Role Of Glutamatergic System Research Articles

Role of Glutamatergic System and its Level of Glutamate in Rat Migraine Model

Glutamate is a major mediator of excitatory signals in the nervous system and is involved in many physiologic and pathologic processes. The understanding of glutamatergic transmission in the nervous system has been greatly expanded and the family of ionotropic and metatropic glutamate receptors. The glutamate receptors are localized at nerve terminals postsynaptic sites and glial cells and thus, they can influence and modulate the action of glutamate at different levels in the synapse. Moreover, there is substantial evidence of glial participation in glutamate nociceptive processes and neuropathic pain. Present study explains the glutamate transporters are responsible for the level of glutamate in the synaptic cleft is principally dependent on neuronal glutamate transporters in rat model.

Moving from the old monoaminergic theory toward the emerging hypothesis in the rational design of rapid-onset novel antidepressants

Antidepressants can be classified into 13 different classes based on their pharmacological mechanisms of action. As of this present moment, 11 out of these 13 classes of antidepressants accomplish their pharmacoactivities by blocking one or more of the reuptake transporter pumps and/or receptors for the three monoaminergic neurotransmitters, namely serotonin, norepinephrine, and dopamine. The 12th class inhibits the enzyme monoamine oxidase, while the 13th class works by blocking the N-methyl-D-aspartate (NMDA)-glutamatergic ionoceptor. Previous experimental results suggest that depression is associated with hyperfunction of NMDA-glutamatergic receptors (NMDARs) in the subcortical regions (i.e., hippocampus, locus coeruleus, and amygdala); whereas at the same time, there is hypofunction of NMDARs in the cortical regions (i.e., prefrontal, perirhinal, and temporal cortices). Moreover, this finding has led to a conclusion that postulates the new “Glutamatergic hypothesis of depression” which is now moving our understanding of the pathophysiology of major depression disorder (MDD), a step further from the several decades' old “Monoaminergic theory of depression.” Collectively, clinical data suggest the involvement of the glutamatergic neurotransmission system in the pathophysiology of MDD or bipolar depression or schizoaffective depression, which includes disruptions in glutamatergic substrate concentrations and NMDAR alterations. Although the role of glutamatergic systems is yet to be fully elucidated, a “proof of concept” clinical study reported that the noncompetitive NMDAR antagonist ketamine produced rapid-onset and prolonged antidepressant effects in patients suffering from MDD or bipolar depression or schizoaffective depression. Still, this has generated tremendous interest in developing new drugs that will target the glutamatergic neurotransmission mechanisms for the treatment of MDD or bipolar depression or schizoaffective depression. These potential drug targets are the NMDAR as antagonist or inverse agonist or partial agonist, metabotropic glutamatergic receptors as positive or negative modulator, excitatory amino acid transporter-2 (EAAT-2) as a reuptake enhancer, and as a terminal presynaptic glutamate release inhibitor.

T180. LOWER GLUTAMATE LEVEL IN TEMPORO-PARIETAL AREA MAY PREDICT A BETTER RESPONSE TO TDCS IN SCHIZOPHRENIA: A PILOT STUDY

BackgroundTranscranial Direct Current Stimulation (tDCS) is a non-invasive neuromodulation technique which uses a weak electric current from electrodes across the scalp to modulate targeted brain areas. It has been suggested that tDCS may be useful in reducing psychotic symptoms such as auditory hallucination. The aim of this study was to find alteration of key neurotransmitters in schizophrenia in temporo-parietal area (TPA) after tDCS intervention, using magnetic resonance spectroscopy (MRS) technique.MethodsTen schizophrenia patients with auditory hallucination were recruited from the outpatient clinic of Seoul National University Hospital (SNUH). The anode was placed over the left dorsolateral prefrontal cortex (DLPFC), and the cathode was placed over the left TPA. Patients underwent MRS scan with the very short echo time phase rotation STEAM sequence before and after the tDCS sessions, respectively.ResultsSeven of the participants completed MRS scans before and after the tDCS sessions. Positive and Negative Symptom Scale (PANSS) total and general psychophathology scale showed a significant improvement after tDCS. There was no significant difference between glutamate/creatinine (Cr) level before and after tDCS sessions. However, a significant positive correlation between the pre-tDCS glutamate/Cr value in left TPA and the improvement in auditory hallucination measured by Auditory Hallucination Rating Scale (AHRS) after tDCS was found.DiscussionThe results of this investigation show that the schizophrenia patients whose auditory hallucination benefits the most from tDCS treatment had lower glutamate/Cr level in left TPA. Previous studies regarding the relationship between glutamatergic system and treatment response mostly have only focused on the frontal area and striatum. However, this study suggests a potential role of glutamatergic system in TPA in predicting treatment response of auditory hallucination.

Correction: Role of Glutamatergic System in Obsessive-Compulsive Disorder with Possible Therapeutic Implications.

Correction: Role of Glutamatergic System in Obsessive-Compulsive Disorder with Possible Therapeutic Implications.

Role of Glutamatergic System in Obsessive-Compulsive Disorder with Possible Therapeutic Implications.

Obsessive-compulsive disorder (OCD) is a chronic psychiatric illness and 1 of the most common anxiety disorders with the prevalence of 3%. Although its pathogenesis remains unclear, the traditional model focused on alternations in the serotonin system. Selective serotonin reuptake inhibitors provide the most effective treatment; however, as much as 40-60% of patients do not respond to antidepressants therapy. Thus, attention has shifted towards other neurotransmitter systems and related neuroanatomical structures. Recently, there is extensive evidence showing a key role of glutamate pathways abnormalities within the cortico-striatal-thalamo-cortical circuitry and temporal lobes in OCD pathogenesis. In this review, we link together the existent neuroanatomical, neurophysiological, and neuropsychological evidence to argue for potential benefits of adjuvant treatment with glutamatergic agents, especially memantine. By a targeted de-excitation effect on the glutamatergic system in the temporal lobes and connected brain regions, memantine might further alleviate OCD symptoms. This effect should be even more pronounced in certain subtypes of patients with specific cognitive deficits and maladaptive compensatory memory processes (e.g., checkers).

Glutamatergic system and mTOR-signaling pathway participate in the antidepressant-like effect of inosine in the tail suspension test.

Glutamatergic system and mTOR signaling pathway have been proposed to be important targets for pharmacological treatment of major depressive disorder. Previous studies have shown that inosine, an endogenous purine, is able to exert a remarkable antidepressant-like effect in mice. Nevertheless, the role of glutamatergic system and mTOR in this effect was not previously determined. This study was designed to investigate the possible modulation of NMDA receptors (NMDAR), AMPA receptors (AMPAR) and mTOR complex 1 (mTORC1) signaling pathway in the inosine anti-immobility effect in the tail suspension test (TST) in mice. Pre-treatment of mice with NMDA (0.1pmol/mouse, NMDAR agonist, i.c.v.) and D-serine (30μg/mouse, NMDAR co-agonist, i.c.v.) prevented inosine (10mg/kg, i.p.) anti-immobility effect in the TST. In addition, a synergistic antidepressant-like effect was observed when a sub-effective dose of inosine (0.1mg/kg, i.p.) was combined with sub-effective doses of NMDAR antagonists MK-801 (0.001mg/kg, p.o.) or ketamine (0.1mg/kg, i.p.). Conversely, the antidepressant-like effect elicited by inosine was not altered by pre-treatment with AMPAR antagonist, DNQX (2.5μg/mouse, i.c.v.). The mTORC1 inhibitor rapamycin (0.2nmol/mouse, i.c.v.) prevented the inosine anti-immobility effect in the TST. Noteworthy, inosine treatment did not change the immunocontent of the synaptic proteins PSD95, GluA1 and synapsin I. Mice locomotor activity assessed by open-field test, was not altered by treatments. Taken together, this study shows a pivotal role of NMDAR inhibition and mTORC1 activation for inosine antidepressant-like effect and extends the knowledge concerning the molecular mechanism and potential of inosine for antidepressant strategies.

Metabotropic glutamate receptor 5 may be involved in macrophage plasticity

BackgroundMacrophages are a functionally heterogeneous cell population and depending on microenvironments they polarize in two main groups: M1 and M2. Glutamic acid and glutamate receptors may participate in the regulation of macrophage plasticity. To investigate the role of glutamatergic systems in macrophages physiology, we performed the transfection of mGluR5 cDNAs into RAW-264.7 cells.ResultsComparative analysis of modified (RAW-mGluR5 macrophages) and non-modified macrophages (RAW-macrophages) has shown that the RAW-mGluR5 macrophages absorbed more glutamate than control cells and the amount of intracellular glutamate correlated with the expression of excitatory amino acid transporters -2 (EAAT-2). Besides, our results have shown that RAW-mGluR5 macrophages expressed a higher level of peroxisome proliferator-activated receptor γ (PPAR-γ) and secreted more IL-10, high mobility group box 1 proteins (HMGB1) and Galectin-3 than control RAW-macrophages.ConclusionsWe propose that elevation of intracellular glutamate and expression of mGluR5 may initiate the metabolic rearrangement in macrophages that could contribute to the formation of an immunosuppressive phenotype.

A brief history of the development of antidepressant drugs: from monoamines to glutamate.

Major depressive disorder (MDD) is a chronic, recurring, and debilitating mental illness that is the most common mood disorder in the United States. It has been almost 50 years since the monoamine hypothesis of depression was articulated, and just over 50 years since the first pharmacological treatment for MDD was discovered. Several monoamine-based pharmacological drug classes have been developed and approved for the treatment of MDD; however, remission rates are low (often less than 60%) and there is a delayed onset before remission of depressive symptoms is achieved. As a result of a "proof-of-concept" study in 2000 with the noncompetitive NMDA antagonist ketamine, a number of studies have examined the glutamatergic systems as viable targets for the treatment of MDD. This review will provide a brief history on the development of clinically available antidepressant drugs, and then review the possible role of glutamatergic systems in the pathophysiology of MDD. Specifically, the glutamatergic review will focus on the N-methyl-D-aspartate (NMDA) receptor and the efficacy of drugs that target the NMDA receptor for the treatment of MDD. The noncompetitive NMDA receptor antagonist ketamine, which has consistently produced rapid and sustained antidepressant effects in MDD patients in a number of clinical studies, has shown the most promise as a novel glutamatergic-based treatment for MDD. However, compounds that target other glutamatergic mechanisms, such as GLYX-13 (a glycine-site partial agonist at NMDA receptors) appear promising in early clinical trials. Thus, the clinical findings to date are encouraging and support the continued search for and the development of novel compounds that target glutamatergic mechanisms.

Disturbance of the glutamatergic system in mood disorders.

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.

Network Effects of Glutamate on Neuronal Activity in the Medial Septum/Diagonal Band Complex In Vitro

Inter-neuronal interactions within the medial septum/diagonal band complex (MSDB) are of great interest as this region is believed to be the hippocampal theta rhythm pacemaker. However, the role of glutamatergic system in functioning of the septal cells is yet unclear. Here, we demonstrate for the first time the effects of glutamate in physiological concentration (1 microM) on the MSDB neuronal spontaneous and evoked activities in vitro. These effects (activation of 70% and inhibition of 30% of responsive neurons) differed in pacemaker and non-pacemaker cells. Pacemaker cells were always activated under glutamate, whereas non-pacemaker neurons could be either activated or inhibited. Indeed, in the burst pacemakers, glutamate increased the frequency of rhythmic activity. In a total MSDB neuron population, in 30% of neurons glutamate applications modified responses to the electrical stimulation by unifying the temporal parameters of neuron responses. Along with the increase in the theta-burst frequency, this indicates that the glutamatergic system is involved in the process ofintraseptal synchronization. Obtained data shed light on the role ofglutamatergic system in septal neuron interactions and broaden our understanding of theta oscillation mechanisms in the septo-hippocampal system.

The role of central 5-HT2C and NMDA receptors on LPS-induced feeding behavior in chickens

In mammals, LPS regulate feeding primarily through the 5-HT(1A) and 5-HT(2c) receptors within the brain. However, the central effect of 5-HT(1A) and 5-HT(2c) on LPS-induced feeding behavior has not been studied in non-mammalian species. Also, the role of glutamatergic system in LPS-induced anorexia has never been examined in either mammalian or non-mammalian species. Therefore, in this study, we examined the role of serotonergic and glutamatergic systems on LPS-induced anorexia in chickens. Food intake was measured in chickens after centrally administered lipopolysaccharide (LPS) (20ng) (0h), followed by intracerebroventricular (ICV) injection of the 5-HT(1A) autoreceptor agonist (8-OH-DPAT, 61nmol), 5-HT(2c) receptor antagonist (SB 242084, 30nm), and NMDA receptor antagonist (DL-AP5, 5nm) at the onset of anorexia (4h). In the following experiments, we used DL-AP5 before 5-HT (10μg) and SB242084 before glutamate (300nm) for evaluation of the interaction between 5-HTergic and glutamatergic systems on food intake. The results of this study showed that SB 242084 and DL-AP5 significantly attenuated food intake reduction caused by LPS (P<0.05) but 8-OH-DPAT had no effect. In addition, 5-HT-induced anorexia was significantly attenuated by DL-AP5 pretreatment (P<0.05), while SB 242084 had no effect on glutamate-induced hypophagia. These results indicated that 5-HT and glutamate (via 5-HT(2c) and NMDA receptor, respectively) dependently regulate LPS-induced hypophagia in chickens.

Glutamate receptors in neuronal and immune system cells

The role of glutamatergic system in synaptic transmission and excitotoxicity is well established. Moreover, expression of glutamate receptors in a number of non-neuronal cells, where they may perform specific, as yet unknown functions, becomes evident. While the role of glutamic acid in the non-neuronal cells is not totally understood, this compound can be considered as a specific regulatory molecule not only for the central nervous system. Actually, recent publications demonstrate that glutamate receptors expressed in lymphocytes take part in the processes of their activation. Therefore, within the framework of the well-known paradigm of interaction between nervous and immune systems, glutamate can be regarded as neuroimmune modulator. Glutamate action on the immune cells may play an important role in the pathogenesis of different diseases, especially those accompanied by inflammatory reactions and/or increased levels of glutamate in brain and peripheral blood stream.

Functional interaction of NMDA and group I metabotropic glutamate receptors in negatively reinforced learning in rats

The role of glutamatergic system in learning and memory has been extensively studied, and especially N-methyl-D: -aspartate (NMDA) receptors have been implicated in different learning and memory processes. Less is known, however, about group I metabotropic glutamate (mGlu) receptors in this field. Recent studies indicated that the coactivation of both NMDA and group I mGlu receptors is required for the induction of long-term potentiation (LTP) and learning. The purpose of the study is to evaluate if there is a functional interaction between NMDA and group I mGlu receptors in two different models of aversive learning. Effects of NMDA, mGlu1, and mGlu5 receptor antagonists on acquisition were tested after systemic coadministration of selected ineffective doses in passive avoidance (PA) and fear-potentiated startle (FPS). Interaction in aversive learning was investigated using selective antagonists: (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM) for mGlu1, [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) for mGlu5, and (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate [(+)MK-801] for NMDA receptors. In PA, the coapplication of MTEP at a dose of 5 mg/kg and (+)MK-801 at a dose of 0.1 mg/kg 30 min before training impaired the acquisition tested 24 h later. Similarly, EMQMCM (2.5 mg/kg) plus (+)MK-801 (0.1 mg/kg), given during the acquisition phase, blocked the acquisition of the PA response. In contrast, neither the combination of MTEP (1.25 mg/kg) nor EMQMCM (5 mg/kg) plus (+)MK-801 (0.05 mg/kg) was effective on the acquisition assessed in the FPS paradigm. The findings suggest differences in the interaction of the NMDA and mGlu group I receptor types in aversive instrumental conditioning vs conditioning to a discrete light cue.

Cognition in Schizophrenia: Impairments, Importance, and Treatment Strategies

Cognition in Schizophrenia: Impairments, Importance, and Treatment Strategies