing long-term antidepressant effects. The brains of maternally deprived rats had an increase in protein oxidative damage and lipid peroxidation, but administration of a single dose of ketamine reversed this damage. The activities of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) were reduced in the deprived rat brains. However, ketamine was also able to reverse these changes. In conclusion, these findings indicate that a single dose of ketamine is able to induce long-term antidepressant effects and protect against neural damage caused by oxidative stress in adulthood rats following maternal deprivation. This article is protected by copyright. All rights reserved. Copyright © 2015 Wiley Periodicals, Inc., a Wiley company.
    Full-text · Article · Feb 2015 · Developmental Neurobiology
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    ABSTRACT: Postpartum depression (PPD) is a common complication following childbirth experienced by one in every five new mothers. Pregnancy stress enhances vulnerability to PPD and has also been shown to increase depressive-like behavior in postpartum rats. Thus, gestational stress may be an important translational risk factor that can be used to investigate the neurobiological mechanisms underlying PPD. Here we examined the effects of gestational stress on depressive-like behavior during the early/mid and late postpartum periods and evaluated whether this was accompanied by altered structural plasticity in the nucleus accumbens (NAc), a brain region that has been linked to PPD. We show that early/mid (postpartum day 8) postpartum female rats exhibited more depressive-like behavior in the forced swim test as compared with late postpartum females (postpartum day 22). However, 2 weeks of restraint stress during pregnancy increased depressive-like behavior regardless of postpartum timepoint. In addition, dendritic length, branching and spine density on medium spiny neurons in the NAc shell were diminished in postpartum rats that experienced gestational stress although stress-induced reductions in spine density were evident only in early/mid postpartum females. In the NAc core, structural plasticity was not affected by gestational stress but late postpartum females exhibited lower spine density and reduced dendritic length. Overall, these data not only demonstrate structural changes in the NAc across the postpartum period, they also show that postpartum depressive-like behavior following exposure to gestational stress is associated with compromised structural plasticity in the NAc and thus may provide insight into the neural changes that could contribute to PPD.
    No preview · Article · Oct 2014 · European Journal of Neuroscience
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