Characterisation of the human NMDA receptor subunit NR3A glycine binding site
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Nilsson, A; Duan, J; Mo-Boquist, L-L
2007-01-01
In this study, we characterise the binding site of the human N-methyl-d-aspartate (NMDA) receptor subunit NR3A. Saturation radioligand binding of the NMDA receptor agonists [(3)H]-glycine and [(3)H]-glutamate showed that only glycine binds to human NR3A (hNR3A) with high affinity (K(d)=535nM (277...
[3H]CGP 61594, the first photoaffinity ligand for the glycine site of NMDA receptors
International Nuclear Information System (INIS)
Benke, D.; Honer, M.; Mohler, H.; Heckendorn, R.; Pozza, M.F.; Allgeier, H.; Angst, C.
1999-01-01
Activation of NMDA receptors requires the presence of glycine as a coagonist which binds to a site that is allosterically linked to the glutamate binding site. To identify the protein constituents of the glycine binding site in situ the photoaffinity label [ 3 H]CGP 61594 was synthesized. In reversible binding assays using crude rat brain membranes, [ 3 H]CGP 61594 labeled with high affinity (K D =23 nM) the glycine site of the NMDA receptor. This was evident from the Scatchard analysis, the displacing potencies of various glycine site ligands and the allosteric modulation of [ 3 H]CGP 61594 binding by ligands of the glutamate and polyamine sites. Electrophysiological experiments in a neocortical slice preparation identified CGP 61594 as a glycine antagonist. Upon UV-irradiation, a protein band of 115 kDa was specifically photolabeled by [ 3 H]CGP 61594 in brain membrane preparations. The photolabeled protein was identified as the NR1 subunit of the NMDA receptor by NR1 subunit-specific immunoaffinity chromatography. Thus, [ 3 H]CGP 61594 is the first photoaffinity label for the glycine site of NMDA receptors. It will serve as a tool for the identification of structural elements that are involved in the formation of the glycine binding domain of NMDA receptors in situ and will thereby complement the mutational analysis of recombinant receptors. (Copyright (c) 1999 Elsevier Science B.V., Amsterdam. All rights reserved.)
[{sup 3}H]CGP 61594, the first photoaffinity ligand for the glycine site of NMDA receptors
Energy Technology Data Exchange (ETDEWEB)
Benke, D.; Honer, M.; Mohler, H. [Institute of Pharmacology, ETH and University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich (Switzerland); Heckendorn, R.; Pozza, M.F.; Allgeier, H.; Angst, C. [NS Research, Novartis Pharma AG, CH-4002 Basle (Switzerland)
1999-02-01
Activation of NMDA receptors requires the presence of glycine as a coagonist which binds to a site that is allosterically linked to the glutamate binding site. To identify the protein constituents of the glycine binding site in situ the photoaffinity label [{sup 3}H]CGP 61594 was synthesized. In reversible binding assays using crude rat brain membranes, [{sup 3}H]CGP 61594 labeled with high affinity (K{sub D}=23 nM) the glycine site of the NMDA receptor. This was evident from the Scatchard analysis, the displacing potencies of various glycine site ligands and the allosteric modulation of [{sup 3}H]CGP 61594 binding by ligands of the glutamate and polyamine sites. Electrophysiological experiments in a neocortical slice preparation identified CGP 61594 as a glycine antagonist. Upon UV-irradiation, a protein band of 115 kDa was specifically photolabeled by [{sup 3}H]CGP 61594 in brain membrane preparations. The photolabeled protein was identified as the NR1 subunit of the NMDA receptor by NR1 subunit-specific immunoaffinity chromatography. Thus, [{sup 3}H]CGP 61594 is the first photoaffinity label for the glycine site of NMDA receptors. It will serve as a tool for the identification of structural elements that are involved in the formation of the glycine binding domain of NMDA receptors in situ and will thereby complement the mutational analysis of recombinant receptors. (Copyright (c) 1999 Elsevier Science B.V., Amsterdam. All rights reserved.)
Potentiation of glycine-gated NR1/NR3A NMDA receptors relieves Ca2+-dependent outward rectification
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Christian Madry
2010-03-01
Full Text Available Glycine has diverse functions within the mammalian central nervous system. It inhibits postsynaptic neurons via strychnine-sensitive glycine receptors (GlyRs and enhances neuronal excitation through co-activation of N-methyl-D-aspartate (NMDA receptors. Classical Ca2+-permeable NMDA receptors are composed of glycine-binding NR1 and glutamate-binding NR2 subunits, and hence require both glutamate and glycine for efficient activation. In contrast, recombinant receptors composed of NR1 and the glycine binding NR3A and/or NR3B subunits lack glutamate binding sites and can be activated by glycine alone. Therefore these receptors are also named excitatory glycine receptors. Co-application of antagonists of the NR1 glycine-binding site or of the divalent cation Zn2+ markedly enhances the glycine responses of these receptors. To gain further insight into the properties of these glycine-gated NMDA receptors, we investigated their current-voltage (I-V dependence. Whole-cell current-voltage relations of glycine currents recorded from NR1/NR3B and NR1/NR3A/NR3B expressing oocytes were found to be linear under our recording conditions. In contrast, NR1/NR3A receptors displayed a strong outwardly rectifying I-V relation. Interestingly, the voltage-dependent inward current block was abolished in the presence of NR1 antagonists, Zn2+ or a combination of both. Further analysis revealed that Ca2+ (1.8 mM present in our recording solutions was responsible for the voltage-dependent inhibition of ion flux through NR1/NR3A receptors. Since physiological concentrations of the divalent cation Mg2+ did not affect the I-V dependence, our data suggest that relief of the voltage-dependent Ca2+ block of NR1/NR3A receptors by Zn2+ may be important for the regulation of excitatory glycinergic transmission, according to the Mg2+-block of conventional NR1/NR2 NMDA receptors.
Musante, Veronica; Summa, Maria; Cunha, Rodrigo A; Raiteri, Maurizio; Pittaluga, Anna
2011-05-01
Rat hippocampal glutamatergic terminals possess NMDA autoreceptors whose activation by low micromolar NMDA elicits glutamate exocytosis in the presence of physiological Mg(2+) (1.2 mM), the release of glutamate being significantly reduced when compared to that in Mg(2+)-free condition. Both glutamate and glycine were required to evoke glutamate exocytosis in 1.2 mM Mg(2+), while dizocilpine, cis-4-[phosphomethyl]-piperidine-2-carboxylic acid and 7-Cl-kynurenic acid prevented it, indicating that occupation of both agonist sites is needed for receptor activation. D-serine mimicked glycine but also inhibited the NMDA/glycine-induced release of [(3H]D-aspartate, thus behaving as a partial agonist. The NMDA/glycine-induced release in 1.2 mM Mg(2+) strictly depended on glycine uptake through the glycine transporter type 1 (GlyT1), because the GlyT1 blocker N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])sarcosine hydrochloride, but not the GlyT2 blocker Org 25534, prevented it. Accordingly, [(3)H]glycine was taken up during superfusion, while lowering the external concentration of Na(+), the monovalent cation co-transported with glycine by GlyT1, abrogated the NMDA-induced effect. Western blot analysis of subsynaptic fractions confirms that GlyT1 and NMDA autoreceptors co-localize at the pre-synaptic level, where GluN3A subunits immunoreactivity was also recovered. It is proposed that GlyT1s coexist with NMDA autoreceptors on rat hippocampal glutamatergic terminals and that glycine taken up by GlyT1 may permit physiological activation of NMDA pre-synaptic autoreceptors. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.
Effects of sarcosine and N, N-dimethylglycine on NMDA receptor-mediated excitatory field potentials.
Lee, Mei-Yi; Lin, Yi-Ruu; Tu, Yi-Shu; Tseng, Yufeng Jane; Chan, Ming-Huan; Chen, Hwei-Hsien
2017-02-28
Sarcosine, a glycine transporter type 1 inhibitor and an N-methyl-D-aspartate (NMDA) receptor co-agonist at the glycine binding site, potentiates NMDA receptor function. Structurally similar to sarcosine, N,N-dimethylglycine (DMG) is also N-methyl glycine-derivative amino acid and commonly used as a dietary supplement. The present study compared the effects of sarcosine and DMG on NMDA receptor-mediated excitatory field potentials (EFPs) in mouse medial prefrontal cortex brain slices using a multi-electrode array system. Glycine, sarcosine and DMG alone did not alter the NMDA receptor-mediated EFPs, but in combination with glutamate, glycine and its N-methyl derivatives significantly increased the frequency and amplitude of EFPs. The enhancing effects of glycine analogs in combination with glutamate on EFPs were remarkably reduced by the glycine binding site antagonist 7-chlorokynurenate (7-CK). However, DMG, but not sarcosine, reduced the frequency and amplitude of EFPs elicited by co-application of glutamate plus glycine. D-cycloserine, a partial agonist at the glycine binding site on NMDA receptors, affected EFPs in a similar manner to DMG. Furthermore, DMG, but not sarcosine, reduced the frequencies and amplitudes of EFPs elicited by glutamate plus D-serine, another endogenous ligand for glycine binding site. These findings suggest that sarcosine acts as a full agonist, yet DMG is a partial agonist at glycine binding site of NMDA receptors. The molecular docking analysis indicated that the interactions of glycine, sarcosine, and DMG to NMDA receptors are highly similar, supporting that the glycine binding site of NMDA receptors is a critical target site for sarcosine and DMG.
Zhou, Shuang-jiang; Xue, Li-fen; Wang, Xue-yi; Jiang, Wen-gao; Xue, Yan-xue; Liu, Jian-feng; He, Yin-yin; Luo, Yi-xiao; Lu, Lin
2012-05-01
Accumulating clinical and preclinical studies have shown that the memories of the rewarding effects of drugs and their paired cues may contribute to relapse and persistent cocaine use. Glutaminergic actions in the ventral tegmental area (VTA) have been shown to regulate the rewarding effect of drugs and conditioned responses to drug-associated cues, but the role of the VTA in the acquisition, retrieval, and reconsolidation of cocaine cues is not yet known. In the present study, we used 7-chlorothiokynurenic acid (7-CTKA), an N-methyl-D-aspartate (NMDA) receptor glycine modulatory site antagonist with no rewarding effects, to examine the role of the NMDA receptor glycine modulatory site in the acquisition, retrieval, and reconsolidation of cocaine-related reward memory using the conditioned place preference (CPP) paradigm. Separate groups of Sprague-Dawley rats were trained to acquire cocaine-induced CPP. Vehicle or 7-CTKA was microinjected into the VTA or substantia nigra (SN) (5 μg/μl) at different time points: 10 min before each CPP training session (acquisition), 10 min before the reactivation of CPP (retrieval), and immediately after the reactivation of CPP (reconsolidation). Cocaine-induced CPP was retested 24 h and 1 and 2 weeks after 7-CTKA administration. 7-CTKA microinjected into the VTA, but not SN, significantly impaired the acquisition, retrieval, and reconsolidation of cocaine-induced CPP without affecting cocaine-induced locomotion. Our findings suggest that the NMDA receptor glycine modulatory site in the VTA plays a major role in cocaine reward memory, and NMDA receptor glycine site antagonists may be potential pharmacotherapies for the management of relapse.
Increased NMDA receptor inhibition at an increased Sevoflurane MAC
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Brosnan Robert J
2012-06-01
Full Text Available Abstract Background Sevoflurane potently enhances glycine receptor currents and more modestly decreases NMDA receptor currents, each of which may contribute to immobility. This modest NMDA receptor antagonism by sevoflurane at a minimum alveolar concentration (MAC could be reciprocally related to large potentiation of other inhibitory ion channels. If so, then reduced glycine receptor potency should increase NMDA receptor antagonism by sevoflurane at MAC. Methods Indwelling lumbar subarachnoid catheters were surgically placed in 14 anesthetized rats. Rats were anesthetized with sevoflurane the next day, and a pre-infusion sevoflurane MAC was measured in duplicate using a tail clamp method. Artificial CSF (aCSF containing either 0 or 4 mg/mL strychnine was then infused intrathecally at 4 μL/min, and the post-infusion baseline sevoflurane MAC was measured. Finally, aCSF containing strychnine (either 0 or 4 mg/mL plus 0.4 mg/mL dizocilpine (MK-801 was administered intrathecally at 4 μL/min, and the post-dizocilpine sevoflurane MAC was measured. Results Pre-infusion sevoflurane MAC was 2.26%. Intrathecal aCSF alone did not affect MAC, but intrathecal strychnine significantly increased sevoflurane requirement. Addition of dizocilpine significantly decreased MAC in all rats, but this decrease was two times larger in rats without intrathecal strychnine compared to rats with intrathecal strychnine, a statistically significant (P Conclusions Glycine receptor antagonism increases NMDA receptor antagonism by sevoflurane at MAC. The magnitude of anesthetic effects on a given ion channel may therefore depend on the magnitude of its effects on other receptors that modulate neuronal excitability.
Ramoino, Paola; Candiani, Simona; Pittaluga, Anna Maria; Usai, Cesare; Gallus, Lorenzo; Ferrando, Sara; Milanese, Marco; Faimali, Marco; Bonanno, Giambattista
2014-02-01
Paramecium primaurelia is a unicellular eukaryote that moves in freshwater by ciliary beating and responds to environmental stimuli by altering motile behaviour. The movements of the cilia are controlled by the electrical changes of the cell membrane: when the intraciliary Ca(2+) concentration associated with plasma membrane depolarization increases, the ciliary beating reverses its direction, and consequently the swimming direction changes. The ciliary reversal duration is correlated with the amount of Ca(2+) influx. Here, we evaluated the effects due to the activation or blockade of N-methyl-d-aspartic acid (NMDA) receptors on swimming behaviour in Paramecium. Paramecia normally swim forward, drawing almost linear tracks. We observed that the simultaneous administration of NMDA and glycine induced a partial ciliary reversal (PaCR) leading to a continuous spiral-like swim. Furthermore, the duration of continuous ciliary reversal (CCR), triggered by high external KCl concentrations, was longer in NMDA+glycine-treated cells. NMDA action required the presence of Ca(2+), as the normal forward swimming was restored when the ion was omitted from the extracellular milieu. The PaCR and the enhancement of CCR duration significantly decreased when the antagonists of the glutamate site D-AP5 or CGS19755, the NMDA channel blocker MK-801 or the glycine site antagonist DCKA was added. The action of NMDA+glycine was also abolished by Zn(2+) or ifenprodil, the GluN2A and the GluN2B NMDA-containing subunit blockers, respectively. Searches of the Paramecium genome database currently available indicate that the NMDA-like receptor with ligand-binding characteristics of an NMDA receptor-like complex, purified from rat brain synaptic membranes and found in some metazoan genomes, is also present in Paramecium. These results provide evidence that functional NMDA receptors similar to those typical of mammalian neuronal cells are present in the single-celled organism Paramecium and thus
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Thorsten Pauly
Full Text Available Functional and structural alterations of clustered postsynaptic ligand gated ion channels in neuronal cells are thought to contribute to synaptic plasticity and memory formation in the human brain. Here, we describe a novel molecular mechanism for structural alterations of NR1 subunits of the NMDA receptor. In cultured rat spinal cord neurons, chronic NMDA receptor stimulation induces disappearance of extracellular epitopes of NMDA receptor NR1 subunits, which was prevented by inhibiting matrix metalloproteinases (MMPs. Immunoblotting revealed the digestion of solubilized NR1 subunits by MMP-3 and identified a fragment of about 60 kDa as MMPs-activity-dependent cleavage product of the NR1 subunit in cultured neurons. The expression of MMP-3 in the spinal cord culture was shown by immunoblotting and immunofluorescence microscopy. Recombinant NR1 glycine binding protein was used to identify MMP-3 cleavage sites within the extracellular S1 and S2-domains. N-terminal sequencing and site-directed mutagenesis revealed S542 and L790 as two putative major MMP-3 cleavage sites of the NR1 subunit. In conclusion, our data indicate that MMPs, and in particular MMP-3, are involved in the activity dependent alteration of NMDA receptor structure at postsynaptic membrane specializations in the CNS.
Pauly, Thorsten; Ratliff, Miriam; Pietrowski, Eweline; Neugebauer, Rainer; Schlicksupp, Andrea; Kirsch, Joachim; Kuhse, Jochen
2008-07-16
Functional and structural alterations of clustered postsynaptic ligand gated ion channels in neuronal cells are thought to contribute to synaptic plasticity and memory formation in the human brain. Here, we describe a novel molecular mechanism for structural alterations of NR1 subunits of the NMDA receptor. In cultured rat spinal cord neurons, chronic NMDA receptor stimulation induces disappearance of extracellular epitopes of NMDA receptor NR1 subunits, which was prevented by inhibiting matrix metalloproteinases (MMPs). Immunoblotting revealed the digestion of solubilized NR1 subunits by MMP-3 and identified a fragment of about 60 kDa as MMPs-activity-dependent cleavage product of the NR1 subunit in cultured neurons. The expression of MMP-3 in the spinal cord culture was shown by immunoblotting and immunofluorescence microscopy. Recombinant NR1 glycine binding protein was used to identify MMP-3 cleavage sites within the extracellular S1 and S2-domains. N-terminal sequencing and site-directed mutagenesis revealed S542 and L790 as two putative major MMP-3 cleavage sites of the NR1 subunit. In conclusion, our data indicate that MMPs, and in particular MMP-3, are involved in the activity dependent alteration of NMDA receptor structure at postsynaptic membrane specializations in the CNS.
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Helga eHöifödt Lidö
2011-03-01
Full Text Available AbstractAccumbal glycine modulates basal and ethanol-induced dopamine levels in the nucleus accumbens (nAc as well as voluntary ethanol consumption. Also, systemic administration of the glycine transporter-1 inhibitor Org25935 elevates dopamine levels in nAc, prevents a further ethanol-induced dopamine elevation and robustly and dose-dependently decreases ethanol consumption in rats. Here we investigated whether Org25935 applied locally in nAc modulates dopamine release, and whether accumbal glycine receptors or NMDA receptors are involved in this tentative effect. We also addressed whether Org25935 and ethanol applied locally in nAc interact with dopamine levels, as seen after systemic administration. We used in vivo microdialysis coupled to HPLC-ED in freely moving male Wistar rats to monitor dopamine output in nAc after local perfusion of Org25935 alone, with ethanol, or Org25935-perfusion after pre-treatment with the glycine receptor antagonist strychnine or the NMDA receptor glycine site antagonist L-701.324. Local Org25935 increased extracellular dopamine levels in a subpopulation of rats. Local strychnine, but not systemic L-701.324, antagonized the dopamine-activating effect of Org25935. Ethanol failed to induce a dopamine overflow in the subpopulation responding to Org25935 with a dopamine elevation. The study supports a role for accumbal glycine receptors rather than NMDA receptor signaling in the dopamine-activating effect of Org25935. The results further indicate that the previously reported systemic Org25935-ethanol interaction with regard to accumbal dopamine is localized to the nAc. This adds to the growing evidence for the glycine receptor as an important player in the dopamine reward circuitry and in ethanol’s effects within this system.
Layer, R T; Bland, L R; Skolnick, P
1993-10-15
Repeated administration of methamphetamine (METH) results in damage to nigrostriatal dopaminergic neurons. Both competitive N-methyl-D-aspartate (NMDA) receptor antagonists and use-dependent cation channel blockers attenuate METH-induced damage. The objectives of the present study were to examine whether comparable reductions in METH-induced damage could be obtained by compounds acting at strychnine-insensitive glycine receptors on the NMDA receptor complex. Four injections of METH (5 mg/kg i.p.) resulted in a approximately 70.9% depletion of striatal dopamine (DA) and approximately 62.7% depletion of dihydroxyphenylacetic acid (DOPAC) content, respectively. A significant protection against METH-induced DA and DOPAC depletion was afforded by the use-dependent channel blocker, MK-801. The competitive glycine antagonist 7-chlorokynurenic acid (7-Cl-KA), the low efficacy glycine partial agonist (+)-3-amino-1-hydroxy-2-pyrrolidone ((+)-HA-966), and the high efficacy partial glycine agonist 1-aminocyclopropane-carboxylic acid (ACPC) were ineffective against METH-induced toxicity despite their abilities to attenuate glutamate-induced neurotoxicity under both in vivo and in vitro conditions. These results indicate that glycinergic ligands do not possess the same broad neuroprotective spectrum as other classes of NMDA antagonists.
DEFF Research Database (Denmark)
Kvist, Trine; Steffensen, Thomas Bielefeldt; Greenwood, Jeremy R
2013-01-01
NMDA receptors are ligand-gated ion channels that mediate excitatory neurotransmission in the brain. They are tetrameric complexes composed of glycine-binding GluN1 and GluN3 subunits together with glutamate-binding GluN2 subunits. Subunit-selective antagonists that discriminate between the glyci...... screening. Furthermore, the structure reveals that the imino acetamido group of TK40 acts as an α-amino acid bioisostere, which could be of importance in bioisosteric replacement strategies for future ligand design....
Characterisation of the Redox Sensitive NMDA Receptor
Alzahrani, Ohood
2016-05-01
Glucose entry into the brain and its subsequent metabolism to L-lactate, regulated by astrocytes, plays a major role in synaptic plasticity and memory formation. A recent study has shown that L-lactate produced by the brain upon stimulation of glycolysis, and glycogen-derived L-lactate from astrocytes and its transport into neurons, is crucial for memory formation. A recent study revealed the molecular mechanisms that underlie the role of L-lactate in neuronal plasticity and long-term memory formation. L-lactate was shown to induce a cascade of molecular events via modulation of redox-sensitive N-Methyl-D-aspartate (NMDA) receptor activity that was mimicked by nicotinamide adenine dinucleotide hydride (NADH) co-enzyme. This indicated that changes in cellular redox state, following L-lactate transport inside the cells and its subsequent metabolism, production of NADH, and favouring a reduced state are the key effects of L-lactate. Therefore, we are investigating the role of L-lactate in modulating NMDA receptor function via redox modulatory sites. Accordingly, crucial redox-sensitive cysteine residues, Cys320 and Cys87, of the NR2A NMDA receptor subunit are mutated using site-directed mutation, transfected, and expressed in HEK293 cells. This cellular system will then be used to characterise and monitor its activity upon Llactate stimulation, compared to the wild type. This will be achieved by calcium imaging, using fluorescent microscopy. Our data shows that L-lactate potentiated NMDA receptor activity and increased intracellular calcium influx in NR1/NR2A wild type compared to the control condition (WT NR1/NR2A perfused with (1μM) glutamate and (1μM) glycine agonist only), showing faster response initiation and slower decay rate of the calcium signal to the baseline. Additionally, stimulating with L-lactate associated with greater numbers of cells having high fluorescent intensity (peak amplitude) compared to the control. Furthermore, L-lactate rescued the
Zanos, Panos; Piantadosi, Sean C; Wu, Hui-Qiu; Pribut, Heather J; Dell, Matthew J; Can, Adem; Snodgrass, H Ralph; Zarate, Carlos A; Schwarcz, Robert; Gould, Todd D
2015-10-01
Currently approved antidepressant drug treatment typically takes several weeks to be effective. The noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has shown efficacy as a rapid-acting treatment of 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, located on the GluN1 subunit, by the selective full antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), delivered by systemic administration of its brain-penetrant prodrug 4-chlorokynurenine (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 pretreatment 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 without the negative side effects seen with ketamine or other channel-blocking NMDA receptor antagonists. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
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Jessen, Maja; Frederiksen, Kristen; Yi, Feng
2017-01-01
N-methyl-d-aspartate (NMDA)-type ionotropic glutamate receptors mediate excitatory neurotransmission in the central nervous system and are critically involved in brain function. NMDA receptors are also implicated in psychiatric and neurological disorders and have received considerable attention....../2A-D), in which DCS is a superagonist at GluN2C-containing receptors compared with glycine and a partial agonist at GluN2B-containing receptors. Here, we identify (R)-2-amino-3-(4-(2-ethylphenyl)-1H-indole-2-carboxamido)propanoic acid (AICP) as a glycine site agonist with unique GluN2-dependent...
Nagy, Katalin; Marko, Bernadett; Zsilla, Gabriella; Matyus, Peter; Pallagi, Katalin; Szabo, Geza; Juranyi, Zsolt; Barkoczy, Jozsef; Levay, Gyorgy; Harsing, Laszlo G
2010-12-01
The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D(2) dopamine receptors. N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors, which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D(2) dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461. Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA, glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed. When risperidone and Org-24461 were added in combination, a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT-1 inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced
Tong, Gary; Takahashi, Hiroto; Tu, Shichun; Shin, Yeonsook; Talantova, Maria; Zago, Wagner; Xia, Peng; Nie, Zhiguo; Goetz, Thomas; Zhang, Dongxian; Lipton, Stuart A.; Nakanishi, Nobuki
2015-01-01
Expression of the NR3A subunit with NR1/NR2 in Xenopus oocytes or mammalian cell lines leads to a reduction in N-methyl-D-aspartate (NMDA)-induced currents and decreased Mg2+ sensitivity and Ca2+ permeability compared with NR1/NR2 receptors. Consistent with these findings, neurons from NR3A knockout (KO) mice exhibit enhanced NMDA-induced currents. Recombinant NR3A can also form excitatory glycine receptors with NR1 in the absence of NR2. However, the effects of NR3A on channel properties in neurons and synaptic transmission have not been fully elucidated. To study physiological roles of NR3A subunits, we generated NR3A transgenic (Tg) mice. Cultured NR3A Tg neurons exhibited two populations of NMDA receptor (NMDAR) channels, reduced Mg2+ sensitivity, and decreased Ca2+ permeability in response to NMDA/glycine, but glycine alone did not elicit excitatory currents. In addition, NMDAR-mediated excitatory postsynaptic currents (EPSCs) in NR3A Tg hippocampal slices showed reduced Mg2+ sensitivity, consistent with the notion that NR3A subunits incorporated into synaptic NMDARs. To study the function of endogenous NR3A subunits, we compared NMDAR-mediated EPSCs in NR3A KO and WT control mice. In NR3A KO mice, the ratio of the amplitudes of the NMDAR-mediated component to α-amino-3-hydroxy-5-methyl-4-isox-azolepropionic acid receptor-mediated component of the EPSC was significantly larger than that seen in WT littermates. This result suggests that NR3A subunits contributed to the NMDAR-mediated component of the EPSC in WT mice. Taken together, these results show that NR3A subunits contribute to NMDAR responses from both synaptic and extra-synaptic receptors, likely composed of NR1, NR2, and NR3 subunits. PMID:18003876
Molecular pharmacology of human NMDA receptors
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Hedegaard, Maiken; Hansen, Kasper Bø; Andersen, Karen Toftegaard
2012-01-01
N-methyl-d-aspartate (NMDA) receptors are ionotropic glutamate receptors that mediate excitatory neurotransmission. NMDA receptors are also important drug targets that are implicated in a number of pathophysiological conditions. To facilitate the transition from lead compounds in pre-clinical ani...
High Concentrations of Tranexamic Acid Inhibit Ionotropic Glutamate Receptors.
Lecker, Irene; Wang, Dian-Shi; Kaneshwaran, Kirusanthy; Mazer, C David; Orser, Beverley A
2017-07-01
The antifibrinolytic drug tranexamic acid is structurally similar to the amino acid glycine and may cause seizures and myoclonus by acting as a competitive antagonist of glycine receptors. Glycine is an obligatory co-agonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. Thus, it is plausible that tranexamic acid inhibits NMDA receptors by acting as a competitive antagonist at the glycine binding site. The aim of this study was to determine whether tranexamic acid inhibits NMDA receptors, as well as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate subtypes of ionotropic glutamate receptors. Tranexamic acid modulation of NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate receptors was studied using whole cell voltage-clamp recordings of current from cultured mouse hippocampal neurons. Tranexamic acid rapidly and reversibly inhibited NMDA receptors (half maximal inhibitory concentration = 241 ± 45 mM, mean ± SD; 95% CI, 200 to 281; n = 5) and shifted the glycine concentration-response curve for NMDA-evoked current to the right. Tranexamic acid also inhibited α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (half maximal inhibitory concentration = 231 ± 91 mM; 95% CI, 148 to 314; n = 5 to 6) and kainate receptors (half maximal inhibitory concentration = 90 ± 24 mM; 95% CI, 68 to 112; n = 5). Tranexamic acid inhibits NMDA receptors likely by reducing the binding of the co-agonist glycine and also inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors. Receptor blockade occurs at high millimolar concentrations of tranexamic acid, similar to the concentrations that occur after topical application to peripheral tissues. Glutamate receptors in tissues including bone, heart, and nerves play various physiologic roles, and tranexamic acid inhibition of these receptors may contribute to adverse drug effects.
NMDA Receptor Modulators in the Treatment of Drug Addiction.
Tomek, Seven E; Lacrosse, Amber L; Nemirovsky, Natali E; Olive, M Foster
2013-02-06
Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA) glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.
NMDA Receptor Modulators in the Treatment of Drug Addiction
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M. Foster Olive
2013-02-01
Full Text Available Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.
NMDA receptor function during senescence: implication on cognitive performance
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Ashok eKumar
2015-12-01
Full Text Available N-methyl-D-aspartate (NMDA receptors, a family of L-glutamate receptors, play an important role in learning and memory, and are critical for spatial memory. These receptors are tetrameric ion channels composed of a family of related subunits. One of the hallmarks of the aging human population is a decline in cognitive function; studies in the past couple of years have demonstrated deterioration in NMDA receptor subunit expression and function with advancing age. However, a direct relationship between impaired memory function and a decline in NMDA receptors is still ambiguous. Recent studies indicate a link between an age-associated NMDA receptor hypofunction and memory impairment and provide evidence that age-associated enhanced oxidative stress might be contributing to the alterations associated with senescence. However, clear evidence is still deficient in demonstrating the underlying mechanisms and a relationship between age-associated impaired cognitive faculties and NMDA receptor hypofunction. The current review intends to present an overview of the research findings regarding changes in expression of various NMDA receptor subunits and deficits in NMDA receptor function during senescence and its implication in age-associated impaired hippocampal-dependent memory function.
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Lewin, A.H.; Lamb, P.B. [Research Triangle Inst., Research Triangle Park, NC (United States); Popik, P.; Skolnick, P. [National Insts. of Health, Bethesda, MD (United States)
1994-11-01
Catalytic hydrogenation of 1-aminocyclopropenecarboxylic acid under tritium gas afforded [2,3-{sup 3}H]1-aminocyclopropanecarboxylic acid with specific activity 26 Ci/mmol, determined by a combination of {sup 1}H and {sup 3}H NMR. Pilot radioligand binding assays indicate this compound will be a useful prove for the NMDA receptor-associated strychnine-insensitive glycine receptor. (author).
Kawaura, Kazuaki; Koike, Hiroyuki; Kinoshita, Kohnosuke; Kambe, Daiji; Kaku, Ayaka; Karasawa, Jun-ichi; Chaki, Shigeyuki; Hikichi, Hirohiko
2015-02-01
Glutamatergic dysfunction, particularly the hypofunction of N-methyl-D-aspartate (NMDA) receptors, is involved in the pathophysiology of schizophrenia. The positive modulation of the glycine site on the NMDA receptor has been proposed as a novel therapeutic approach for schizophrenia. However, its efficacy against negative symptoms, which are poorly managed by current medications, has not been fully addressed. In the present study, the effects of the positive modulation of the glycine site on the NMDA receptor were investigated in an animal model of negative symptoms of schizophrenia. The subchronic administration of MK-801 increased immobility in the forced swimming test in rats without affecting spontaneous locomotor activity. The increased immobility induced by MK-801 was attenuated by the atypical antipsychotic clozapine but not by either the typical antipsychotic haloperidol or the antidepressant imipramine, indicating that the increased immobility induced by subchronic treatment with MK-801 in the forced swimming test may represent a negative symptom of schizophrenia. Likewise, positive modulation of the glycine sites on the NMDA receptor using an agonist for the glycine site, D-serine, and a glycine transporter-1 inhibitor, N-[(3R)-3-([1,1'-biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine hydrochloride (NFPS), significantly reversed the increase in immobility in MK-801-treated rats without reducing the immobility time in vehicle-treated rats. The present results show that the stimulation of the NMDA receptor through the glycine site on the receptor either directly with D-serine or by blocking glycine transporter-1 attenuates the immobility elicited by the subchronic administration of MK-801 and may be potentially useful for the treatment of negative symptoms of schizophrenia. Copyright © 2014 Elsevier B.V. All rights reserved.
The role of striatal NMDA receptors in drug addiction.
Ma, Yao-Ying; Cepeda, Carlos; Cui, Cai-Lian
2009-01-01
The past decade has witnessed an impressive accumulation of evidence indicating that the excitatory amino acid glutamate and its receptors, in particular the N-methyl-D-aspartate (NMDA) receptor subtype, play an important role in drug addiction. Various lines of research using animal models of drug addiction have demonstrated that drug-induced craving is accompanied by significant upregulation of NR2B subunit expression. Furthermore, selective blockade of NR2B-containing NMDA receptors in the striatum, especially in the nucleus accumbens (NAc) can inhibit drug craving and reinstatement. The purpose of this review is to examine the role of striatal NMDA receptors in drug addiction. After a brief description of glutamatergic innervation and NMDA receptor subunit distribution in the striatum, we discuss potential mechanisms to explain the role of striatal NMDA receptors in drug addiction by elucidating signaling cascades involved in the regulation of subunit expression and redistribution, phosphorylation of receptor subunits, as well as activation of intracellular signals triggered by drug experience. Understanding the mechanisms regulating striatal NMDA receptor changes in drug addiction will provide more specific and rational targets to counteract the deleterious effects of drug addiction.
NMDA Receptors in Glial Cells: Pending Questions.
Dzamba, David; Honsa, Pavel; Anderova, Miroslava
2013-05-01
Glutamate receptors of the N-methyl-D-aspartate (NMDA) type are involved in many cognitive processes, including behavior, learning and synaptic plasticity. For a long time NMDA receptors were thought to be the privileged domain of neurons; however, discoveries of the last 25 years have demonstrated their active role in glial cells as well. Despite the large number of studies in the field, there are many unresolved questions connected with NMDA receptors in glia that are still a matter of debate. The main objective of this review is to shed light on these controversies by summarizing results from all relevant works concerning astrocytes, oligodendrocytes and polydendrocytes (also known as NG2 glial cells) in experimental animals, further extended by studies performed on human glia. The results are divided according to the study approach to enable a better comparison of how findings obtained at the mRNA level correspond with protein expression or functionality. Furthermore, special attention is focused on the NMDA receptor subunits present in the particular glial cell types, which give them special characteristics different from those of neurons - for example, the absence of Mg(2+) block and decreased Ca(2+) permeability. Since glial cells are implicated in important physiological and pathophysiological roles in the central nervous system (CNS), the last part of this review provides an overview of glial NMDA receptors with respect to ischemic brain injury.
Modulation of NMDA receptor function by ketamine and magnesium: Part I
Liu, H. T.; Hollmann, M. W.; Liu, W. H.; Hoenemann, C. W.; Durieux, M. E.
2001-01-01
N-methyl-D-aspartate (NMDA) receptors are important components of pain processing. Ketamine and Mg2+ block NMDA receptors and might therefore be useful analgesics, and combinations of Mg2+ and ketamine provide more effective analgesia. We investigated their interactions at NMDA receptors. Xenopus
Functional reconstitution of the glycine receptor
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Garcia-Calvo, M.; Ruiz-Gomez, A.; Vazquez, J.; Morato, E.; Valdivieso, F.; Mayor, F. Jr. (Universidad Autonoma de Madrid (Spain))
1989-07-25
The functional reconstitution of the chloride channel coupled glycine receptor is described. Glycine receptors were purified from the cholate extract of rat spinal cord membranes by affinity chromatography and incorporated into phospholipid vesicles by the addition of phosphatidylcholine and removal of detergent by gel filtration. The reconstituted vesicles showed the same polypeptide composition as the purified receptor. The pharmacological characteristics of the glycine receptor were also preserved in the proteoliposomes, as demonstrated by the displacement of ({sup 3}H)strychnine binding by several glycinergic ligands and by photoaffinity labeling experiments. In order to observe functional responses (i.e., specific agonist-induced anion translocation), the authors have developed an assay based on the fluorescence quenching of an anion-sensitive entrapped probe, SPQ (6-methoxy-N-(3-sulfopropyl)quinolinium). Reconstituted vesicles were loaded with the fluorescent probe during a freeze-thaw-sonication cycle in the presence of added liposomes containing cholesterol. In such a reconstituted system, glycine receptor agonists are able to increase the rate of anion influx into the vesicles. The action of agonists is blocked by the simultaneous presence of strychnine or other glycine antagonists. The results show that the purified 48,000- and 58,000-dalton polypeptides reconstituted into phospholipid vesicles can bind ligands and promote specific ion translocation in a way similar to the glycine receptor in its native environment.
NMDA receptors are not required for pattern completion during associative memory recall.
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Bing Mei
2011-04-01
Full Text Available Pattern completion, the ability to retrieve complete memories initiated by subsets of external cues, has been a major focus of many computation models. A previously study reports that such pattern completion requires NMDA receptors in the hippocampus. However, such a claim was derived from a non-inducible gene knockout experiment in which the NMDA receptors were absent throughout all stages of memory processes as well as animal's adult life. This raises the critical question regarding whether the previously described results were truly resulting from the requirement of the NMDA receptors in retrieval. Here, we have examined the role of the NMDA receptors in pattern completion via inducible knockout of NMDA receptors limited to the memory retrieval stage. By using two independent mouse lines, we found that inducible knockout mice, lacking NMDA receptor in either forebrain or hippocampus CA1 region at the time of memory retrieval, exhibited normal recall of associative spatial reference memory regardless of whether retrievals took place under full-cue or partial-cue conditions. Moreover, systemic antagonism of NMDA receptor during retention tests also had no effect on full-cue or partial-cue recall of spatial water maze memories. Thus, both genetic and pharmacological experiments collectively demonstrate that pattern completion during spatial associative memory recall does not require the NMDA receptor in the hippocampus or forebrain.
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Singh, L.; Donald, A.E.; Foster, A.C.; Hutson, P.H.; Iversen, L.L.; Iversen, S.D.; Kemp, J.A.; Leeson, P.D.; Marshall, G.R.; Oles, R.J.; Priestley, T.; Thorn, L.; Tricklebank, M.D.; Vass, C.A.; Williams, B.J.
1990-01-01
The antagonist effect of ±-3-amino-1-hydroxypyrrolid-2-one (HA-966) at the N-methyl-D-aspartate (NMDA) receptor occurs through a selective interaction with the glycine modulatory site within the receptor complex. When the enantiomers of ±-HA-966 were resolved, the (R)-(+)-enantiomer was found to be a selective glycine/NMDA receptor antagonist, a property that accounts for its anticonvulsant activity in vivo. In contrast, the (S)-(-)-enantiomer was only weakly active as an NMDA-receptor antagonist, but nevertheless it possessed a marked sedative and muscle relaxant action in vivo. In radioligand binding experiments, (+)-HA-966 inhibited strychnine-insensitive [ 3 H]glycine binding to rat cerebral cortex synaptic membranes with an IC 50 of 12.5 μM, whereas (-)-HA-966 had an IC 50 value of 339 μM. In mice, (+)-HA-966 antagonized sound and N-methyl-DL-aspartic acid (NMDLA)-induced seizures. The coadministration of D-serine dose-dependently antagonized the anticonvulsant effect of a submaximal dose of (+)-HA-966 against NMDLA-induced seizures. The sedative/ataxic effect of racemic HA-966 was mainly attributable to the (-)-enantiomer. It is suggested that, as in the case of the sedative γ-butyrolactone, disruption of striatal dopaminergic mechanisms may be responsible for this action
NMDA receptor antagonists for the treatment of neuropathic pain
Collins, S.; Sigtermans, M.J.; Dahan, A.; Zuurmond, W.W.A.; Perez, R.S.G.M.
2010-01-01
Objective. The N-methyl-D-Aspartate (NMDA) receptor has been proposed as a primary target for the treatment of neuropathic pain. The aim of the present study was to perform a meta-analysis evaluating the effects of (individual) NMDA receptor antagonists on neuropathic pain, and the response
NMDA receptors and memory encoding.
Morris, Richard G M
2013-11-01
It is humbling to think that 30 years have passed since the paper by Collingridge, Kehl and McLennan showing that one of Jeff Watkins most interesting compounds, R-2-amino-5-phosphonopentanoate (d-AP5), blocked the induction of long-term potentiation in vitro at synapses from area CA3 of the hippocampus to CA1 without apparent effect on baseline synaptic transmission (Collingridge et al., 1983). This dissociation was one of the key triggers for an explosion of interest in glutamate receptors, and much has been discovered since that collectively contributes to our contemporary understanding of glutamatergic synapses - their biophysics and subunit composition, of the agonists and antagonists acting on them, and their diverse functions in different networks of the brain and spinal cord. It can be fairly said that Collingridge et al.'s (1983) observation was the stimulus that has led, on the one hand, to structural biological work at the atomic scale describing the key features of NMDA receptors that enables their coincidence function to happen; and, on the other, to work with whole animals investigating the contributions that calcium signalling via this receptor can have on rhythmical activities controlled by spinal circuits, memory encoding in the hippocampus (the topic of this article), visual cortical plasticity, sensitization in pain, and other functions. In this article, I lay out how my then interest in long-term potentiation (LTP) as a model of memory enabled me to recognise the importance of Collingridge et al.'s discovery - and how I and my colleagues endeavoured to take things forward in the area of learning and memory. This is in some respects a personal story, and I tell it as such. The idea that NMDA receptor activation is essential for memory encoding, though not for storage, took time to develop and to be accepted. Along the way, there have been confusions, challenges, and surprises surrounding the idea that activation of NMDA receptors can
Naylor, David E; Liu, Hantao; Niquet, Jerome; Wasterlain, Claude G
2013-06-01
After 1h of lithium-pilocarpine status epilepticus (SE), immunocytochemical labeling of NMDA receptor NR1 subunits reveals relocation of subunits from the interior to the cell surface of dentate gyrus granule cells and CA3 pyramidal cells. Simultaneously, an increase in NMDA-miniature excitatory postsynaptic currents (mEPSC) as well as an increase in NMDA receptor-mediated tonic currents is observed in hippocampal slices after SE. Mean-variance analysis of NMDA-mEPSCs estimates that the number of functional postsynaptic NMDA receptors per synapse increases 38% during SE, and antagonism by ifenprodil suggests that an increase in the surface representation of NR2B-containing NMDA receptors is responsible for the augmentation of both the phasic and tonic excitatory currents with SE. These results provide a potential mechanism for an enhancement of glutamatergic excitation that maintains SE and may contribute to excitotoxic injury during SE. Therapies that directly antagonize NMDA receptors may be a useful therapeutic strategy during refractory SE. Copyright © 2013 Elsevier Inc. All rights reserved.
A family of photoswitchable NMDA receptors
Berlin, Shai; Szobota, Stephanie; Reiner, Andreas; Carroll, Elizabeth C; Kienzler, Michael A; Guyon, Alice; Xiao, Tong; Trauner, Dirk; Isacoff, Ehud Y
2016-01-01
NMDA receptors, which regulate synaptic strength and are implicated in learning and memory, consist of several subtypes with distinct subunit compositions and functional properties. To enable spatiotemporally defined, rapid and reproducible manipulation of function of specific subtypes, we engineered a set of photoswitchable GluN subunits ('LiGluNs'). Photo-agonism of GluN2A or GluN2B elicits an excitatory drive to hippocampal neurons that can be shaped in time to mimic synaptic activation. Photo-agonism of GluN2A at single dendritic spines evokes spine-specific calcium elevation and expansion, the morphological correlate of LTP. Photo-antagonism of GluN2A alone, or in combination with photo-antagonism of GluN1a, reversibly blocks excitatory synaptic currents, prevents the induction of long-term potentiation and prevents spine expansion. In addition, photo-antagonism in vivo disrupts synaptic pruning of developing retino-tectal projections in larval zebrafish. By providing precise and rapidly reversible optical control of NMDA receptor subtypes, LiGluNs should help unravel the contribution of specific NMDA receptors to synaptic transmission, integration and plasticity. DOI: http://dx.doi.org/10.7554/eLife.12040.001 PMID:26929991
Fang, Xiao-Qian; Qiao, Haifa; Groveman, Bradley R; Feng, Shuang; Pflueger, Melissa; Xin, Wen-Kuan; Ali, Mohammad K; Lin, Shuang-Xiu; Xu, Jindong; Duclot, Florian; Kabbaj, Mohamed; Wang, Wei; Ding, Xin-Sheng; Santiago-Sim, Teresa; Jiang, Xing-Hong; Salter, Michael W; Yu, Xian-Min
2015-11-19
Constitutive and regulated internalization of cell surface proteins has been extensively investigated. The regulated internalization has been characterized as a principal mechanism for removing cell-surface receptors from the plasma membrane, and signaling to downstream targets of receptors. However, so far it is still not known whether the functional properties of remaining (non-internalized) receptor/channels may be regulated by internalization of the same class of receptor/channels. The N-methyl-D-aspartate receptor (NMDAR) is a principal subtype of glutamate-gated ion channel and plays key roles in neuronal plasticity and memory functions. NMDARs are well-known to undergo two types of regulated internalization - homologous and heterologous, which can be induced by high NMDA/glycine and DHPG, respectively. In the present work, we investigated effects of regulated NMDAR internalization on the activity of residual cell-surface NMDARs and neuronal functions. In electrophysiological experiments we discovered that the regulated internalization of NMDARs not only reduced the number of cell surface NMDARs but also caused an inhibition of the activity of remaining (non-internalized) surface NMDARs. In biochemical experiments we identified that this functional inhibition of remaining surface NMDARs was mediated by increased serine phosphorylation of surface NMDARs, resulting from the activation of protein kinase D1 (PKD1). Knockdown of PKD1 did not affect NMDAR internalization but prevented the phosphorylation and inhibition of remaining surface NMDARs and NMDAR-mediated synaptic functions. These data demonstrate a novel concept that regulated internalization of cell surface NMDARs not only reduces the number of NMDARs on the cell surface but also causes an inhibition of the activity of remaining surface NMDARs through intracellular signaling pathway(s). Furthermore, modulating the activity of remaining surface receptors may be an effective approach for treating receptor
Oscillations and NMDA Receptors: Their Interplay Create Memories
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Chris Cadonic
2014-06-01
Full Text Available Oscillatory activity is inherent in many types of normal cellular function. Importantly, oscillations contribute to cellular network activity and cellular decision making, which are driving forces for cognition. Theta oscillations have been correlated with learning and memory encoding and gamma oscillations have been associated with attention and working memory. NMDA receptors are also implicated in oscillatory activity and contribute to normal function and in disease-related pathology. The interplay between oscillatory activity and NMDA receptors are intellectually curious and a fascinating dimension of inquiry. In this review we introduce some of the essential mathematical characteristics of oscillatory activity in order to provide a platform for additional discussion on recent studies concerning oscillations involving neuronal firing and NMDA receptor activity, and the effect of these dynamic mechanisms on cognitive processing in health and disease.
Moore, N A; Blackman, A; Awere, S; Leander, J D
1993-06-11
In the present study, we investigated the ability of NMDA receptor antagonists to inhibit catalepsy induced by haloperidol, or SCH23390 and clebopride, selective dopamine D1 and D2 receptor antagonists respectively. Catalepsy was measured by recording the time the animal remained with its forepaws placed over a rod 6 cm above the bench. Pretreatment with either the non-competitive NMDA receptor antagonist, MK-801 (0.25-0.5 mg/kg i.p.) or the competitive antagonist, LY274614 (10-20 mg/kg i.p.) reduced the cataleptic response produced by haloperidol (10 mg/kg), SCH23390 (2.5-10 mg/kp i.p.) or clebopride (5-20 mg/kg i.p.). This demonstrates that NMDA receptor antagonists will reduce both dopamine D1 and D2 receptor antagonist-induced catalepsy. Muscle relaxant doses of chlordiazepoxide (10 mg/kg i.p.) failed to reduce the catalepsy induced by haloperidol, suggesting that the anticataleptic effect of the NMDA receptor antagonists was not due to a non-specific action. These results support the hypothesis that NMDA receptor antagonists may have beneficial effects in disorders involving reduced dopaminergic function, such as Parkinson's disease.
Ion channels in EEG: isolating channel dysfunction in NMDA receptor antibody encephalitis.
Symmonds, Mkael; Moran, Catherine H; Leite, M Isabel; Buckley, Camilla; Irani, Sarosh R; Stephan, Klaas Enno; Friston, Karl J; Moran, Rosalyn J
2018-04-30
Neurological and psychiatric practice frequently lack diagnostic probes that can assess mechanisms of neuronal communication non-invasively in humans. In N-methyl-d-aspartate (NMDA) receptor antibody encephalitis, functional molecular assays are particularly important given the presence of NMDA antibodies in healthy populations, the multifarious symptomology and the lack of radiological signs. Recent advances in biophysical modelling techniques suggest that inferring cellular-level properties of neural circuits from macroscopic measures of brain activity is possible. Here, we estimated receptor function from EEG in patients with NMDA receptor antibody encephalitis (n = 29) as well as from encephalopathic and neurological patient controls (n = 36). We show that the autoimmune patients exhibit distinct fronto-parietal network changes from which ion channel estimates can be obtained using a microcircuit model. Specifically, a dynamic causal model of EEG data applied to spontaneous brain responses identifies a selective deficit in signalling at NMDA receptors in patients with NMDA receptor antibody encephalitis but not at other ionotropic receptors. Moreover, though these changes are observed across brain regions, these effects predominate at the NMDA receptors of excitatory neurons rather than at inhibitory interneurons. Given that EEG is a ubiquitously available clinical method, our findings suggest a unique re-purposing of EEG data as an assay of brain network dysfunction at the molecular level.
Ablation of NMDA receptors enhances the excitability of hippocampal CA3 neurons.
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Fumiaki Fukushima
Full Text Available Synchronized discharges in the hippocampal CA3 recurrent network are supposed to underlie network oscillations, memory formation and seizure generation. In the hippocampal CA3 network, NMDA receptors are abundant at the recurrent synapses but scarce at the mossy fiber synapses. We generated mutant mice in which NMDA receptors were abolished in hippocampal CA3 pyramidal neurons by postnatal day 14. The histological and cytological organizations of the hippocampal CA3 region were indistinguishable between control and mutant mice. We found that mutant mice lacking NMDA receptors selectively in CA3 pyramidal neurons became more susceptible to kainate-induced seizures. Consistently, mutant mice showed characteristic large EEG spikes associated with multiple unit activities (MUA, suggesting enhanced synchronous firing of CA3 neurons. The electrophysiological balance between fast excitatory and inhibitory synaptic transmission was comparable between control and mutant pyramidal neurons in the hippocampal CA3 region, while the NMDA receptor-slow AHP coupling was diminished in the mutant neurons. In the adult brain, inducible ablation of NMDA receptors in the hippocampal CA3 region by the viral expression vector for Cre recombinase also induced similar large EEG spikes. Furthermore, pharmacological blockade of CA3 NMDA receptors enhanced the susceptibility to kainate-induced seizures. These results raise an intriguing possibility that hippocampal CA3 NMDA receptors may suppress the excitability of the recurrent network as a whole in vivo by restricting synchronous firing of CA3 neurons.
LOCALIZATION OF NMDA AND AMPA RECEPTORS IN RAT BARREL FIELD
JAARSMA, D; SEBENS, JB; KORF, J
1991-01-01
The aim of this study was to asses the distribution of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-S-methyl-4-isoxazole propionic acid (AMPA) receptors in the barrel field of rat primary somatosensory (SI) cortex using light-microscopic in vitro autoradiography. NMDA receptors were labeled
Burgdorf, Jeffrey; Zhang, Xiao-lei; Nicholson, Katherine L; Balster, Robert L; Leander, J David; Stanton, Patric K; Gross, Amanda L; Kroes, Roger A; Moskal, Joseph R
2013-04-01
Recent human clinical studies with the NMDA receptor (NMDAR) antagonist ketamine have revealed profound and long-lasting antidepressant effects with rapid onset in several clinical trials, but antidepressant effects were preceded by dissociative side effects. Here we show that GLYX-13, a novel NMDAR glycine-site functional partial agonist, produces an antidepressant-like effect in the Porsolt, novelty induced hypophagia, and learned helplessness tests in rats without exhibiting substance abuse-related, gating, and sedative side effects of ketamine in the drug discrimination, conditioned place preference, pre-pulse inhibition and open-field tests. Like ketamine, the GLYX-13-induced antidepressant-like effects required AMPA/kainate receptor activation, as evidenced by the ability of NBQX to abolish the antidepressant-like effect. Both GLYX-13 and ketamine persistently (24 h) enhanced the induction of long-term potentiation of synaptic transmission and the magnitude of NMDAR-NR2B conductance at rat Schaffer collateral-CA1 synapses in vitro. Cell surface biotinylation studies showed that both GLYX-13 and ketamine led to increases in both NR2B and GluR1 protein levels, as measured by Western analysis, whereas no changes were seen in mRNA expression (microarray and qRT-PCR). GLYX-13, unlike ketamine, produced its antidepressant-like effect when injected directly into the medial prefrontal cortex (MPFC). These results suggest that GLYX-13 produces an antidepressant-like effect without the side effects seen with ketamine at least in part by directly modulating NR2B-containing NMDARs in the MPFC. Furthermore, the enhancement of 'metaplasticity' by both GLYX-13 and ketamine may help explain the long-lasting antidepressant effects of these NMDAR modulators. GLYX-13 is currently in a Phase II clinical development program for treatment-resistant depression.
Preliminary studies of 99mTc-memantine derivatives for NMDA receptor imaging
International Nuclear Information System (INIS)
Zhou Xingqin; Zhang Jiankang; Yan Chenglong; Cao Guoxian; Zhang Rongjun; Cai Gangming; Jiang Mengjun; Wang Songpei
2012-01-01
Introduction: Novel technetium-labeled ligands, 99m Tc-NCAM and 99m Tc-NHAM were developed from the N-methyl-D-aspartate (NMDA) receptor agonist memantine as a lead compound by coupling with N 2 S 2 . This study evaluated the binding affinity and specificity of the ligands for the NMDA receptor. Methods: Ligand biodistribution and uptake specificity in the brain were investigated in mice. Binding affinity and specificity were determined by radioligand receptor binding assay. Three antagonists were used for competitive binding analysis. In addition, uptake of the complexes into SH-SY5Y nerve cells was evaluated. Results: The radiochemical purity of 99m Tc-labeled ligands was more than 95%. Analysis of brain regional uptake showed higher concentration in the frontal lobe and specific uptake in the hippocampus. 99m Tc-NCAM reached a higher target to nontarget ratio than 99m Tc-NHAM. The results indicated that 99m Tc-NCAM bound to a single site on the NMDA receptor with a K d of 701.21 nmol/l and a B max of 62.47 nmol/mg. Specific inhibitors of the NMDA receptor, ketamine and dizocilpine, but not the dopamine D 2 and 5HT 1A receptor partial agonist aripiprazole, inhibited specific binding of 99m Tc-NCAM to the NMDA receptor. Cell physiology experiments showed that NCAM can increase the viability of SH-SY5Y cells after glutamate-induced injury. Conclusions: The new radioligand 99m Tc-NCAM has good affinity for and specific binding to the NMDA receptor, and easily crosses the blood–brain barrier; suggesting that it might be a potentially useful tracer for NMDA receptor expression.
Nishikawa, H; Hashino, A; Kume, T; Katsuki, H; Kaneko, S; Akaike, A
2000-09-15
This study was performed to examine the roles of the N-methyl-D-aspartate (NMDA) receptor/phencyclidine (PCP) channel complex in the protective effects of sigma-receptor ligands against glutamate neurotoxicity in cultured cortical neurons derived from fetal rats. A 1-h exposure of cultures to glutamate caused a marked loss of viability, as determined by Trypan blue exclusion. This acute neurotoxicity of glutamate was prevented by NMDA receptor antagonists. Expression of sigma(1) receptor mRNA in cortical cultures was confirmed by reverse transcription polymerase chain reaction (RT-PCR). sigma Receptor ligands with affinity for NMDA receptor channels including the PCP site, such as (+)-N-allylnormetazocine ((+)-SKF10,047), haloperidol, and R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane ((-)-PPAP), prevented glutamate neurotoxicity in a concentration-dependent manner. In contrast, other sigma-receptor ligands without affinity for NMDA receptors, such as carbetapentane and R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine ((+)-3-PPP), did not show neuroprotective effects. Putative endogenous sigma receptor ligands such as pregnenolone, progesterone, and dehydroepiandrosterone did not affect glutamate neurotoxicity. The protective effects of (+)-SKF10,047, haloperidol, and (-)-PPAP were not affected by the sigma(1) receptor antagonist rimcazole. These results suggested that a direct interaction with NMDA receptors but not with sigma receptors plays a crucial role in the neuroprotective effects of sigma receptor ligands with affinity for NMDA receptors.
Anti-NMDA Receptor Encephalitis in the Polar Bear (Ursus maritimus) Knut.
Prüss, H; Leubner, J; Wenke, N K; Czirják, G Á; Szentiks, C A; Greenwood, A D
2015-08-27
Knut the polar bear of the Berlin Zoological Garden drowned in 2011 following seizures and was diagnosed as having suffered encephalitis of unknown etiology after exhaustive pathogen screening. Using the diagnostic criteria applied to human patients, we demonstrate that Knut's encephalitis is almost identical to anti-NMDA receptor encephalitis which is a severe autoimmune disease representing the most common non-infectious encephalitis in humans. High concentrations of antibodies specific against the NR1 subunit of the NMDA receptor were detected in Knut's cerebrospinal fluid. Histological examination demonstrated very similar patterns of plasma cell infiltration and minimal neuronal loss in affected brain areas. We conclude that Knut suffered anti-NMDA receptor encephalitis making his the first reported non-human case of this treatable disease. The results suggest that anti-NMDA receptor encephalitis may be a disease of broad relevance to mammals that until now has remained undiagnosed.
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Krebs, M.O.; Trovero, F.; Desban, M.; Gauchy, C.; Glowinski, J.; Kemel, M.L. (College de France, Paris (France))
1991-05-01
Striosome- and matrix-enriched striatal zones were defined in coronal and sagittal brain sections of the rat, on the basis of {sup 3}H-naloxone binding to mu-opiate receptors (a striosome-specific marker). Then, using a new in vitro microsuperfusion device, the NMDA (50 microM)-evoked release of newly synthesized {sup 3}H-dopamine ({sup 3}H-DA) was examined in these four striatal areas under Mg(2+)-free conditions. The amplitudes of the responses were different in striosomal (171 +/- 6% and 161 +/- 5% of the spontaneous release) than in matrix areas (223 +/- 6% and 248 +/- 12%), even when glycine (1 or 100 microM) was coapplied (in the presence of 1 microM strychnine). In the four areas, the NMDA-evoked release of {sup 3}H-DA was blocked completely by Mg{sup 2}{sup +} (1 mM) or (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801; 1 microM) and almost totally abolished by kynurenate (100 microM). Because the tetrodotoxin (TTX)-resistant NMDA-evoked release of {sup 3}H-DA was similar in striosome- (148 +/- 5% and 152 +/- 6%) or matrix-enriched (161 +/- 5% and 156 +/- 7%) areas, the indirect (TTX-sensitive) component of NMDA-evoked responses, which involves striatal neurons and/or afferent fibers, seems more important in the matrix- than in the striosome-enriched areas. The modulation of DA release by cortical glutamate and/or aspartate-containing inputs through NMDA receptors in the matrix appears thus to be partly distinct from that observed in the striosomes, providing some functional basis for the histochemical striatal heterogeneity.
D-Serine and Glycine Differentially Control Neurotransmission during Visual Cortex Critical Period.
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Claire N J Meunier
Full Text Available N-methyl-D-aspartate receptors (NMDARs play a central role in synaptic plasticity. Their activation requires the binding of both glutamate and d-serine or glycine as co-agonist. The prevalence of either co-agonist on NMDA-receptor function differs between brain regions and remains undetermined in the visual cortex (VC at the critical period of postnatal development. Here, we therefore investigated the regulatory role that d-serine and/or glycine may exert on NMDARs function and on synaptic plasticity in the rat VC layer 5 pyramidal neurons of young rats. Using selective enzymatic depletion of d-serine or glycine, we demonstrate that d-serine and not glycine is the endogenous co-agonist of synaptic NMDARs required for the induction and expression of Long Term Potentiation (LTP at both excitatory and inhibitory synapses. Glycine on the other hand is not involved in synaptic efficacy per se but regulates excitatory and inhibitory neurotransmission by activating strychnine-sensitive glycine receptors, then producing a shunting inhibition that controls neuronal gain and results in a depression of synaptic inputs at the somatic level after dendritic integration. In conclusion, we describe for the first time that in the VC both D-serine and glycine differentially regulate somatic depolarization through the activation of distinct synaptic and extrasynaptic receptors.
NMDA receptors mediate neuron-to-glia signaling in mouse cortical astrocytes.
Lalo, Ulyana; Pankratov, Yuri; Kirchhoff, Frank; North, R Alan; Verkhratsky, Alexei
2006-03-08
Chemical transmission between neurons and glial cells is an important element of integration in the CNS. Here, we describe currents activated by NMDA in cortical astrocytes, identified in transgenic mice that express enhanced green fluorescent protein under control of the human glial fibrillary acidic protein promoter. Astrocytes were studied by whole-cell voltage clamp either in slices or after gentle nonenzymatic mechanical dissociation. Acutely isolated astrocytes showed a three-component response to glutamate. The initial rapid component was blocked by 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), which is an antagonist of AMPA receptors (IC50, 2 microM), and the NMDA receptor antagonist D-AP-5 blocked the later sustained component (IC50, 0.6 microM). The third component of glutamate application response was sensitive to D,L-threo-beta-benzyloxyaspartate, a glutamate transporter blocker. Fast application of NMDA evoked concentration-dependent inward currents (EC50, 0.3 microM); these showed use-dependent block by (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801). These NMDA-evoked currents were linearly dependent on membrane potential and were not affected by extracellular magnesium at concentrations up to 10 mM. Electrical stimulation of axons in layer IV-VI induced a complex inward current in astrocytes situated in the cortical layer II, part of which was sensitive to MK-801 at holding potential -80 mV and was not affected by the AMPA glutamate receptor antagonist NBQX. The fast miniature spontaneous currents were observed in cortical astrocytes in slices as well. These currents exhibited both AMPA and NMDA receptor-mediated components. We conclude that cortical astrocytes express functional NMDA receptors that are devoid of Mg2+ block, and these receptors are involved in neuronal-glial signal transmission.
Anti-NMDA receptor encephalitis: an important differential diagnosis in psychosis.
LENUS (Irish Health Repository)
Barry, Helen
2012-02-01
We present four cases of confirmed anti-NMDA receptor encephalitis; three presented initially with serious psychiatric symptoms and the other developed significant psychiatric symptoms during the initial phase of illness. Brain biopsy findings of one patient are also described. Psychiatrists should consider anti-NMDA receptor encephalitis in patients presenting with psychosis and additional features of dyskinesias, seizures and catatonia, particularly where there is no previous history of psychiatric disorder.
Differential trafficking of AMPA receptors following activation of NMDA receptors and mGluRs
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Sanderson Thomas M
2011-07-01
Full Text Available Abstract The removal of AMPA receptors from synapses is a major component of long-term depression (LTD. How this occurs, however, is still only partially understood. To investigate the trafficking of AMPA receptors in real-time we previously tagged the GluA2 subunit of AMPA receptors with ecliptic pHluorin and studied the effects of NMDA receptor activation. In the present study we have compared the effect of NMDA receptor and group I mGluR activation, using GluA2 tagged with super ecliptic pHluorin (SEP-GluA2 expressed in cultured hippocampal neurons. Surprisingly, agonists of the two receptors, which are both able to induce chemical forms of LTD, had clearly distinct effects on AMPA receptor trafficking. In agreement with our previous work we found that transient NMDA receptor activation results in an initial decrease in surface GluA2 from extrasynaptic sites followed by a delayed reduction in GluA2 from puncta (putative synapses. In contrast, transient activation of group I mGluRs, using DHPG, led to a pronounced but more delayed decrease in GluA2 from the dendritic shafts. Surprisingly, there was no average change in the fluorescence of the puncta. Examination of fluorescence at individual puncta, however, indicated that alterations did take place, with some puncta showing an increase and others a decrease in fluorescence. The effects of DHPG were, like DHPG-induced LTD, prevented by treatment with a protein tyrosine phosphatase (PTP inhibitor. The electrophysiological correlate of the effects of DHPG in the SEP-GluA2 infected cultures was a reduction in mEPSC frequency with no change in amplitude. The implications of these findings for the initial mechanisms of expression of both NMDA receptor- and mGluR-induced LTD are discussed.
DEFF Research Database (Denmark)
Collins, C; Duff, C; Duncan, A M
1993-01-01
to human chromosome 8 using a somatic cell hybrid panel. Because the gene causing HD has been localized to chromosome 4p16.3, the chromosome assignments reported here are inconsistent with either of these genes playing a causative role in the molecular pathology of HD. However, it is noteworthy......A role for the N-methyl-D-aspartate (NMDA) receptor in the molecular pathology underlying Huntington disease (HD) has been proposed on the basis of neurochemical studies in HD and the ability of the NMDA receptor to mediate neuronal cell death. The molecular cloning of the human NMDA receptor...
Jentsch, J D; Roth, R H
1999-03-01
Administration of noncompetitive NMDA/glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, to humans induces a broad range of schizophrenic-like symptomatology, findings that have contributed to a hypoglutamatergic hypothesis of schizophrenia. Moreover, a history of experimental investigations of the effects of these drugs in animals suggests that NMDA receptor antagonists may model some behavioral symptoms of schizophrenia in nonhuman subjects. In this review, the usefulness of PCP administration as a potential animal model of schizophrenia is considered. To support the contention that NMDA receptor antagonist administration represents a viable model of schizophrenia, the behavioral and neurobiological effects of these drugs are discussed, especially with regard to differing profiles following single-dose and long-term exposure. The neurochemical effects of NMDA receptor antagonist administration are argued to support a neurobiological hypothesis of schizophrenia, which includes pathophysiology within several neurotransmitter systems, manifested in behavioral pathology. Future directions for the application of NMDA receptor antagonist models of schizophrenia to preclinical and pathophysiological research are offered.
Decreased occipital lobe metabolism by FDG-PET/CT: An anti-NMDA receptor encephalitis biomarker.
Probasco, John C; Solnes, Lilja; Nalluri, Abhinav; Cohen, Jesse; Jones, Krystyna M; Zan, Elcin; Javadi, Mehrbod S; Venkatesan, Arun
2018-01-01
To compare brain metabolism patterns on fluorodeoxyglucose (FDG)-PET/CT in anti-NMDA receptor and other definite autoimmune encephalitis (AE) and to assess how these patterns differ between anti-NMDA receptor neurologic disability groups. Retrospective review of clinical data and initial dedicated brain FDG-PET/CT studies for neurology inpatients with definite AE, per published consensus criteria, treated at a single academic medical center over a 10-year period. Z-score maps of FDG-PET/CT were made using 3-dimensional stereotactic surface projections in comparison to age group-matched controls. Brain region mean Z scores with magnitudes ≥2.00 were interpreted as significant. Comparisons were made between anti-NMDA receptor and other definite AE patients as well as among patients with anti-NMDA receptor based on modified Rankin Scale (mRS) scores at the time of FDG-PET/CT. The medial occipital lobes were markedly hypometabolic in 6 of 8 patients with anti-NMDA receptor encephalitis and as a group (Z = -4.02, interquartile range [IQR] 2.14) relative to those with definite AE (Z = -2.32, 1.46; p = 0.004). Among patients with anti-NMDA receptor encephalitis, the lateral and medial occipital lobes were markedly hypometabolic for patients with mRS 4-5 (lateral occipital lobe Z = -3.69, IQR 1; medial occipital lobe Z = -4.08, 1) compared with those with mRS 0-3 (lateral occipital lobe Z = -0.83, 2; p occipital lobe Z = -1.07, 2; p = 0.001). Marked medial occipital lobe hypometabolism by dedicated brain FDG-PET/CT may serve as an early biomarker for discriminating anti-NMDA receptor encephalitis from other AE. Resolution of lateral and medial occipital hypometabolism may correlate with improved neurologic status in anti-NMDA receptor encephalitis.
Tan, Huibing; Rosen, Laura G; Ng, Garye A; Rushlow, Walter J; Laviolette, Steven R
2014-12-01
N-Methyl-D-aspartate (NMDA) receptors in the medial prefrontal cortex (mPFC) are involved in opiate reward processing and modulate sub-cortical dopamine (DA) activity. NMDA receptor blockade in the prelimbic (PLC) division of the mPFC strongly potentiates the rewarding behavioural properties of normally sub-reward threshold doses of opiates. However, the possible functional interactions between cortical NMDA and sub-cortical DAergic motivational neural pathways underlying these effects are not understood. This study examines how NMDA receptor modulation in the PLC influences opiate reward processing via interactions with sub-cortical DAergic transmission. We further examined whether direct intra-PLC NMDA receptor modulation may activate DA-dependent opiate reward signaling via interactions with the ventral tegmental area (VTA). Using an unbiased place conditioning procedure (CPP) in rats, we performed bilateral intra-PLC microinfusions of the competitive NMDA receptor antagonist, (2R)-amino-5-phosphonovaleric acid (AP-5), prior to behavioural morphine place conditioning and challenged the rewarding effects of morphine with DA receptor blockade. We next examined the effects of intra-PLC NMDA receptor blockade on the spontaneous activity patterns of presumptive VTA DA or GABAergic neurons, using single-unit, extracellular in vivo neuronal recordings. We show that intra-PLC NMDA receptor blockade strongly activates sub-cortical DA neurons within the VTA while inhibiting presumptive non-DA GABAergic neurons. Behaviourally, NMDA receptor blockade activates a DA-dependent opiate reward system, as pharmacological blockade of DA transmission blocked morphine reward only in the presence of intra-PLC NMDA receptor antagonism. These findings demonstrate a cortical NMDA-mediated mechanism controlling mesolimbic DAergic modulation of opiate reward processing.
N-Methyl D-Aspartic Acid (NMDA Receptors and Depression
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Enver Yusuf Sivrioglu
2009-06-01
Full Text Available The monoaminergic hypothesis of depression has provided the basis for extensive research into the pathophysiology of mood disorders and has been of great significance for the development of effective antidepressants. Current antidepressant treatments not only increase serotonin and/or noradrenaline bioavailability but also originate adaptive changes increasing synaptic plasticity. Novel approaches to depression and to antidepressant therapy are now focused on intracellular targets that regulate neuroplasticity and cell survival. Accumulating evidence indicates that there is an anatomical substrate for such a devastating neuropsychiatric disease as major depression. Loss of synaptic plasticity and hippocampal atrophy appear to be prominent features of this highly prevalent disorder. A combination of genetic susceptibility and environmental factors make hippocampal neurons more vulnerable to stress. Abundant experimental evidence indicates that stress causes neuronal damage in brain regions, notably in hippocampal subfields. Stress-induced activation of glutamatergic transmission may induce neuronal cell death through excessive stimulation of N-methyl-D-aspartic acid (NMDA receptors. Recent studies mention that the increase of nitric oxide synthesis and inflammation in major depression may contribute to neurotoxicity through NMDA receptor. Both standard antidepressants and NMDA receptor antagonists are able to prevent stress-induced neuronal damage. NMDA antagonists are effective in widely used animal models of depression and some of them appear to be effective also in the few clinical trials performed to date. We are still far from understanding the complex cellular and molecular events involved in mood disorders. There appears to be an emerging role for glutamate neurotransmission in the search for the pathogenesis of major depression. Attenuation of NMDA receptor function mechanism appears to be a promising target in the search for a more
Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists
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Nuno A. L. Pereira
2016-08-01
Full Text Available Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool, and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl d-Aspartate (NMDA receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i a stereoselective cyclocondensation of (S- or (R-tryptophanol with appropriate racemic δ-oxoesters; (ii a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson’s disease. This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors.
Nothdurfter, Caroline; Tanasic, Sascha; Di Benedetto, Barbara; Uhr, Manfred; Wagner, Eva-Maria; Gilling, Kate E; Parsons, Chris G; Rein, Theo; Holsboer, Florian; Rupprecht, Rainer; Rammes, Gerhard
2013-07-01
Lipid rafts have been shown to play an important role for G-protein mediated signal transduction and the function of ligand-gated ion channels including their modulation by psychopharmacological compounds. In this study, we investigated the functional significance of the membrane distribution of NMDA and GABAA receptor subunits in relation to the accumulation of the tricyclic antidepressant desipramine (DMI) and the benzodiazepine diazepam (Diaz). In the presence of Triton X-100, which allowed proper separation of the lipid raft marker proteins caveolin-1 and flotillin-1 from the transferrin receptor, all receptor subunits were shifted to the non-raft fractions. In contrast, under detergent-free conditions, NMDA and GABAA receptor subunits were detected both in raft and non-raft fractions. Diaz was enriched in non-raft fractions without Triton X-100 in contrast to DMI, which preferentially accumulated in lipid rafts. Impairment of lipid raft integrity by methyl-β-cyclodextrine (MβCD)-induced cholesterol depletion did not change the inhibitory effect of DMI at the NMDA receptor, whereas it enhanced the potentiating effect of Diaz at the GABAA receptor at non-saturating concentrations of GABA. These results support the hypothesis that the interaction of benzodiazepines with the GABAA receptor likely occurs outside of lipid rafts while the antidepressant DMI acts on ionotropic receptors both within and outside these membrane microdomains.
Adult forebrain NMDA receptors gate social motivation and social memory.
Jacobs, Stephanie; Tsien, Joe Z
2017-02-01
Motivation to engage in social interaction is critical to ensure normal social behaviors, whereas dysregulation in social motivation can contribute to psychiatric diseases such as schizophrenia, autism, social anxiety disorders and post-traumatic stress disorder (PTSD). While dopamine is well known to regulate motivation, its downstream targets are poorly understood. Given the fact that the dopamine 1 (D1) receptors are often physically coupled with the NMDA receptors, we hypothesize that the NMDA receptor activity in the adult forebrain principal neurons are crucial not only for learning and memory, but also for the proper gating of social motivation. Here, we tested this hypothesis by examining sociability and social memory in inducible forebrain-specific NR1 knockout mice. These mice are ideal for exploring the role of the NR1 subunit in social behavior because the NR1 subunit can be selectively knocked out after the critical developmental period, in which NR1 is required for normal development. We found that the inducible deletion of the NMDA receptors prior to behavioral assays impaired, not only object and social recognition memory tests, but also resulted in profound deficits in social motivation. Mice with ablated NR1 subunits in the forebrain demonstrated significant decreases in sociability compared to their wild type counterparts. These results suggest that in addition to its crucial role in learning and memory, the NMDA receptors in the adult forebrain principal neurons gate social motivation, independent of neuronal development. Copyright © 2016 Elsevier Inc. All rights reserved.
Directory of Open Access Journals (Sweden)
Kwi-Hyung Choi
2013-01-01
Full Text Available The periaqueductal gray (PAG is involved in the central regulation of nociceptive transmission by affecting the descending inhibitory pathway. In the present study, we have addressed the functional role of presynaptic glycine receptors in spontaneous glutamatergic transmission. Spontaneous EPSCs (sEPSCs were recorded in mechanically dissociated rat PAG neurons using a conventional whole-cell patch recording technique under voltage-clamp conditions. The application of glycine (100 µM significantly increased the frequency of sEPSCs, without affecting the amplitude of sEPSCs. The glycine-induced increase in sEPSC frequency was blocked by 1 µM strychnine, a specific glycine receptor antagonist. The results suggest that glycine acts on presynaptic glycine receptors to increase the probability of glutamate release from excitatory nerve terminals. The glycine-induced increase in sEPSC frequency completely disappeared either in the presence of tetrodotoxin or Cd2+, voltage-gated Na+, or Ca2+ channel blockers, suggesting that the activation of presynaptic glycine receptors might depolarize excitatory nerve terminals. The present results suggest that presynaptic glycine receptors can regulate the excitability of PAG neurons by enhancing glutamatergic transmission and therefore play an important role in the regulation of various physiological functions mediated by the PAG.
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Saba Taheri
2013-02-01
Full Text Available Background and Objectives: Whereas studies have indicated the interaction between NMDA and cholinergic systems, this study was performed with the aim of determining the role of NMDA receptors in the nucleus accumbens (NAc in scopolamine-induced amnesia.Methods: In this study, at first rats were anesthetized with intra-peritoneal injection of ketamine hydrochloride plus xylazine, and then placed in a stereotaxic apparatus. Two stainless-steel cannulas were placed 2mm above nucleus accumbens shell. All animals were allowed to recover for one week, before beginning the behavioral testing. Then, animals were trained in a step-through type inhibitory avoidance task. The drugs were injected after successful training and before testing. The animals were tested 24h after training, and the step-through latency time was measured as the memory criterion in male Wistar rats. One-way analysis of variance and Tukey’s test were used for analysis of the data. p<0.05 was considered statistically significant.Results: Intra-nucleus accumbens (intra-NAc injection of scopolamine or NMDA caused impairment in memory in rats. Although, co-administration of an ineffective dose of NMDA with an ineffective dose of scopolamine had no significant effect on memory performance, effective doses of NMDA prevented the amnesic effect of scopolamine on inhibitory avoidance memory. On the other hand, intra-NAc injection of NMDA receptor antagonist, i.e., MK-801 caused no change in memory performance by itself, and its co-administration with an effective dose of scopolamine could not prevent the impairing effect of the latter drug. Conclusion: The finding of this study indicated that NMDA receptors in the nucleus accumbens are involved in the modulation of scopolamine-induced amnesia.
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Yang Qi
2009-12-01
Full Text Available Abstract The midbrain periaqueductal grey (PAG is a structure known for its roles in pain transmission and modulation. Noxious stimuli potentiate the glutamate synaptic transmission and enhance glutamate NMDA receptor expression in the PAG. However, little is known about roles of NMDA receptor subunits in the PAG in processing the persistent inflammatory pain. The present study was undertaken to investigate NR2A- and NR2B-containing NMDA receptors in the PAG and their modulation to the peripheral painful inflammation. Noxious stimuli induced by hind-paw injection of complete Freund's adjuvant (CFA caused up-regulation of NR2B-containing NMDA receptors in the PAG, while NR2A-containing NMDA receptors were not altered. Whole-cell patch-clamp recordings revealed that NMDA receptor mediated mEPSCs were increased significantly in the PAG synapse during the chronic phases of inflammatory pain in mice. PAG local infusion of Ro 25-6981, an NR2B antagonist, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in rats. Hyperoside (Hyp, one of the flavonoids compound isolated from Rhododendron ponticum L., significantly reversed up-regulation of NR2B-containing NMDA receptors in the PAG and exhibited analgesic activities against persistent inflammatory stimuli in mice. Our findings provide strong evidence that up-regulation of NR2B-containing NMDA receptors in the PAG involves in the modulation to the peripheral persistent inflammatory pain.
Bidirectional modulation of windup by NMDA receptors in the rat spinal trigeminal nucleus.
Woda, Alain; Blanc, Olivier; Voisin, Daniel L; Coste, Jérôme; Molat, Jean-Louis; Luccarini, Philippe
2004-04-01
Activation of afferent nociceptive pathways is subject to activity-dependent plasticity, which may manifest as windup, a progressive increase in the response of dorsal horn nociceptive neurons to repeated stimuli. At the cellular level, N-methyl-d-aspartate (NMDA) receptor activation by glutamate released from nociceptive C-afferent terminals is currently thought to generate windup. Most of the wide dynamic range nociceptive neurons that display windup, however, do not receive direct C-fibre input. It is thus unknown where the NMDA mechanisms for windup operate. Here, using the Sprague-Dawley rat trigeminal system as a model, we anatomically identify a subpopulation of interneurons that relay nociceptive information from the superficial dorsal horn where C-fibres terminate, to downstream wide dynamic range nociceptive neurons. Using in vivo electrophysiological recordings, we show that at the end of this pathway, windup was reduced (24 +/- 6%, n = 7) by the NMDA receptor antagonist AP-5 (2.0 fmol) and enhanced (62 +/- 19%, n = 12) by NMDA (1 nmol). In contrast, microinjections of AP-5 (1.0 fmol) within the superficial laminae increased windup (83 +/- 44%, n = 9), whereas NMDA dose dependently decreased windup (n = 19). These results indicate that NMDA receptor function at the segmental level depends on their precise location in nociceptive neural networks. While some NMDA receptors actually amplify pain information, the new evidence for NMDA dependent inhibition of windup we show here indicates that, simultaneously, others act in the opposite direction. Working together, the two mechanisms may provide a fine tuning of gain in pain.
Moskal, Joseph R; Burch, Ronald; Burgdorf, Jeffrey S; Kroes, Roger A; Stanton, Patric K; Disterhoft, John F; Leander, J David
2014-02-01
The N-methyl-d-aspartate receptor-ionophore complex plays a key role in learning and memory and has efficacy in animals and humans with affective disorders. GLYX-13 is an N-methyl-d-aspartate receptor (NMDAR) glycine-site functional partial agonist and cognitive enhancer that also shows rapid antidepressant activity without psychotomimetic side effects. The authors review the mechanism of action of GLYX-13 that was investigated in preclinical studies and evaluated in clinical studies. Specifically, the authors review its pharmacology, pharmacokinetics, and drug safety that were demonstrated in clinical studies. NMDAR full antagonists can produce rapid antidepressant effects in treatment-resistant subjects; however, they are often accompanied by psychotomimetic effects that make chronic use outside of a clinical trial inpatient setting problematic. GLYX-13 appears to exert its antidepressant effects in the frontal cortex via NMDAR-triggered synaptic plasticity. Understanding the mechanistic underpinning of GLYX-13's antidepressant action should provide both novel insights into the role of the glutamatergic system in depression and identify new targets for therapeutic development.
NMDA receptor antagonist ketamine impairs feature integration in visual perception.
Meuwese, Julia D I; van Loon, Anouk M; Scholte, H Steven; Lirk, Philipp B; Vulink, Nienke C C; Hollmann, Markus W; Lamme, Victor A F
2013-01-01
Recurrent interactions between neurons in the visual cortex are crucial for the integration of image elements into coherent objects, such as in figure-ground segregation of textured images. Blocking N-methyl-D-aspartate (NMDA) receptors in monkeys can abolish neural signals related to figure-ground segregation and feature integration. However, it is unknown whether this also affects perceptual integration itself. Therefore, we tested whether ketamine, a non-competitive NMDA receptor antagonist, reduces feature integration in humans. We administered a subanesthetic dose of ketamine to healthy subjects who performed a texture discrimination task in a placebo-controlled double blind within-subject design. We found that ketamine significantly impaired performance on the texture discrimination task compared to the placebo condition, while performance on a control fixation task was much less impaired. This effect is not merely due to task difficulty or a difference in sedation levels. We are the first to show a behavioral effect on feature integration by manipulating the NMDA receptor in humans.
NMDA receptor antagonist ketamine impairs feature integration in visual perception.
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Julia D I Meuwese
Full Text Available Recurrent interactions between neurons in the visual cortex are crucial for the integration of image elements into coherent objects, such as in figure-ground segregation of textured images. Blocking N-methyl-D-aspartate (NMDA receptors in monkeys can abolish neural signals related to figure-ground segregation and feature integration. However, it is unknown whether this also affects perceptual integration itself. Therefore, we tested whether ketamine, a non-competitive NMDA receptor antagonist, reduces feature integration in humans. We administered a subanesthetic dose of ketamine to healthy subjects who performed a texture discrimination task in a placebo-controlled double blind within-subject design. We found that ketamine significantly impaired performance on the texture discrimination task compared to the placebo condition, while performance on a control fixation task was much less impaired. This effect is not merely due to task difficulty or a difference in sedation levels. We are the first to show a behavioral effect on feature integration by manipulating the NMDA receptor in humans.
Conantokin probes of NMDA receptors in normal and Alzheimer disease human cerebral cortex
International Nuclear Information System (INIS)
Ragnarsson, L.; Dodd, P.R.; Lewis, R.J.
2002-01-01
Full text: The pharmacology of the N-methyl-D-aspartate (NMDA) receptor site was examined in pathologically affected and relatively spared regions of cerebral cortex tissue obtained at autopsy from Alzheimer disease cases and matched controls. The affinity and density of the [ 3 H]MK-801 binding site were delineated along with the enhancement of [ 3 H]MK-801 binding by glutamate and spermine. Sites with distinct pharmacologies were distributed regionally through the cortex. The differences could not be explained by variations in the parameters of [ 3 H]MK-801 binding; rather, the data suggest that the subunit composition of NMDA receptors may be locally variable. Selective differences were also found between controls and Alzheimer disease cases in certain brain regions. The interactions of human NMDA sites with the Ala(7) and Lys(7) derivatives of conantokin-G (Con-G) were also characterized. Ala(7)-con-G showed the higher affinity of the two peptides, and also defined two distinct binding sites in controls. In distinction to the Ala(7) peptide, Lys(7)- con-G showed preferential binding to receptor sites in Alzheimer disease cf. control brain. Modified conantokins are useful for identifying differences in subunit composition of the NMDA receptors between brain areas. They may also have potential as protective agents against over-excitation mediated by specific NMDA receptors, which might contribute to localized brain damage in Alzheimer disease. For further characterization of the pharmacology of different NMDA receptor subunits, a mammalian expression system has been developed for the analysis of their responses to selected ligands, including conantokins. Copyright (2002) Australian Neuroscience Society
Stern, Javier E; Potapenko, Evgeniy S
2013-08-15
An enhanced glutamate excitatory function within the hypothalamic supraoptic and paraventricluar nuclei is known to contribute to increased neurosecretory and presympathetic neuronal activity, and hence, neurohumoral activation, during heart failure (HF). Still, the precise mechanisms underlying enhanced glutamate-driven neuronal activity in HF remain to be elucidated. Here, we performed simultaneous electrophysiology and fast confocal Ca²⁺ imaging to determine whether altered N-methyl-d-aspartate (NMDA) receptor-mediated changes in intracellular Ca²⁺ levels (NMDA-ΔCa²⁺) occurred in hypothalamic magnocellular neurosecretory cells (MNCs) in HF rats. We found that activation of NMDA receptors resulted in a larger ΔCa²⁺ in MNCs from HF when compared with sham rats. The enhanced NMDA-ΔCa²⁺ was neither dependent on the magnitude of the NMDA-mediated current (voltage clamp) nor on the degree of membrane depolarization or firing activity evoked by NMDA (current clamp). Differently from NMDA receptor activation, firing activity evoked by direct membrane depolarization resulted in similar changes in intracellular Ca²⁺ in sham and HF rats. Taken together, our results support a relatively selective alteration of intracellular Ca²⁺ homeostasis and signaling following activation of NMDA receptors in MNCs during HF. The downstream functional consequences of such altered ΔCa²⁺ signaling during HF are discussed.
Actions of Bupivacaine, a Widely Used Local Anesthetic, on NMDA Receptor Responses
Paganelli, Meaghan A.
2015-01-01
NMDA receptors mediate excitatory neurotransmission in brain and spinal cord and play a pivotal role in the neurological disease state of chronic pain, which is caused by central sensitization. Bupivacaine is the indicated local anesthetic in caudal, epidural, and spinal anesthesia and is widely used clinically to manage acute and chronic pain. In addition to blocking Na+ channels, bupivacaine affects the activity of many other channels, including NMDA receptors. Importantly, bupivacaine inhibits NMDA receptor-mediated synaptic transmission in the dorsal horn of the spinal cord, an area critically involved in central sensitization. We used recombinant NMDA receptors expressed in HEK293 cells and found that increasing concentrations of bupivacaine decreased channel open probability in GluN2 subunit- and pH-independent manner by increasing the mean duration of closures and decreasing the mean duration of openings. Using kinetic modeling of one-channel currents, we attributed the observed current decrease to two main mechanisms: a voltage-dependent “foot-in-the-door” pore block and an allosteric gating effect. Further, the inhibition was state-independent because it occurred to the same degree whether the drug was applied before or after glutamate stimulation and was mediated by extracellular and intracellular inhibitory sites, via hydrophilic and hydrophobic pathways. These results predict that clinical doses of bupivacaine would decrease the peak and accelerate the decay of synaptic NMDA receptor currents during normal synaptic transmission. These quantitative predictions inform possible applications of bupivacaine as preventative and therapeutic approaches in chronic pain. PMID:25589775
DEFF Research Database (Denmark)
Hansen, H.H.; Ramos, J.A.; Fernández-Ruiz, J.
2002-01-01
-induced excitotoxic damage in the ipsilateral forebrain was not influenced by agonist-stimulated CB receptor function. In contrast, blockade of CB, but not CB, receptor activity evoked a robust neuroprotective response by reducing the infarct area and the number of cortical degenerating neurons. These results suggest...... receptor function on NMDA-induced excitotoxicity. Neonatal (6-day-old) rat pups received a systemic injection of a mixed CB/CB receptor agonist (WIN55,212-2) or their respective antagonists (SR141716A for CB and SR144528 for CB) prior to an unilateral intrastriatal microinjection of NMDA. The NMDA...... a critical involvement of CB receptor tonus on neuronal survival following NMDA receptor-induced excitotoxicity in vivo....
Oxidative stress upregulates the NMDA receptor on cerebrovascular endothelium.
Betzen, Christian; White, Robin; Zehendner, Christoph M; Pietrowski, Eweline; Bender, Bianca; Luhmann, Heiko J; Kuhlmann, Christoph R W
2009-10-15
N-methyl-d-aspartate receptor (NMDA-R)-mediated oxidative stress has been implicated in blood-brain barrier (BBB) disruption in a variety of neuropathological diseases. Although some interactions between both phenomena have been elucidated, possible influences of reactive oxygen species (ROS) on the NMDA-R itself have so far been neglected. The objective of this study was to examine how the cerebroendothelial NMDA-R is affected by exposure to oxidative stress and to assess possible influences on BBB integrity. RT-PCR confirmed several NMDA-R subunits (NR1, NR2B-D) expressed in the bEnd3 cell line (murine cerebrovascular endothelial cells). NR1 protein expression after exposure to ROS was observed via in-cell Western. The functionality of the expressed NMDA-R was determined by measuring DiBAC fluorescence in ROS-preexposed cells upon stimulation with the specific agonist NMDA. Finally, the effects on barrier integrity were evaluated using the ECIS system to detect changes in monolayer impedance upon NMDA-R stimulation after exposure to ROS. The expression of NR1 significantly (p<0.001) increased 72 h after 30 min exposure to superoxide (+33.8+/-7.5%), peroxynitrite (+84.9+/-10.7%), or hydrogen peroxide (+92.8+/-7.6%), resulting in increased cellular response to NMDA-R stimulation and diminished monolayer impedance. We conclude that oxidative stress upregulates NMDA-R on cerebrovascular endothelium and thus heightens susceptibility to glutamate-induced BBB disruption.
Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.
Dalmau, Josep; Gleichman, Amy J; Hughes, Ethan G; Rossi, Jeffrey E; Peng, Xiaoyu; Lai, Meizan; Dessain, Scott K; Rosenfeld, Myrna R; Balice-Gordon, Rita; Lynch, David R
2008-12-01
A severe form of encephalitis associated with antibodies against NR1-NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures. We describe the clinical characteristics of 100 patients with encephalitis and NR1-NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1-NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters. Median age of patients was 23 years (range 5-76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased consciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0.004) and fewer neurological relapses (p=0.009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients' antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal. A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies.
Serial EEG findings in anti-NMDA receptor encephalitis: correlation between clinical course and EEG.
Ueda, Jun; Kawamoto, Michi; Hikiami, Ryota; Ishii, Junko; Yoshimura, Hajime; Matsumoto, Riki; Kohara, Nobuo
2017-12-01
Anti-NMDA receptor encephalitis is a paraneoplastic encephalitis characterised by psychiatric features, involuntary movement, and autonomic instability. Various EEG findings in patients with anti-NMDA receptor encephalitis have been reported, however, the correlation between the EEG findings and clinical course of anti-NMDA receptor encephalitis remains unclear. We describe a patient with anti-NMDA receptor encephalitis with a focus on EEG findings, which included: status epilepticus, generalised rhythmic delta activity, excess beta activity, extreme delta brush, and paroxysmal alpha activity upon arousal from sleep, which we term"arousal alpha pattern". Initially, status epilepticus was observed on the EEG when the patient was comatose with conjugate deviation. The EEG then indicated excess beta activity, followed by the emergence of continuous slow activity, including generalised rhythmic delta activity and extreme delta brush, in the most severe phase. Slow activity gradually faded in parallel with clinical amelioration. Excess beta activity persisted, even after the patient became almost independent in daily activities, and finally disappeared with full recovery. In summary, our patient with anti-NMDA receptor encephalitis demonstrated slow activity on the EEG, including extreme delta brush during the most severe phase, which gradually faded in parallel with clinical amelioration, with excess beta activity persisting into the recovery phase.
Involvement of NMDA receptor in low-frequency magnetic field-induced anxiety in mice.
Salunke, Balwant P; Umathe, Sudhir N; Chavan, Jagatpalsingh G
2014-12-01
It had been reported that exposure to extremely low-frequency magnetic field (ELFMF) induces anxiety in human and rodents. Anxiety mediates via the activation of N-methyl-d-aspartate (NMDA) receptor, whereas activation of γ-aminobutyric acid (GABA) receptor attenuates the same. Hence, the present study was carried out to understand the contribution of NMDA and/or GABA receptors modulation in ELFMF-induced anxiety for which Swiss albino mice were exposed to ELFMF (50 Hz, 10 G) by subjecting them to Helmholtz coils. The exposure was for 8 h/day for 7, 30, 60, 90 and 120 days. Anxiety level was assessed in elevated plus maze, open field test and social interaction test, on 7th, 30th, 60th, 90th and 120th exposure day, respectively. Moreover, the role of GABA and glutamate in ELFMF-induced anxiety was assessed by treating mice with muscimol [0.25 mg/kg intraperitoneally (i.p.)], bicuculline (1.0 mg/kg i.p.), NMDA (15 mg/kg i.p.) and MK-801 (0.03 mg/kg i.p.), as a GABAA and NMDA receptor agonist and antagonist, respectively. Glutamate receptor agonist exacerbated while inhibitor attenuated the ELFMF-induced anxiety. In addition, levels of GABA and glutamate were determined in regions of the brain viz, cortex, striatum, hippocampus and hypothalamus. Experiments demonstrated significant elevation of GABA and glutamate levels in the hippocampus and hypothalamus. However, GABA receptor modulators did not produce significant effect on ELFMF-induced anxiety and elevated levels of GABA at tested dose. Together, these findings suggest that ELFMF significantly induced anxiety behavior, and indicated the involvement of NMDA receptor in its effect.
Blockade of NMDA receptors blocks the acquisition of cocaine conditioned approach in rats.
Galaj, Ewa; Seepersad, Neal; Dakmak, Zena; Ranaldi, Robert
2018-01-05
Conditioned stimuli (CSs) exert motivational effects on both adaptive and pathological reward-related behaviors, including drug taking and seeking. We developed a paradigm that allows us to investigate the neuropharmacology by which previously neutral stimuli acquire the capacity to function as CSs and elicit (intravenous) cocaine conditioned approach and used this paradigm to test the role of NMDA receptor stimulation in the acquisition of cocaine conditioned approach. Rats were injected systemically with the NMDA receptor antagonist, MK-801, before the start of 4 consecutive conditioning sessions, each of which consisted of 20 randomly presented light/tone (CS) presentations paired with cocaine infusion contingent upon nose pokes. Rats later were subjected to a CS-only test. To test the role of NMDA receptor stimulation in the already established conditioned approach, rats were injected with MK-801 prior to the CS-only test that occurred after 18 CS-cocaine conditioning sessions. Blockade of NMDA receptors significantly impaired the acquisition of cocaine-conditioned approach as indicated by the emission of significantly fewer nose pokes and significantly longer latencies to nose poke during CS presentations. When MK-801 treatment was applied after the acquisition of conditioned approach responding it had no effect on these measures. These results suggest that NMDA receptor stimulation plays an important role in the acquisition of reward-related conditioned responses driven by intravenous cocaine-associated CSs. Copyright © 2017 Elsevier B.V. All rights reserved.
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F. A. Zeiler
2015-01-01
Full Text Available Refractory status epilepticus (RSE and superrefractory status epilepticus (SRSE pose a difficult clinical challenge. Multiple cerebral receptor and transporter changes occur with prolonged status epilepticus leading to pharmacoresistance patterns unfavorable for conventional antiepileptics. In particular, n-methyl-d-aspartate (NMDA receptor upregulation leads to glutamate mediated excitotoxicity. Targeting these NMDA receptors may provide a novel approach to otherwise refractory seizures. Ketamine has been utilized in RSE. Recent systematic review indicates 56.5% and 63.5% cessation in seizures in adults and pediatrics, respectively. No complications were described. We should consider earlier implementation of ketamine or other NMDA receptor antagonists, for RSE. Prospective study of early implementation of ketamine should shed light on the role of such medications in RSE.
Structure-activity relationships of strychnine analogues at glycine receptors
DEFF Research Database (Denmark)
Mohsen, A.M.Y.; Heller, Eberhard; Holzgrabe, Ulrike
2014-01-01
Nine strychnine derivatives including neostrychnine, strychnidine, isostrychnine, 21,22-dihydro-21-hydroxy-22-oxo-strychnine, and several hydrogenated analogs were synthesized, and their antagonistic activities at human α1 and α1β glycine receptors were evaluated. Isostrychnine has shown the best...... pharmacological profile exhibiting an IC50 value of 1.6 μM at α1 glycine receptors and 3.7-fold preference towards the α1 subtype. SAR Analysis indicates that the lactam moiety and the C(21)[DOUBLE BOND]C(22) bond in strychnine are essential structural features for its high antagonistic potency at glycine...
Lu, Lingling; Mamiya, Takayoshi; Lu, Ping; Toriumi, Kazuya; Mouri, Akihiro; Hiramatsu, Masayuki; Kim, Hyoung-Chun; Zou, Li-Bo; Nagai, Taku; Nabeshima, Toshitaka
2010-08-01
Several studies have shown the disruptive effects of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists on neurobehavioural development. Based on the neurodevelopment hypothesis of schizophrenia, there is growing interest in animal models treated with NMDA antagonists at developing stages to investigate the pathogenesis of psychological disturbances in humans. Previous studies have reported that perinatal treatment with phencyclidine (PCP) impairs the development of neuronal systems and induces schizophrenia-like behaviour. However, the adverse effects of prenatal exposure to PCP on behaviour and the function of NMDA receptors are not well understood. This study investigated the long-term effects of prenatal exposure to PCP in mice. The prenatal PCP-treated mice showed hypersensitivity to a low dose of PCP in locomotor activity and impairment of recognition memory in the novel object recognition test at age 7 wk. Meanwhile, the prenatal exposure reduced the phosphorylation of NR1, although it increased the expression of NR1 itself. Furthermore, these behavioural changes were attenuated by atypical antipsychotic treatment. Taken together, prenatal exposure to PCP produced long-lasting behavioural deficits, accompanied by the abnormal expression and dysfunction of NMDA receptors in postpubertal mice. It is worth investigating the influences of disrupted NMDA receptors during the prenatal period on behaviour in later life.
NMDA receptors are important regulators of pancreatic cancer and are potential targets for treatment
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North WG
2017-07-01
Full Text Available William G North,1,2 Fuli Liu,1 Liz Z Lin,1 Ruiyang Tian,2 Bonnie Akerman1 1Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, 2Woomera Therapeutics Inc, Lebanon, NH, USA Abstract: Pancreatic cancer, particularly adenocarcinoma of the pancreas, is a common disease with a poor prognosis. In this study, the importance of N-methyl-D-aspartate (NMDA receptors for the growth and survival of pancreatic cancer was investigated. Immunohistochemistry performed with antibodies against GluN1 and GluN2B revealed that all invasive adenocarcinoma and neuroendocrine pancreatic tumors likely express these two NMDA receptor proteins. These proteins were found to be membrane components of pancreatic cancer cell lines, and both channel-blocker antagonist and GluN2B antagonist significantly reduced cell viability in vitro. Both types of antagonists caused an internalization of the receptors. Dizocilpine maleate (MK-801 and ifenprodil hemitartrate both significantly inhibited the growth of pancreatic tumor xenografts in nu/nu mice. These findings predict that, as for other solid tumors investigated by us, pancreatic cancer could be successfully treated, alone or in combination, with NMDA receptor antagonists or other receptor-inhibiting blocking agents. Keywords: pancreatic cancer, NMDA receptors, inhibitors, potential therapy
Glycine receptor: light microscopic autoradiographic localization with [3H]strychnine
International Nuclear Information System (INIS)
Zarbin, M.A.; Wamsley, J.K.; Kuhar, M.J.
1981-01-01
Glycine receptors have been localized by autoradiography in the rat central nervous system (CNS) using [ 3 H]strychnine. The gross distribution of receptors is in excellent accord with the distribution determined by filtration binding assays. Specifically, the density of glycine receptors is greatest in the gray matter of the spinal cord and decreases progressively in regions more rostral in the neuraxis. Glycine receptors were found to be associated with both sensory and motor systems in the CNS. Moreover, there is a striking correlation between areas of high strychnine binding site density and areas in which glycine has been found to be electrophysiologically active. Finally, the anatomic localization of strychnine binding sites may help explain many of the signs and symptoms of strychnine ingestion. For example, individuals consuming subconvulsive doses of strychnine frequently experience altered cutaneous and auditory sensation. We have localized strychnine receptors in areas of the acoustic system known to influence discriminative aspects of audition and in areas of the spinal cord and trigeminal nuclei which modulate discriminative aspects of cutaneous sensation. The alteration of visceral functions (e.g., blood pressure and respiratory rate) associated with strychnine ingestion may be accounted for in a similar manner
Involvement of ERK in NMDA receptor-independent cortical neurotoxicity of hydrogen sulfide
International Nuclear Information System (INIS)
Kurokawa, Yuko; Sekiguchi, Fumiko; Kubo, Satoko; Yamasaki, Yoshiko; Matsuda, Sachi; Okamoto, Yukari; Sekimoto, Teruki; Fukatsu, Anna; Nishikawa, Hiroyuki; Kume, Toshiaki; Fukushima, Nobuyuki; Akaike, Akinori; Kawabata, Atsufumi
2011-01-01
Highlights: ► Hydrogen sulfide causes NMDA receptor-independent neurotoxicity in mouse fetal cortical neurons. ► Activation of ERK mediates the toxicity of hydrogen sulfide. ► Apoptotic mechanisms are involved in the hydrogen-induced cell death. -- Abstract: Hydrogen sulfide (H 2 S), a gasotransmitter, exerts both neurotoxicity and neuroprotection, and targets multiple molecules including NMDA receptors, T-type calcium channels and NO synthase (NOS) that might affect neuronal viability. Here, we determined and characterized effects of NaHS, an H 2 S donor, on cell viability in the primary cultures of mouse fetal cortical neurons. NaHS caused neuronal death, as assessed by LDH release and trypan blue staining, but did not significantly reduce the glutamate toxicity. The neurotoxicity of NaHS was resistant to inhibitors of NMDA receptors, T-type calcium channels and NOS, and was blocked by inhibitors of MEK, but not JNK, p38 MAP kinase, PKC and Src. NaHS caused prompt phosphorylation of ERK and upregulation of Bad, followed by translocation of Bax to mitochondria and release of mitochondrial cytochrome c, leading to the nuclear condensation/fragmentation. These effects of NaHS were suppressed by the MEK inhibitor. Our data suggest that the NMDA receptor-independent neurotoxicity of H 2 S involves activation of the MEK/ERK pathway and some apoptotic mechanisms.
Alaghband, Yasaman; Marshall, John F
2013-04-01
Environmental stimuli or contexts previously associated with rewarding drugs contribute importantly to relapse among addicts, and research has focused on neurobiological processes maintaining those memories. Much research shows contributions of cell surface receptors and intracellular signaling pathways in maintaining associations between rewarding drugs (e.g., cocaine) and concurrent cues/contexts; these memories can be degraded at the time of their retrieval through reconsolidation interference. Much less studied is the consolidation of drug-cue memories during their acquisition. The present experiments use the cocaine-conditioned place preference (CPP) paradigm in rats to directly compare, in a consistent setting, the effects of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists MK-801 and memantine on the consolidation and reconsolidation of cocaine-cue memories. For the consolidation studies, animals were systemically administered MK-801 or memantine immediately following training sessions. To investigate the effects of these NMDA receptor antagonists on the retention of previously established cocaine-cue memories, animals were systemically administered MK-801 or memantine immediately after memory retrieval. Animals given either NMDA receptor antagonist immediately following training sessions did not establish a preference for the cocaine-paired compartment. Post-retrieval administration of either NMDA receptor antagonist attenuated the animals' preference for the cocaine-paired compartment. Furthermore, animals given NMDA receptor antagonists post-retrieval showed a blunted response to cocaine-primed reinstatement. Using two distinct NMDA receptor antagonists in a common setting, these findings demonstrate that NMDA receptor-dependent processes contribute both to the consolidation and reconsolidation of cocaine-cue memories, and they point to the potential utility of treatments that interfere with drug-cue memory reconsolidation.
Bhattarai, Janardhan Prasad; Park, Soo Joung; Chun, Sang Woo; Cho, Dong Hyu; Han, Seong Kyu
2015-11-03
Taurine is an essential amino-sulfonic acid having a fundamental function in the brain, participating in both cell volume regulation and neurotransmission. Using a whole cell voltage patch clamp technique, the taurine-activated neurotransmitter receptors in the preoptic hypothalamic area (PHA) neurons were investigated. In the first set of experiments, different concentrations of taurine were applied on PHA neurons. Taurine-induced responses were concentration-dependent. Taurine-induced currents were action potential-independent and sensitive to strychnine, suggesting the involvement of glycine receptors. In addition, taurine activated not only α-homomeric, but also αβ-heteromeric glycine receptors in PHA neurons. Interestingly, a low concentration of taurine (0.5mM) activated glycine receptors, whereas a higher concentration (3mM) activated both glycine and gamma-aminobutyric acid A (GABAA) receptors in PHA neurons. These results suggest that PHA neurons are influenced by taurine and respond via glycine and GABAA receptors. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
The meth brain: methamphetamines alter brain functions via NMDA receptors
Czech Academy of Sciences Publication Activity Database
Proft, Juliane; Weiss, Norbert
2015-01-01
Roč. 34, č. 1 (2015), s. 1-3 ISSN 0231-5882 R&D Projects: GA ČR GA15-13556S Institutional support: RVO:61388963 Keywords : ion channel * methamphetamine * piriform cortex * NMDA receptor * AMPA receptor Subject RIV: CE - Biochemistry Impact factor: 0.892, year: 2015
NMDA Receptors in Glial Cells: Pending Questions
Czech Academy of Sciences Publication Activity Database
Džamba, Dávid; Honsa, Pavel; Anděrová, Miroslava
2013-01-01
Roč. 11, č. 3 (2013), s. 250-262 ISSN 1570-159X R&D Projects: GA ČR GA309/08/1381; GA ČR(CZ) GBP304/12/G069 Grant - others:GA UK(CZ) 604212 Institutional support: RVO:68378041 Keywords : astrocytes * ischemia * NMDA receptors Subject RIV: FH - Neurology Impact factor: 2.347, year: 2013
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Chun-Lei Zhang
Full Text Available Methylphenidate (MPH, commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD. Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and α2A receptor. Here we showed that higher dose of MPH facilitates NMDA-receptor mediated synaptic transmission via a catecholamine-independent mechanism, in layer V∼VI pyramidal cells of the rat medial prefrontal cortex (PFC. To indicate its postsynaptic action, we next found that MPH facilitates NMDA-induced current and such facilitation could be blocked by σ1 but not D1/5 and α2 receptor antagonists. And this MPH eliciting enhancement of NMDA-receptor activity involves PLC, PKC and IP3 receptor mediated intracellular Ca(2+ increase, but does not require PKA and extracellular Ca(2+ influx. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with σ1 receptor. Together, the present study demonstrates for the first time that MPH facilitates NMDA-receptor mediated synaptic transmission via σ1 receptor, and such facilitation requires PLC/IP3/PKC signaling pathway. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects.
Activation of the ζ receptor 1 suppresses NMDA responses in rat retinal ganglion cells.
Zhang, X-J; Liu, L-L; Jiang, S-X; Zhong, Y-M; Yang, X-L
2011-03-17
The sigma receptor 1 (σR1) has been shown to modulate the activity of several voltage- and ligand-gated channels. Using patch-clamp techniques in rat retinal slice preparations, we demonstrated that activation of σR1 by SKF10047 (SKF) or PRE-084 suppressed N-methyl-D-aspartate (NMDA) receptor-mediated current responses from both ON and OFF type ganglion cells (GCs), dose-dependently, and the effect could be blocked by the σR1 antagonist BD1047 or the σR antagonist haloperidol. The suppression by SKF of NMDA currents was abolished with pre-incubation of the G protein inhibitor GDP-β-S or the Gi/o activator mastoparan. We further explored the intracellular signaling pathway responsible for the SKF-induced suppression of NMDA responses. Application of either cAMP/the PKA inhibitor Rp-cAMP or cGMP/the PKG inhibitor KT5823 did not change the SKF-induced effect, suggesting the involvement of neither cAMP/PKA nor cGMP/PKG pathway. In contrast, suppression of NMDA responses by SKF was abolished by internal infusion of the phosphatidylinostiol-specific phospholipase C (PLC) inhibitor U73122, but not by the phosphatidylcholine-PLC inhibitor D609. SKF-induced suppression of NMDA responses was dependent on intracellular Ca2+ concentration ([Ca2+]i), as evidenced by the fact that the effect was abolished when [Ca2+]i was buffered with 10 mM BAPTA. The SKF effect was blocked by xestospongin-C/heparin, IP3 receptor antagonists, but unchanged by ryanodine/caffeine, ryanodine receptor modulators. Furthermore, application of protein kinase C inhibitors Bis IV and Gö6976 eliminated the SKF effect. These results suggest that the suppression of NMDA responses of rat retinal GCs caused by the activation of σR1 may be mediated by a distinct [Ca2+]i-dependent PLC-PKC pathway. This effect of SKF could help ameliorate malfunction of GCs caused by excessive stimulation of NMDA receptors under pathological conditions. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights
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Paes, Paulo Cesar de Arruda
2002-07-01
The basal ganglia play an important role in the motor control of rats and humans. This control involves different neurotransmitters and the mutual control of these key elements has been subject to several studies. In this work we determined the role of glutamate on the release of radioactively labelled dopamine and acetylcholine from chopped striatal tissue in vitro. The values of Effective Concentration 50% for glutamate, NMDA, kainic, quisqualic acids and AMPA on the release of dopamine and acetylcholine were obtained. The inhibitory effects of magnesium, tetrodotoxin, MK-801, AP5 and MCPG, as well as the effects of glycin were evaluated. The results suggested that dopamine is influenced by the NMDA type glutamate receptor while acetylcholine seems to be influenced by NMDA, kainate and AMPA receptors. Tetrodotoxin experiments suggested that kainate receptors are both present in cholinergic terminals and cell bodies while AMPA and NMDA receptors are preferentially distributed in cell bodies. Magnesium effectively blocked the NMDA stimulation and unexpectedly also AMPA- and quisqualate-induced acetylcholine release. The latter could not be blocked by MCPG ruling out the participation of methabotropic receptors. MK-801 also blocked NMDA-receptors. Results point out the importance of the glutamic acid control of dopamine and acetylcholine release in striatal tissue. (author)
Zhang, Yanmin; Sheng, Hui; Qi, Jinshun; Ma, Bei; Sun, Jihu; Li, Shaofeng; Ni, Xin
2012-04-01
Glucocorticoids (GCs) have been demonstrated to act through both genomic and nongenomic mechanisms. The present study demonstrated that corticosterone rapidly suppressed the activity of N-methyl-D-aspartate (NMDA) receptors in cultured hippocampal neurons. The effect was maintained with corticosterone conjugated to bovine serum albumin and blocked by inhibition of G protein activity with intracellular GDP-β-S application. Corticosterone increased GTP-bound G(s) protein and cyclic AMP (cAMP) production, activated phospholipase Cβ(3) (PLC-β(3)), and induced inositol-1,4,5-triphosphate (IP(3)) production. Blocking PLC and the downstream cascades with PLC inhibitor, IP(3) receptor antagonist, Ca(2+) chelator, and protein kinase C (PKC) inhibitors prevented the actions of corticosterone. Blocking adenylate cyclase (AC) and protein kinase A (PKA) caused a decrease in NMDA-evoked currents. Application of corticosterone partly reversed the inhibition of NMDA currents caused by blockage of AC and PKA. Intracerebroventricular administration of corticosterone significantly suppressed long-term potentiation (LTP) in the CA1 region of the hippocampus within 30 min in vivo, implicating the possibly physiological significance of rapid effects of GC on NMDA receptors. Taken together, our results indicate that GCs act on a putative G protein-coupled receptor to activate multiple signaling pathways in hippocampal neurons, and the rapid suppression of NMDA activity by GCs is dependent on PLC and downstream signaling.
Dravolina, O A; Zvartau, E E; Bespalov, A Y
2000-04-01
Current perspectives on the clinical use of NMDA receptor antagonists infer repeated administration schedules for the management of different pathological states. The development of tolerance and cross-tolerance between different NMDA receptor antagonists may be an important factor contributing to the clinical efficacy of these drugs. The present study aimed to characterize the development of tolerance and cross-tolerance to the ability of various site-selective NMDA receptor antagonists to produce a decrement of operant responding (multiple extinction 9 s fixed-interval 1-s schedule of water reinforcement). Acute administration of D-CPPen (SDZ EAA 494; 1-5.6 mg/kg), dizocilpine (MK-801; 0.03-0.3 mg/kg), memantine (0.3-17 mg/kg), ACEA-1021 (10-56 mg/kg), and eliprodil (1-30 mg/kg) differentially affected operant responding. Both increases and decreases in response rates and accuracy of responding were observed. Repeated preexposure to D-CPPen (5.6 mg/kg, once a day for 7 days) attenuated a behavioral disruption produced by an acute challenge with D-CPPen or ACEA-1021, but potentiated the effects of dizocilpine, memantine, and eliprodil. Based on the present results, one can suggest that the repeated administration of a competitive NMDA receptor antagonist differentially affects the functional activity of various sites on NMDA receptor complex.
Suryavanshi, P S; Ugale, R R; Yilmazer-Hanke, D; Stairs, D J; Dravid, S M
2014-01-01
Background and Purpose Despite ample evidence supporting the N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia, progress in the development of effective therapeutics based on this hypothesis has been limited. Facilitation of NMDA receptor function by co-agonists (d-serine or glycine) only partially alleviates the symptoms in schizophrenia; other means to facilitate NMDA receptors are required. NMDA receptor sub-types differ in their subunit composition, with varied GluN2 subunits (GluN2A-GluN2D) imparting different physiological, biochemical and pharmacological properties. CIQ is a positive allosteric modulator that is selective for GluN2C/GluN2D-containing NMDA receptors (Mullasseril et al.). Experimental Approach The effect of systemic administration of CIQ was tested on impairment in prepulse inhibition (PPI), hyperlocomotion and stereotypy induced by i.p. administration of MK-801 and methamphetamine. The effect of CIQ was also tested on MK-801-induced impairment in working memory in Y-maze spontaneous alternation test. Key Results We found that systemic administration of CIQ (20 mg·kg−1, i.p.) in mice reversed MK-801 (0.15 mg·kg−1, i.p.)-induced, but not methamphetamine (3 mg·kg−1, i.p.)-induced, deficit in PPI. MK-801 increased the startle amplitude to pulse alone, which was not reversed by CIQ. In contrast, methamphetamine reduced the startle amplitude to pulse alone, which was reversed by CIQ. CIQ also partially attenuated MK-801- and methamphetamine-induced hyperlocomotion and stereotyped behaviours. Additionally, CIQ reversed the MK-801-induced working memory deficit in spontaneous alternation in a Y-maze. Conclusion and Implications Together, these results suggest that facilitation of GluN2C/GluN2D-containing receptors may serve as an important therapeutic strategy for treating positive and cognitive symptoms in schizophrenia. PMID:24236947
Jelitai, Márta; Schlett, Katalin; Varju, Patrícia; Eisel, Ulrich; Madarász, Emília
2002-04-01
The schedule of NMDA receptor subunit expression and the appearance of functional NMDA-gated ion channels were investigated during the retinoic acid (RA) induced neuronal differentiation of NE-4C, a p53-deficient mouse neuroectodermal progenitor cell line. NR2A, NR2B, and NR2D subunit transcripts were present in both nondifferentiated and neuronally differentiated cultures, while NR2C subunits were expressed only transiently, during the early period of neural differentiation. Several splice variants of NR1 were detected in noninduced progenitors and in RA-induced cells, except the N1 exon containing transcripts that appeared after the fourth day of induction, when neuronal processes were already formed. NR1 and NR2A subunit proteins were detected both in nondifferentiated progenitor cells and in neurons, while the mature form of NR2B subunit protein appeared only at the time of neuronal process elongation. Despite the early presence of NR1 and NR2A subunits, NMDA-evoked responses could be detected in NE-4C neurons only after the sixth day of induction, coinciding in time with the expression of the mature NR2B subunit. The formation of functional NMDA receptors also coincided with the appearance of synapsin I and synaptophysin. The lag period between the production of the subunits and the onset of channel function suggests that subunits capable of channel formation cannot form functional NMDA receptors until a certain stage of neuronal commitment. Thus, the in vitro neurogenesis by NE-4C cells provides a suitable tool to investigate some inherent regulatory processes involved in the initial maturation of NMDA receptor complexes. Copyright 2002 Wiley Periodicals, Inc.
The role of GluN2B-containing NMDA receptors in short- and long-term fear recall.
Mikics, Eva; Toth, Mate; Biro, Laszlo; Bruzsik, Biborka; Nagy, Boglarka; Haller, Jozsef
2017-08-01
N-methyl-d-aspartate (NMDA) receptors are crucial synaptic elements in long-term memory formation, including the associative learning of fearful events. Although NMDA blockers were consistently shown to inhibit fear memory acquisition and recall, the clinical use of general NMDA blockers is hampered by their side effects. Recent studies revealed significant heterogeneity in the distribution and neurophysiological characteristics of NMDA receptors with different GluN2 (NR2) subunit composition, which may have differential role in fear learning and recall. To investigate the specific role of NMDA receptor subpopulations with different GluN2 subunit compositions in the formation of lasting traumatic memories, we contrasted the effects of general NMDA receptor blockade with GluN2A-, GluN2B-, and GluN2C/D subunit selective antagonists (MK-801, PEAQX, Ro25-6981, PPDA, respectively). To investigate acute and lasting consequences, behavioral responses were investigated 1 and 28days after fear conditioning. We found that MK-801 (0.05 and 0.1mg/kg) decreased fear recall at both time points. GluN2B receptor subunit blockade produced highly similar effects, albeit efficacy was somewhat smaller 28days after fear conditioning. Unlike MK-801, Ro25-6981 (3 and 10mg/kg) did not affect locomotor activity in the open-field. In contrast, GluN2A and GluN2C/D blockers (6 and 20mg/kg PEAQX; 3 and 10mg/kg PPDA, respectively) had no effect on conditioned fear recall at any time point and dose. This sharp contrast between GluN2B- and other subunit-containing NMDA receptor function indicates that GluN2B receptor subunits are intimately involved in fear memory formation, and may provide a novel pharmacological target in post-traumatic stress disorder or other fear-related disorders. Copyright © 2017 Elsevier Inc. All rights reserved.
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de la Roche Jeanne
2012-09-01
Full Text Available Abstract Background The mammalian neurological disorder hereditary hyperekplexia can be attributed to various mutations of strychnine sensitive glycine receptors. The clinical symptoms of “startle disease” predominantly occur in the newborn leading to convulsive hypertonia and an exaggerated startle response to unexpected mild stimuli. Amongst others, point mutations R271Q and R271L in the α1-subunit of strychnine sensitive glycine receptors show reduced glycine sensitivity and cause the clinical symptoms of hyperekplexia. Halogenation has been shown to be a crucial structural determinant for the potency of a phenolic compound to positively modulate glycine receptor function. The aim of this in vitro study was to characterize the effects of 4-chloropropofol (4-chloro-2,6-dimethylphenol at four glycine receptor mutations. Methods Glycine receptor subunits were expressed in HEK 293 cells and experiments were performed using the whole-cell patch-clamp technique. Results 4-chloropropofol exerted a positive allosteric modulatory effect in a low sub-nanomolar concentration range at the wild type receptor (EC50 value of 0.08 ± 0.02 nM and in a micromolar concentration range at the mutations (1.3 ± 0.6 μM, 0.1 ± 0.2 μM, 6.0 ± 2.3 μM and 55 ± 28 μM for R271Q, L, K and S267I, respectively. Conclusions 4-chloropropofol might be an effective compound for the activation of mutated glycine receptors in experimental models of startle disease.
Ostadhadi, Sattar; Norouzi-Javidan, Abbas; Chamanara, Mohsen; Akbarian, Reyhaneh; Imran-Khan, Muhammad; Ghasemi, Mehdi; Dehpour, Ahmad-Reza
2017-09-01
Tramadol is an analgesic agent that is mainly used to treat moderate to severe pain. There is evidence that tramadol may have antidepressant property. However, the mechanisms underlying the antidepressant effects of tramadol have not been elucidated yet. Considering that fact that N-methyl-d-aspartate (NMDA) receptor signaling may play an important role in the pathophysiology of depression, the aim of the present study was to investigate the role of NMDA receptor signaling in the possible antidepressant-like effects of tramadol in the mouse forced swimming test (mFST). We found that tramadol exerted antidepressant-like effects at high dose (40mg/kg, intraperitoneally [i.p.]) in the mFST. Co-administration of non-effective doses of NMDA receptor antagonists (ketamine [1mg/kg, i.p.], MK-801 [0.05mg/kg, i.p.], or magnesium sulfate [10mg/kg, i.p.]) with sub-effective dose of tramadol (20mg/kg, i.p.) exerted significant antidepressant-like effects in the mFST. The antidepressant-like effects of tramadol (40mg/kg) was also inhibited by pre-treatment with non-effective dose of the NMDA receptor agonist NMDA (75mg/kg, i.p.). Our data suggest a role for NMDA receptor signaling in the antidepressant-like effects of tramadol in the mFST. Copyright © 2017 Elsevier Inc. All rights reserved.
Islam, Robiul; Lynch, Joseph W
2012-04-01
Docking studies predict that the insecticides, lindane and fipronil, block GABA(A) receptors by binding to 6' pore-lining residues. However, this has never been tested at any Cys-loop receptor. The neurotoxic effects of these insecticides are also thought to be mediated by GABA(A) receptors, although a recent morphological study suggested glycine receptors mediated fipronil toxicity in zebrafish. Here we investigated whether human α1, α1β, α2 and α3 glycine receptors were sufficiently sensitive to block by either compound as to represent possible neurotoxicity targets. We also investigated the mechanisms by which lindane and fipronil inhibit α1 glycine receptors. Glycine receptors were recombinantly expressed in HEK293 cells and insecticide effects were studied using patch-clamp electrophysiology. Both compounds completely inhibited all tested glycine receptor subtypes with IC(50) values ranging from 0.2-2 µM, similar to their potencies at vertebrate GABA(A) receptors. Consistent with molecular docking predictions, both lindane and fipronil interacted with 6' threonine residues via hydrophobic interactions and hydrogen bonds. In contrast with predictions, we found no evidence for lindane interacting at the 2' level. We present evidence for fipronil binding in a non-blocking mode in the anaesthetic binding pocket, and for lindane as an excellent pharmacological tool for identifying the presence of β subunits in αβ heteromeric glycine receptors. This study implicates glycine receptors as novel vertebrate toxicity targets for fipronil and lindane. Furthermore, lindane interacted with pore-lining 6' threonine residues, whereas fipronil may have both pore and non-pore binding sites. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Toriumi, Kazuya; Mouri, Akihiro; Narusawa, Shiho; Aoyama, Yuki; Ikawa, Natsumi; Lu, Lingling; Nagai, Taku; Mamiya, Takayoshi; Kim, Hyoung-Chun; Nabeshima, Toshitaka
2012-01-01
N-methyl--aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression. PMID:22257896
MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction
DEFF Research Database (Denmark)
Kocerha, Jannet; Faghihi, Mohammad Ali; Lopez-Toledano, Miguel A
2009-01-01
significantly modulated behavioral responses associated with disrupted NMDA receptor transmission. Furthermore, pretreatment with the antipsychotic drugs haloperidol and clozapine prevented dizocilpine-induced effects on miR-219. Taken together, these data support an integral role for miR-219 in the expression...
Aspects of dopamine and acetylcholine release induced by glutamate receptors
International Nuclear Information System (INIS)
Paes, Paulo Cesar de Arruda
2002-01-01
The basal ganglia play an important role in the motor control of rats and humans. This control involves different neurotransmitters and the mutual control of these key elements has been subject to several studies. In this work we determined the role of glutamate on the release of radioactively labelled dopamine and acetylcholine from chopped striatal tissue in vitro. The values of Effective Concentration 50% for glutamate, NMDA, kainic, quisqualic acids and AMPA on the release of dopamine and acetylcholine were obtained. The inhibitory effects of magnesium, tetrodotoxin, MK-801, AP5 and MCPG, as well as the effects of glycin were evaluated. The results suggested that dopamine is influenced by the NMDA type glutamate receptor while acetylcholine seems to be influenced by NMDA, kainate and AMPA receptors. Tetrodotoxin experiments suggested that kainate receptors are both present in cholinergic terminals and cell bodies while AMPA and NMDA receptors are preferentially distributed in cell bodies. Magnesium effectively blocked the NMDA stimulation and unexpectedly also AMPA- and quisqualate-induced acetylcholine release. The latter could not be blocked by MCPG ruling out the participation of methabotropic receptors. MK-801 also blocked NMDA-receptors. Results point out the importance of the glutamic acid control of dopamine and acetylcholine release in striatal tissue. (author)
Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade
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Elena eNosyreva
2014-12-01
Full Text Available Ketamine is a NMDA receptor antagonist that produces rapid antidepressant responses in individuals with major depressive disorder. The antidepressant action of ketamine has been linked to blocking NMDA receptor activation at rest, which inhibits eukaryotic elongation factor2 kinase leading to desuppression of protein synthesis and synaptic potentiation in the CA1 region of the hippocampus. Here, we investigated ketamine mediated antidepressant response and the resulting synaptic potentiation in juvenile animals. We found that ketamine did not produce an antidepressant response in juvenile animals in the novelty suppressed feeding or the forced swim test. In addition ketamine application failed to trigger synaptic potentiation in hippocampal slices obtained from juvenile animals, unlike its action in slices from older animals (6-9 weeks old. The inability of ketamine to trigger an antidepressant response or subsequent synaptic plasticity processes suggests a developmental component to ketamine mediated antidepressant efficacy. We also show that the NMDAR antagonist AP5 triggers synaptic potentiation in mature hippocampus similar to the action of ketamine, demonstrating that global competitive blockade of NMDA receptors is sufficient to trigger this effect. These findings suggest that global blockade of NMDA receptors in developmentally mature hippocampal synapses are required for the antidepressant efficacy of ketamine.
McDonald, Robert J; Hong, Nancy S; Craig, Laura A; Holahan, Matthew R; Louis, Meira; Muller, Robert U
2005-09-01
Recent evidence suggests that N-methyl-D-aspartate (NMDA)-receptor mediated plasticity in hippocampus has a more subtle role in memory-based behaviours than originally thought. One idea is that NMDA-based plasticity is essential for the consolidation of post-training memory but not for the initial encoding or for short-term memory. To further test this idea we used a three-phase variant of the hidden goal water maze task. In the first phase, rats were pre-trained to an initial location. Next, intense, massed training was done in a 2-h interval to teach the rats to go to a new location after either an injection of the NMDA receptor antagonist (6)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) or of vehicle. Finally, under drug-free conditions 24 h after new location training, a competition test was done between the original and new locations. We find that N-methyl-D-aspartate (NMDA)-receptor blockade has little or no effect on new location training. In contrast, when tested 24 h later, the strength of the trace for the new location learned during NMDA-receptor blockade was much weaker compared with the trace for the new location learned after saline injection. Further experiments showed similar effects when NMDA-receptors were blocked immediately after the new location training, suggesting that this is a memory consolidation effect. Our results therefore reinforce the notion that hippocampal NMDA-receptors participate in post-training memory consolidation but are not essential for the processes necessary to learn or retain navigational information in the short term.
Synaptic glutamate spillover increases NMDA receptor reliability at the cerebellar glomerulus
Mitchell, Cassie S.; Lee, Robert H.
2011-01-01
Glutamate spillover in the mossy fiber to granule cell cerebellar glomeruli has been hypothesized to increase neurotransmission reliability. In this study, we evaluate this hypothesis using an experimentally-based quantitative model of glutamate spillover on the N-methyl-d-aspartate receptors (NMDA-Rs) at the cerebellar glomerulus. The transient and steady-state responses of NMDA-Rs were examined over a physiological range of firing rates. Examined cases included direct glutamate release acti...
Towards a Novel Class of Multitarget-Directed Ligands: Dual P2X7–NMDA Receptor Antagonists
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Olga Karoutzou
2018-01-01
Full Text Available Multi-target-directed ligands (MTDLs offer new hope for the treatment of multifactorial complex diseases such as Alzheimer’s Disease (AD. Herein, we present compounds aimed at targeting the NMDA and the P2X7 receptors, which embody a different approach to AD therapy. On one hand, we are seeking to delay neurodegeneration targeting the glutamatergic NMDA receptors; on the other hand, we also aim to reduce neuroinflammation, targeting P2X7 receptors. Although the NMDA receptor is a widely recognized therapeutic target in treating AD, the P2X7 receptor remains largely unexplored for this purpose; therefore, the dual inhibitor presented herein—which is open to further optimization—represents the first member of a new class of MTDLs.
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Florian Wegner
Full Text Available BACKGROUND: Human fetal midbrain-derived neural progenitor cells (NPCs may deliver a tissue source for drug screening and regenerative cell therapy to treat Parkinson's disease. While glutamate and GABA(A receptors play an important role in neurogenesis, the involvement of glycine receptors during human neurogenesis and dopaminergic differentiation as well as their molecular and functional characteristics in NPCs are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we investigated NPCs in respect to their glycine receptor function and subunit expression using electrophysiology, calcium imaging, immunocytochemistry, and quantitative real-time PCR. Whole-cell recordings demonstrate the ability of NPCs to express functional strychnine-sensitive glycine receptors after differentiation for 3 weeks in vitro. Pharmacological and molecular analyses indicate a predominance of glycine receptor heteromers containing α2β subunits. Intracellular calcium measurements of differentiated NPCs suggest that glycine evokes depolarisations mediated by strychnine-sensitive glycine receptors and not by D-serine-sensitive excitatory glycine receptors. Culturing NPCs with additional glycine, the glycine-receptor antagonist strychnine, or the Na(+-K(+-Cl(- co-transporter 1 (NKCC1-inhibitor bumetanide did not significantly influence cell proliferation and differentiation in vitro. CONCLUSIONS/SIGNIFICANCE: These data indicate that NPCs derived from human fetal midbrain tissue acquire essential glycine receptor properties during neuronal maturation. However, glycine receptors seem to have a limited functional impact on neurogenesis and dopaminergic differentiation of NPCs in vitro.
Cochlear NMDA Receptors as a Therapeutic Target of Noise-Induced Tinnitus
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Dan Bing
2015-03-01
Full Text Available Background: Accumulating evidence suggests that tinnitus may occur despite normal auditory sensitivity, probably linked to partial degeneration of the cochlear nerve and damage of the inner hair cell (IHC synapse. Damage to the IHC synapses and deafferentation may occur even after moderate noise exposure. For both salicylate- and noise-induced tinnitus, aberrant N-methyl-d-aspartate (NMDA receptor activation and related auditory nerve excitation have been suggested as origin of cochlear tinnitus. Accordingly, NMDA receptor inhibition has been proposed as a pharmacologic approach for treatment of synaptopathic tinnitus. Methods: Round-window application of the NMDA receptor antagonist AM-101 (Esketamine hydrochloride gel; Auris Medical AG, Basel, Switzerland was tested in an animal model of tinnitus induced by acute traumatic noise. The study included the quantification of IHC ribbon synapses as a correlate for deafferentation as well as the measurement of the auditory brainstem response (ABR to close-threshold sensation level stimuli as an indication of sound-induced auditory nerve activity. Results: We have shown that AM-101 reduced the trauma-induced loss of IHC ribbons and counteracted the decline of ABR wave I amplitude generated in the cochlea/auditory nerve. Conclusion: Local round-window application of AM-101 may be a promising therapeutic intervention for the treatment of synaptopathic tinnitus.
[Learning and Memory Capacity and NMDA Receptor Expression in Shen Deficiency Constitution Rats].
Sun, Yu-ru; Sun, Yao-guang; Zhang, Qi; Wang, Xiao-di; Wang, Xing; Sun, Li-jun
2016-05-01
To explore material bases and neurobiological mechanisms of "Shen storing will" by observing learning and memory capacities and N-methyl-D-aspartic acid (NMDA) receptor expressions in Shen deficiency constitution (SDC) rats. Totally 40 SD rats were randomly divided into the model group, the Zuogui Pill (ZP) group, the Yougui Pill (YP) group, the blank control group (consisting of normal pregnant rats), 10 in each group. SDC young rat model (inherent deficiency and postnatal malnutrition) was prepared by the classic way of "cat scaring rat". Medication started when they were scared by cat. Rats in the ZP group and the YP group were administered by gastrogavage with ZP suspension 0.1875 g/mL and YP suspension 0.0938 g/mL respectively. Equal volume of normal saline was administered to rats in the blank control group and the model group by gastrogavage. All medication was given once per day, 5 days in a week for 2 consecutive months. Learning and memory capacities were detected by Morris water maze test. Expressions of NMDA receptor subunits NR2A and NR2B in hippocamus were detected by immunohistochemical method. Compared with the blank control group, the latency period, total distance in Morris water maze test were longer in the model group (P learning and memory capacities and lowered NMDA receptor expressions. ZP and YP could up-regulate learning and memory capacities and NMDA receptor expressions, thereby improving deterioration of brain functions in SDC rats.
TAAR1 Modulates Cortical Glutamate NMDA Receptor Function
Espinoza, Stefano; Lignani, Gabriele; Caffino, Lucia; Maggi, Silvia; Sukhanov, Ilya; Leo, Damiana; Mus, Liudmila; Emanuele, Marco; Ronzitti, Giuseppe; Harmeier, Anja; Medrihan, Lucian; Sotnikova, Tatyana D; Chieregatti, Evelina; Hoener, Marius C; Benfenati, Fabio; Tucci, Valter; Fumagalli, Fabio; Gainetdinov, Raul R
2015-01-01
Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor expressed in the mammalian brain and known to influence subcortical monoaminergic transmission. Monoamines, such as dopamine, also play an important role within the prefrontal cortex (PFC) circuitry, which is critically involved in high-o5rder cognitive processes. TAAR1-selective ligands have shown potential antipsychotic, antidepressant, and pro-cognitive effects in experimental animal models; however, it remains unclear whether TAAR1 can affect PFC-related processes and functions. In this study, we document a distinct pattern of expression of TAAR1 in the PFC, as well as altered subunit composition and deficient functionality of the glutamate N-methyl-D-aspartate (NMDA) receptors in the pyramidal neurons of layer V of PFC in mice lacking TAAR1. The dysregulated cortical glutamate transmission in TAAR1-KO mice was associated with aberrant behaviors in several tests, indicating a perseverative and impulsive phenotype of mutants. Conversely, pharmacological activation of TAAR1 with selective agonists reduced premature impulsive responses observed in the fixed-interval conditioning schedule in normal mice. Our study indicates that TAAR1 plays an important role in the modulation of NMDA receptor-mediated glutamate transmission in the PFC and related functions. Furthermore, these data suggest that the development of TAAR1-based drugs could provide a novel therapeutic approach for the treatment of disorders related to aberrant cortical functions. PMID:25749299
Stress-induced changes of hippocampal NMDA receptors: modulation by duloxetine treatment.
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Francesca Calabrese
Full Text Available It is now well established that the glutamatergic system contributes to the pathophysiology of depression. Exposure to stress, a major precipitating factor for depression, enhances glutamate release that can contribute to structural abnormalities observed in the brain of depressed subjects. On the other hand, it has been demonstrated that NMDA antagonists, like ketamine, exert an antidepressant effect at preclinical and clinical levels. On these bases, the purpose of our study was to investigate whether chronic mild stress is associated with specific alterations of the NMDA receptor complex, in adult rats, and to establish whether concomitant antidepressant treatment could normalize such deficits. We found that chronic stress increases the expression of the obligatory GluN1 subunit, as well as of the accessory subunits GluN2A and GluN2B at transcriptional and translational levels, particularly in the ventral hippocampus. Concomitant treatment with the antidepressant duloxetine was able to normalize the increase of glutamatergic receptor subunit expression, and correct the changes in receptor phosphorylation produced by stress exposure. Our data suggest that prolonged stress, a condition that has etiologic relevance for depression, may enhance glutamate activity through post-synaptic mechanisms, by regulating NMDA receptors, and that antidepressants may in part normalize such changes. Our results provide support to the notion that antidepressants may exert their activity in the long-term also via modulation of the glutamatergic synapse.
Kalirin-7 is necessary for normal NMDA receptor-dependent synaptic plasticity
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Lemtiri-Chlieh Fouad
2011-12-01
Full Text Available Abstract Background Dendritic spines represent the postsynaptic component of the vast majority of excitatory synapses present in the mammalian forebrain. The ability of spines to rapidly alter their shape, size, number and receptor content in response to stimulation is considered to be of paramount importance during the development of synaptic plasticity. Indeed, long-term potentiation (LTP, widely believed to be a cellular correlate of learning and memory, has been repeatedly shown to induce both spine enlargement and the formation of new dendritic spines. In our studies, we focus on Kalirin-7 (Kal7, a Rho GDP/GTP exchange factor (Rho-GEF localized to the postsynaptic density that plays a crucial role in the development and maintenance of dendritic spines both in vitro and in vivo. Previous studies have shown that mice lacking Kal7 (Kal7KO have decreased dendritic spine density in the hippocampus as well as focal hippocampal-dependent learning impairments. Results We have performed a detailed electrophysiological characterization of the role of Kal7 in hippocampal synaptic plasticity. We show that loss of Kal7 results in impaired NMDA receptor-dependent LTP and long-term depression, whereas a NMDA receptor-independent form of LTP is shown to be normal in the absence of Kal7. Conclusions These results indicate that Kal7 is an essential and selective modulator of NMDA receptor-dependent synaptic plasticity in the hippocampus.
Kalirin-7 is necessary for normal NMDA receptor-dependent synaptic plasticity
Lemtiri-Chlieh, Fouad
2011-12-19
Background: Dendritic spines represent the postsynaptic component of the vast majority of excitatory synapses present in the mammalian forebrain. The ability of spines to rapidly alter their shape, size, number and receptor content in response to stimulation is considered to be of paramount importance during the development of synaptic plasticity. Indeed, long-term potentiation (LTP), widely believed to be a cellular correlate of learning and memory, has been repeatedly shown to induce both spine enlargement and the formation of new dendritic spines. In our studies, we focus on Kalirin-7 (Kal7), a Rho GDP/GTP exchange factor (Rho-GEF) localized to the postsynaptic density that plays a crucial role in the development and maintenance of dendritic spines both in vitro and in vivo. Previous studies have shown that mice lacking Kal7 (Kal7 KO) have decreased dendritic spine density in the hippocampus as well as focal hippocampal-dependent learning impairments.Results: We have performed a detailed electrophysiological characterization of the role of Kal7 in hippocampal synaptic plasticity. We show that loss of Kal7 results in impaired NMDA receptor-dependent LTP and long-term depression, whereas a NMDA receptor-independent form of LTP is shown to be normal in the absence of Kal7.Conclusions: These results indicate that Kal7 is an essential and selective modulator of NMDA receptor-dependent synaptic plasticity in the hippocampus. 2011 Lemtiri-Chlieh et al; licensee BioMed Central Ltd.
Toxicological Differences Between NMDA Receptor Antagonists and Cholinesterase Inhibitors.
Shi, Xiaodong; Lin, Xiaotian; Hu, Rui; Sun, Nan; Hao, Jingru; Gao, Can
2016-08-01
Cholinesterase inhibitors (ChEIs), represented by donepezil, rivastigmine, and galantamine, used to be the only approved class of drugs for the treatment of Alzheimer's disease. After the approval of memantine by the Food and Drug Administration (FDA), N-methyl-d-aspartic acid (NMDA) receptor antagonists have been recognized by authorities and broadly used in the treatment of Alzheimer's disease. Along with complementary mechanisms of action, NMDA antagonists and ChEIs differ not only in therapeutic effects but also in adverse reactions, which is an important consideration in clinical drug use. And the number of patients using NMDA antagonists and ChEIs concomitantly has increased, making the matter more complicated. Here we used the FDA Adverse Event Reporting System for statistical analysis , in order to compare the adverse events of memantine and ChEIs. In general, the clinical evidence confirmed the safety advantages of memantine over ChEIs, reiterating the precautions of clinical drug use and the future direction of antidementia drug development. © The Author(s) 2016.
Jelitai, Márta; Schlett, Katalin; Varju, Patrícia; Eisel, Ulrich; Madarász, Emília
The schedule of NMDA receptor subunit expression and the appearance of functional NMDA-gated ion channels were investigated during the retinoic acid (RA) induced neuronal differentiation of NE-4C, a p53-deficient mouse neuroectodermal progenitor cell line. NR2A. NR2B, and NR2D subunit transcripts
NMDA receptor antagonist ketamine impairs feature integration in visual perception
Meuwese, Julia D I; van Loon, Anouk M; Scholte, H Steven; Lirk, Philipp B; Vulink, Nienke C C; Hollmann, Markus W; Lamme, Victor A F
2013-01-01
Recurrent interactions between neurons in the visual cortex are crucial for the integration of image elements into coherent objects, such as in figure-ground segregation of textured images. Blocking N-methyl-D-aspartate (NMDA) receptors in monkeys can abolish neural signals related to figure-ground
Harmaline competitively inhibits [3H]MK-801 binding to the NMDA receptor in rabbit brain.
Du, W; Aloyo, V J; Harvey, J A
1997-10-03
Harmaline, a beta-carboline derivative, is known to produce tremor through a direct activation of cells in the inferior olive. However, the receptor(s) through which harmaline acts remains unknown. It was recently reported that the tremorogenic actions of harmaline could be blocked by the noncompetitive NMDA channel blocker, MK-801. This study examined whether the blockade of harmaline's action, in the rabbit, by MK-801 was due to a pharmacological antagonism at the MK-801 binding site. This was accomplished by measurement of [3H]MK-801 binding in membrane fractions derived from tissue containing the inferior olivary nucleus and from cerebral cortex. Harmaline completely displaced saturable [3H]MK-801 binding in both the inferior olive and cortex with apparent IC50 values of 60 and 170 microM, respectively. These IC50 values are consistent with the high doses of harmaline required to produce tremor, e.g., 10-30 mg/kg. Non-linear curve fitting analysis of [3H]MK-801 saturation experiments indicated that [3H]MK-801 bound to a single site and that harmaline's displacement of [3H]MK-801 binding to the NMDA receptor was competitive as indicated by a shift in Kd but not in Bmax. In addition, a Schild plot gave a slope that was not significantly different from 1 indicating that harmaline was producing a displacement of [3H]MK-801 from its binding site within the NMDA cation channel and not through an action at the glutamate or other allosteric sites on the NMDA receptor. These findings provide in vitro evidence that the competitive blockade of harmaline-induced tremor by MK-801 occurs within the calcium channel coupled to the NMDA receptor. Our hypothesis is that harmaline produces tremor by acting as an inverse agonist at the MK-801 binding site and thus opening the cation channel.
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Goodchild Ann K
2010-10-01
Full Text Available Abstract Background Cardiac vagal preganglionic neurons (CVPN are responsible for the tonic, reflex and respiratory modulation of heart rate (HR. Although CVPN receive GABAergic and glutamatergic inputs, likely involved in respiratory and reflex modulation of HR respectively, little else is known regarding the functions controlled by ionotropic inputs. Activation of g-protein coupled receptors (GPCR alters these inputs, but the functional consequence is largely unknown. The present study aimed to delineate how ionotropic GABAergic, glycinergic and glutamatergic inputs contribute to the tonic and reflex control of HR and in particular determine which receptor subtypes were involved. Furthermore, we wished to establish how activation of the 5-HT1A GPCR affects tonic and reflex control of HR and what ionotropic interactions this might involve. Results Microinjection of the GABAA antagonist picrotoxin into CVPN decreased HR but did not affect baroreflex bradycardia. The glycine antagonist strychnine did not alter HR or baroreflex bradycardia. Combined microinjection of the NMDA antagonist, MK801, and AMPA antagonist, CNQX, into CVPN evoked a small bradycardia and abolished baroreflex bradycardia. MK801 attenuated whereas CNQX abolished baroreceptor bradycardia. Control intravenous injections of the 5-HT1A agonist 8-OH-DPAT evoked a small bradycardia and potentiated baroreflex bradycardia. These effects were still observed following microinjection of picrotoxin but not strychnine into CVPN. Conclusions We conclude that activation of GABAA receptors set the level of HR whereas AMPA to a greater extent than NMDA receptors elicit baroreflex changes in HR. Furthermore, activation of 5-HT1A receptors evokes bradycardia and enhances baroreflex changes in HR due to interactions with glycinergic neurons involving strychnine receptors. This study provides reference for future studies investigating how diseases alter neurochemical inputs to CVPN.
Retrieval-induced NMDA receptor-dependent Arc expression in two models of cocaine-cue memory.
Alaghband, Yasaman; O'Dell, Steven J; Azarnia, Siavash; Khalaj, Anna J; Guzowski, John F; Marshall, John F
2014-12-01
The association of environmental cues with drugs of abuse results in persistent drug-cue memories. These memories contribute significantly to relapse among addicts. While conditioned place preference (CPP) is a well-established paradigm frequently used to examine the modulation of drug-cue memories, very few studies have used the non-preference-based model conditioned activity (CA) for this purpose. Here, we used both experimental approaches to investigate the neural substrates of cocaine-cue memories. First, we directly compared, in a consistent setting, the involvement of cortical and subcortical brain regions in cocaine-cue memory retrieval by quantifying activity-regulated cytoskeletal-associated (Arc) protein expression in both the CPP and CA models. Second, because NMDA receptor activation is required for Arc expression, we investigated the NMDA receptor dependency of memory persistence using the CA model. In both the CPP and CA models, drug-paired animals showed significant increases in Arc immunoreactivity in regions of the frontal cortex and amygdala compared to unpaired controls. Additionally, administration of a NMDA receptor antagonist (MK-801 or memantine) immediately after cocaine-CA memory reactivation impaired the subsequent conditioned locomotion associated with the cocaine-paired environment. The enhanced Arc expression evident in a subset of corticolimbic regions after retrieval of a cocaine-context memory, observed in both the CPP and CA paradigms, likely signifies that these regions: (i) are activated during retrieval of these memories irrespective of preference-based decisions, and (ii) undergo neuroplasticity in order to update information about cues previously associated with cocaine. This study also establishes the involvement of NMDA receptors in maintaining memories established using the CA model, a characteristic previously demonstrated using CPP. Overall, these results demonstrate the utility of the CA model for studies of cocaine
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Lind, Genevieve E.; Mou, Tung-Chung; Tamborini, Lucia; Pomper, Martin G.; De Micheli, Carlo; Conti, Paola; Pinto, Andrea; Hansen, Kasper B. (JHU); (Milan); (Montana)
2017-07-31
NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA receptors comprise two glycine-binding GluN1 and two glutamate-binding GluN2 subunits (GluN2A–D). We describe highly potent (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) competitive GluN2 antagonists, of which ST3 has a binding affinity of 52 nM at GluN1/2A and 782 nM at GluN1/2B receptors. This 15-fold preference of ST3 for GluN1/2A over GluN1/2B is improved compared with NVP-AAM077, a widely used GluN2A-selective antagonist, which we show has 11-fold preference for GluN1/2A over GluN1/2B. Crystal structures of the GluN1/2A agonist binding domain (ABD) heterodimer with bound ACEPC antagonists reveal a binding mode in which the ligands occupy a cavity that extends toward the subunit interface between GluN1 and GluN2A ABDs. Mutational analyses show that the GluN2A preference of ST3 is primarily mediated by four nonconserved residues that are not directly contacting the ligand, but positioned within 12 Å of the glutamate binding site. Two of these residues influence the cavity occupied by ST3 in a manner that results in favorable binding to GluN2A, but occludes binding to GluN2B. Thus, we reveal opportunities for the design of subunit-selective competitive NMDA receptor antagonists by identifying a cavity for ligand binding in which variations exist between GluN2A and GluN2B subunits. This structural insight suggests that subunit selectivity of glutamate-site antagonists can be mediated by mechanisms in addition to direct contributions of contact residues to binding affinity.
The effect of infectious brain edema on NMDA receptor binding in rat's brain
International Nuclear Information System (INIS)
Cheng Guansheng; Chen Jianfang; Chen Xiang
1997-01-01
PURPOSE: The effect of the infectious brain edema (IBE) induced by Bordetella Pertussis (BP) on the specific binding of 3 H MK-801 in rat's brain in vivo was determined. METHODS: BP was injected via left internal carotid artery in rat model of infectious brain edema. Male SD rats were divided into three groups: 1) Group control (NS, n = 11); 2) Group IBF (BP, n = 12); 3) Group pretreatment of MK-801 + PB (MK-801, n = 4). Normal saline or BP 0.2 ml/kg was injected into left internal carotid artery in NS and BP group respectively. MK-801 0.5 mg/kg per day was injected i.p. two days before injection of BP in group MK-801. Rats were killed by decapitation at 24 hours after injection of BP. The specific binding of N-methyl-D-aspartate (NMDA) receptor were measured with 3 H-MK-801 in the neuronal membrane of cerebral cortex. The Scatchard plots were performed. RESULTS: The B max values were 0.623 +- 0.082 and 0.606 +- 0.087 pmol/mg protein in group NS and BP respectively (t = 0.48, P>0.05). The Kd values were 43.1 +- 4.2 and 30.5 +- 3.0 nmol/L in group NS and BP respectively (t = 7.8, P<0.05). The specific binding of NMDA receptor was decreased by pretreatment of MK-801. CONCLUSIONS: The total number of NMDA receptor had not changed, whereas its affinity increased significantly in the model of brain edema induced by pertussis bacilli in rat. The increase of affinity of NMDA receptor can be blockaded by MK-801 pretreatment in vivo
De Sarro, Giovambattista; Chimirri, Alba; Meldrum, Brian S
2002-09-06
We report the anticonvulsant action in DBA/2 mice of two mGlu Group III receptor agonists: (R,S)-4-phosphonophenylglycine, (R,S)-PPG, a compound with moderate mGlu8 selectivity, and of (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid, ACPT-1, a selective agonist for mGlu4alpha receptors. Both compounds, given intracerebroventricularly at doses which did not show marked anticonvulsant activity, produced a consistent shift to the left of the dose-response curves (i.e. enhanced the anticonvulsant properties) of 1-(4'-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one hydrochloride, CFM-2, a noncompetitive AMPA receptor antagonist, and 3-((+/-)-2-carboxypiperazin-4-yl)-1-phosphonic acid, CPPene, a competitive NMDA receptor antagonist, in DBA/2 mice. In addition, (R,S)-PPG and ACPT-1 administered intracerebroventricularly prolonged the time course of the anticonvulsant properties of CFM-2 (33 micromol/kg, i.p.) and CPPene (3.3 micromol/kg, i.p.) administered intraperitoneally. We conclude that modest reduction of synaptic glutamate release by activation of Group III metabotropic receptors potentiates the anticonvulsant effect of AMPA and NMDA receptor blockade. Copyright 2002 Elsevier Science B.V.
Banerjee, Abhishek; Meredith, Rhiannon M; Rodríguez-Moreno, Antonio; Mierau, Susanna B; Auberson, Yves P; Paulsen, Ole
2009-12-01
Spike timing-dependent plasticity (STDP) is a strong candidate for an N-methyl-D-aspartate (NMDA) receptor-dependent form of synaptic plasticity that could underlie the development of receptive field properties in sensory neocortices. Whilst induction of timing-dependent long-term potentiation (t-LTP) requires postsynaptic NMDA receptors, timing-dependent long-term depression (t-LTD) requires the activation of presynaptic NMDA receptors at layer 4-to-layer 2/3 synapses in barrel cortex. Here we investigated the developmental profile of t-LTD at layer 4-to-layer 2/3 synapses of mouse barrel cortex and studied their NMDA receptor subunit dependence. Timing-dependent LTD emerged in the first postnatal week, was present during the second week and disappeared in the adult, whereas t-LTP persisted in adulthood. An antagonist at GluN2C/D subunit-containing NMDA receptors blocked t-LTD but not t-LTP. Conversely, a GluN2A subunit-preferring antagonist blocked t-LTP but not t-LTD. The GluN2C/D subunit requirement for t-LTD appears to be synapse specific, as GluN2C/D antagonists did not block t-LTD at horizontal cross-columnar layer 2/3-to-layer 2/3 synapses, which was blocked by a GluN2B antagonist instead. These data demonstrate an NMDA receptor subunit-dependent double dissociation of t-LTD and t-LTP mechanisms at layer 4-to-layer 2/3 synapses, and suggest that t-LTD is mediated by distinct molecular mechanisms at different synapses on the same postsynaptic neuron.
D'Souza, Deepak Cyril; Singh, Nagendra; Elander, Jacqueline; Carbuto, Michelle; Pittman, Brian; de Haes, Joanna Udo; Sjogren, Magnus; Peeters, Pierre; Ranganathan, Mohini; Schipper, Jacques
2012-01-01
Enhancing glutamate function by stimulating the glycine site of the NMDA receptor with glycine, -serine, or with drugs that inhibit glycine reuptake may have therapeutic potential in schizophrenia. The effects of a single oral dose of cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) amino-methylcarboxylic acid hydrochloride (Org 25935), a glycine transporter-1 (GlyT1) inhibitor, and placebo pretreatment on ketamine-induced schizophrenia-like psychotic symptoms, perceptual alterations, and subjective effects were evaluated in 12 healthy male subjects in a randomized, counter-balanced, within-subjects, crossover design. At 2.5 h after administration of the Org 25935 or placebo, subjects received a ketamine bolus and constant infusion lasting 100 min. Psychotic symptoms, perceptual, and a number of subjective effects were assessed repeatedly before, several times during, and after completion of ketamine administration. A cognitive battery was administered once per test day. Ketamine produced behavioral, subjective, and cognitive effects consistent with its known effects. Org 25935 reduced the ketamine-induced increases in measures of psychosis (Positive and Negative Syndrome Scale (PANSS)) and perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)). The magnitude of the effect of Org 25935 on ketamine-induced increases in Total PANSS and CADSS Clinician-rated scores was 0.71 and 0.98 (SD units), respectively. None of the behavioral effects of ketamine were increased by Org 25935 pretreatment. Org 25935 worsened some aspects of learning and delayed recall, and trended to improve choice reaction time. This study demonstrates for the first time in humans that a GlyT1 inhibitor reduces the effects induced by NMDA receptor antagonism. These findings provide preliminary support for further study of the antipsychotic potential of GlyT1 inhibitors. PMID:22113087
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Xujiao Zhou
2017-12-01
Full Text Available Presynaptic modulation of γ-aminobutyric acid (GABA release by an alpha7 nicotinic acetylcholine receptor (α7-nAChR agonist promotes retinal ganglion cell (RGC survival and function, as suggested by a previous study on a chronic glaucomatous model from our laboratory. However, the role of excitatory and inhibitory amino acid receptors and their interaction with α7-nAChR in physiological and glaucomatous events remains unknown. In this study, we investigated GABAA and N-methyl-D-aspartate (NMDA receptor activity in control and glaucomatous retinal slices and the regulation of amino acid receptor expression and function by α7-nAChR. Whole-cell patch-clamp recordings from RGCs revealed that the α7-nAChR specific agonist PNU-282987 enhanced the amplitude of currents elicited by GABA and reduced the amplitude of currents elicited by NMDA. The positive modulation of GABAA receptor and the negative modulation of NMDA receptor (NMDAR by PNU-282987-evoked were prevented by pre-administration of the α7-nAChR antagonist methyllycaconitine (MLA. The frequency and the amplitude of glutamate receptor-mediated miniature glutamatergic excitatory postsynaptic currents (mEPSCs were not significantly different between the control and glaucomatous RGCs. Additionally, PNU-282987-treated slices showed no alteration in the frequency or amplitude of mEPSCs relative to control RGCs. Moreover, we showed that expression of the α1 subunit of the GABAA receptor was downregulated and the expression of the NMDAR NR2B subunit was upregulated by intraocular pressure (IOP elevation, and the changes of high IOP were blocked by PNU-282987. In conclusion, retina GABAA and NMDARs are modulated positively and negatively, respectively, by activation of α7-nAChR in in vivo chronic glaucomatous models.
Choudhury, Sabanum; Borah, Anupom
2015-07-01
Liver diseases lead to a complex syndrome characterized by neurological, neuro-psychiatric and motor complications, called hepatic encephalopathy, which is prevalent in patients and animal models of acute, sub-chronic and chronic liver failure. Although alterations in GABAergic, glutamatergic, cholinergic and serotonergic neuronal functions have been implicated in HE, the molecular mechanisms that lead to HE in chronic liver disease (CLD) is least illustrated. Due to hepatocellular failure, levels of ammonia and homocysteine (Hcy), in addition to others, are found to increase in the brain as well as plasma. Hcy, a non-protein forming amino acid and an excitotoxin, activates ionotropic glutamate (n-methyl-d-aspartate; NMDA) receptors, and thereby leads to influx of Ca(2+) into neurons, which in turn activates several pathways that trigger oxidative stress, inflammation and apoptosis, collectively called excitotoxicity. Elevated levels of Hcy in the plasma and brain, a condition called Hyperhomocysteinemia (HHcy), and the resultant NMDA receptor-mediated excitotoxicity has been implicated in several diseases, including Parkinson's disease and Alzheimer's disease. Although, hyperammonemia has been shown to cause excitotoxicity, the role of HHcy in the development of behavioral and neurochemical alterations that occur in HE has not been illustrated yet. It is hypothesized that CLD-induced HHcy plays a major role in the development of HE through activation of NMDA receptors. It is further hypothesized that HHcy synergizes with hyperammonemia to activate NMDA receptor in the brain, and thereby cause oxidative stress, inflammation and apoptosis, and neuronal loss that leads to HE. Copyright © 2015 Elsevier Ltd. All rights reserved.
A glycine residue essential for high ivermectin sensitivity in Cys-loop ion channel receptors
DEFF Research Database (Denmark)
Lynagh, Timothy; Lynch, Joseph W.
2010-01-01
Ivermectin exerts its anthelmintic effect by activating nematode Cys-loop glutamate-gated receptors. Here we show that a glycine residue at a specific transmembrane domain location is essential for high ivermectin sensitivity in both glycine- and glutamate-gated Cys-loop receptors. We also show...
Ducrot, Charles; Fortier, Emmanuel; Bouchard, Claude; Rompré, Pierre-Paul
2013-01-01
Previous studies have shown that blockade of ventral tegmental area (VTA) glutamate N-Methyl-D-Aspartate (NMDA) receptors induces reward, stimulates forward locomotion and enhances brain stimulation reward. Glutamate induces two types of excitatory response on VTA neurons, a fast and short lasting depolarization mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors and a longer lasting depolarization mediated by NMDA receptors. A role for the two glutamate receptors in modulation of VTA neuronal activity is evidenced by the functional change in AMPA and NMDA synaptic responses that result from repeated exposure to reward. Since both receptors contribute to the action of glutamate on VTA neuronal activity, we studied the effects of VTA AMPA and NMDA receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer electrical pulses in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and for 2 h after bilateral VTA microinjections of the AMPA antagonist, NBQX (2,3,-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulfonamide, 0, 80, and 800 pmol/0.5 μl/side) and of a single dose (0.825 nmol/0.5 μl/side) of the NMDA antagonist, PPPA (2R,4S)-4-(3-Phosphonopropyl)-2-piperidinecarboxylic acid). NBQX produced a dose-dependent increase in reward threshold with no significant change in maximum rate of responding. Whereas PPPA injected at the same VTA sites produced a significant time dependent decrease in reward threshold and increase in maximum rate of responding. We found a negative correlation between the magnitude of the attenuation effect of NBQX and the enhancement effect of PPPA; moreover, NBQX and PPPA were most effective when injected, respectively, into the anterior and posterior VTA. These results suggest that glutamate acts on different receptor sub-types, most likely located on different VTA neurons, to
Directory of Open Access Journals (Sweden)
Charles eDucrot
2013-10-01
Full Text Available Previous studies have shown that blockade of ventral midbrain (VM glutamate N-Methyl-D-Aspartate (NMDA receptors induces reward, stimulates forward locomotion and enhances brain stimulation reward. Glutamate induces two types of excitatory response on VM neurons, a fast and short lasting depolarisation mediated by a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA receptors and a longer lasting depolarization mediated by NMDA receptors. A role for the two glutamate receptors in modulation of VM neuronal activity is evidenced by the functional change in AMPA and NMDA synaptic responses that result from repeated exposure to reward. Since both receptors contribute to the action of glutamate on VM neuronal activity, we studied the effects of VM AMPA and NMDA receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer electrical pulses in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and for two hours after bilateral VM microinjections of the AMPA antagonist, NBQX (2,3,-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(fquinoxaline-7-sulfonamide, 0, 80, and 800 pmol/0.5ul/side and of a single dose (0.825 nmol/0.5ul/side of the NMDA antagonist, PPPA (2R,4S-4-(3-Phosphonopropyl-2-piperidinecarboxylic acid. NBQX produced a dose-dependent increase in reward threshold with no significant change in maximum rate of responding. Whereas PPPA injected at the same VM sites produced a significant time dependent decrease in reward threshold and increase in maximum rate of responding. We found a negative correlation between the magnitude of the attenuation effect of NBQX and the enhancement effect of PPPA; moreover, NBQX and PPPA were most effective when injected respectively into the anterior and posterior VM. These results suggest that glutamate acts on different receptor sub-types, most likely located on different VM neurons, to modulate
Marinho da Silva, Sergio; Carrettiero, Daniel C; Chadi, Débora R F
2014-04-03
α2 Adrenoceptors (α2-ARs) are important in regulating the central control of blood pressure in medulla oblongata. However, it is unclear how this receptor is modulated by different receptors, especially the glutamatergic. In the present study, we studied the influence of ionotropic glutamatergic receptors over the α2-ARs in cultured cells of the medulla oblongata of newborn rats. For this purpose, the protein level of the α2-ARs was assessed after administration to the cultured cells of glutamate (glu), the agonists NMDA and kainate (KA), the NMDA receptor antagonist MK801 and the KA receptor antagonist DNQX. Results indicate that the α2-AR protein levels were increased after the treatments with glu and NMDA, and the addition of MK801 to this treatment thwarted this increase. Notwithstanding the fact that KA did not alter the receptor protein level, the combined treatment of DNQX with glu prevented the α2-AR protein modulation. In conclusion, the present study suggests that ionotropic glutamatergic receptors could be related to the α2-AR protein regulation in the medulla oblongata. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Schankin, Christoph J; Kästele, Fabian; Gerdes, Lisa Ann; Winkler, Tobias; Csanadi, Endy; Högen, Tobias; Pellkofer, Hannah; Paulus, Walter; Kümpfel, Tania; Straube, Andreas
2016-06-01
We tested the hypotheses (i) that autoimmune encephalitis is associated with new-onset headache, and (ii) that the occurrence of headache is associated with the presence of anti-N-methyl-D-aspartate (NMDA)-receptor antibodies. Autoimmune encephalitis presents with cognitive dysfunction as well as neuro-psychiatric symptoms. Its pathophysiology might involve antibody-mediated dysfunction of the glutamatergic system as indicated by the presence of anti-NMDA-receptor antibodies in some patients. In this cross-sectional study, patients with autoimmune encephalitis were assessed with a standardized interview for previous headache and headache associated with autoimmune encephalitis. Headache was classified according to the International Classification of Headache Disorders, second edition. Clinical and paraclinical findings were correlated with the occurrence of headache. Of 40 patients with autoimmune encephalitis, 19 did not have a history of headache. Of those, nine suffered from encephalitis-associated headache. Seven of these nine had anti-NMDA-receptor antibodies in contrast to only two among the remaining 10 patients without new-onset headache (P = .023, odds ratio: 14, 95% confidence interval: 1.5; 127). In most patients headache occurred in attacks on more than 15 days/month, was severe, and of short duration (less than 4 hours). International Headache Society criteria for migraine were met in three patients. New-onset headache is a relevant symptom in patients with autoimmune encephalitis who have no history of previous headache, especially in the subgroup with anti-NMDA-receptor antibodies. This indicates a thorough investigation for secondary headaches including anti-NMDA-R antibodies for patients with new-onset headache and neuropsychiatric findings. Glutamatergic dysfunction might be important for the generation of head pain but may only occasionally be sufficient to trigger migraine-like attacks in nonmigraineurs. © 2016 American Headache Society.
Latusz, Joachim; Radaszkiewicz, Aleksandra; Bator, Ewelina; Wędzony, Krzysztof; Maćkowiak, Marzena
2017-02-01
Epidemiological data have indicated that memory impairment is observed during adolescence in groups at high risk for schizophrenia and might precede the appearance of schizophrenia symptoms in adulthood. In the present study, we used a neurodevelopmental model of schizophrenia based on the postnatal blockade of N-methyl-d-aspartate (NMDA) receptors in rats to investigate fear memory in adolescence and adulthood. The rats were treated with increasing doses of CGP 37849 (CGP), a competitive antagonist of the NMDA receptor (1.25mg/kg on days 1, 3, 6, 9; 2.5mg/kg on days 12, 15, 18 and 5mg/kg on day 21). Fear memory was analysed in delay and trace fear conditioning. Sensorimotor gating deficit, which is another cognitive symptom of schizophrenia, was also determined in adolescent and adult CGP-treated rats. Postnatal CGP administration disrupted cue- and context-dependent fear memory in adolescent rats in both delay and trace conditioning. In contrast, CGP administration evoked impairment only in cue-dependent fear memory in rats exposed to trace but not delay fear conditioning. The postnatal blockade of NMDA receptors induced sensorimotor gating deficits in adult rats but not in adolescent rats. The postnatal blockade of NMDA receptors induced fear memory impairment in adolescent rats before the onset of neurobehavioral deficits associated with schizophrenia. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.
Glycine Receptor α2 Subunit Activation Promotes Cortical Interneuron Migration
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Ariel Avila
2013-08-01
Full Text Available Glycine receptors (GlyRs are detected in the developing CNS before synaptogenesis, but their function remains elusive. This study demonstrates that functional GlyRs are expressed by embryonic cortical interneurons in vivo. Furthermore, genetic disruption of these receptors leads to interneuron migration defects. We discovered that extrasynaptic activation of GlyRs containing the α2 subunit in cortical interneurons by endogenous glycine activates voltage-gated calcium channels and promotes calcium influx, which further modulates actomyosin contractility to fine-tune nuclear translocation during migration. Taken together, our data highlight the molecular events triggered by GlyR α2 activation that control cortical tangential migration during embryogenesis.
Moreau, J. L.; Pieri, L.; Prud'hon, B.
1989-01-01
1. Convulsions were induced reproducibly by intracerebroventricular injection of N-methyl-D-aspartic acid (NMDA) to conscious mice. 2. Competitive (carboxypiperazine-propylphosphonic acid, CPP; 2-amino-7-phosphonoheptanoic acid, AP7) and non-competitive (MK801; phencyclidine, PCP; thienylcyclohexylpiperidine, TCP; dextrorphan; dextromethorphan) NMDA antagonists prevented NMDA-induced convulsions. 3. Benzodiazepine receptor agonists and partial agonists (triazolam, diazepam, clonazepam, Ro 16-6028), classical anticonvulsants (diphenylhydantoin, phenobarbitone, sodium valproate) and meprobamate were also found to prevent NMDA-induced convulsions. 4. Flumazenil (a benzodiazepine receptor antagonist) and the GABA agonists THIP and muscimol (up to subtoxic doses) were without effect. 5. Flumazenil reversed the anticonvulsant action of diazepam, but not that of MK801. 6. Results obtained in this model differ somewhat from those described in a seizure model with systemic administration of NMDA. An explanation for this discrepancy is offered. 7. This model is a simple test for assessing the in vivo activity of NMDA antagonists and also expands the battery of chemically-induced seizure models for characterizing anticonvulsants not acting at NMDA receptors. PMID:2574061
Sikora, Magdalena; Tokarski, Krzysztof; Bobula, Bartosz; Zajdel, Joanna; Jastrzębska, Kamila; Cieślak, Przemysław Eligiusz; Zygmunt, Magdalena; Sowa, Joanna; Smutek, Magdalena; Kamińska, Katarzyna; Gołembiowska, Krystyna; Engblom, David; Hess, Grzegorz; Przewlocki, Ryszard; Rodriguez Parkitna, Jan
2016-01-01
Plasticity of the brain's dopamine system plays a crucial role in adaptive behavior by regulating appetitive motivation and the control of reinforcement learning. In this study, we investigated drug- and natural-reward conditioned behaviors in a mouse model in which the NMDA receptor-dependent plasticity of dopaminoceptive neurons was disrupted. We generated a transgenic mouse line with inducible selective inactivation of the NR1 subunit in neurons expressing dopamine D1 receptors (the NR1(D1CreERT2) mice). Whole-cell recordings of spontaneous EPSCs on neurons in the nucleus accumbens confirmed that a population of neurons lacked the NMDA receptor-dependent component of the current. This effect was accompanied by impaired long-term potentiation in the nucleus accumbens and in the CA1 area of the ventral, but not the dorsal, hippocampus. Mutant mice did not differ from control animals when tested for pavlovian or instrumental conditioning. However, NR1(D1CreERT2) mice acquired no preference for a context associated with administration of drugs of abuse. In the conditioned place preference paradigm, mutant mice did not spend more time in the context paired with cocaine, morphine, or ethanol, although these mice acquired a preference for sucrose jelly and an aversion to naloxone injections, as normal. Thus, we observed that the selective inducible ablation of the NMDA receptors specifically blocks drug-associated context memory with no effect on positive reinforcement in general.
Czech Academy of Sciences Publication Activity Database
Rambousek, Lukáš; Kletečková, Lenka; Kubesová, A.; Jirák, D.; Valeš, Karel; Fritschy, J.M.
2016-01-01
Roč. 105, Jun (2016), s. 594-606 ISSN 0028-3908 R&D Projects: GA ČR(CZ) GBP304/12/G069; GA ČR(CZ) GA14-20613S; GA ČR(CZ) GAP303/12/1464 Institutional support: RVO:67985823 Keywords : excitotoxicity * NMDA receptor * GABA A receptor * hippocampus * neuroinflammation * neurodegeneration * interneurons * spatial learning * carousel maze Subject RIV: FH - Neurology Impact factor: 5.012, year: 2016
Desai, Sagar J; Allman, Brian L; Rajakumar, Nagalingam
2017-04-14
Impairment of executive function is a core feature of schizophrenia. Preclinical studies indicate that injections of either N-methyl d-aspartate (NMDA) or dopamine D 1 receptor blockers impair executive function. Despite the prevailing notion based on postmortem findings in schizophrenia that cortical areas have marked suppression of glutamate and dopamine, recent in vivo imaging studies suggest that abnormalities of these neurotransmitters in living patients may be quite subtle. Thus, we hypothesized that modest impairments in both glutamate and dopamine function can act synergistically to cause executive dysfunction. In the present study, we investigated the effect of combined administration of "behaviorally sub-effective" doses of NMDA and dopamine D 1 receptor antagonists on executive function. An operant conditioning-based set-shifting task was used to assess behavioral flexibility in rats that were systemically injected with NMDA and dopamine D 1 receptor antagonists individually or in combination prior to task performance. Separate injections of the NMDA receptor antagonist, MK-801, and the dopamine D 1 receptor antagonist, SCH 23390, at low doses did not impair set-shifting; however, the combined administration of these same behaviorally sub-effective doses of the antagonists significantly impaired the performance during set-shifting without affecting learning, retrieval of the memory of the initial rule, latency of responses or the number of omissions. The combined treatment also produced an increased number of perseverative errors. Our results indicate that NMDA and D 1 receptor blockade act synergistically to cause behavioral inflexibility, and as such, subtle abnormalities in glutamatergic and dopaminergic systems may act cooperatively to cause deficits in executive function. Copyright © 2017 Elsevier B.V. All rights reserved.
Ketamine displaces the novel NMDA receptor SPET probe [123I]CNS-1261 in humans in vivo
International Nuclear Information System (INIS)
Stone, James M.; Erlandsson, Kjell; Arstad, Erik; Bressan, Rodrigo A.; Squassante, Lisa; Teneggi, Vincenza; Ell, Peter J.; Pilowsky, Lyn S.
2006-01-01
[ 123 I]CNS-1261 [N-(1-naphthyl)-N'-(3-iodophenyl)-N-methylguanidine] is a high-affinity SPET ligand with selectivity for the intrachannel PCP/ketamine/MK-801 site of the N-methyl-D-aspartate (NMDA) receptor. This study evaluated the effects of ketamine (a specific competitor for the intrachannel PCP/ketamine/MK-801 site) on [ 123 I]CNS-1261 binding to NMDA receptors in vivo. Ten healthy volunteers underwent 2 bolus-plus-infusion [ 123 I]CNS-1261 scans, one during placebo and the other during a ketamine challenge. Ketamine administration led to a significant decrease in [ 123 I]CNS-1261 V T in most of the brain regions examined (P 123 I]CNS-1261 appears to be a specific ligand in vivo for the intrachannel PCP/ketamine/MK-801 NMDA binding site
Burgdorf, Jeffrey; Moskal, Joseph R; Brudzynski, Stefan M; Panksepp, Jaak
2013-08-15
Early childhood autism is characterized by deficits in social approach and play behaviors, socio-emotional relatedness, and communication/speech abnormalities, as well as repetitive behaviors. These core neuropsychological features of autism can be modeled in laboratory rats, and the results may be useful for drug discovery and therapeutic development. We review data that show that rats selectively bred for low rates of play-related pro-social ultrasonic vocalizations (USVs) can be used to model social deficit symptoms of autism. Low-line animals engage in less social contact time with conspecifics, show lower rates of play induced pro-social USVs, and show an increased proportion of non-frequency modulated (i.e. monotonous) ultrasonic vocalizations compared to non-selectively bred random-line animals. Gene expression patterns in the low-line animals show significant enrichment in autism-associated genes, and the NMDA receptor family was identified as a significant hub. Treatment of low-line animals with the NMDAR functional glycine site partial agonist, GLYX-13, rescued the deficits in play-induced pro-social 50-kHz USVs and reduced monotonous USVs. Since the NMDA receptor has been implicated in the genesis of autistic symptoms, it is possible that GLYX-13 may be of therapeutic value in the treatment of autism. Copyright © 2013 Elsevier B.V. All rights reserved.
International Nuclear Information System (INIS)
Waterhouse, Rikki N.; Sultana, Abida; Laruelle, M.
2002-01-01
Alterations in normal NMDA receptor composition, densities and function have been implicated in the pathophysiology of certain neurological and neuropsychiatric disorders such as Parkinson's Disease, Huntington's Chorea, schizophrenia, alcoholism and stroke. In our first effort to provide PET ligands for the NMDA/glycine site, we reported the synthesis of a novel high affinity glycine site ligand, 3-[2-[(3-methoxyphenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2 -carboxylic acid ((3MPICA), Ki=4.8±0.9 nM) and the corresponding carbon-11 labeled PET ligand, [ 11 C]3MPICA. We report here the in vivo evaluation of [ 11 C]3MPICA in rats. Biodistribution analysis revealed that [ 11 C]3MPICA exhibited low degree of brain penetration and high blood concentration. The average uptake at two minutes was highest in the cerebellum (0.19±0.04 %ID/g) and thalamus (0.18±0.05 %ID/g) and lower in the hippocampus (0.13±0.03) and frontal cortex (0.11±0.04 %ID/g). The radioactivity cleared quickly from all brain regions examined. Administration of unlabeled 3MPICA (1 mg/kg, i.v.) revealed at 60 minutes a small general reduction in regional brain radioactivity concentrations in treated animals versus controls, however, the blood radioactivity concentration was also lowered, confounding the assessment of the degree of saturable binding. Warfarin co-administration (100 mg/kg, i.v.) significantly lowered blood activity at 5 minutes post-injection (-27%, P 11 C]3MPICA does not appear to be a promising PET radiotracer for in vivo use
Harsing, Laszlo G; Matyus, Peter
2013-04-01
Glycine is an amino acid neurotransmitter that is involved in both inhibitory and excitatory neurochemical transmission in the central nervous system. The role of glycine in excitatory neurotransmission is related to its coagonist action at glutamatergic N-methyl-D-aspartate receptors. The glycine levels in the synaptic cleft rise many times higher during synaptic activation assuring that glycine spills over into the extrasynaptic space. Another possible origin of extrasynaptic glycine is the efflux of glycine occurring from astrocytes associated with glutamatergic synapses. The release of glycine from neuronal or glial origins exhibits several differences compared to that of biogenic amines or other amino acid neurotransmitters. These differences appear in an external Ca(2+)- and temperature-dependent manner, conferring unique characteristics on glycine as a neurotransmitter. Glycine transporter type-1 at synapses may exhibit neural and glial forms and plays a role in controlling synaptic glycine levels and the spill over rate of glycine from the synaptic cleft into the extrasynaptic biophase. Non-synaptic glycine transporter type-1 regulates extrasynaptic glycine concentrations, either increasing or decreasing them depending on the reverse or normal mode operation of the carrier molecule. While we can, at best, only estimate synaptic glycine levels at rest and during synaptic activation, glycine concentrations are readily measurable via brain microdialysis technique applied in the extrasynaptic space. The non-synaptic N-methyl-D-aspartate receptor may obtain glycine for activation following its spill over from highly active synapses or from its release mediated by the reverse operation of non-synaptic glycine transporter-1. The sensitivity of non-synaptic N-methyl-D-aspartate receptors to glutamate and glycine is many times higher than that of synaptic N-methyl-D-aspartate receptors making the former type of receptor the primary target for drug action. Synaptic
International Nuclear Information System (INIS)
Daen, B.; Hussain, T.; Scarr, E.; Tomaskovic, E.; Kitsoulis, S.; Pavey, G.; Hill, C.; Keks, N.; Opeskin, K.; Copolov, D.L.
1998-01-01
Full text: Having shown changed 5HT 2A receptor density in the frontal cortex (FC) from schizophrenic subjects (1) we now report on further studies of the molecular neuroanatomy of the FC in schizophrenia. We used in situ radioligand binding and autoradiography to measure the density of [ 3 H]8OH-DPAT (1 nM) binding (5HT 1A receptors) and [ 3 H]GR113808 (2.4nM) binding (5HT 4 receptors) in Brodmann's areas (BA) 8, 9 and 10 from 10 schizophrenic and 10 controls subjects. In addition, [ 3 H]muscimol (100 nM) binding (GABA A receptors), [ 3 H]TCP (20nM) binding (NMDA receptors), [ 3 H]SCH 23390 (3nM) binding (DA D 1 like receptors) and [ 3 H]YM-09151-2 (4nM) binding (DA D 2 -like receptors) was measured in BA 9 from 17 schizophrenic and 17 control subjects. Subjects were matched for age and sex and the post-mortem interval for tissue collection did not differ. There was a significant increase (18%) in the density of GABA A receptors in BA 9 from subjects with schizophrenia (p<0.05) with no change in NMDA, dopamine or serotonin receptors. These data support the hypothesis that there are selective changes in neurotransmitter receptors in the FC of subjects with schizophrenia. It is not yet clear if such changes contribute to the pathology of the illness. Copyright (1998) Australian Neuroscience Society
Molecular determinants of ivermectin sensitivity at the glycine receptor chloride channel
DEFF Research Database (Denmark)
Lynagh, Timothy; Webb, Timothy I.; Dixon, Christine L.
2011-01-01
Ivermectin is an anthelmintic drug that works by activating glutamate-gated chloride channel receptors (GluClRs) in nematode parasites. GluClRs belong to the Cys-loop receptor family that also includes glycine receptor (GlyR) chloride channels. GluClRs and A288G mutant GlyRs are both activated...
Fellini, Laetitia; Florian, Cedrick; Courtey, Julie; Roullet, Pascal
2009-01-01
Pattern completion is the ability to retrieve complete information on the basis of incomplete retrieval cues. Although it has been demonstrated that this cognitive capacity depends on the NMDA receptors (NMDA-Rs) of the hippocampal CA3 region, the role played by these glutamatergic receptors in the pattern completion process has not yet been…
Yates, Justin R; Breitenstein, Kerry A; Gunkel, Benjamin T; Hughes, Mallory N; Johnson, Anthony B; Rogers, Katherine K; Shape, Sara M
Risky decision making can be measured using a probability-discounting procedure, in which animals choose between a small, certain reinforcer and a large, uncertain reinforcer. Recent evidence has identified glutamate as a mediator of risky decision making, as blocking the N-methyl-d-aspartate (NMDA) receptor with MK-801 increases preference for a large, uncertain reinforcer. Because the order in which probabilities associated with the large reinforcer can modulate the effects of drugs on choice, the current study determined if NMDA receptor ligands alter probability discounting using ascending and descending schedules. Sixteen rats were trained in a probability-discounting procedure in which the odds against obtaining the large reinforcer increased (n=8) or decreased (n=8) across blocks of trials. Following behavioral training, rats received treatments of the NMDA receptor ligands MK-801 (uncompetitive antagonist; 0, 0.003, 0.01, or 0.03mg/kg), ketamine (uncompetitive antagonist; 0, 1.0, 5.0, or 10.0mg/kg), and ifenprodil (NR2B-selective non-competitive antagonist; 0, 1.0, 3.0, or 10.0mg/kg). Results showed discounting was steeper (indicating increased risk aversion) for rats on an ascending schedule relative to rats on the descending schedule. Furthermore, the effects of MK-801, ketamine, and ifenprodil on discounting were dependent on the schedule used. Specifically, the highest dose of each drug decreased risk taking in rats in the descending schedule, but only MK-801 (0.03mg/kg) increased risk taking in rats on an ascending schedule. These results show that probability presentation order modulates the effects of NMDA receptor ligands on risky decision making. Copyright © 2016 Elsevier Inc. All rights reserved.
Tokarski, Krzysztof; Bobula, Bartosz; Zygmunt, Magdalena; Smutek, Magdalena; Kamińska, Katarzyna; Gołembiowska, Krystyna; Hess, Grzegorz; Przewlocki, Ryszard
2016-01-01
Abstract Plasticity of the brain’s dopamine system plays a crucial role in adaptive behavior by regulating appetitive motivation and the control of reinforcement learning. In this study, we investigated drug- and natural-reward conditioned behaviors in a mouse model in which the NMDA receptor-dependent plasticity of dopaminoceptive neurons was disrupted. We generated a transgenic mouse line with inducible selective inactivation of the NR1 subunit in neurons expressing dopamine D1 receptors (the NR1D1CreERT2 mice). Whole-cell recordings of spontaneous EPSCs on neurons in the nucleus accumbens confirmed that a population of neurons lacked the NMDA receptor-dependent component of the current. This effect was accompanied by impaired long-term potentiation in the nucleus accumbens and in the CA1 area of the ventral, but not the dorsal, hippocampus. Mutant mice did not differ from control animals when tested for pavlovian or instrumental conditioning. However, NR1D1CreERT2 mice acquired no preference for a context associated with administration of drugs of abuse. In the conditioned place preference paradigm, mutant mice did not spend more time in the context paired with cocaine, morphine, or ethanol, although these mice acquired a preference for sucrose jelly and an aversion to naloxone injections, as normal. Thus, we observed that the selective inducible ablation of the NMDA receptors specifically blocks drug-associated context memory with no effect on positive reinforcement in general. PMID:27294197
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Biegon, A.; Alvarado, M.; Budinger, T.F.; Grossman, R.; Hensley, K.; West, M.S.; Kotake, Y.; Ono, M.; Floyd, R.A.
2001-12-10
Following induction of acute neuroinflammation by intracisternal injection of endotoxin (lipopolysaccharide) in rats, quantitative autoradiography was used to assess the regional level of microglial activation and glutamate (NMDA) receptor binding. The possible protective action of the antioxidant phenyl-tert-butyl nitrone in this model was tested by administering the drug in the drinking water for 6 days starting 24 hours after endotoxin injection. Animals were killed 7 days post-injection and consecutive cryostat brain sections labeled with [3H]PK11195 as a marker of activated microglia and [125I]iodoMK801 as a marker of the open-channel, activated state of NMDA receptors. Lipopolysaccharide increased [3H]PK11195 binding in the brain, with the largest increases (2-3 fold) in temporal and entorhinal cortex, hippocampus, and substantia innominata. A significant (>50 percent) decrease in [125I]iodoMK801 binding was found in the same brain regions. Phenyl-tert-butyl nitrone treatment resulted in a partial inhibition ({approx}25 percent decrease) of the lipopolysaccharide-induced increase in [3H]PK11195 binding but completely reversed the lipopolysaccharide-induced decrease in [125I]iodoMK80 binding in the entorhinal cortex, hippocampus, and substantia innominata. Loss of NMDA receptor function in cortical and hippocampal regions may contribute to the cognitive deficits observed in diseases with a neuroinflammatory component, such as meningitis or Alzheimer's disease.
Wei, Ting-Jia; Chen, Hui-Ying; Huang, Xi; Weng, Jing-Jin; Qin, Jiang-Yuan; Su, Ji-Ping
2017-06-25
The aim of the present study was to observe whether dopamine receptor (DR) was involved in the effects of sodium salicylate (SS) on the expressions of N-methyl-D-aspartic acid (NMDA) and γ-aminobutyric acid (GABA) receptors in rat cochlear spiral ganglion neurons (SGNs). Forty-eight hours after primary culture of rat SGNs, immunofluorescence technique was applied to detect expressions of DR1 and DR2, the two subtypes of dopamine receptors. Western blot was performed to assess NMDA receptor NR1 subunit and GABA A receptor subunit α2 (GABRα2) protein expressions in the SGNs after the treatments of SS alone or in combination with DR antagonists. The results demonstrated that: (1) The DR1 and DR2 were expressed in the bodies and axons of the SGN; (2) After the treatment with SS, the surface protein expressions of GABRα2 and NR1 were decreased by 44.69% and 21.57%, respectively, while the total protein expressions showed no significant changes; (3) Neither SS + SCH23390 (DR1 antagonist) group nor SS + Eticlopride (DR2 antagonist) group showed significant differences in GABRα2 and NR1 surface protein expressions compared with the control group. These results suggest that SS regulates the surface GABA A and NMDA receptors trafficking on SGN, and the mechanism may involve DR mediation.
Handford, Charlotte E; Tan, Shawn; Lawrence, Andrew J; Kim, Jee Hyun
2014-09-01
The metabotropic glutamate receptor 5 (mGlu5) and N-methyl-D-aspartate (NMDA) receptor are critical for processes underlying synaptic plasticity, such as long-term potentiation. mGlu5 signaling increases neuronal excitability and potentiates NMDA receptor currents in the amygdala and the hippocampus. The present study examined the involvement of mGlu5 in the acquisition and consolidation of conditioned fear to a tone and context in mice, and explored the functional relationship between mGlu5 and NMDA receptors in this regard. Experiment 1 showed that systemic administration of the mGlu5 negative allosteric modulator 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) prior to conditioning significantly attenuated cue-elicited freezing during fear conditioning, which suggests that mGlu5 is necessary for the formation of a tone-shock association. This effect was dose-related (Experiment 2) and not due to any effects of MTEP on shock sensitivity or state-dependency (Experiment 3). Post-conditioning injection of MTEP had no effects (Experiment 4). Although post-conditioning injection of the NMDA receptor partial agonist D-cycloserine (DCS) alone facilitated consolidation of conditioned fear (Experiment 6), it was not able to rescue the acquisition deficit caused by MTEP (Experiment 5). Taken together, these findings indicate a crucial role for mGlu5 signaling in acquisition and NMDA receptor signaling in consolidation of conditioned fear.
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Conti, Paola; Pinto, Andrea; Tamborini, Lucia
2010-01-01
The design and synthesis of new N1-substituted 3-carboxy- and 3-phosphonopyrazoline and pyrazole amino acids that target the glutamate binding site of NMDA receptors are described. An analysis of the stereochemical requirements for high-affinity interaction with these receptors was performed. We...
de Freitas, Renato Leonardo; Salgado-Rohner, Carlos José; Biagioni, Audrey Francisco; Medeiros, Priscila; Hallak, Jaime Eduardo Cecílio; Crippa, José Alexandre S; Coimbra, Norberto Cysne
2014-06-01
The aim of the present study was to investigate the involvement of N-methyl-d-aspartate (NMDA) and amino-3-hydroxy-5-methyl-isoxazole-4-proprionate (AMPA)/kainate receptors of the prelimbic (PL) division of the medial prefrontal cortex (MPFC) on the panic attack-like reactions evoked by γ-aminobutyric acid-A receptor blockade in the medial hypothalamus (MH). Rats were pretreated with NaCl 0.9%, LY235959 (NMDA receptor antagonist), and NBQX (AMPA/kainate receptor antagonist) in the PL at 3 different concentrations. Ten minutes later, the MH was treated with bicuculline, and the defensive responses were recorded for 10 min. The antagonism of NMDA receptors in the PL decreased the frequency and duration of all defensive behaviors evoked by the stimulation of the MH and reduced the innate fear-induced antinociception. However, the pretreatment of the PL cortex with NBQX was able to decrease only part of defensive responses and innate fear-induced antinociception. The present findings suggest that the NMDA-glutamatergic system of the PL is critically involved in panic-like responses and innate fear-induced antinociception and those AMPA/kainate receptors are also recruited during the elaboration of fear-induced antinociception and in panic attack-related response. The activation of the glutamatergic neurotransmission of PL division of the MPFC during the elaboration of oriented behavioral reactions elicited by the chemical stimulation of the MH recruits mainly NMDA receptors in comparison with AMPA/kainate receptors.
Age-dependent effects on social interaction of NMDA GluN2A receptor subtype-selective antagonism.
Green, Torrian L; Burket, Jessica A; Deutsch, Stephen I
2016-07-01
NMDA receptor-mediated neurotransmission is implicated in the regulation of normal sociability in mice. The heterotetrameric NMDA receptor is composed of two obligatory GluN1 and either two "modulatory" GluN2A or GluN2B receptor subunits. GluN2A and GluN2B-containing receptors differ in terms of their developmental expression, distribution between synaptic and extrasynaptic locations, and channel kinetic properties, among other differences. Because age-dependent differences in disruptive effects of GluN2A and GluN2B subtype-selective antagonists on sociability and locomotor activity have been reported in rats, the current investigation explored age-dependent effects of PEAQX, a GluN2A subtype-selective antagonist, on sociability, stereotypic behaviors emerging during social interaction, and spatial working memory in 4- and 8-week old male Swiss Webster mice. The data implicate an age-dependent contribution of GluN2A-containing NMDA receptors to the regulation of normal social interaction in mice. Specifically, at a dose of PEAQX devoid of any effect on locomotor activity and mouse rotarod performance, the social interaction of 8-week old mice was disrupted without any effect on the social salience of a stimulus mouse. Moreover, PEAQX attenuated stereotypic behavior emerging during social interaction in 4- and 8-week old mice. However, PEAQX had no effect on spontaneous alternations, a measure of spatial working memory, suggesting that neural circuits mediating sociability and spatial working memory may be discrete and dissociable from each other. Also, the data suggest that the regulation of stereotypic behaviors and sociability may occur independently of each other. Because expression of GluN2A-containing NMDA receptors occurs at a later developmental stage, they may be more involved in mediating the pathogenesis of ASDs in patients with histories of "regression" after a period of normal development than GluN2B receptors. Copyright © 2016 Elsevier Inc. All rights
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Price Donald D
2006-01-01
Full Text Available Abstract Background N-methyl-D-aspartic acid (NMDA spinal cord receptors play an important role in the development of hyperalgesia following inflammation. It is unclear, however, if changes in NMDA subunit receptor gene expression in the colonic myenteric plexus are associated with colonic inflammation. We investigated regulation of NMDA-NR1 receptor gene expression in TNBS induced colitis in rats. Male Sprague-Dawley rats (150 g–250 g were treated with 20 mg trinitrobenzene sulfonic acid (TNBS diluted in 50% ethanol. The agents were delivered with a 24 gauge catheter inserted into the lumen of the colon. The animals were sacrificed at 2, 7, 14, 21, and 28 days after induction of the colitis, their descending colon was retrieved for reverse transcription-polymerase chain reaction; a subset of animals' distal colon was used for two-dimensional (2-D western analysis and immunocytochemistry. Results NR1-exon 5 (N1 and NR1-exon 21 (C1 appeared 14, 21 and 28 days after TNBS treatment. NR1 pan mRNA was up-regulated at 14, 21, and 28 days. The NR1-exon 22 (C2 mRNA did not show significant changes. Using 2-D western analysis, untreated control rats were found to express only NR1001 whereas TNBS treated rats expressed NR1001, NR1011, and NR1111. Immunocytochemistry demonstrated NR1-N1 and NR1-C1 to be present in the myenteric plexus of TNBS treated rats. Conclusion These results suggest a role for colonic myenteric plexus NMDA receptors in the development of neuronal plasticity and visceral hypersensitivity in the colon. Up-regulation of NMDA receptor subunits may reflect part of the basis for chronic visceral hypersensitivity in conditions such as post-infectious irritable bowel syndrome.
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Rebecca Lethbridge
Full Text Available Rat pup odor preference learning follows pairing of bulbar beta-adrenoceptor activation with olfactory input. We hypothesize that NMDA receptor (NMDAR-mediated olfactory input to mitral cells is enhanced during training, such that increased calcium facilitates and shapes the critical cAMP pattern. Here, we demonstrate, in vitro, that olfactory nerve stimulation, at sniffing frequencies, paired with beta-adrenoceptor activation, potentiates olfactory nerve-evoked mitral cell firing. This potentiation is blocked by a NMDAR antagonist and by increased inhibition. Glomerular disinhibition also induces NMDAR-sensitive potentiation. In vivo, in parallel, behavioral learning is prevented by glomerular infusion of an NMDAR antagonist or a GABA(A receptor agonist. A glomerular GABA(A receptor antagonist paired with odor can induce NMDAR-dependent learning. The NMDA GluN1 subunit is phosphorylated in odor-specific glomeruli within 5 min of training suggesting early activation, and enhanced calcium entry, during acquisition. The GluN1 subunit is down-regulated 3 h after learning; and at 24 h post-training the GluN2B subunit is down-regulated. These events may assist memory stability. Ex vivo experiments using bulbs from trained rat pups reveal an increase in the AMPA/NMDA EPSC ratio post-training, consistent with an increase in AMPA receptor insertion and/or the decrease in NMDAR subunits. These results support a model of a cAMP/NMDA interaction in generating rat pup odor preference learning.
Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists
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Ebert, B; Thorkildsen, C; Andersen, S
1998-01-01
Much evidence points to the involvement of N-methyl-D-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However...... for the NMDA receptor antagonism of these compounds and its relevance for clinical pain treatment; an overview of structure-activity relationships for the relevant opioids as noncompetitive NMDA receptor antagonists also is given. It is concluded that although the finding that some opioids are weak...
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Jensen, Anders A.; Gharagozloo, Parviz; Birdsall, Nigel J M
2006-01-01
of tertiary and quaternary analogues as well as bisquaternary dimers of strychnine and brucine at human alpha1 and alpha1beta glycine receptors and at a chimera consisting of the amino-terminal domain of the alpha7 nicotinic receptor (containing the orthosteric ligand binding site) and the ion channel domain...... of strychnine and brucine, none of the analogues displayed significant selectivity between the alpha1 and alpha1beta subtypes. The structure-activity relationships for the compounds at the alpha7/5-HT3 chimera were significantly different from those at the glycine receptors. Most strikingly, quaternization...... of strychnine and brucine with substituents possessing different steric and electronic properties completely eliminated the activity at the glycine receptors, whereas binding affinity to the alpha7/5-HT3 chimera was retained for the majority of the quaternary analogues. This study provides an insight...
Okuda, Kosuke; Kobayashi, Shizuka; Fukaya, Masahiro; Watanabe, Aya; Murakami, Takuto; Hagiwara, Mai; Sato, Tempei; Ueno, Hiroe; Ogonuki, Narumi; Komano-Inoue, Sayaka; Manabe, Hiroyuki; Yamaguchi, Masahiro; Ogura, Atsuo; Asahara, Hiroshi; Sakagami, Hiroyuki; Mizuguchi, Masashi; Manabe, Toshiya; Tanaka, Teruyuki
2017-10-01
Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders accompanied by intractable epilepsies, i.e. West syndrome or atypical Rett syndrome. Here we report generation of the Cdkl5 knockout mouse and show that CDKL5 controls postsynaptic localization of GluN2B-containing N-methyl-d-aspartate (NMDA) receptors in the hippocampus and regulates seizure susceptibility. Cdkl5 -/Y mice showed normal sensitivity to kainic acid; however, they displayed significant hyperexcitability to NMDA. In concordance with this result, electrophysiological analysis in the hippocampal CA1 region disclosed an increased ratio of NMDA/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs) and a significantly larger decay time constant of NMDA receptor-mediated EPSCs (NMDA-EPSCs) as well as a stronger inhibition of the NMDA-EPSCs by the GluN2B-selective antagonist ifenprodil in Cdkl5 -/Y mice. Subcellular fractionation of the hippocampus from Cdkl5 -/Y mice revealed a significant increase of GluN2B and SAP102 in the PSD (postsynaptic density)-1T fraction, without changes in the S1 (post-nuclear) fraction or mRNA transcripts, indicating an intracellular distribution shift of these proteins to the PSD. Immunoelectron microscopic analysis of the hippocampal CA1 region further confirmed postsynaptic overaccumulation of GluN2B and SAP102 in Cdkl5 -/Y mice. Furthermore, ifenprodil abrogated the NMDA-induced hyperexcitability in Cdkl5 -/Y mice, suggesting that upregulation of GluN2B accounts for the enhanced seizure susceptibility. These data indicate that CDKL5 plays an important role in controlling postsynaptic localization of the GluN2B-SAP102 complex in the hippocampus and thereby regulates seizure susceptibility, and that aberrant NMDA receptor-mediated synaptic transmission underlies the pathological mechanisms of the CDKL5 loss-of-function. Copyright © 2017 Elsevier Inc. All rights
Yamada, Kazuo; Arai, Misaki; Suenaga, Toshiko; Ichitani, Yukio
2017-07-28
The hippocampus is thought to be involved in object location recognition memory, yet the contribution of hippocampal NMDA receptors to the memory processes, such as encoding, retention and retrieval, is unknown. First, we confirmed that hippocampal infusion of a competitive NMDA receptor antagonist, AP5 (2-amino-5-phosphonopentanoic acid, 20-40nmol), impaired performance of spontaneous object location recognition test but not that of novel object recognition test in Wistar rats. Next, the effects of hippocampal AP5 treatment on each process of object location recognition memory were examined with three different injection times using a 120min delay-interposed test: 15min before the sample phase (Time I), immediately after the sample phase (Time II), and 15min before the test phase (Time III). The blockade of hippocampal NMDA receptors before and immediately after the sample phase, but not before the test phase, markedly impaired performance of object location recognition test, suggesting that hippocampal NMDA receptors play an important role in encoding and consolidation/retention, but not retrieval, of spontaneous object location memory. Copyright © 2017 Elsevier B.V. All rights reserved.
Wolak, Małgorzata; Siwek, Agata; Szewczyk, Bernadeta; Poleszak, Ewa; Bystrowska, Beata; Moniczewski, Andrzej; Rutkowska, Anita; Młyniec, Katarzyna; Nowak, Gabriel
2015-06-01
The NMDA/glutamate receptors are involved in the mechanism of antidepressant activity. The present study was designed to investigate the effect of NMDA receptor ligands (agonists and antagonists of glutamate sites) on the antidepressant-like activity of selective serotonin reuptake inhibitors (SSRIs), citalopram and fluoxetine, in the forced swim test in mice. The antidepressant activity (reduction in immobility time) of citalopram but not of fluoxetine was antagonized by N-methyl-D-aspartate acid and enhanced by CGP37849 (antagonist of the NMDA receptor). The present literature data indicate that the antidepressant-like activity of conventional antidepressants is generally affected by the NMDA receptor, although by modulation from different sites of the complex. Thus, it supports the issue of the ability of NMDA receptor antagonists to enhance the antidepressant action in human depression. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
Labedi, Adnan; Benali, Alia; Mix, Annika; Neubacher, Ute; Funke, Klaus
2014-01-01
Intermittent theta-burst stimulation (iTBS) applied via transcranial magnetic stimulation has been shown to increase cortical excitability in humans. In the rat brain it strongly reduced the number of neurons expressing the 67-kD isoform of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67) and those expressing the calcium-binding proteins parvalbumin (PV) and calbindin (CB), specific markers of fast-spiking (FS) and non-FS inhibitory interneurons, respectively, an indication of modified cortical inhibition. Since iTBS effects in humans have been shown to be NMDA receptor sensitive, we wondered whether the iTBS-induced changes in the molecular phenotype of interneurons may be also sensitive to glutamatergic synaptic transmission mediated by NMDA receptors. In a sham-controlled fashion, five iTBS-blocks of 600 stimuli were applied to rats either lightly anesthetized by only urethane or by an additional low (subnarcotic) or high dose of the NMDA receptor antagonist ketamine before immunohistochemical analysis. iTBS reduced the number of neurons expressing GAD67, PV and CB. Except for CB, a low dose of ketamine partially prevented these effects while a higher dose almost completely abolished the iTBS effects. Our findings indicate that iTBS modulates the molecular, and likely also the electric, activity of cortical inhibitory interneurons and that the modulation of FS-type but less that of non-FS-type neurons is mediated by NMDA receptors. A combination of iTBS with pharmacological interventions affecting distinct receptor subtypes may thus offer options to enhance its selectivity in modulating the activity of distinct cell types and preventing others from being modulated. Copyright © 2014 Elsevier Inc. All rights reserved.
Iwamura, Etsushi; Yamada, Kazuo; Ichitani, Yukio
2016-07-01
The involvement of hippocampal N-methyl-d-aspartate (NMDA) receptors in the retrieval process of spontaneous object recognition memory was investigated. The spontaneous object recognition test consisted of three phases. In the sample phase, rats were exposed to two identical objects several (2-5) times in the arena. After the sample phase, various lengths of delay intervals (24h-6 weeks) were inserted (delay phase). In the test phase in which both the familiar and the novel objects were placed in the arena, rats' novel object exploration behavior under the hippocampal treatment of NMDA receptor antagonist, AP5, or vehicle was observed. With 5 exposure sessions in the sample phase (experiment 1), AP5 treatment in the test phase significantly decreased discrimination ratio when the delay was 3 weeks but not when it was one week. On the other hand, with 2 exposure sessions in the sample phase (experiment 2) in which even vehicle-injected control animals could not discriminate the novel object from the familiar one with a 3 week delay, AP5 treatment significantly decreased discrimination ratio when the delay was one week, but not when it was 24h. Additional experiment (experiment 3) showed that the hippocampal treatment of an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, NBQX, decreased discrimination ratio with all delay intervals tested (24h-3 weeks). Results suggest that hippocampal NMDA receptors play an important role in the retrieval of spontaneous object recognition memory especially when the memory trace weakens. Copyright © 2016. Published by Elsevier B.V.
Ashabi, Ghorbangol; Sadat-Shirazi, Mitra-Sadat; Khalifeh, Solmaz; Elhampour, Laleh; Zarrindast, Mohammad-Reza
2017-04-01
Consumption of cannabinoid receptor-1 (CB-1) agonist such as cannabis is widely taken in 3,4- methylenedioxymethamphetamine (MDMA) or ecstasy users; it has been hypothesized that co-consumption of CB-1 agonist might protect neurons against MDMA toxicity. N-methyl-d-aspartate (NMDA) receptors regulate neuronal plasticity and firing rate in the brain through Tyrosine-kinase B (Trk-B) activation. The molecular and electrophysiological association among NMDA and MDMA/Arachidonylcyclopropylamide (ACPA, a selective CB-1 receptor agonist) co-consumption was not well-known. Here, neuronal spontaneous activity, Brain-derived neurotrophic factor (BDNF), Trk-B and cAMP response element binding protein (CREB) phosphorylation levels were recognized in ACPA and MDMA co-injected rats. Besides, we proved the role of NMDA receptor on MDMA and ACPA combination on neuronal spontaneous activity and Trk-B/BDNF pathway in the central amygdala (CeA). Male rats were anesthetized with intra-peritoneal injections of urethane; MDMA, D-2-amino-5-phosphonopentanoate (D-AP5, NMDA receptor antagonist) were injected into CeA. ACPA was administrated by intra-cerebroventricular injection. Thirty minutes following injections, neuronal firing rate was recorded from CeA. Two hours after drug injection, amygdala was collected from brain for molecular evaluations. Single administration of MDMA and/or ACPA reduced firing rates compared with sham group in the CeA dose-dependently. Injection of D-AP5, ACPA and MDMA reduced firing rate compared with sham group (P<0.001). Interestingly, injection of ACPA+MDMA enhanced BDNF, Trk-B and CREB phosphorylation compared with MDMA groups. D-AP5, ACPA and MDMA co-injection decreased BDNF, Trk-B and CREB phosphorylation levels compared with ACPA+MDMA in the amygdala (P<0.01). Probably, NMDA receptors are involved in the protective role of acute MDMA+ACPA co-injection via BDNF/Trk-B/CREB pathways. Copyright © 2017 Elsevier Inc. All rights reserved.
Directory of Open Access Journals (Sweden)
Yano Takahisa
2011-01-01
Full Text Available Abstract Background Oxaliplatin is a platinum-based chemotherapy drug characterized by the development of acute and chronic peripheral neuropathies. The chronic neuropathy is a dose-limiting toxicity. We previously reported that repeated administration of oxaliplatin induced cold hyperalgesia in the early phase and mechanical allodynia in the late phase in rats. In the present study, we investigated the involvement of NR2B-containing N-methyl-D-aspartate (NMDA receptors in oxaliplatin-induced mechanical allodynia in rats. Results Repeated administration of oxaliplatin (4 mg/kg, i.p., twice a week caused mechanical allodynia in the fourth week, which was reversed by intrathecal injection of MK-801 (10 nmol and memantine (1 μmol, NMDA receptor antagonists. Similarly, selective NR2B antagonists Ro25-6981 (300 nmol, i.t. and ifenprodil (50 mg/kg, p.o. significantly attenuated the oxaliplatin-induced pain behavior. In addition, the expression of NR2B protein and mRNA in the rat spinal cord was increased by oxaliplatin on Day 25 (late phase but not on Day 5 (early phase. Moreover, we examined the involvement of nitric oxide synthase (NOS as a downstream target of NMDA receptor. L-NAME, a non-selective NOS inhibitor, and 7-nitroindazole, a neuronal NOS (nNOS inhibitor, significantly suppressed the oxaliplatin-induced pain behavior. The intensity of NADPH diaphorase staining, a histochemical marker for NOS, in the superficial layer of spinal dorsal horn was obviously increased by oxaliplatin, and this increased intensity was reversed by intrathecal injection of Ro25-6981. Conclusion These results indicated that spinal NR2B-containing NMDA receptors are involved in the oxaliplatin-induced mechanical allodynia.
Peterson, Bethany L; Park, Thomas J; Larson, John
2012-01-11
Adult naked mole-rats show a number of systemic adaptations to a crowded underground habitat that is low in oxygen and high in carbon dioxide. Remarkably, brain slice tissue from adult naked mole-rats also is extremely tolerant to oxygen deprivation as indicated by maintenance of synaptic transmission under hypoxic conditions as well as by a delayed neuronal depolarization during anoxia. These characteristics resemble hypoxia tolerance in brain slices from neonates in a variety of mammal species. An important component of neonatal tolerance to hypoxia involves the subunit composition of NMDA receptors. Neonates have a high proportion of NMDA receptors with GluN2D subunits which are protective because they retard calcium entry into neurons during hypoxic episodes. Therefore, we hypothesized that adult naked mole-rats retain a protective, neonatal-like, NMDA receptor subunit profile. We used immunoblotting to assess age-related changes in NMDA receptor subunits in naked mole-rats and mice. The results show that adult naked mole-rat brain retains a much greater proportion of the hypoxia-protective GluN2D subunit compared to adult mice. However, age-related changes in other subunits (GluN2A and GluN2B) from the neonatal period to adulthood were comparable in mice and naked mole-rats. Hence, adult naked mole-rat brain only retains the neonatal NMDA receptor subunit that is associated with hypoxia tolerance. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Ketamine displaces the novel NMDA receptor SPET probe [{sup 123}I]CNS-1261 in humans in vivo
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Stone, James M. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom)]. E-mail: j.stone@iop.kcl.ac.uk; Erlandsson, Kjell [Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom); Arstad, Erik [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Bressan, Rodrigo A. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Squassante, Lisa [GlaxoSmithKline (GSK), Verona 37135 (Italy); Teneggi, Vincenza [GlaxoSmithKline (GSK), Verona 37135 (Italy); Ell, Peter J. [Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom); Pilowsky, Lyn S. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom)
2006-02-15
[{sup 123}I]CNS-1261 [N-(1-naphthyl)-N'-(3-iodophenyl)-N-methylguanidine] is a high-affinity SPET ligand with selectivity for the intrachannel PCP/ketamine/MK-801 site of the N-methyl-D-aspartate (NMDA) receptor. This study evaluated the effects of ketamine (a specific competitor for the intrachannel PCP/ketamine/MK-801 site) on [{sup 123}I]CNS-1261 binding to NMDA receptors in vivo. Ten healthy volunteers underwent 2 bolus-plus-infusion [{sup 123}I]CNS-1261 scans, one during placebo and the other during a ketamine challenge. Ketamine administration led to a significant decrease in [{sup 123}I]CNS-1261 V {sub T} in most of the brain regions examined (P<.05). [{sup 123}I]CNS-1261 appears to be a specific ligand in vivo for the intrachannel PCP/ketamine/MK-801 NMDA binding site.
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Antje Brand
Full Text Available Naked mole-rats are extremely unusual among mammals in that their cutaneous C-fibers lack the neuropeptide Substance P (SP. In other mammals, SP plays an important role in nociception: it is released from C-fibers onto spinal neurons where it facilitates NMDA receptor activity and causes sensitization that can last for minutes, hours or days. In the present study, we tested the effects of intrathecal application of: 1 SP, 2 an SP antagonist (GR-82334, and 3 an NMDA antagonist (APV on heat-evoked foot withdrawal. In the naked mole-rat, at a high enough concentration, application of SP caused a large, immediate, and long-lasting sensitization of foot withdrawal latency that was transiently reversed by application of either antagonist. However, neither SP nor NMDA antagonists had an effect when administered alone to naïve animals. In contrast, both antagonists induced an increase in basal withdrawal latency in mice. These results indicate that spinal neurons in naked mole-rats have functional SP and NMDA receptors, but that these receptors do not participate in heat-evoked foot withdrawal unless SP is experimentally introduced. We propose that the natural lack of SP in naked mole-rat C-fibers may have resulted during adaptation to living in a chronically high carbon dioxide, high ammonia environment that, in other mammals, would stimulate C-fibers and evoke nocifensive behavior.
Brand, Antje; Smith, Ewan St J; Lewin, Gary R; Park, Thomas J
2010-12-21
Naked mole-rats are extremely unusual among mammals in that their cutaneous C-fibers lack the neuropeptide Substance P (SP). In other mammals, SP plays an important role in nociception: it is released from C-fibers onto spinal neurons where it facilitates NMDA receptor activity and causes sensitization that can last for minutes, hours or days. In the present study, we tested the effects of intrathecal application of: 1) SP, 2) an SP antagonist (GR-82334), and 3) an NMDA antagonist (APV) on heat-evoked foot withdrawal. In the naked mole-rat, at a high enough concentration, application of SP caused a large, immediate, and long-lasting sensitization of foot withdrawal latency that was transiently reversed by application of either antagonist. However, neither SP nor NMDA antagonists had an effect when administered alone to naïve animals. In contrast, both antagonists induced an increase in basal withdrawal latency in mice. These results indicate that spinal neurons in naked mole-rats have functional SP and NMDA receptors, but that these receptors do not participate in heat-evoked foot withdrawal unless SP is experimentally introduced. We propose that the natural lack of SP in naked mole-rat C-fibers may have resulted during adaptation to living in a chronically high carbon dioxide, high ammonia environment that, in other mammals, would stimulate C-fibers and evoke nocifensive behavior.
Haj-Mirzaian, Arya; Kordjazy, Nastaran; Haj-Mirzaian, Arvin; Ostadhadi, Sattar; Ghasemi, Mehdi; Amiri, Shayan; Faizi, Mehrdad; Dehpour, AhmadReza
2015-10-01
The antidepressant action of acute nicotine administration in clinical and animal studies is well recognized. But the underlying mechanism for this effect has not been carefully discovered. We attempted to evaluate the possible role of N-Methyl-D-aspartate (NMDA) receptors in the antidepressant-like effect of nicotine. After the assessment of locomotor activity in the open-field test, forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant-like effect of nicotine in mice. We performed intraperitoneal administration of nicotine at different doses and periods before the tests. To assess the possible involvement of NMDA receptors, non-effective doses of NMDA antagonists and an NMDA agonist were obtained and were administered simultaneously with the non-effective and effective doses of nicotine, respectively. Nicotine (0.2 mg/kg, 30 min before FST/TST) significantly reduced the immobility time of mice similar to fluoxetine (20 mg/kg). Nicotine did not affect the locomotor behavior of mice in open-field test. Co-administration of non-effective doses of NMDA receptor antagonists, ketamine (1 or 0.3 mg/kg), MK-801 (0.05 or 0.005 mg/kg), and magnesium sulfate (10 or 5 mg/kg) with nicotine (0.1 or 0.03 mg/kg) had remarkable synergistic antidepressant effect in both FST and TST. Also, non-effective NMDA (75 or 30 mg/kg) reversed the anti-immobility effect of nicotine (0.2 mg/kg) on mouse FST and TST. Our study has for the first time confirmed that the antidepressant-like effect of nicotine on mice is NMDA-mediated, and nicotine presumably exerts this effect by antagonizing the glutamatergic NMDA receptors.
Li, Li; Wu, Yongfang; Bai, Zhifeng; Hu, Yuyan; Li, Wenbin
2017-03-01
Microglial cells in spinal dorsal horn can be activated by nociceptive stimuli and the activated microglial cells release various cytokines enhancing the nociceptive transmission. However, the mechanisms underlying the activation of spinal microglia during nociceptive stimuli have not been well understood. In order to define the role of NMDA receptors in the activation of spinal microglia during nociceptive stimuli, the present study was undertaken to investigate the effect of blockade of NMDA receptors on the spinal microglial activation induced by acute peripheral inflammatory pain in rats. The acute inflammatory pain was induced by subcutaneous bee venom injection to the plantar surface of hind paw of rats. Spontaneous pain behavior, thermal withdrawal latency and mechanical withdrawal threshold were rated. The expression of specific microglia marker CD11b/c was assayed by immunohistochemistry and western blot. After bee venom treatment, it was found that rats produced a monophasic nociception characterized by constantly lifting and licking the injected hind paws, decreased thermal withdrawal latency and mechanical withdrawal threshold; immunohistochemistry displayed microglia with enlarged cell bodies, thickened, extended cellular processes with few ramifications, small spines, and intensive immunostaining; western blot showed upregulated expression level of CD11b/c within the period of hyperalgesia. Prior intrathecal injection of MK-801, a selective antagonist of NMDA receptors, attenuated the pain behaviors and suppressed up-regulation of CD11b/c induced by bee venom. It can be concluded that NMDA receptors take part in the mediation of spinal microglia activation in bee venom induced peripheral inflammatory pain and hyperalgesia in rats.
Neutrophil depletion after subarachnoid hemorrhage improves memory via NMDA receptors.
Provencio, Jose Javier; Swank, Valerie; Lu, Haiyan; Brunet, Sylvain; Baltan, Selva; Khapre, Rohini V; Seerapu, Himabindu; Kokiko-Cochran, Olga N; Lamb, Bruce T; Ransohoff, Richard M
2016-05-01
Cognitive deficits after aneurysmal subarachnoid hemorrhage (SAH) are common and disabling. Patients who experience delayed deterioration associated with vasospasm are likely to have cognitive deficits, particularly problems with executive function, verbal and spatial memory. Here, we report neurophysiological and pathological mechanisms underlying behavioral deficits in a murine model of SAH. On tests of spatial memory, animals with SAH performed worse than sham animals in the first week and one month after SAH suggesting a prolonged injury. Between three and six days after experimental hemorrhage, mice demonstrated loss of late long-term potentiation (L-LTP) due to dysfunction of the NMDA receptor. Suppression of innate immune cell activation prevents delayed vasospasm after murine SAH. We therefore explored the role of neutrophil-mediated innate inflammation on memory deficits after SAH. Depletion of neutrophils three days after SAH mitigates tissue inflammation, reverses cerebral vasoconstriction in the middle cerebral artery, and rescues L-LTP dysfunction at day 6. Spatial memory deficits in both the short and long-term are improved and associated with a shift of NMDA receptor subunit composition toward a memory sparing phenotype. This work supports further investigating suppression of innate immunity after SAH as a target for preventative therapies in SAH. Copyright © 2016 Elsevier Inc. All rights reserved.
Schurov, I L; McNulty, S; Best, J D; Sloper, P J; Hastings, M H
1999-01-01
Exposure of Syrian hamsters to light 1 h after lights-off rapidly (10 min) induced nuclear immunoreactivity (-ir) to the phospho-Ser133 form of the Ca2+/cAMP response element (CRE) binding protein (pCREB) in the retinorecipient zone of the suprachiasmatic nuclei (SCN). Light also induced nuclear Fos-ir in the same region of the SCN after 1 h. The glutamatergic N-methyl-D-aspartate (NMDA) receptor blocker MK801 attenuated the photic induction of both factors. To investigate glutamatergic regulation of pCREB and Fos further, tissue blocks and primary cultures of neonatal hamster SCN were examined by Western blotting and immunocytochemistry in vitro. On Western blots of SCN tissue, the pCREB-ir signal at 45 kDa was enhanced by glutamate or a mixture of glutamatergic agonists (NMDA, amino-methyl proprionic acid (AMPA), and Kainate (KA)), whereas total CREB did not change. Glutamate or the mixture of agonists also induced a 56 kDa band identified as Fos protein in SCN tissue. In dissociated cultures of SCN, glutamate caused a rapid (15 min) induction of nuclear pCREB-ir and Fos-ir (after 60 min) exclusively in neurones, both GABA-ir and others. Treatment with NMDA alone had no effect on pCREB-ir. AMPA alone caused a slight increase in pCREB-ir. However, kainate alone or in combination with NMDA and AMPA induced nuclear pCREB-ir equal to that induced by glutamate. The effects of glutamate on pCREB-ir and Fos-ir were blocked by antagonists of both NMDA (MK801) and AMPA/KA (NBQX) receptors. In the absence of extracellular Mg2+, MK801 blocked glutamatergic induction of Fos-ir. However, the AMPA/KA receptor antagonist was no longer effective at blocking glutamatergic induction of either Fos-ir or pCREB-ir, consistent with the model that glutamate regulates gene expression in the SCN by a co-ordinate action through both NMDA and AMPA/KA receptors. Glutamatergic induction of nuclear pCREB-ir in GABA-ir neurones was blocked by KN-62 an inhibitor of Ca2+/Calmodulin (Ca
Glycine receptors support excitatory neurotransmitter release in developing mouse visual cortex
Kunz, Portia A; Burette, Alain C; Weinberg, Richard J; Philpot, Benjamin D
2012-01-01
Glycine receptors (GlyRs) are found in most areas of the brain, and their dysfunction can cause severe neurological disorders. While traditionally thought of as inhibitory receptors, presynaptic-acting GlyRs (preGlyRs) can also facilitate glutamate release under certain circumstances, although the underlying molecular mechanisms are unknown. In the current study, we sought to better understand the role of GlyRs in the facilitation of excitatory neurotransmitter release in mouse visual cortex. Using whole-cell recordings, we found that preGlyRs facilitate glutamate release in developing, but not adult, visual cortex. The glycinergic enhancement of neurotransmitter release in early development depends on the high intracellular to extracellular Cl− gradient maintained by the Na+–K+–2Cl− cotransporter and requires Ca2+ entry through voltage-gated Ca2+ channels. The glycine transporter 1, localized to glial cells, regulates extracellular glycine concentration and the activation of these preGlyRs. Our findings demonstrate a developmentally regulated mechanism for controlling excitatory neurotransmitter release in the neocortex. PMID:22988142
D-aspartate and NMDA, but not L-aspartate, block AMPA receptors in rat hippocampal neurons
DEFF Research Database (Denmark)
Gong, Xiang-Qun; Frandsen, Anne; Lu, Wei-Yang
2005-01-01
1 The amino acid, D-aspartate, exists in the mammalian brain and is an agonist at the N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptors. Here, for the first time, we studied the actions of D-aspartate on alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptors (AMPARs......) in acutely isolated rat hippocampal neurons. 2 In the presence of the NMDA receptor channel blocker, MK801, D-aspartate inhibited kainate-induced AMPAR current in hippocampal neurons. The inhibitory action of D-aspartate on kainate-induced AMPAR current was concentration-dependent and was voltage......-independent in the tested voltage range (-80 to +60 mV). 3 The estimated EC50 of the L-glutamate-induced AMPAR current was increased in the presence of D-aspartate, while the estimated maximum L-glutamate-induced AMPAR current was not changed. D-aspartate concentration-dependently shifted the dose-response curve of kainate...
Expression of NMDA receptor-dependent LTP in the hippocampus: bridging the divide
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Bliss Tim VP
2013-01-01
Full Text Available Abstract A consensus has famously yet to emerge on the locus and mechanisms underlying the expression of the canonical NMDA receptor-dependent form of LTP. An objective assessment of the evidence leads us to conclude that both presynaptic and postsynaptic expression mechanisms contribute to this type of synaptic plasticity.
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Bénédicte Rossi
Full Text Available In developing cerebellar molecular layer interneurons (MLIs, NMDA increases spontaneous GABA release. This effect had been attributed to either direct activation of presynaptic NMDA receptors (preNMDARs or an indirect pathway involving activation of somato-dendritic NMDARs followed by passive spread of somatic depolarization along the axon and activation of axonal voltage dependent Ca(2+ channels (VDCCs. Using Ca(2+ imaging and electrophysiology, we searched for preNMDARs by uncaging NMDAR agonists either broadly throughout the whole field or locally at specific axonal locations. Releasing either NMDA or glutamate in the presence of NBQX using short laser pulses elicited current transients that were highly sensitive to the location of the spot and restricted to a small number of varicosities. The signal was abolished in the presence of high Mg(2+ or by the addition of APV. Similar paradigms yielded restricted Ca(2+ transients in interneurons loaded with a Ca(2+ indicator. We found that the synaptic effects of NMDA were not inhibited by blocking VDCCs but were impaired in the presence of the ryanodine receptor antagonist dantrolene. Furthermore, in voltage clamped cells, bath applied NMDA triggers Ca(2+ elevations and induces neurotransmitter release in the axonal compartment. Our results suggest the existence of preNMDARs in developing MLIs and propose their involvement in the NMDA-evoked increase in GABA release by triggering a Ca(2+-induced Ca(2+ release process mediated by presynaptic Ca(2+ stores. Such a mechanism is likely to exert a crucial role in various forms of Ca(2+-mediated synaptic plasticity.
Alterations in NMDA receptor expression during retinal degeneration in the RCS rat.
Gründer, T; Kohler, K; Guenther, E
2001-01-01
To determine how a progressive loss of photoreceptor cells and the concomitant loss of glutamatergic input to second-order neurons can affect inner-retinal signaling, glutamate receptor expression was analyzed in the Royal College of Surgeons (RCS) rat, an animal model of retinitis pigmentosa. Immunohistochemistry was performed on retinal sections of RCS rats and congenic controls between postnatal (P) day 3 and the aged adult (up to P350) using specific antibodies against N-methyl-D-aspartate (NMDA) subunits. All NMDA subunits (NR1, NR2A-2D) were expressed in control and dystrophic retinas at all ages, and distinct patterns of labeling were found in horizontal cells, subpopulations of amacrine cells and ganglion cells, as well as in the outer and inner plexiform layer (IPL). NRI immunoreactivity in the inner plexiform layer of adult control retinas was concentrated in two distinct bands, indicating a synaptic localization of NMDA receptors in the OFF and ON signal pathways. In the RCS retina, these bands of NRI immunoreactivity in the IPL were much weaker in animals older than P40. In parallel, NR2B immunoreactivity in the outer plexiform layer (OPL) of RCS rats was always reduced compared to controls and vanished between P40 and P120. The most striking alteration observed in the degenerating retina, however, was a strong expression of NRI immunoreactivity in Müller cell processes in the inner retina which was not observed in control animals and which was present prior to any visible sign of photoreceptor degeneration. The results suggest functional changes in glutamatergic receptor signaling in the dystrophic retina and a possible involvement of Müller cells in early processes of this disease.
Effects of ibuprofen on cognition and NMDA receptor subunit expression across aging.
Márquez Loza, Alejandra; Elias, Valerie; Wong, Carmen P; Ho, Emily; Bermudez, Michelle; Magnusson, Kathy R
2017-03-06
Age-related declines in long- and short-term memory show relationships to decreases in N-methyl-d-aspartate (NMDA) receptor expression, which may involve inflammation. This study was designed to determine effects of an anti-inflammatory drug, ibuprofen, on cognitive function and NMDA receptor expression across aging. Male C57BL/6 mice (ages 5, 14, 20, and 26months) were fed ibuprofen (375ppm) in NIH31 diet or diet alone for 6weeks prior to testing. Behavioral testing using the Morris water maze showed that older mice performed significantly worse than younger in spatial long-term memory, reversal, and short-term memory tasks. Ibuprofen enhanced overall performance in the short-term memory task, but this appeared to be more related to improved executive function than memory. Ibuprofen induced significant decreases over all ages in the mRNA densities for GluN2B subunit, all GluN1 splice variants, and GluN1-1 splice forms in the frontal cortex and in protein expression of GluN2A, GluN2B and GluN1 C2' cassettes in the hippocampus. GluN1-3 splice form mRNA and C2' cassette protein were significantly increased across ages in frontal lobes of ibuprofen-treated mice. Ibuprofen did not alter expression of pro-inflammatory cytokines IL-1β and TNFα, but did reduce the area of reactive astrocyte immunostaining in frontal cortex of aged mice. Enhancement in executive function showed a relationship to increased GluN1-3 mRNA and decreased gliosis. These findings suggest that inflammation may play a role in executive function declines in aged animals, but other effects of ibuprofen on NMDA receptors appeared to be unrelated to aging or inflammation. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
Goodman, Jarid; Ressler, Reed L; Packard, Mark G
2017-06-03
The present experiments investigated the involvement of N-methyl-d-aspartate (NMDA) receptors of the dorsolateral striatum (DLS) in consolidation of extinction in a habit memory task. Adult male Long-Evans rats were initially trained in a food-reinforced response learning version of a plus-maze task and were subsequently given extinction training in which the food was removed from the maze. In experiment 1, immediately after the first day of extinction training, rats received bilateral intra-DLS injections of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 2µg/side) or physiological saline. In experiment 2, immediately following the first day of extinction training, animals were given intra-DLS injections of NMDA receptor partial agonist d-cycloserine (DCS; 10 or 20µg/side) or saline. In both experiments, the number of perseverative trials (a trial in which a rat made the same previously reinforced body-turn response) and latency to reach the previously correct food well were used as measures of extinction behavior. Results indicated that post-training intra-DLS injections of AP5 impaired extinction. In contrast, post-training intra-DLS infusions of DCS (20µg) enhanced extinction. Intra-DLS administration of AP5 or DCS given two hours after extinction training did not influence extinction of response learning, indicating that immediate post-training administration of AP5 and DCS specifically influenced consolidation of the extinction memory. The present results indicate a critical role for DLS NMDA receptors in modulating extinction of habit memory and may be relevant to developing therapeutic approaches to combat the maladaptive habits observed in human psychopathologies in which DLS-dependent memory has been implicated (e.g. drug addiction and relapse and obsessive compulsive disorder). Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.
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Melvin Baidya
Full Text Available The nematode C. elegans utilizes a relatively simple neural circuit to mediate avoidance responses to noxious stimuli such as the volatile odorant octanol. This avoidance behavior is modulated by dopamine. cat-2 mutant animals that are deficient in dopamine biosynthesis have an increased response latency to octanol compared to wild type animals, and this defect can be fully restored with the application of exogenous dopamine. Because this avoidance behavior is mediated by glutamatergic signaling between sensory neurons and premotor interneurons, we investigated the genetic interactions between dopaminergic signaling and ionotropic glutamate receptors. cat-2 mutant animals lacking either the GLR-1 or GLR-2 AMPA/kainate receptors displayed an increased response latency to octanol, which could be restored via exogenous dopamine. However, whereas cat-2 mutant animals lacking the NMR-1 NMDA receptor had increased response latency to octanol they were insensitive to exogenous dopamine. Mutants that lacked both AMPA/kainate and NMDA receptors were also insensitive to exogenous dopamine. Our results indicate that dopamine modulation of octanol avoidance requires NMR-1, consistent with NMR-1 as a potential downstream signaling target for dopamine.
Liu, Xiao; Li, Jitao; Guo, Chunmei; Wang, Hongli; Sun, Yaxin; Wang, Han; Su, Yun-Ai; Li, Keqing; Si, Tianmei
2018-01-01
Cognitive dysfunction constitutes an essential component in schizophrenia for its early presence in the pathophysiology of the disease and close relatedness to life quality of patients. To develop effective treatment of cognitive deficits, it is important to understand their neurobiological causes and to identify potential therapeutic targets. In this study, adopting repeated MK-801 treatment as an animal model of schizophrenia, we investigated whether antipsychotic drugs, olanzapine and haloperidol, can reverse MK-801-induced cognitive deficits and how the reversal processes recruited proteins involved in glutamate neurotransmission in rat medial prefrontal cortex (mPFC) and hippocampus. We found that low-dose chronic MK-801 treatment impaired object-in-context recognition memory and reversal learning in the Morris water maze, leaving reference memory relatively unaffected, and that these cognitive deficits can be partially reversed by olanzapine, not haloperidol, treatment. At the molecular level, chronic MK-801 treatment resulted in the reduction of multiple N-methyl-D-aspartate (NMDA) receptor subunits in rat mPFC and olanzapine, not haloperidol, treatment restored the levels of GluN1 and phosphorylated GluN2B in this region. Taken together, MK-801-induced cognitive deficits may be associated with region-specific changes in NMDA receptor subunits and the reversal of specific NMDA receptor subunits may underlie the cognition-enhancing effects of olanzapine. PMID:29375333
Glycine receptors in CNS neurons as a target for nonretrograde action of cannabinoids
Lozovaya, N.; Yatsenko, N.; Beketov, A.; Tsintsadze, T.; Burnashev, N.
2005-01-01
At many central synapses, endocannabinoids released by postsynaptic cells act retrogradely on presynaptic G-protein-coupled cannabinoid receptors to inhibit neurotransmitter release. Here, we demonstrate that cannabinoids may directly affect the functioning of inhibitory glycine receptor (GlyR)
Cholesterol modulates open probability and desensitization of NMDA receptors
Czech Academy of Sciences Publication Activity Database
Kořínek, Miloslav; Vyklický, Vojtěch; Borovská, Jiřina; Lichnerová, Katarina; Kaniaková, Martina; Krausová, Barbora; Krůšek, Jan; Balík, Aleš; Smejkalová, Tereza; Horák, Martin; Vyklický ml., Ladislav
2015-01-01
Roč. 593, č. 10 (2015), s. 2279-2293 ISSN 0022-3751 R&D Projects: GA ČR(CZ) GPP303/11/P391; GA ČR(CZ) GAP303/12/1464; GA ČR(CZ) GBP304/12/G069; GA ČR(CZ) GA14-02219S; GA ČR(CZ) GP14-09220P; GA TA ČR(CZ) TE01020028; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:67985823 Keywords : NMDA receptor * glutamate-gated * cholesterol Subject RIV: ED - Physiology Impact factor: 4.731, year: 2015
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Michelle Molina
2012-12-01
Full Text Available Sporadic Creutzfeldt-Jakob disease (sCJD and anti-NMDA receptor antibody encephalitis (NMDAE can both produce a rapidly progressive dementia with resulting state of catatonia or akinetic mutism. Both are associated with movement disorders. In published case series, myoclonus appears to be the most frequent movement disorder in sCJD, while stereotypic, synchronized, one-cycle-per-second movements such as arm or leg elevation, jaw opening, grimacing, head turning, and eye deviation are seen in NMDAE. We report a case of a 59-year-old woman with rapidly worsening cognitive disturbance leading to a nearly catatonic state interrupted by stereotypic movements. sCJD was diagnosed via periodic sharp wave complexes on EEG as well as cerebrospinal fluid (CSF 14-3-3 and tau protein elevation. Characteristic movement disorder of NMDAE was present in absence of ovarian mass or CSF pleiocytosis. Given prior case reports of presence of anti-NMDA receptor antibodies in sCJD, we propose that the movement disorder in this case was caused by anti-NMDA receptor antibodies whose formation was secondary to neuronal damage from prion disease. It is important to consider sCJD even in cases that have some clinical features suggestive of NMDAE.
Imaging the PCP site of the NMDA ion channel
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Waterhouse, Rikki N. E-mail: rnw7@columbia.edu
2003-11-01
The N-methyl-D-aspartate (NMDA) ion channel plays a role in neuroprotection, neurodegeneration, long-term potentiation, memory, and cognition. It is implicated in the pathophysiology of several neurological and neuropsychiatric disorders including Parkinson's Disease, Huntington's Chorea, schizophrenia, alcoholism and stroke. The development of effective radiotracers for the study of NMDA receptors is critical for our understanding of their function, and their modulation by endogenousr substances or therapeutic drugs. Since the NMDA/PCP receptor lies within the channel, it is a unique target and is theoretically accessible only when the channel is in the active and 'open' state, but not when it is in the inactive or 'closed' state. The physical location of the NMDA/PCP receptor not only makes it an important imaging target but also complicates the development of suitable PET and SPECT radiotracers for this site. An intimate understanding of the biochemical, pharmacological, physiological and behavioral processes associated with the NMDA ion channel is essential to develop improved imaging agents. This review outlines progress made towards the development of radiolabeled agents for PCP sites of the NMDA ion channel. In addition, the animal and pharmacological models used for in vitro and in vivo assessment of NMDA receptor targeted agents are discussed.
Imaging the PCP site of the NMDA ion channel
International Nuclear Information System (INIS)
Waterhouse, Rikki N.
2003-01-01
The N-methyl-D-aspartate (NMDA) ion channel plays a role in neuroprotection, neurodegeneration, long-term potentiation, memory, and cognition. It is implicated in the pathophysiology of several neurological and neuropsychiatric disorders including Parkinson's Disease, Huntington's Chorea, schizophrenia, alcoholism and stroke. The development of effective radiotracers for the study of NMDA receptors is critical for our understanding of their function, and their modulation by endogenousr substances or therapeutic drugs. Since the NMDA/PCP receptor lies within the channel, it is a unique target and is theoretically accessible only when the channel is in the active and 'open' state, but not when it is in the inactive or 'closed' state. The physical location of the NMDA/PCP receptor not only makes it an important imaging target but also complicates the development of suitable PET and SPECT radiotracers for this site. An intimate understanding of the biochemical, pharmacological, physiological and behavioral processes associated with the NMDA ion channel is essential to develop improved imaging agents. This review outlines progress made towards the development of radiolabeled agents for PCP sites of the NMDA ion channel. In addition, the animal and pharmacological models used for in vitro and in vivo assessment of NMDA receptor targeted agents are discussed
Oxime Ethers of (E)-11-Isonitrosostrychnine as Highly Potent Glycine Receptor Antagonists
DEFF Research Database (Denmark)
Mohsen, Amal M Y; Mandour, Yasmine M; Sarukhanyan, Edita
2016-01-01
of the crystal structure of the α3 glycine receptor indicated the same orientation of the strychnine core for all analogues. For the most potent oxime ethers, the ether substituent was accommodated in a lipophilic receptor binding pocket. The findings identify the oxime hydroxy group as a suitable attachment...
Mechanical stress activates NMDA receptors in the absence of agonists.
Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K; Sachs, Frederick; Hua, Susan Z
2017-01-03
While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca 2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor ifenprodil reduced NMDA-activated currents, but had no effect on the mechanically induced Ca 2+ influx. Extracellular Mg 2+ at 2 mM did not significantly affect the shear induced Ca 2+ influx, but at 10 mM it produced significant inhibition. Patch clamp experiments showed mechanical activation of NMDAR and inhibition by MK-801. The mechanical sensitivity of NMDARs may play a role in the normal physiology of fluid flow in the glymphatic system and it has obvious relevance to TBI.
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Francy Johanna Moreno-Pedraza
2010-12-01
Full Text Available Computational study of the evolutionary relationships of the ionotropic receptors NMDA, AMPA and kainate in four species ofprimates. Objective. To identify the influence of changes on the secondary structure and evolutionary relationship of NMDA, AMPA andkainate receptors in Homo sapiens, Pan troglodytes, Pongo pygmaeus and Macaca mulatta. Materials and methods. We identified 91sequences for NMDA, AMPA and kainate receptors and analyzed with software for predicting secondary structure, phosphorylation sites,multiple alignments, selection of protein evolution models and phylogenetic prediction. Results. We found that subunits GLUR5, NR2A,NR2C and NR3A showed structural changes in the C-terminal region and formation or loss of phosphorylation sites in this zone.Additionally the phylogenetic prediction suggests that the NMDA NR2 subunits are the closest to the ancestral node that gives rise to theother subunits. Conclusions. Changes in structure and phosphorylation sites in GLUR5, NR2A, NR2C and NR3A subunits suggestvariations in the interaction of the C-terminal region with kinase proteins and with proteins with PDZ domains, which could affect thetrafficking and anchoring of the subunits. On the other hand, the phylogenetic prediction suggests that the changes that occurred in the NR2subunits gave rise to the other subunits of glutamate ionotropic receptors, primarily because the NMDA and particularly the NR2D subunitsare the most closely related to the ancestral node that possibly gave rise to the iGluRs.
Searsia species with affinity to the N-methyl-d-aspartic acid (NMDA) receptor
DEFF Research Database (Denmark)
Jäger, Anna; Knap, D.M.; Nielsen, Birgitte
2012-01-01
Species of Searsia are used in traditional medicine to treat epilepsy. Previous studies on S. dentata and S. pyroides have shown that this is likely mediated via the N-methyl-d-aspartic acid (NMDA) receptor. Ethanolic extracts of leaves of six Searsia species were tested in a binding assay...
Ferreira, G; Gutiérrez, R; De La Cruz, V; Bermúdez-Rattoni, F
2002-09-01
In conditioned taste aversion, an animal avoids a taste previously associated with toxic effects, and this aversive memory formation requires an intact insular cortex. In this paper, we investigated the possible differential involvement of cholinergic and glutamatergic receptors in the insular cortex in short-term memory (STM) and long-term memory (LTM) of taste aversion in rats. Taste aversion was induced by intraperitoneal administration of lithium chloride (a malaise-inducing drug) 15 min after experience with an unfamiliar taste. In order to test STM and LTM of taste aversion, taste stimulus was again presented 4 h and 72 h after lithium injection, respectively. During the acquisition, microinjection of the muscarinic antagonist, scopolamine, in the insular cortex before, but not after, the presentation of the new taste, abolished STM as well as LTM. Blockade of the NMDA receptor, in the insular cortex, by AP5 before, but not after, the presentation of the taste stimulus, impaired LTM but left STM intact. Moreover, when injected 1 h after malaise induction (i.e., during taste-illness association), AP5 disrupted both STM and LTM. These results suggest that activation of muscarinic receptors in the insular cortex is involved in the acquisition of taste memory, whereas NMDA receptors participate in taste memory consolidation. These data demonstrate that different neurochemical mechanisms subserve different memory phases. NMDA receptors are also probably involved in processing the visceral input, thus allowing subsequent taste-illness association. This indicates that in the same cortical area the same neurotransmitter system can be involved in distinct processes: taste memory consolidation vs. taste-illness association.
International Nuclear Information System (INIS)
Owens, Jonathan; Tebbutt, Andrew A.; McGregor, Ailsa L.; Kodama, K.; Magar, Sharad S.; Perlman, Michael E.; Robins, David J.; Durant, Graham J.; McCulloch, James
2000-01-01
N-(1-Naphthyl)-N'-(3-[ 125 I]-iodophenyl)-N'-methylguanidine ([ 125 I]-CNS 1261) was synthesized as a potential radioligand to image N-methyl-D-aspartate (NMDA) receptor activation. [ 125 I]-CNS 1261 was prepared by radioiodination of N-(1-naphthyl)-N'-(3-tributylstannylphenyl)-N'-methylguanidine using Na 125 I and peracetic acid. [ 125 I]-CNS 1261 uptake in vivo reflected NMDA receptor distribution in normal rat brain, whereas in ischemic rat brain, uptake was markedly increased in areas of NMDA receptor activation. Radiolabeled CNS 1261 appears to be a good candidate for further development as a single photon emission computed tomography tracer in the investigation of NMDA receptor activation in cerebral ischemia
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Jitao eLi
2016-03-01
Full Text Available Adolescence is of particular significance to schizophrenia, since psychosis onset typically occurs in this critical period. Based on the N-methyl-D-aspartate (NMDA receptor hypofunction hypothesis of schizophrenia, in this study, we investigated whether and how repeated NMDA receptor blockade during adolescence would affect GABAergic interneurons in rat medial prefrontal cortex (mPFC and mPFC-mediated cognitive functions. Specifically, adolescent rats were subjected to intraperitoneal administration of MK-801 (0.1, 0.2, 0.4 mg/kg, a non-competitive NMDA receptor antagonist, for 14 days and then tested for reference memory and reversal learning in the water maze. The density of parvabumin (PV-, calbindin (CB- and calretinin (CR-positive neurons in mPFC were analyzed at either 24 hours or 7 days after drug cessation. We found that MK-801 treatment delayed reversal learning in the water maze without affecting initial acquisition. Strikingly, MK-801 treatment also significantly reduced the density of PV+ and CB+ neurons, and this effect persisted for 7 days after drug cessation at the dose of 0.2 mg/kg. We further demonstrated that the reduction in PV+ and CB+ neuron densities was ascribed to a downregulation of the expression levels of PV and CB, but not to neuronal death. These results parallel the behavioral and neuropathological changes of schizophrenia and provide evidence that adolescent NMDA receptors antagonism offers a useful tool for unraveling the etiology of the disease.
Czech Academy of Sciences Publication Activity Database
Šlamberová, Romana; Mareš, Pavel
2005-01-01
Roč. 516, č. 1 (2005), s. 10-17 ISSN 0014-2999 R&D Projects: GA MŠk(CZ) LN00B122 Institutional research plan: CEZ:AV0Z5011922 Keywords : epileptic seizure * cerebral cortex * NMDA receptor antagonist Subject RIV: FH - Neuro logy Impact factor: 2.477, year: 2005
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Leila eChaieb
2015-04-01
Full Text Available Background: Application of transcranial random noise stimulation (tRNS between 0.1 and 640 Hz of the primary motor cortex (M1 for 10 minutes induces a persistent excitability increase lasting for at least 60 minutes. However, the mechanism of tRNS-induced cortical excitability alterations is not yet fully understood. Objective: The main aim of this study was to get first efficacy data with regard to the possible neuronal effect of tRNS. Methods: Single-pulse transcranial magnetic stimulation (TMS was used to measure levels of cortical excitability before and after combined application of tRNS at an intensity of 1mA for 10mins stimulation duration and a pharmacological agent (or sham on 8 healthy male participants. Results: The sodium channel blocker carbamazepine showed a tendency towards inhibiting MEPs 5-60 mins poststimulation. The GABAA agonist lorazepam suppressed tRNS-induced cortical excitability increases at 0-20 and 60 min time points. The partial NMDA receptor agonist D-cycloserine, the NMDA receptor antagonist dextromethorphan and the D2/D3 receptor agonist ropinirole had no significant effects on the excitability increases seen with tRNS.Conclusions: In contrast to transcranial direct current stimulation (tDCS, aftereffects of tRNS are seem to be not NMDA receptor dependent and can be suppressed by benzodiazepines suggesting that tDCS and tRNS depend upon different mechanisms.
Olmos, G; DeGregorio-Rocasolano, N; Paz Regalado, M; Gasull, T; Assumpció Boronat, M; Trullas, R; Villarroel, A; Lerma, J; García-Sevilla, J A
1999-07-01
This study was designed to assess the potential neuroprotective effect of several imidazol(ine) drugs and agmatine on glutamate-induced necrosis and on apoptosis induced by low extracellular K+ in cultured cerebellar granule cells. Exposure (30 min) of energy deprived cells to L-glutamate (1-100 microM) caused a concentration-dependent neurotoxicity, as determined 24 h later by a decrease in the ability of the cells to metabolize 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) into a reduced formazan product. L-glutamate-induced neurotoxicity (EC50=5 microM) was blocked by the specific NMDA receptor antagonist MK-801 (dizocilpine). Imidazol(ine) drugs and agmatine fully prevented neurotoxicity induced by 20 microM (EC100) L-glutamate with the rank order (EC50 in microM): antazoline (13)>cirazoline (44)>LSL 61122 [2-styryl-2-imidazoline] (54)>LSL 60101 [2-(2-benzofuranyl) imidazole] (75)>idazoxan (90)>LSL 60129 [2-(1,4-benzodioxan-6-yl)-4,5-dihydroimidazole](101)>RX82 1002 (2-methoxy idazoxan) (106)>agmatine (196). No neuroprotective effect of these drugs was observed in a model of apoptotic neuronal cell death (reduction of extracellular K+) which does not involve stimulation of NMDA receptors. Imidazol(ine) drugs and agmatine fully inhibited [3H]-(+)-MK-801 binding to the phencyclidine site of NMDA receptors in rat brain. The profile of drug potency protecting against L-glutamate neurotoxicity correlated well (r=0.90) with the potency of the same compounds competing against [3H]-(+)-MK-801 binding. In HEK-293 cells transfected to express the NR1-1a and NR2C subunits of the NMDA receptor, antazoline and agmatine produced a voltage- and concentration-dependent block of glutamate-induced currents. Analysis of the voltage dependence of the block was consistent with the presence of a binding site for antazoline located within the NMDA channel pore with an IC50 of 10-12 microM at 0 mV. It is concluded that imidazol(ine) drugs and agmatine are
Ostadhadi, Sattar; Imran Khan, Muhammad; Norouzi-Javidan, Abbas; Dehpour, Ahmad-Reza
2016-07-01
Pramipexole is a dopamine D2 receptor agonist indicated for treating Parkinson disorder. This study was aimed to investigate the effect of pramipexole in forced swimming test (FST) in mice and the possible involvement of activation of D2 receptors and inhibition of N-methyl-d-aspartate (NMDA) receptors and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) on this effect. Intraperitoneal administration of pramipexole (1-3mg/kg) reduced the immobility time in the FST similar to fluoxetine (20mg/kg, i.p.). This effect of pramipexole (1mg/kg, i.p.) was ceased when mice were pretreated with haloperidol (0.15mg/kg, i.p,) and sulpiride (5mg/kg, i.p) as D2 receptor antagonists, NMDA (75mg/kg,i.p.), l-arginine (750mg/kg, i.p., a substrate for nitric oxide synthase) or sildenafil (5mg/kg, i.p., a phosphodiesterase 5 inhibitor). The administration of MK-801 (0.05mg/kg, i.p., a NMDA receptor antagonist) l-NG-Nitro arginine methyl ester (l-NAME, 10mg/kg, i.p., a non-specific nitric oxide synthase (NOS) inhibitor), 7-nitroindazole (30mg/kg, i.p., a neuronal NOS inhibitor) and methylene blue (10mg/kg, i.p.), an inhibitor of both NOS and soluble guanylyl cyclase (sGC) in combination with the sub-effective dose of pramipexole (0.3mg/kg, i.p.) reduced the immobility. Altogether, our data suggest that the antidepressant-like effect of pramipexole is dependent on the activation of D2 receptor and inhibition of either NMDA receptors and/or NO-cGMP synthesis. These results contribute to the understanding of the mechanisms underlying the antidepressant-like effect of pramipexole and reinforce the role of D2 receptors, NMDA receptors and l-arginine-NO-GMP pathway in the antidepressant mechanism of this agent. Copyright © 2016. Published by Elsevier Masson SAS.
Uttl, Libor; Petrasek, Tomas; Sengul, Hilal; Svojanovska, Marketa; Lobellova, Veronika; Vales, Karel; Radostova, Dominika; Tsenov, Grygoriy; Kubova, Hana; Mikulecka, Anna; Svoboda, Jan; Stuchlik, Ales
2018-01-01
The role of NMDA receptors in learning, memory and hippocampal function has long been recognized. Post-mortem studies have indicated that the expression or subunit composition of the NMDA glutamate receptor subtype might be related to the impaired cognitive functions found in schizophrenia patients. NMDA receptor antagonists have been used to develop animal models of this disorder. There is accumulating evidence showing that not only the acute but also the chronic application of NMDA receptor antagonists may induce schizophrenia-like alterations in behavior and brain functions. However, limited evidence is available regarding the consequences of NMDA receptor blockage during periods of adolescence and early adulthood. This study tested the hypothesis that a 2-week treatment of male Long-Evans and Wistar rats with dizocilpine (MK-801; 0.5 mg/kg daily) starting at postnatal days (PD) 30 and 60 would cause a long-term cognitive deficit and changes in the levels of NMDA receptor subunits. The working memory version of the Morris water maze (MWM) and active place avoidance with reversal on a rotating arena (Carousel) requiring cognitive coordination and flexibility probed cognitive functions and an elevated-plus maze (EPM) was used to measure anxiety-like behavior. The western blot method was used to determine changes in NMDA receptor subunit levels in the hippocampus. Our results showed no significant changes in behaviors in Wistar rats. Slightly elevated anxiety-like behavior was observed in the EPM in Long-Evans rats with the onset of treatment on PD 30. Furthermore, Long-Evans rats treated from PD 60 displayed impaired working memory in the MWM. There were; however, no significant changes in the levels of NMDA receptor subunits because of MK-801 administration. These findings suggest that a 2-week treatment starting on PD 60 in Long-Evans rats leads to long-term changes in working memory, but this deficit is not paralleled by changes in NMDA receptor subunits. These
Effects of NR1 splicing on NR1/NR3B-type excitatory glycine receptors
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Orth Angela
2009-04-01
Full Text Available Abstract Background N-methyl-D-aspartate receptors (NMDARs are the most complex of ionotropic glutamate receptors (iGluRs. Subunits of this subfamily assemble into heteromers, which – depending on the subunit combination – may display very different pharmacological and electrophysiological properties. The least studied members of the NMDAR family, the NR3 subunits, have been reported to assemble with NR1 to form excitatory glycine receptors in heterologous expression systems. The heterogeneity of NMDARs in vivo is in part conferred to the receptors by splicing of the NR1 subunit, especially with regard to proton sensitivity. Results Here, we have investigated whether the NR3B subunit is capable of assembly with each of the eight functional NR1 splice variants, and whether the resulting receptors share the unique functional properties described for NR1-1a/NR3. We provide evidence that functional excitatory glycine receptors formed regardless of the NR1 isoform, and their pharmacological profile matched the one reported for NR1-1a/NR3: glycine alone fully activated the receptors, which were insensitive to glutamate and block by Mg2+. Surprisingly, amplitudes of agonist-induced currents showed little dependency on the C-terminally spliced NR1 variants in NR1/NR3B diheteromers. Even more strikingly, NR3B conferred proton sensitivity also to receptors containing NR1b variants – possibly via disturbing the "proton shield" of NR1b splice variants. Conclusion While functional assembly could be demonstrated for all combinations, not all of the specific interactions seen for NR1 isoforms with coexpressed NR2 subunits could be corroborated for NR1 assembly with NR3. Rather, NR3 abates trafficking effects mediated by the NR1 C terminus as well as the N-terminally mediated proton insensitivity. Thus, this study establishes that NR3B overrides important NR1 splice variant-specific receptor properties in NR1/NR3B excitatory glycine receptors.
Kalirin Binds the NR2B Subunit of the NMDA Receptor, Altering Its Synaptic Localization and Function
Kiraly, D. D.
2011-08-31
The ability of dendritic spines to change size and shape rapidly is critical in modulating synaptic strength; these morphological changes are dependent upon rearrangements of the actin cytoskeleton. Kalirin-7 (Kal7), a Rho guanine nucleotide exchange factor localized to the postsynaptic density (PSD), modulates dendritic spine morphology in vitro and in vivo. Kal7 activates Rac and interacts with several PSD proteins, including PSD-95, DISC-1, AF-6, and Arf6. Mice genetically lacking Kal7 (Kal7KO) exhibit deficient hippocampal long-term potentiation (LTP) as well as behavioral abnormalities in models of addiction and learning. Purified PSDs from Kal7KO mice contain diminished levels of NR2B, an NMDA receptor subunit that plays a critical role in LTP induction. Here we demonstrate that Kal7KO animals have decreased levels of NR2B-dependent NMDA receptor currents in cortical pyramidal neurons as well as a specific deficit in cell surface expression of NR2B. Additionally, we demonstrate that the genotypic differences in conditioned place preference and passive avoidance learning seen in Kal7KO mice are abrogated when animals are treated with an NR2B-specific antagonist during conditioning. Finally, we identify a stable interaction between the pleckstrin homology domain of Kal7 and the juxtamembrane region of NR2B preceding its cytosolic C-terminal domain. Binding of NR2B to a protein that modulates the actin cytoskeleton is important, as NMDA receptors require actin integrity for synaptic localization and function. These studies demonstrate a novel and functionally important interaction between the NR2B subunit of the NMDA receptor and Kalirin, proteins known to be essential for normal synaptic plasticity.
Kalirin Binds the NR2B Subunit of the NMDA Receptor, Altering Its Synaptic Localization and Function
Kiraly, D. D.; Lemtiri-Chlieh, Fouad; Levine, E. S.; Mains, R. E.; Eipper, B. A.
2011-01-01
The ability of dendritic spines to change size and shape rapidly is critical in modulating synaptic strength; these morphological changes are dependent upon rearrangements of the actin cytoskeleton. Kalirin-7 (Kal7), a Rho guanine nucleotide exchange factor localized to the postsynaptic density (PSD), modulates dendritic spine morphology in vitro and in vivo. Kal7 activates Rac and interacts with several PSD proteins, including PSD-95, DISC-1, AF-6, and Arf6. Mice genetically lacking Kal7 (Kal7KO) exhibit deficient hippocampal long-term potentiation (LTP) as well as behavioral abnormalities in models of addiction and learning. Purified PSDs from Kal7KO mice contain diminished levels of NR2B, an NMDA receptor subunit that plays a critical role in LTP induction. Here we demonstrate that Kal7KO animals have decreased levels of NR2B-dependent NMDA receptor currents in cortical pyramidal neurons as well as a specific deficit in cell surface expression of NR2B. Additionally, we demonstrate that the genotypic differences in conditioned place preference and passive avoidance learning seen in Kal7KO mice are abrogated when animals are treated with an NR2B-specific antagonist during conditioning. Finally, we identify a stable interaction between the pleckstrin homology domain of Kal7 and the juxtamembrane region of NR2B preceding its cytosolic C-terminal domain. Binding of NR2B to a protein that modulates the actin cytoskeleton is important, as NMDA receptors require actin integrity for synaptic localization and function. These studies demonstrate a novel and functionally important interaction between the NR2B subunit of the NMDA receptor and Kalirin, proteins known to be essential for normal synaptic plasticity.
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Serena Y. Kuang
2016-09-01
Full Text Available We have established a long-term, stable primary chick forebrain neuron (FBN culture on a microelectrode array platform as a biosensor system for neurotoxicant screening and for neuroelectrophysiological studies for multiple purposes. This paper reports some of our results, which characterize the biosensor pharmacologically. Dose-response experiments were conducted using NMDA receptor antagonist AP5 and GABAA receptor agonist musimol (MUS. The chick FBN biosensor (C-FBN-biosensor responds to the two agents in a pattern similar to that of rodent counterparts; the estimated EC50s (the effective concentration that causes 50% inhibition of the maximal effect are 2.3 μM and 0.25 μM, respectively. Intercultural and intracultural reproducibility and long-term reusability of the C-FBN-biosensor are addressed and discussed. A phenomenon of sensitization of the biosensor that accompanies intracultural reproducibility in paired dose-response experiments for the same agent (AP5 or MUS is reported. The potential application of the C-FBN-biosensor as an alternative to rodent biosensors in shared sensing domains (NMDA receptor and GABAA receptor is suggested. Keywords: Biosensor, Microelectrode array, Neurotoxicity, Chick forebrain neuron, AP5, Musimol
Mechanical stress activates NMDA receptors in the absence of agonists
Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K.; Sachs, Frederick; Hua, Susan Z.
2017-01-01
While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor i...
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Rosenegger David
2010-08-01
Full Text Available Abstract Background Memory is the ability to store, retain, and later retrieve information that has been learned. Intermediate term memory (ITM that persists for up to 3 h requires new protein synthesis. Long term memory (LTM that persists for at least 24 h requires: DNA transcription, RNA translation, and the trafficking of newly synthesized proteins. It has been shown in a number of different model systems that NMDA receptors, protein kinase C (PKC and mitogen activated protein kinase (MAPK are all involved in the memory formation process. Results Here we show that snails trained in control conditions are capable of forming, depending on the training procedure used, either ITM or LTM. However, blockage of NMDA receptors (MK 801, inhibition of PKC (GF109203X hydrochloride and MAPK activity (UO126 prevent the formation of both ITM and LTM. Conclusions The injection of either U0126 or GF109203X, which inhibit MAPK and PKC activity respectively, 1 hour prior to training results in the inhibition of both ITM and LTM formation. We further found that NMDA receptor activity was necessary in order for both ITM and LTM formation.
DEFF Research Database (Denmark)
Pless, Stephan Alexander; Lynch, Joseph W
2009-01-01
Ligand binding to Cys-loop receptors produces either global conformational changes that lead to activation or local conformational changes that do not. We found that the fluorescence of a fluorophore tethered to R271C in the extracellular M2 region of the alpha1 glycine receptor increases during ...
Increased NMDA and AMPA receptor densities in the anterior cingulate cortex in schizophrenia
International Nuclear Information System (INIS)
Zavitsanou, K.; Huang, X.-F.
2002-01-01
Full text: The anterior cingulate cortex (ACC) is a brain area of potential importance to our understanding of the pathophysiology of schizophrenia. Since a disturbed balance between excitatory and inhibitory activity is suggested to occur in the ACC in schizophrenia, the present study has focused on the analysis of binding of [ 3 H]MK801, [ 3 H]AMPA and [ 3 H]kainate, radioligands which respectively label the NMDA, AMPA and kainate receptors of the ionotropic glutamate receptor family in the ACC of 10 schizophrenia patients and 10 matched controls, using quantitative autoradiography. AMPA receptor densities were higher in cortical layer II whereas NMDA receptor densities were higher in cortical layers II-III in the ACC of both control and schizophrenia group. In contrast, kainate receptors displayed the highest density in cortical layer V. [ 3 H]AMPA binding was significantly increased by 25% in layer II in the schizophrenia group as compared to the control group. Similarly, a significant 17% increase of [ 3 H]MK801 binding was observed in layers II-III in the schizophrenia group. No statistically significant differences were observed for [ 3 H] kainate binding between the two groups. These results suggest that ionotropic glutamate receptors are differentially altered in the ACC of schizophrenia. The increase in [ 3 H]AMPA and [ 3 H]MK801 binding points to a postsynaptic compensation for impaired glutamatergic neurotransmission in the ACC in schizophrenia. Such abnormality could lead to an imbalance between the excitatory and inhibitory neurotransmission in this brain area that may contribute to the emergence of some schizophrenia symptoms. Copyright (2002) Australian Neuroscience Society
Adamec, R E
1998-01-01
The hypothesis that N-methyl-D-aspartate (NMDA) receptors mediate initiation of lasting behavioral changes induced by the anxiogenic beta-carboline, FG-7142, was supported in this study. Behavioral changes normally induced by FG-7142 were blocked when the competitive NMDA receptor blocker, 7-amino-phosphono-heptanoic acid, was given prior to administration of FG-7142. When cats were subsequently given FG-7142 alone, the drug produced lasting behavioral changes like those reported previously. Flumazenil, a benzodiazepine receptor antagonist, reversed an increase in defensiveness produced by FG-7142 alone, replicating previous findings. The data are consistent with the hypothesis that NMDA-dependent long-term potentiation in limbic pathways subserving defensive response to threat mediates lasting increases in defensiveness produced by FG-7142.
Energy Technology Data Exchange (ETDEWEB)
Waterhouse, Rikki N. E-mail: rnw7@columbia.edu; Sultana, Abida; Laruelle, M
2002-11-01
Alterations in normal NMDA receptor composition, densities and function have been implicated in the pathophysiology of certain neurological and neuropsychiatric disorders such as Parkinson's Disease, Huntington's Chorea, schizophrenia, alcoholism and stroke. In our first effort to provide PET ligands for the NMDA/glycine site, we reported the synthesis of a novel high affinity glycine site ligand, 3-[2-[(3-methoxyphenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2 -carboxylic acid ((3MPICA), Ki=4.8{+-}0.9 nM) and the corresponding carbon-11 labeled PET ligand, [{sup 11}C]3MPICA. We report here the in vivo evaluation of [{sup 11}C]3MPICA in rats. Biodistribution analysis revealed that [{sup 11}C]3MPICA exhibited low degree of brain penetration and high blood concentration. The average uptake at two minutes was highest in the cerebellum (0.19{+-}0.04 %ID/g) and thalamus (0.18{+-}0.05 %ID/g) and lower in the hippocampus (0.13{+-}0.03) and frontal cortex (0.11{+-}0.04 %ID/g). The radioactivity cleared quickly from all brain regions examined. Administration of unlabeled 3MPICA (1 mg/kg, i.v.) revealed at 60 minutes a small general reduction in regional brain radioactivity concentrations in treated animals versus controls, however, the blood radioactivity concentration was also lowered, confounding the assessment of the degree of saturable binding. Warfarin co-administration (100 mg/kg, i.v.) significantly lowered blood activity at 5 minutes post-injection (-27%, P<0.01) but failed to significantly increase the brain uptake of the radiotracer. In view of these results, and especially considering the low brain penetration of this tracer, [{sup 11}C]3MPICA does not appear to be a promising PET radiotracer for in vivo use.
Eto, Kei; Murakoshi, Hideji; Watanabe, Miho; Hirata, Hiromi; Moorhouse, Andrew J.; Ishibashi, Hitoshi
2017-01-01
Abstract Inhibitory synapses are established during development but continue to be generated and modulated in strength in the mature nervous system. In the spinal cord and brainstem, presynaptically released inhibitory neurotransmitter dominantly switches from GABA to glycine during normal development in vivo. While presynaptic mechanisms of the shift of inhibitory neurotransmission are well investigated, the contribution of postsynaptic neurotransmitter receptors to this shift is not fully elucidated. Synaptic clustering of glycine receptors (GlyRs) is regulated by activation-dependent depolarization in early development. However, GlyR activation induces hyperpolarization after the first postnatal week, and little is known whether and how presynaptically released glycine regulates postsynaptic receptors in a depolarization-independent manner in mature developmental stage. Here we developed spinal cord neuronal culture of rodents using chronic strychnine application to investigate whether initial activation of GlyRs in mature stage could change postsynaptic localization of GlyRs. Immunocytochemical analyses demonstrate that chronic blockade of GlyR activation until mature developmental stage resulted in smaller clusters of postsynaptic GlyRs that could be enlarged upon receptor activation for 1 h in the mature stage. Furthermore, live cell-imaging techniques show that GlyR activation decreases its lateral diffusion at synapses, and this phenomenon is dependent on PKC, but neither Ca2+ nor CaMKII activity. These results suggest that the GlyR activation can regulate receptor diffusion and cluster size at inhibitory synapses in mature stage, providing not only new insights into the postsynaptic mechanism of shifting inhibitory neurotransmission but also the inhibitory synaptic plasticity in mature nervous system. PMID:28197549
Sharma, Sunita; Darland, Diane; Lei, Saobo; Rakoczy, Sharlene; Brown-Borg, Holly M
2012-06-01
In the current study, we investigated changes in N-methyl D-aspartate (NMDA) and kainate receptor expression, long-term potentiation (LTP), and neurogenesis in response to neurotoxic stress in long-living Ames dwarf mice. We hypothesized that Ames dwarf mice have enhanced neurogenesis that enables retention of spatial learning and memory with age and promotes neurogenesis in response to injury. Levels of the NMDA receptors (NR)1, NR2A, NR2B, and the kainate receptor (KAR)2 were increased in Ames dwarf mice, relative to wild-type littermates. Quantitative assessment of the excitatory postsynaptic potential in Schaffer collaterals in hippocampal slices from Ames dwarf mice showed an increased response in high-frequency induced LTP over time compared with wild type. Kainic acid (KA) injection was used to promote neurotoxic stress-induced neurogenesis. KA mildly increased the number of doublecortin-positive neurons in wild-type mice, but the response was significantly enhanced in the Ames dwarf mice. Collectively, these data support our hypothesis that the enhanced learning and memory associated with the Ames dwarf mouse may be due to elevated levels of NMDA and KA receptors in hippocampus and their ability to continue producing new neurons in response to neuronal damage.
Haj-Mirzaian, Arya; Ostadhadi, Sattar; Kordjazy, Nastaran; Dehpour, Ahmad Reza; Ejtemaei Mehr, Shahram
2014-07-15
Opioid and glutamatergic receptors have a key role in depression following stress. In this study, we assessed opioid and glutamatergic receptors interaction with the depressant-like behavior of acute foot-shock stress in the mouse forced swimming test. Stress was induced by intermittent foot shock stimulation during 30min and swim periods were afterwards conducted by placing mice in separated glass cylinders filled with water for 6min. The immobility time during the last 4min of the test was considered. Acute foot-shock stress significantly increased the immobility time of mice compared to non-stressed control group (P≤0.01). Administration of non-selective opioid receptors antagonist, naltrexone (1 and 2mg/kg, i.p.), and the selective non-competitive NMDA receptor antagonist, MK-801 (0.05mg/kg, i.p.), and the selective serotonin reuptake inhibitor, fluoxetine (5mg/kg), significantly reduced the immobility time in stressed animals (P≤0.01). Lower doses of MK-801 (0.01mg/kg), naltrexone (0.3mg/kg), NMDA (75mg/kg) and morphine(5mg/kg) had no effect on foot-shock stressed mice. Combined treatment of sub-effective doses of naltrexone and MK-801 significantly showed an antidepressant-like effect (P≤0.001). On the other hand, co-administration of non-effective doses of NMDA and morphine with effective doses of naltrexone and MK-801 reversed the anti-immobility effect of these drugs. Taken together, we have for the first time demonstrated the possible role of opioid/NMDA receptors signaling in the depressant-like effect of foot-shock stress, and proposed the use of drugs that act like standard anti-depressants in stress-induced depression. Copyright © 2014. Published by Elsevier B.V.
An NMDA Receptor-Dependent Mechanism Underlies Inhibitory Synapse Development
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Xinglong Gu
2016-01-01
Full Text Available In the mammalian brain, GABAergic synaptic transmission provides inhibitory balance to glutamatergic excitatory drive and controls neuronal output. The molecular mechanisms underlying the development of GABAergic synapses remain largely unclear. Here, we report that NMDA-type ionotropic glutamate receptors (NMDARs in individual immature neurons are the upstream signaling molecules essential for GABAergic synapse development, which requires signaling via Calmodulin binding motif in the C0 domain of the NMDAR GluN1 subunit. Interestingly, in neurons lacking NMDARs, whereas GABAergic synaptic transmission is strongly reduced, the tonic inhibition mediated by extrasynaptic GABAA receptors is increased, suggesting a compensatory mechanism for the lack of synaptic inhibition. These results demonstrate a crucial role for NMDARs in specifying the development of inhibitory synapses, and suggest an important mechanism for controlling the establishment of the balance between synaptic excitation and inhibition in the developing brain.
Luo, Yun; Zhu, Wenjing; Jia, Jia; Zhang, Chenyu; Xu, Yun
2009-09-01
The peroxisome proliferator activated receptor coactivator 1 alpha (PGC-1alpha) is a nuclear transcriptional coactivator that is widely expressed in the brain areas. Over-expression of PGC-1alpha can protect neuronal cells from oxidant-induced injury. The purpose of the current study is to investigate the role of PGC-1alpha in the oxygen (anoxia) deprivation (OGD) neurons. The PGC-1alpha mRNA and protein level between control and OGD neurons were examined by real-time PCR and Western blot. More PGC-1alpha expression was found in the OGD neurons compared with the normal group. Over-expression of PGC-1alpha suppressed cell apoptosis while inhibition of the PGC-1alpha expression induced cell apoptosis in OGD neurons. Furthermore, increase of PGC-1alpha resulted in activation of N-methyl-D-aspartate (NMDA) receptor, p38, and ERK mitogen-activated protein kinase (MAPK) pathway. The blocking of the NMDA receptor by its antagonists MK-801 reduced PGC-1alpha mRNA expression in OGD neurons, while NMDA itself can directly induce the expression of PGC-1alpha in neuronal cells. At the same time, PD98059 (ERK MAPK inhibitor) and SB203580 (P38 MAPK inhibitor) also prevented the up-regulation of PGC-1alpha in OGD neurons and MK801 can inhibit the expression of P38 and ERK MAPK. These data suggested that the expression of PGC-1alpha was up-regulated in OGD mice cortical neurons, which protected the neurons against OGD injury. Moreover, this effect was correlated to the NMDA receptor and the ERK and P38 MAPK pathway. The protective effect of PGC-1alpha on OGD cortical neurons may be useful for stroke therapy.
International Nuclear Information System (INIS)
Clow, D.W.; Lee, S.J.; Hammer, R.P. Jr.
1991-01-01
The effects of D,L-2-amino-7-phosphonoheptanoic acid (AP7), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, and MK-801, a non-competitive NMDA receptor antagonist, on regional brain metabolism were studied in unanesthetized, freely moving rats by using the quantitative 14 C2-deoxyglucose autoradiographic procedure. AP7 (338 or 901 mg/kg) produced a dose-dependent decrease of metabolic activity throughout most of the regions studied including sensory, motor, and limbic cortices. In contrast, MK-801 (0.1 or 1.0 mg/kg) resulted in a dose-dependent decrease of metabolic activity in sensory cortices, and an increase in limbic regions such as the hippocampal stratum lacunosum moleculare and entorhinal cortex. MK-801 also produced a biphasic response in agranular motor cortex, whereby the low dose increased while the high dose decreased labeling. In addition, MK-801 produced heterogeneous effects on regional cerebral metabolism in sensory cortices. Metabolic activity decreased in layer IV relative to layer Va following MK-801 treatment in primary somatosensory (SI) and visual (VI) cortices, suggesting a shift in activity from afferent fibers innervating layer IV to those innervating layer Va. MK-801 administration also decreased metabolic activity in granular SI relative to dysgranular SI, and in VI relative to secondary visual cortex (VII), thus providing a relative sparing of activity in dysgranular SI and VII. Thus, the non-competitive NMDA receptor antagonist suppressed activity from extrinsic neocortical sources, enhancing relative intracortical activity and stimulating limbic regions, while the competitive NMDA antagonist depressed metabolic activity in all cortical regions
NMDA modulates oligodendrocyte differentiation of subventricular zone cells through PKC activation
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Fabio eCavaliere
2013-12-01
Full Text Available Multipotent cells from the juvenile subventricular zone (SVZ possess the ability to differentiate into new neural cells. Depending on local signals, SVZ can generate new neurons, astrocytes or oligodendrocytes. We previously demonstrated that activation of NMDA receptors in SVZ progenitors increases the rate of oligodendrocyte differentiation. Here we investigated the mechanisms involved in NMDA receptor-dependent differentiation. Using functional studies performed with the reporter gene luciferase we found that activation of NMDA receptor stimulates PKC. In turn, stimulation of PKC precedes the activation of NADPH oxidase (NOX as demonstrated by translocation of the p67phox subunit to the cellular membrane. We propose that NOX2 is involved in the transduction of the signal from NMDA receptors through PKC activation as the inhibitor gp91 reduced their pro-differentiation effect. In addition, our data and that from other groups suggest that signaling through the NMDA receptor/PKC/NOX2 cascade generates ROS that activate the PI3/mTOR pathway and finally leads to the generation of new oligodendrocytes.
Snijdelaar, D.G.
2005-01-01
This thesis concerns the effects of combining opioids with clinically available NMDA receptor antagonists in the treatment of acute and chronic pain. There are a number of problems with the use of opioids, such as, the development of tolerance/hyperalgesia, the reduced effectiveness in (central)
International Nuclear Information System (INIS)
Gibson, R.E.; Burns, H.D.; Thorpe, H.H.; Waisi Eng; Ransom, R.; Solomon, H.
1992-01-01
Radioiodinated (+)-3-Iodo-MK-801 is a high affinity radioligand for the N-methyl-D-aspartate (NMDA) receptor-channel complex. We have demonstrated in vivo localization in the CNS of rat which is stereoselective and blocked by coinjection of unlabeled MK-801. Autoradiography indicates localization in vivo which is in concordance with in vitro autoradiographic studies. These results indicate that radioiodinated (+)-3-Iodo-MK-801 is a useful probe for in vitro and in vivo autoradiographic studies and suggest that radioligands for the NMDA receptor may be developed which will provide in vivo images of receptor distribution in man. (author)
Molecular basis of the alternative recruitment of GABA(A) versus glycine receptors through gephyrin
DEFF Research Database (Denmark)
Maric, Hans-Michael; Kasaragod, Vikram Babu; Hausrat, Torben Johann
2014-01-01
γ-Aminobutyric acid type A and glycine receptors (GABA(A)Rs, GlyRs) are the major inhibitory neurotransmitter receptors and contribute to many synaptic functions, dysfunctions and human diseases. GABA(A)Rs are important drug targets regulated by direct interactions with the scaffolding protein ge...
NMDA-dependent phase synchronization between septal and temporal CA3 hippocampal networks.
Gu, Ning; Jackson, Jesse; Goutagny, Romain; Lowe, Germaine; Manseau, Frédéric; Williams, Sylvain
2013-05-08
Increasing evidence suggests that synchronization between brain regions is essential for information exchange and memory processes. However, it remains incompletely known which synaptic mechanisms contribute to the process of synchronization. Here, we investigated whether NMDA receptor-mediated synaptic plasticity was an important player in synchronization between septal and temporal CA3 areas of the rat hippocampus. We found that both the septal and temporal CA3 regions intrinsically generate weakly synchronized δ frequency oscillations in the complete hippocampus in vitro. Septal and temporal oscillators differed in frequency, power, and rhythmicity, but both required GABAA and AMPA receptors. NMDA receptor activation, and most particularly the NR2B subunit, contributed considerably more to rhythm generation at the temporal than the septal region. Brief activation of NMDA receptors by application of extracellular calcium dramatically potentiated the septal-temporal coherence for long durations (>40 min), an effect blocked by the NMDA antagonist AP-5. This long-lasting NMDA-receptor-dependent increase in coherence was also associated with an elevated phase locking of spikes locally and across regions. Changes in coherence between oscillators were associated with increases in phase locking between oscillators independent of oscillator amplitude. Finally, although the septal CA3 rhythm preceded the oscillations in temporal regions in control conditions, this was reversed during the NMDA-dependent enhancement in coherence, suggesting that NMDA receptor activation can change the direction of information flow along the septotemporal CA3 axis. These data demonstrate that plastic changes in communication between septal and temporal hippocampal regions can arise from the NMDA-dependent phase locking of neural oscillators.
Diurnal inhibition of NMDA-EPSCs at rat hippocampal mossy fibre synapses through orexin-2 receptors
Perin, Martina; Longordo, Fabio; Massonnet, Christine; Welker, Egbert; Lüthi, Anita
2014-01-01
Diurnal release of the orexin neuropeptides orexin-A (Ox-A, hypocretin-1) and orexin-B (Ox-B, hypocretin-2) stabilises arousal, regulates energy homeostasis and contributes to cognition and learning. However, whether cellular correlates of brain plasticity are regulated through orexins, and whether they do so in a time-of-day-dependent manner, has never been assessed. Immunohistochemically we found sparse but widespread innervation of hippocampal subfields through Ox-A- and Ox-B-containing fibres in young adult rats. The actions of Ox-A were studied on NMDA receptor (NMDAR)-mediated excitatory synaptic transmission in acute hippocampal slices prepared around the trough (Zeitgeber time (ZT) 4–8, corresponding to 4–8 h into the resting phase) and peak (ZT 23) of intracerebroventricular orexin levels. At ZT 4–8, exogenous Ox-A (100 nm in bath) inhibited NMDA receptor-mediated excitatory postsynaptic currents (NMDA-EPSCs) at mossy fibre (MF)–CA3 (to 55.6 ± 6.8% of control, P = 0.0003) and at Schaffer collateral–CA1 synapses (70.8 ± 6.3%, P = 0.013), whereas it remained ineffective at non-MF excitatory synapses in CA3. Ox-A actions were mediated postsynaptically and blocked by the orexin-2 receptor (OX2R) antagonist JNJ10397049 (1 μm), but not by orexin-1 receptor inhibition (SB334867, 1 μm) or by adrenergic and cholinergic antagonists. At ZT 23, inhibitory effects of exogenous Ox-A were absent (97.6 ± 2.9%, P = 0.42), but reinstated (87.2 ± 3.3%, P = 0.002) when endogenous orexin signalling was attenuated for 5 h through i.p. injections of almorexant (100 mg kg−1), a dual orexin receptor antagonist. In conclusion, endogenous orexins modulate hippocampal NMDAR function in a time-of-day-dependent manner, suggesting that they may influence cellular plasticity and consequent variations in memory performance across the sleep–wake cycle. PMID:25085886
Kumamoto, E
1996-12-01
Excitatory amino-acid currents in rodent central neurones are mediated by the activation of glutamate receptors. Ionotropic types of the receptors are divided into alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate and N-methyl-D-aspartate (NMDA) receptors, and the former two are collectively called non-NMDA receptors. The NMDA receptor is modulated by a number of endogenous neuromodulators including Mg2+, polyamines, glycine and protons in extracellular solutions. Although it has been generally thought that each of the neuromodulators acts on a distinct site in the NMDA receptor, recent studies have revealed that these actions may be not necessarily independent of each other. The NMDA receptor response is not only inhibited but also potentiated by Mg2+, and the latter action is due to an interaction of a Mg2+ site with either glycine- or proton-binding site. In the presence of polyamines, a tonic inhibition by protons of the NMDA receptor response is relieved, resulting in a potentiation of the response. Alternatively, it has been recently revealed that there are some subtypes of non-NMDA receptors which are negatively modulated by polyamines in either extra- or intra cellular solutions. The difference in polyamine sensitivity among non-NMDA receptors is attributed to a distinction in their constituted subunits. The inhibition of non-NMDA receptor by intracellular polyamines results in inward rectification of the current-voltage relation which is not seen for polyamine-insensitive ones. This polyamine action is not mimicked by intracellular Mg2+.
Schwarz, Jaclyn M.; McCarthy, Margaret M.
2008-01-01
Normal development of the male rat brain involves two distinct processes, masculinization and defeminization, that occur during a critical period of brain sexual differentiation. Masculinization allows for the capacity to express male sex behavior in adulthood, and defeminization eliminates or suppresses the capacity to express female sex behavior in adulthood. Despite being separate processes, both masculinization and defeminization are induced by neonatal estradiol exposure. Though the mechanisms underlying estradiol-mediated masculinization of behavior during development have been identified, the mechanisms underlying defeminization are still unknown. We sought to determine whether neonatal activation of glutamate NMDA receptors is a necessary component of estradiol-induced defeminization of behavior. We report here that antagonizing glutamate receptors during the critical period of sexual differentiation blocks estradiol-induced defeminization but not masculinization of behavior in adulthood. However, enhancing NMDA receptor activation during the same critical period mimics estradiol to permanently induce both defeminization and masculinization of sexual behavior. PMID:18687334
DEFF Research Database (Denmark)
Jensen, Anders A.
2005-01-01
The human glycine receptor subtypes alpha1beta and alpha2 have been expressed stably in HEK293 cells, and the functional characteristics of the receptors have been characterised in the FLIPR Membrane Potential Assay. The pharmacological properties obtained for nine standard ligands at the two rec...
Hannan, Md Abdul; Mohibbullah, Md; Hong, Yong-Ki; Nam, Joo Hyun; Moon, Il Soo
2014-01-01
Neurotrophic factors are essential for the differentiation and maturation of developing neurons as well as providing survival support to the mature neurons. Moreover, therapeutically neurotrophic factors are promising to reconstruct partially damaged neuronal networks in neurodegenerative diseases. In the previous study, we reported that the ethanol extract of an edible marine alga, Gelidium amansii (GAE) had shown promising effects in the development and maturation of both axon and dendrites of hippocampal neurons. Here, we demonstrate that in primary culture of hippocampal neurons (1) GAE promotes a significant increase in the number of filopodia and dendritic spines; (2) promotes synaptogenesis; (3) enhances N-methyl-D-aspartic acid (NMDA) receptor recruitment; and (4) modulates NMDA-receptor-mediated postsynaptic current. Taken together these findings that GAE might be involved in both morphological and functional maturation of neurons suggest the possibility that GAE may constitute a promising candidate for novel compounds for the prevention and treatment of neurodegenerative diseases.
Bespalov, A Y; Medvedev, I O; Sukhotina, I A; Zvartau, E E
2001-04-01
Sensitization to the rate-decreasing effects of opioid antagonists induced by acute pretreatment with opioid agonists has been suggested to reflect initial changes in opioid systems that underlie physical dependence. Glutamate receptors are implicated in the development and expression of opioid dependence, and antagonists acting at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors have been shown repeatedly to attenuate the severity of opioid withdrawal. The present study evaluated the ability of a competitive NMDA receptor antagonist, D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid), to affect morphine-induced sensitization to naloxone in rats trained to lever-press on a multiple-trial, fixed-ratio 10 schedule of food reinforcement. D-CPPene (0.3-3 mg/kg) was administered either 4 h or 30 min prior to the test session. Morphine (10 mg/kg) or its vehicle was administered 4 h before naloxone challenge (0.3-3 mg/kg). D-CPPene failed to prevent morphine-induced potentiation of the naloxone-produced decrement in operant performance. Thus, these results suggest that agonist-induced sensitization to behavioral effects of opioid antagonists may be insensitive to NMDA receptor blockade.
Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism.
Bangash, M Ali; Park, Joo Min; Melnikova, Tatiana; Wang, Dehua; Jeon, Soo Kyeong; Lee, Deidre; Syeda, Sbaa; Kim, Juno; Kouser, Mehreen; Schwartz, Joshua; Cui, Yiyuan; Zhao, Xia; Speed, Haley E; Kee, Sara E; Tu, Jian Cheng; Hu, Jia-Hua; Petralia, Ronald S; Linden, David J; Powell, Craig M; Savonenko, Alena; Xiao, Bo; Worley, Paul F
2011-05-27
We have created a mouse genetic model that mimics a human mutation of Shank3 that deletes the C terminus and is associated with autism. Expressed as a single copy [Shank3(+/ΔC) mice], Shank3ΔC protein interacts with the wild-type (WT) gene product and results in >90% reduction of Shank3 at synapses. This "gain-of-function" phenotype is linked to increased polyubiquitination of WT Shank3 and its redistribution into proteasomes. Similarly, the NR1 subunit of the NMDA receptor is reduced at synapses with increased polyubiquitination. Assays of postsynaptic density proteins, spine morphology, and synapse number are unchanged in Shank3(+/ΔC) mice, but the amplitude of NMDAR responses is reduced together with reduced NMDAR-dependent LTP and LTD. Reciprocally, mGluR-dependent LTD is markedly enhanced. Shank3(+/ΔC) mice show behavioral deficits suggestive of autism and reduced NMDA receptor function. These studies reveal a mechanism distinct from haploinsufficiency by which mutations of Shank3 can evoke an autism-like disorder. Copyright © 2011 Elsevier Inc. All rights reserved.
Kirson, Dean; Todorovic, Jelena; Mihic, S John
2018-01-01
The amino acid taurine is an endogenous ligand acting on glycine receptors (GlyRs), which is released by astrocytes in many brain regions, such as the nucleus accumbens and prefrontal cortex. Taurine is a partial agonist with an efficacy significantly lower than that of glycine. Allosteric modulators such as ethanol and isoflurane produce leftward shifts of glycine concentration-response curves but have no effects at saturating glycine concentrations. In contrast, in whole-cell electrophysiology studies these modulators increase the effects of saturating taurine concentrations. A number of possible mechanisms may explain these enhancing effects, including modulator effects on conductance, channel open times, or channel closed times. We used outside-out patch-clamp single channel electrophysiology to investigate the mechanism of action of 200 mM ethanol and 0.55 mM isoflurane in enhancing the effects of a saturating concentration of taurine. Neither modulator enhanced taurine-mediated conductance. Isoflurane increased the probability of channel opening. Isoflurane also increased the lifetimes of the two shortest open dwell times while both agents decreased the likelihood of occurrence of the longest-lived intracluster channel-closing events. The mechanism of enhancement of GlyR functioning by these modulators is dependent on the efficacy of the agonist activating the receptor and the concentration of agonist tested. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.
Im, Doo Soon; Jeon, Jeong Wook; Lee, Jin Soo; Won, Seok Joon; Cho, Sung Ig; Lee, Yong Beom; Gwag, Byoung Joo
2012-05-21
Excess activation of ionotropic glutamate receptors and iron is believed to contribute to free radical production and neuronal death following hypoxic ischemia. We examined the possibility that both NMDA receptor activation and iron overload determine spatial and temporal patterns of free radical production after transient middle cerebral artery occlusion (tMCAO) in male Sprague-Dawley rats. Mitochondrial free radical (MFR) levels were maximally increased in neurons in the core at 1 h and 24 h after tMCAO. Early MFR production was blocked by administration of MK-801, an NMDA receptor antagonist, but not deferoxamine, an iron chelator. Neither MK-801 nor deferoxamine attenuated late MFR production in the core. Increased MFRs were observed in penumbral neurons within 6 h and gradually increased over 24 h after tMCAO. Slowly-evolving MFRs in the core and penumbra were accompanied by iron overload. Deferoxamine blocked iron overload but reduced MFR production only in the penumbra. Combined MK-801/deferoxamine reduced late MFR production in both core and penumbra in an additive manner. Combination therapy significantly ameliorated infarction compared with monotherapy. These findings suggest that the NMDA receptor activation and iron overload mediate late MFR production and infarction after tMCAO. Copyright © 2012 Elsevier B.V. All rights reserved.
Directory of Open Access Journals (Sweden)
Louise eAdermark
2011-10-01
Full Text Available The flow of cortical information through the basal ganglia is a complex spatiotemporal pattern of increased and decreased firing. The striatum is the biggest input nucleus to the basal ganglia and the aim of this study was to assess the role of inhibitory GABAA and glycine receptors in regulating synaptic activity in the dorsolateral (DLS and ventral striatum (nucleus accumbens, nAc. Local field potential recordings from coronal brain slices of juvenile and adult Wistar rats showed that GABAA receptors and strychnine-sensitive glycine receptors are tonically activated and inhibit excitatory input to the DLS and to the nAc. Strychnine-induced disinhibition of glutamatergic transmission was insensitive to the muscarinic receptor inhibitor scopolamine (10 µM, inhibited by the nicotinic acetylcholine receptor antagonist mecamylamine (10 µM and blocked by GABAA receptor inhibitors, suggesting that tonically activated glycine receptors depress excitatory input to the striatum through modulation of cholinergic and GABAergic neurotransmission. As an end-product example of striatal GABAergic output in vivo we measured dopamine release in the DLS and nAc by microdialysis in the awake and freely moving rat. Reversed dialysis of bicuculline (50 μM in perfusate only increased extrasynaptic dopamine levels in the nAc, while strychnine administered locally (200 μM in perfusate decreased dopamine output by 60% in both the DLS and nAc. Our data suggest that GABAA and glycine receptors are tonically activated and modulate striatal transmission in a partially sub-region specific manner.
Vogels, B. A.; Maas, M. A.; Daalhuisen, J.; Quack, G.; Chamuleau, R. A.
1997-01-01
The aim of this study was to investigate the possible role of N-methyl-D-aspartate (NMDA)-receptor overactivity in two different experimental rat models of encephalopathy: subacute encephalopathy caused by severe hyperammonemia in portacaval-shunted rats (AI-PCS rats) and acute hepatic
Directory of Open Access Journals (Sweden)
Andrew Chay
2016-02-01
Full Text Available Norepinephrine, a neuromodulator that activates β-adrenergic receptors (βARs, facilitates learning and memory as well as the induction of synaptic plasticity in the hippocampus. Several forms of long-term potentiation (LTP at the Schaffer collateral CA1 synapse require stimulation of both βARs and N-methyl-D-aspartate receptors (NMDARs. To understand the mechanisms mediating the interactions between βAR and NMDAR signaling pathways, we combined FRET imaging of cAMP in hippocampal neuron cultures with spatial mechanistic modeling of signaling pathways in the CA1 pyramidal neuron. Previous work implied that cAMP is synergistically produced in the presence of the βAR agonist isoproterenol and intracellular calcium. In contrast, we show that when application of isoproterenol precedes application of NMDA by several minutes, as is typical of βAR-facilitated LTP experiments, the average amplitude of the cAMP response to NMDA is attenuated compared with the response to NMDA alone. Models simulations suggest that, although the negative feedback loop formed by cAMP, cAMP-dependent protein kinase (PKA, and type 4 phosphodiesterase may be involved in attenuating the cAMP response to NMDA, it is insufficient to explain the range of experimental observations. Instead, attenuation of the cAMP response requires mechanisms upstream of adenylyl cyclase. Our model demonstrates that Gs-to-Gi switching due to PKA phosphorylation of βARs as well as Gi inhibition of type 1 adenylyl cyclase may underlie the experimental observations. This suggests that signaling by β-adrenergic receptors depends on temporal pattern of stimulation, and that switching may represent a novel mechanism for recruiting kinases involved in synaptic plasticity and memory.
Iriondo, O; Zaldibar-Gerrikagoitia, J; Rodríguez, T; García, J M; Aguilera, L
2017-03-01
A 19-year-old male came to the Emergency Room of our hospital due to an episode of dystonic movements and disorientation 4 days after consuming methamphetamine, which evolved to a catatonic frank syndrome and eventually to status epilepticus. Definitive diagnosis was anti-NMDA receptor encephalitis, an acute inflammation of the limbic area of autoimmune origin in which early diagnosis and treatment are key elements for the final outcome. In this case, initial normal tests and previous methamphetamine poisoning delayed diagnosis, because inhaled-methamphetamine poisoning causes similar clinical symptoms to anti-NMDA receptor encephalitis. Methamphetamine poisoning may have caused an immune response in the patient, bringing on the progress of the pathology. Copyright © 2016 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.
DEFF Research Database (Denmark)
Johansen, T N; Frydenvang, Karla Andrea; Ebert, B
1994-01-01
The 3-isoxazolol amino acids (S)-2-amino-3-(3-hydroxy-5-methyl-4- isoxazolyl)propionic acid [(S)-AMPA, 2] and (R,S)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid (AMAA, 5a) (Figure 1) are potent and specific agonists at the AMPA and N-methyl-D-aspartic acid (NMDA) subtypes, respectively......, of (S)-glutamic acid (1) receptors. A number of amino acids and diacids structurally related to AMAA were synthesized and tested electrophysiologically and in receptor-binding assays. The hydroxymethyl analogue 7c of AMAA was an NMDA agonist approximately equipotent with AMAA in the [3H...... by molecular mechanics calculations. Compound 7a possesses extra steric bulk and shows significant restriction of conformational flexibility compared to AMAA and 7c, which may be determining factors for the observed differences in biological activity. Although the nitrogen atom of quinolinic acid (6) has very...
Directory of Open Access Journals (Sweden)
Manuela eMellone
2015-07-01
Full Text Available Levodopa-induced dyskinesias (LIDs are major complications in the pharmacological management of Parkinson’s disease (PD. Abnormal glutamatergic transmission in the striatum is considered a key factor in the development of LIDs. This work aims at i. characterizing NMDA receptor GluN2A/GluN2B subunit ratio as a common synaptic trait in rat and primate models of LIDs and in dyskinetic PD patients, and ii. validating the potential therapeutic effect of a cell-permeable peptide interfering with GluN2A synaptic localization on the dyskinetic behavior of these experimental models of LIDs. Here we demonstrate an altered ratio of synaptic GluN2A/GluN2B-containing NMDA receptors in the striatum of levodopa-treated dyskinetic rats and monkeys as well as in post-mortem tissue from dyskinetic PD patients. The modulation of synaptic NMDA receptor composition by a cell-permeable peptide interfering with GluN2A subunit interaction with the scaffolding protein PSD-95 leads to a reduction in the dyskinetic motor behavior in the two animal models of LIDs. Our results indicate that targeting synaptic NMDA receptor subunit composition may represent an intriguing therapeutic approach aimed at ameliorating levodopa motor side effects.
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Bryan L Roth
Full Text Available In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as 'designer drugs' and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS-2-(ethylamino-2-(3-methoxyphenylcyclohexanone and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenylcyclohexanamine and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenylcyclohexyl]piperidine and 1-[1-(4-methoxyphenylcyclohexyl]piperidine, were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects.
Flynn, K. M.; Schreibman, M. P.; Yablonsky-Alter, E.; Banerjee, S. P.
1999-01-01
This study investigated age- and gender-specific variations in properties of the glutamate N-methyl-d-aspartate receptor (NMDAR) in a freshwater teleost, the platyfish (Xiphophorus maculatus). Prior localization of the immunoreactive (ir)-R1 subunit of the NMDAR protein (R1) in cells of the nucleus olfactoretinalis (NOR), a primary gonadotropin-releasing hormone (GnRH)-containing brain nucleus in the platyfish, suggests that NMDAR, as in mammals, is involved in modulation of the platyfish brain-pituitary-gonad (BPG) axis. The current study shows that the number of cells in the NOR displaying ir-R1 is significantly increased in pubescent and mature female platyfish when compared to immature and senescent animals. In males, there is no significant change in ir-R1 expression in the NOR at any time in their lifespan. The affinity of the noncompetitive antagonist ((3)H)MK-801 for the NMDAR is significantly increased in pubescent females while maximum binding of ((3)H)MK-801 to the receptor reaches a significant maximum in mature females. In males, both MK-801 affinity and maximum binding remain unchanged throughout development. This is the first report of gender differences in the association of NMDA receptors with neuroendocrine brain areas during development. It is also the first report to suggest NMDA receptor involvement in the development of the BPG axis in a nonmammalian vertebrate. Copyright 1999 Academic Press.
Energy Technology Data Exchange (ETDEWEB)
Owens, Jonathan E-mail: j.owens@clinmed.gla.ac.uk; Tebbutt, Andrew A.; McGregor, Ailsa L.; Kodama, K.; Magar, Sharad S.; Perlman, Michael E.; Robins, David J.; Durant, Graham J.; McCulloch, James
2000-06-01
N-(1-Naphthyl)-N'-(3-[{sup 125}I]-iodophenyl)-N'-methylguanidine ([{sup 125}I]-CNS 1261) was synthesized as a potential radioligand to image N-methyl-D-aspartate (NMDA) receptor activation. [{sup 125}I]-CNS 1261 was prepared by radioiodination of N-(1-naphthyl)-N'-(3-tributylstannylphenyl)-N'-methylguanidine using Na{sup 125}I and peracetic acid. [{sup 125}I]-CNS 1261 uptake in vivo reflected NMDA receptor distribution in normal rat brain, whereas in ischemic rat brain, uptake was markedly increased in areas of NMDA receptor activation. Radiolabeled CNS 1261 appears to be a good candidate for further development as a single photon emission computed tomography tracer in the investigation of NMDA receptor activation in cerebral ischemia.
PURIFICACIÓN DE IgY CONTRA LA SUBUNIDAD NR3 DEL RECEPTOR NMDA DE CEREBRO DE RATA
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Gina Méndez C
2008-04-01
Full Text Available Objetivo. Obtener anticuerpos tipo IgY contra péptidos sintéticos de las subunidades NR3A y NR3B del receptor NMDA de ratas, para reconocer y seguir la expresión de estas subunidades en extractos de cerebro de rata de diferentes edades. Materiales y métodos. Se diseñaron dos péptidos empleando los sistemas de la base de datos Entrez y el programa ClustalW-PBIL de alineamientos múltiples contra las subunidades NR3A y NR3B del receptor NMDA; una vez sintetizados por el método SSPS-fmoc fueron utilizados para inocular gallinas (Gallus gallus, variedad Hy Line Brown de 16 semanas de edad; al cabo de 57 días postinoculación se purificó IgY específica y se enfrentaron a extractos de cerebro de rata postnatal y adulta. Resultados. Se detectaron las subunidades NR3A y NR3B y se relacionó su expresión con la edad del animal; siendo mayor la expresión de la subunidad NR3A en extracto de cerebro de rata postnatal. No se encontró diferencia marcada en la expresión de la subunidad NR3B en las edades mencionadas. Conclusiones. Esta es la primera investigación que emplea proteína nativa para el reconocimiento de la subunidad NR3 del receptor NMDA, lo cual muestra la especificidad de los anticuerpos generados y contribuye con el entendimiento de las funciones de este receptor y su relación con la regulación de la memoria espacial.
Interactions of neurotoxins with non-NMDA glutamate receptors: an autoradiographic study
International Nuclear Information System (INIS)
Kuenig, G.; Niedermeyer, B.; Krause, F.; Hartmann, J.; Deckert, J.; Heinsen, H.; Beckmann, H.; Riederer, P.; Ransmayr, G.
1994-01-01
Neurotoxic substances are discussed to cause neurode-generation by acting as excitotoxins on glutamate receptors. We investigated the properties of L-beta-oxalyl-amino-alanine (L-BOAA) and 3,4,6-trihydroxyphenlyalanine (6-OH-Dopa) at the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor and that of L-BOAA and domoic acid at the kainate glutamate receptor in human hippocampus. (3 H)AMPA binding in hippocampal subfields was inhibited by L-BOAA and 6-OH-Dopa with mean IC50-values in the low micromolar range. (3H)Kainate binding was inhibited by L-BOAA with similar potency as (3H)AMPA binding and by domoic acid with mean IC50-values in the low nanomolar range. These results support the notion that symptoms like anterograde amnesia and epileptic seizures seen in domoic acid intoxication and limbic symptoms, e.g. cognitive and mood impairment observed in neurolathyrism may be caused by excitotoxic action on non-NMDA receptors. The potent interaction of 6-OH-Dopa with the AMPA-receptor may point to a possible dopaminergic-glutamatergic interaction in the development of neurodegenerative diseases like Parkinson's and Huntington's disease. (author)
Kenny, Paul J; Chartoff, Elena; Roberto, Marisa; Carlezon, William A; Markou, Athina
2009-01-01
Nicotine is considered an important component of tobacco responsible for the smoking habit in humans. Nicotine increases glutamate-mediated transmission throughout brain reward circuitries. This action of nicotine could potentially contribute to its intrinsic rewarding and reward-enhancing properties, which motivate consumption of the drug. Here we show that the competitive N-methyl-D-aspartate (NMDA) receptor antagonist LY235959 (0.5-2.5 mg per kg) abolished nicotine-enhanced brain reward function, reflected in blockade of the lowering of intracranial self-stimulation (ICSS) thresholds usually observed after experimenter-administered (0.25 mg per kg) or intravenously self-administered (0.03 mg per kg per infusion) nicotine injections. The highest LY235959 dose (5 mg per kg) tested reversed the hedonic valence of nicotine from positive to negative, reflected in nicotine-induced elevations of ICSS thresholds. LY235959 doses that reversed nicotine-induced lowering of ICSS thresholds also markedly decreased nicotine self-administration without altering responding for food reinforcement, whereas the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist NBQX had no effects on nicotine intake. In addition, nicotine self-administration upregulated NMDA receptor subunit expression in the central nucleus of the amygdala (CeA) and ventral tegmental area (VTA), suggesting important interactions between nicotine and the NMDA receptor. Furthermore, nicotine (1 microM) increased NMDA receptor-mediated excitatory postsynaptic currents in rat CeA slices, similar to its previously described effects in the VTA. Finally, infusion of LY235959 (0.1-10 ng per side) into the CeA or VTA decreased nicotine self-administration. Taken together, these data suggest that NMDA receptors, including those in the CeA and VTA, gate the magnitude and valence of the effects of nicotine on brain reward systems, thereby regulating motivation to consume the drug.
Dietmann, Anelia; Wallner, Bernd; König, Rebekka; Friedrich, Katrin; Pfausler, Bettina; Deisenhammer, Florian; Griesmacher, Andrea; Seger, Christoph; Matuja, William; JilekAall, Louise; Winkler, Andrea S; Schmutzhard, Erich
2014-06-01
Nodding syndrome (NS) is a seemingly progressive epilepsy disorder of unknown underlying cause. We investigated association of pyridoxal-phosphate serum levels and occurrence of anti-neuronal antibodies against N-methyl-D-aspartate (NMDA) receptor and voltage gated potassium channel (VGKC) complex in NS patients. Sera of a Tanzanian cohort of epilepsy and NS patients and community controls were tested for the presence of anti-NMDA-receptor and anti-VGKC complex antibodies by indirect immunofluorescence assay. Furthermore pyridoxal-phosphate levels were measured. Auto-antibodies against NMDA receptor or VGKC (LG1 or Caspr2) complex were not detected in sera of patients suffering from NS (n=6), NS plus other seizure types (n=16), primary generalized epilepsy (n=1) and community controls without epilepsy (n=7). Median Pyridoxal-phosphate levels in patients with NS compared to patients with primary generalized seizures and community controls were not significantly different. However, these median pyridoxal-phosphate levels are significantly lower compared to the range considered normal in Europeans. In this pilot study NS was not associated with serum anti-NMDA receptor or anti-VGKC complex antibodies and no association to pyridoxal-phosphate serum levels was found.
International Nuclear Information System (INIS)
Labas, R.
2007-01-01
The aim of this thesis was to develop new radioactive tracers for imaging NR2B subtype NMDA receptors with positron emission tomography. Several compounds including 4-(4-fluoro-benzyl)piperidine and presenting interesting in vivo biological properties were the object of a labelling with a positrons emitter atom ( 11 C or 18 F)
Hegoburu, Chloé; Parrot, Sandrine; Ferreira, Guilaume; Mouly, Anne-Marie
2014-01-01
Although the basolateral amygdala (BLA) plays a crucial role for the acquisition of fear memories, sensory cortices are involved in their long-term storage in rats. However, the time course of their respective involvement has received little investigation. Here we assessed the role of the glutamatergic N-methyl-D-aspartate (NMDA) receptors in the…
Investigations into the involvement of NMDA mechanisms in recognition memory.
Warburton, E Clea; Barker, Gareth R I; Brown, Malcom W
2013-11-01
This review will focus on evidence showing that NMDA receptor neurotransmission is critical for synaptic plasticity processes within brain regions known to be necessary for the formation of object recognition memories. The aim will be to provide evidence concerning NMDA mechanisms related to recognition memory processes and show that recognition memory for objects, places or associations between objects and places depends on NMDA neurotransmission within the perirhinal cortex, temporal association cortex medial prefrontal cortex and hippocampus. Administration of the NMDA antagonist AP5, selectively into each of these brain regions has revealed that the extent of the involvement NMDA receptors appears dependent on the type of information required to solve the recognition memory task; thus NMDA receptors in the perirhinal cortex are crucial for the encoding of long-term recognition memory for objects, and object-in-place associations, but not for short-term recognition memory or for retrieval. In contrast the hippocampus and medial prefrontal cortex are required for both long-term and short-term recognition memory for places or associations between objects and places, or for recognition memory tasks that have a temporal component. Such studies have therefore confirmed that the multiple brain regions make distinct contributions to recognition memory but in addition that more than one synaptic plasticity process must be involved. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.
DEFF Research Database (Denmark)
Pless, Stephan Alexander; Dibas, Mohammed I; Lester, Henry A
2007-01-01
change. Although taurine and beta-alanine were weak partial agonists at the alpha1R19'C glycine receptor, they induced large fluorescence changes. Propofol, which drastically enhanced these currents, did not induce a glycine-like blue shift in the spectral emission peak. The inhibitors strychnine...... and picrotoxin elicited fluorescence and current changes as expected for a competitive antagonist and an open channel blocker, respectively. Glycine and taurine (or beta-alanine) also produced an increase and a decrease, respectively, in the fluorescence of a label attached to the nearby L22'C residue. Thus...
McKay, Sean; Bengtson, C. Peter; Bading, Hilmar; Wyllie, David J.A.; Hardingham, Giles E.
2013-01-01
MK-801 is a use-dependent NMDA receptor open channel blocker with a very slow off-rate. These properties can be exploited to ‘pre-block’ a population of NMDARs, such as synaptic ones, enabling the selective activation of a different population, such as extrasynaptic NMDARs. However, the usefulness of this approach is dependent on the stability of MK-801 blockade after washout. We have revisited this issue, and confirm that recovery of NMDAR currents from MK-801 blockade is enhanced by channel opening by NMDA, and find that it is further increased when Mg2+ is also present. In the presence of Mg2+, 50% recovery from MK-801 blockade is achieved after 10′ of 100 μM NMDA, or 30′ of 15 μM NMDA exposure. In Mg2+-free medium, NMDA-induced MK-801 dissociation was found to be much slower. Memantine, another PCP-site antagonist, could substitute for Mg2+ in accelerating the unblock of MK-801 in the presence of NMDA. This suggests a model whereby, upon dissociation from its binding site in the pore, MK-801 is able to re-bind in a process antagonized by Mg2+ or another PCP-site antagonist. Finally we show that even when all NMDARs are pre-blocked by MK-801, incubation of neurons with 100 μM NMDA in the presence of Mg2+ for 2.5 h triggers sufficient unblocking to kill >80% of neurons. We conclude that while synaptic MK-801 ‘pre-block’ protocols are useful for pharmacologically assessing synaptic vs. extrasynaptic contributions to NMDAR currents, or studying short-term effects, it is problematic to use this technique to attempt to study the effects of long-term selective extrasynaptic NMDAR activation. This article is part of the Special Issue entitled ‘Glutamate Receptor-Dependent Synaptic Plasticity’. PMID:23402996
Age-Related Differences in NMDA Receptor Subunits of Prenatally Methamphetamine-Exposed Male Rats
Czech Academy of Sciences Publication Activity Database
Vrajová, M.; Schutová, B.; Klaschka, Jan; Štěpánková, H.; Řípová, D.; Šlamberová, R.
2014-01-01
Roč. 39, č. 11 (2014), s. 2040-2046 ISSN 0364-3190 Grant - others:GA ČR(CZ) GAP303/10/0580; Ministerstvo školství(CZ) CSM 7/CRP/2014; Univerzita Karlova(CZ) Prvouk P34; Univerzita Karlova(CZ) 260045/SVV/2014; Prague Psychiatric Center(CZ) MH CZ–DRO: 00023752 Institutional support: RVO:67985807 Keywords : methamphetamine * in-utero * NMDA receptor subunits * hippocampus Subject RIV: FH - Neurology Impact factor: 2.593, year: 2014
Sheardown, M J
1988-04-13
L(+)-AP4 (2-amino-4-phosphonobutyrate) depolarized slices of rat cerebral cortex, when applied following a 2 min priming application of quisqualate. This response diminishes with time and is not seen after NMDA application. A new selective non-N-methyl-D-aspartate (NMDA) antagonist, 6-cyano-7-nitro-2,3-dihydroxyquinoxaline (FG 9065), inhibits the L(+)-AP4 depolarization. It is argued that the response is mediated indirectly by postsynaptic quisqualate receptors.
Morris, R G M; Steele, R J; Bell, J E; Martin, S J
2013-03-01
Three experiments were conducted to contrast the hypothesis that hippocampal N-methyl-d-aspartate (NMDA) receptors participate directly in the mechanisms of hippocampus-dependent learning with an alternative view that apparent impairments of learning induced by NMDA receptor antagonists arise because of drug-induced neuropathological and/or sensorimotor disturbances. In experiment 1, rats given a chronic i.c.v. infusion of d-AP5 (30 mm) at 0.5 μL/h were selectively impaired, relative to aCSF-infused animals, in place but not cued navigation learning when they were trained during the 14-day drug infusion period, but were unimpaired on both tasks if trained 11 days after the minipumps were exhausted. d-AP5 caused sensorimotor disturbances in the spatial task, but these gradually worsened as the animals failed to learn. Histological assessment of potential neuropathological changes revealed no abnormalities in d-AP5-treated rats whether killed during or after chronic drug infusion. In experiment 2, a deficit in spatial learning was also apparent in d-AP5-treated rats trained on a spatial reference memory task involving two identical but visible platforms, a task chosen and shown to minimise sensorimotor disturbances. HPLC was used to identify the presence of d-AP5 in selected brain areas. In Experiment 3, rats treated with d-AP5 showed a delay-dependent deficit in spatial memory in the delayed matching-to-place protocol for the water maze. These data are discussed with respect to the learning mechanism and sensorimotor accounts of the impact of NMDA receptor antagonists on brain function. We argue that NMDA receptor mechanisms participate directly in spatial learning. © 2013 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.
Computational study of NMDA conductance and cortical oscillations in schizophrenia
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Kubra eKomek Kirli
2014-10-01
Full Text Available N-methyl-D-aspartate (NMDA receptor hypofunction has been implicated in the pathophysiology of schizophrenia. The illness is also characterized by gamma oscillatory disturbances, which can be evaluated with precise frequency specificity employing auditory cortical entrainment paradigms. This computational study investigates how synaptic NMDA hypofunction may give rise to network level oscillatory deficits as indexed by entrainment paradigms. We developed a computational model of a local cortical circuit with pyramidal cells and fast-spiking interneurons (FSI, incorporating NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA, and γ-aminobutyric acid (GABA synaptic kinetics. We evaluated the effects of varying NMDA conductance on FSIs and pyramidal cells, as well as AMPA to NMDA ratio. We also examined the differential effects across a broad range of entrainment frequencies as a function of NMDA conductance. Varying NMDA conductance onto FSIs revealed an inverted-U relation with network gamma whereas NMDA conductance onto the pyramidal cells had a more monotonic relationship. Varying NMDA vs. AMPA conductance onto FSIs demonstrated the necessity of AMPA in the generation of gamma while NMDA receptors had a modulatory role. Finally, reducing NMDA conductance onto FSI and varying the stimulus input frequency reproduced the specific reductions in gamma range (~40 Hz as observed in schizophrenia studies. Our computational study showed that reductions in NMDA conductance onto FSIs can reproduce similar disturbances in entrainment to periodic stimuli within the gamma range as reported in schizophrenia studies. These findings provide a mechanistic account of how specific cellular level disturbances can give rise to circuitry level pathophysiologic disturbance in schizophrenia.
Sadat-Shirazi, Mitra-Sadat; Vousooghi, Nasim; Alizadeh, Bentolhoda; Makki, Seyed Mohammad; Zarei, Seyed Zeinolabedin; Nazari, Shahrzad; Zarrindast, Mohammad Reza
2018-05-23
Background and aims Repeated performance of some behaviors such as playing computer games could result in addiction. The NMDA receptor is critically involved in the development of behavioral and drug addictions. It has been claimed that the expression level of neurotransmitter receptors in the brain may be reflected in peripheral blood lymphocytes (PBLs). Methods Here, using a real-time PCR method, we have investigated the mRNA expression of GluN2A, GluN2D, GluN3A, and GluN3B subunits of the NMDA receptor in PBLs of male online computer game addicts (n = 25) in comparison with normal subjects (n = 26). Results Expression levels of GluN2A, GluN2D, and GluN3B subunits were not statistically different between game addicts and the control group. However, the mRNA expression of the GluN3A subunit was downregulated in PBLs of game addicts. Discussion and conclusions Transcriptional levels of GluN2A and GluN2D subunits in online computer game addicts are similar to our previously reported data of opioid addiction and are not different from the control group. However, unlike our earlier finding of drug addiction, the mRNA expression levels of GluN3A and GluN3B subunits in PBLs of game addicts are reduced and unchanged, respectively, compared with control subjects. It seems that the downregulated state of the GluN3A subunit of NMDA receptor in online computer game addicts is a finding that deserves more studies in the future to see whether it can serve as a peripheral biomarker in addiction studies, where the researcher wants to rule out the confusing effects of abused drugs.
Facilitation of neocortical presynaptic terminal development by NMDA receptor activation
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Sceniak Michael P
2012-02-01
Full Text Available Abstract Background Neocortical circuits are established through the formation of synapses between cortical neurons, but the molecular mechanisms of synapse formation are only beginning to be understood. The mechanisms that control synaptic vesicle (SV and active zone (AZ protein assembly at developing presynaptic terminals have not yet been defined. Similarly, the role of glutamate receptor activation in control of presynaptic development remains unclear. Results Here, we use confocal imaging to demonstrate that NMDA receptor (NMDAR activation regulates accumulation of multiple SV and AZ proteins at nascent presynaptic terminals of visual cortical neurons. NMDAR-dependent regulation of presynaptic assembly occurs even at synapses that lack postsynaptic NMDARs. We also provide evidence that this control of presynaptic terminal development is independent of glia. Conclusions Based on these data, we propose a novel NMDAR-dependent mechanism for control of presynaptic terminal development in excitatory neocortical neurons. Control of presynaptic development by NMDARs could ultimately contribute to activity-dependent development of cortical receptive fields.
Yan, Binbin; Li, Lihua; Harden, Scott W; Gozal, David; Lin, Ying; Wead, William B; Wurster, Robert D; Cheng, Zixi Jack
2009-02-01
Chronic intermittent hypoxia (CIH), as occurs in sleep apnea, impairs baroreflex-mediated reductions in heart rate (HR) and enhances HR responses to electrical stimulation of vagal efferent. We tested the hypotheses that HR responses to activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the nucleus ambiguous (NA) are reduced in CIH-exposed rats and that this impairment is associated with degeneration of glutamate receptor (GluR)-immunoreactive NA neurons. Fischer 344 rats (3-4 mo) were exposed to room air (RA) or CIH for 35-50 days (n = 18/group). At the end of the exposures, AMPA (4 pmol, 20 nl) and NMDA (80 pmol, 20 nl) were microinjected into the same location of the left NA (-200 microm to +200 microm relative to caudal end of area postrema; n = 6/group), and HR and arterial blood pressure responses were measured. In addition, brain stem sections at the level of -800, -400, 0, +400, and +800 microm relative to obex were processed for AMPA and NMDA receptor immunohistochemistry. The number of NA neurons expressing AMPA receptors and NMDA receptors (NMDARs) was quantified. Compared with RA, we found that after CIH 1) HR responses to microinjection of AMPA into the left NA were reduced (RA -290 +/- 30 vs. CIH -227 +/- 15 beats/min, P neurons expressing GluRs contributes to impaired baroreflex control of HR in rats exposed to CIH.
DEFF Research Database (Denmark)
Korshunova, Irina; Gjørlund, Michelle D; Jacobsen, Sylwia Owczarek
2015-01-01
neurolide-1 effects on short- and long-term social and spatial memory in social recognition, Morris water-maze, and Y-maze tests. We found that subcutaneous neurolide-1 administration, restored hippocampal LTP compromised by NMDA receptor inhibitor MK-801. It counteracted MK-801-induced memory deficit...... in the water-maze and Y-maze tests after long-term treatment (24 h and 1-2 h before the test), but not after short-term exposure (1-2 h). Long-term exposure to neurolide-1 also facilitated social recognition memory. In addition, neurolide-1-induced phosphorylation of the NMDA receptor NR1 subunit on a site...... receptor phosphorylation after treatment with NL1 or a mimetic peptide, neurolide-1, was quantified by immunoblotting. Subsequently, we investigated effects of neurolide-1 on long-term potentiation (LTP) induction in hippocampal slices compromised by NMDA receptor inhibitor MK-801. Finally, we investigated...
Ghaderi, Marzieh; Rezayof, Ameneh; Vousooghi, Nasim; Zarrindast, Mohammad-Reza
2016-04-03
A combination of cannabis and ecstasy may change the cognitive functions more than either drug alone. The present study was designed to investigate the possible involvement of dorsal hippocampal NMDA receptors in the interactive effects of arachidonylcyclopropylamide (ACPA) and ecstasy/MDMA on memory retrieval. Adult male Wistar rats were cannulated into the CA1 regions of the dorsal hippocampus (intra-CA1) and memory retrieval was examined using the step-through type of passive avoidance task. Intra-CA1 microinjection of a selective CB1 receptor agonist, ACPA (0.5-4ng/rat) immediately before the testing phase (pre-test), but not after the training phase (post-training), impaired memory retrieval. In addition, pre-test intra-CA1 microinjection of MDMA (0.5-1μg/rat) dose-dependently decreased step-through latency, indicating an amnesic effect of the drug by itself. Interestingly, pre-test microinjection of a higher dose of MDMA into the CA1 regions significantly improved ACPA-induced memory impairment. Moreover, pre-test intra-CA1 microinjection of a selective NMDA receptor antagonist, D-AP5 (1 and 2μg/rat) inhibited the reversal effect of MDMA on the impairment of memory retrieval induced by ACPA. Pre-test intra-CA1 microinjection of the same doses of D-AP5 had no effect on memory retrieval alone. These findings suggest that ACPA or MDMA consumption can induce memory retrieval impairment, while their co-administration improves this amnesic effect through interacting with hippocampal glutamatergic-NMDA receptor mechanism. Thus, it seems that the tendency to abuse cannabis with ecstasy may be for avoiding cognitive dysfunction. Copyright © 2015. Published by Elsevier Inc.
Novel dimeric bis(7)-tacrine proton-dependently inhibits NMDA-activated currents
International Nuclear Information System (INIS)
Luo, Jialie; Li, Wenming; Liu, Yuwei; Zhang, Wei; Fu, Hongjun; Lee, Nelson T.K.; Yu, Hua; Pang, Yuanping; Huang, Pingbo; Xia, Jun; Li, Zhi-Wang; Li, Chaoying; Han, Yifan
2007-01-01
Bis(7)-tacrine has been shown to prevent glutamate-induced neuronal apoptosis by blocking NMDA receptors. However, the characteristics of the inhibition have not been fully elucidated. In this study, we further characterize the features of bis(7)-tacrine inhibition of NMDA-activated current in cultured rat hippocampal neurons. The results show that with the increase of extracellular pH, the inhibitory effect decreases dramatically. At pH 8.0, the concentration-response curve of bis(7)-tacrine is shifted rightwards with the IC 50 value increased from 0.19 ± 0.03 μM to 0.41 ± 0.04 μM. In addition, bis(7)-tacrine shifts the proton inhibition curve rightwards. Furthermore, the inhibitory effect of bis(7)-tacrine is not altered by the presence of the NMDA receptor proton sensor shield spermidine. These results indicate that bis(7)-tacrine inhibits NMDA-activated current in a pH-dependent manner by sensitizing NMDA receptors to proton inhibition, rendering it potentially beneficial therapeutic effects under acidic conditions associated with stroke and ischemia
deBacker, Julian; Hawken, Emily R; Normandeau, Catherine P; Jones, Andrea A; Di Prospero, Cynthia; Mechefske, Elysia; Gardner Gregory, James; Hayton, Scott J; Dumont, Éric C
2015-01-01
Drugs of abuse have detrimental effects on homeostatic synaptic plasticity in the motivational brain network. Bidirectional plasticity at excitatory synapses helps keep neural circuits within a functional range to allow for behavioral flexibility. Therefore, impaired bidirectional plasticity of excitatory synapses may contribute to the behavioral hallmarks of addiction, yet this relationship remains unclear. Here we tracked excitatory synaptic strength in the oval bed nucleus of the stria terminalis (ovBNST) using whole-cell voltage-clamp recordings in brain slices from rats self-administering sucrose or cocaine. In the cocaine group, we measured both a persistent increase in AMPA to NMDA ratio (A:N) and slow decay time of NMDA currents throughout the self-administration period and after withdrawal from cocaine. In contrast, the sucrose group exhibited an early increase in A:N ratios (acquisition) that returned toward baseline values with continued self-administration (maintenance) and after withdrawal. The sucrose rats also displayed a decrease in NMDA current decay time with continued self-administration (maintenance), which normalized after withdrawal. Cocaine self-administering rats exhibited impairment in NMDA-dependent long-term depression (LTD) that could be rescued by GluN2B-containing NMDA receptor blockade. Sucrose self-administering rats demonstrated no impairment in NMDA-dependent LTD. During the maintenance period of self-administration, in vivo (daily intraperitoneally for 5 days) pharmacologic blockade of GluN2B-containing NMDA receptors did not reduce lever pressing for cocaine. However, in vivo GluN2B blockade did normalize A:N ratios in cocaine self-administrating rats, and dissociated the magnitude of ovBNST A:N ratios from drug-seeking behavior after protracted withdrawal. Altogether, our data demonstrate when and how bidirectional plasticity at ovBNST excitatory synapses becomes dysfunctional with cocaine self-administration and that NMDA
International Nuclear Information System (INIS)
Ragnarsson, L.; Dodd, P.R.; Lewis, R.; University of Queensland, QLD
1998-01-01
Full text: The pharmacological characteristics of human N-methyl-D-aspartate (NMDA) receptors were examined in 12 control and 6 pathologically confirmed Alzheimer disease (AD) cases in six different brain areas, by studying their responses to MK-801, glutamate, spermine, and the NMDA receptor antagonists Ala(7)-conantokinG and Lys(7)-conantokinG. [ 3 H]MK801 binding assays performed by standard protocols on well-washed synoptic plasma membranes showed little variation in k D in all six brain areas, including comparisons between control and matched AD cases. b MAX values showed regional differences within control and AD cases, but there was no significant difference between groups in any of the brain regions. Maximal glutamate-enhanced [ 3 H]MK801 binding did not vary much between the brain regions or between control and AD cases, whereas maximal spermine-enhanced [ 3 H]MK-801 binding differed significantly between certain brain regions and between control and AD cases. In absolute terms in the control cases, the activation values were much lower in the spared regions, occipital and motor cortex, than in other areas; further, areas which are susceptible to damage showed reduced spermine activation in AD cases. These regional differences in the efficacy of spermine activation might be the result of local variations in the subunit composition of the NMDA receptor. Ala(7)-conantokinG and Lys(7)-conantokinG showed slight differences in potency, with the Ala(7) compound as the more potent. Both peptides produced 100% inhibition of spermine-enhanced [ 3 H]MK-801 binding in all brain areas, ana both gave lower IC 50 values in AD cases than in control cases. The significant differences in the inhibition of spermine-enhanced [ 3 H]MK-801 binding by the peptides between control and AD cases suggest that AD cases have a particular receptor subunit composition that is responsive to polyamines and which might make them more susceptible to excitotoxic damage. The spermine site
DEFF Research Database (Denmark)
Pless, Stephan Alexander; Lynch, Joseph W
2009-01-01
associated with the closed-flip transition in the alpha1-glycine receptor. We employed voltage-clamp fluorometry to compare ligand-binding domain conformational changes induced by the following agonists, listed from highest to lowest affinity and efficacy: glycine > beta-alanine > taurine. Voltage...
White, Theresa L; Youngentob, Steven L
2004-09-17
The N-methyl-D-aspartate (NMDA) receptor in the forebrain is thought to modulate some forms of memory formation, with the NR2B subunit being particularly relevant to this process. Relative to wild-type mice, transgenic animals in which the NR2B subunit was over-expressed demonstrate superior memory in a number of behavioral tasks, including object recognition [Nature 401 (1999) 63]. The purpose of the present study was to explore the generality of such phenomena, interpreted as the effect of increasing NR2B expression on the retention of other types of sensory-related information. To accomplish this, we focused our evaluation on the highly salient sensory modality of olfaction. In the first experiment, mice performed both a novel-object-recognition task identical to that performed by Tang et al. [Nature 401 (1999) 63] and a novel-odor-recognition task analogously constructed. Although the results of the object recognition task were consistent with the previous literature, there was no evidence of an effect of NR2B over-expression on the retention of odor recognition memory in the specific task performed. As it was possible that, unlike object recognition memory, novel odor recognition is not NMDA-receptor-dependent, a second task was designed using the social transmission of food preference paradigm. In contrast to the foregoing olfactory task, there is evidence that the latter procedure is, indeed, NMDA-dependent. The results of the second study demonstrated that transgenic mice with NR2B over-expression had a clear memory advantage in this alternative odor memory paradigm. Taken together, these results suggest the NR2B subunit is an important component in some but not all forms of olfactory memory organization. Moreover, for those functions that are NMDA-receptor-dependent, these data support the growing literature demonstrating the importance of the NR2B subunit.
Ridge, Justin P; Dodd, Peter R
2009-10-01
Real-time RT-PCR normalized to GAPDH was used to assay N-methyl-D-aspartate (NMDA) receptor NR1, NR2A and NR2B subunit mRNA in human autopsy cortex tissue from chronic alcoholics with and without comorbid cirrhosis of the liver and matched controls. Subunit expression was influenced by the subject's genotype. The TaqIA polymorphism selectively modulated NMDA receptor mean transcript expression in cirrhotic-alcoholic superior frontal cortex, in diametrically opposite ways in male and female subjects. Genetic make-up may differentially influence vulnerability to brain damage by altering the excitation: inhibition balance, particularly in alcoholics with comorbid cirrhosis of the liver. The TaqIA polymorphism occurs within the poorly characterised ankyrin-repeat containing kinase 1 (ANKK1) gene. Using PCR, ANKK1 mRNA transcript was detected in inferior temporal, occipital, superior frontal and primary motor cortex of control human brain. ANKK1 expression may mediate the influence of the TaqIA polymorphism on phenotype.
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Hussain zeinali
2015-04-01
Full Text Available Background: Induced neuropathic pain following nerve injury has behavioral signs such as allodynia and hyperalgesia. There are reports about the age dependent differences in severity and incidence and even therapeutic response of this pain. In this study, we have tried to evaluate behavioral differences of this pain in an induced neuropathic model in different ages, according to important role of N-methyl, D-aspartate (NMDA receptor and spinal microglia on induction and maintenance of pain. Material and methods: Male rats were grouped in young (5-6 week and mature (10-11 week. Under general anesthesia, the spinal nerve ligation (SNL surgery was operated on right leg. The effect of different doses of dextromethorphan (NMDA blocker and minocycline (microglia inhibitor on 5th day after surgery was evaluated and compared in two age-groups. Results: In this study, both Minocycline and dextromethorphan diminished neuropathic pain in a dose dependent manner in these two ages. Minocycline in contrast to dextromethorphan was more effective in young rats. The co-administration of ineffective doses of minocycline and dextromethorphan could be effective. Conclusion: Microglia and NMDA receptor function in neuropathic pain is different in different ages and the role of microglia is more evident. On the other hand the inhibition of both microglia and NMDA receptor can be considered for lowering neuropathic pain.
Czech Academy of Sciences Publication Activity Database
Vyklický, Vojtěch; Smejkalová, Tereza; Krausová, Barbora; Balík, Aleš; Kořínek, Miloslav; Borovská, Jiřina; Horák, Martin; Chvojková, Markéta; Kletečková, Lenka; Valeš, Karel; Černý, Jiří; Nekardová, Michaela; Chodounská, Hana; Kudová, Eva; Vyklický ml., Ladislav
2016-01-01
Roč. 36, č. 7 (2016), s. 2161-2175 ISSN 0270-6474 R&D Projects: GA ČR(CZ) GAP303/12/1464; GA ČR(CZ) GBP304/12/G069; GA TA ČR(CZ) TE01020028; GA ČR(CZ) GBP208/12/G016; GA MŠk(CZ) EE2.3.30.0025; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:67985823 ; RVO:61388963 Keywords : memantine * neuroprotection * neurosteroid * NMDA receptor * pregnanolone sulfate * synaptic transmission Subject RIV: ED - Physiology Impact factor: 5.988, year: 2016
Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors
Energy Technology Data Exchange (ETDEWEB)
Yao, Yongneng; Harrison, Chris B.; Freddolino, Peter L.; Schulten, Klaus; Mayer, Mark L. (UIUC); (NIH)
2008-10-27
NR3 subtype glutamate receptors have a unique developmental expression profile, but are the least well-characterized members of the NMDA receptor gene family, which have key roles in synaptic plasticity and brain development. Using ligand binding assays, crystallographic analysis, and all atom MD simulations, we investigate mechanisms underlying the binding by NR3A and NR3B of glycine and D-serine, which are candidate neurotransmitters for NMDA receptors containing NR3 subunits. The ligand binding domains of both NR3 subunits adopt a similar extent of domain closure as found in the corresponding NR1 complexes, but have a unique loop 1 structure distinct from that in all other glutamate receptor ion channels. Within their ligand binding pockets, NR3A and NR3B have strikingly different hydrogen bonding networks and solvent structures from those found in NR1, and fail to undergo a conformational rearrangement observed in NR1 upon binding the partial agonist ACPC. MD simulations revealed numerous interdomain contacts, which stabilize the agonist-bound closed-cleft conformation, and a novel twisting motion for the loop 1 helix that is unique in NR3 subunits.
Carvalho, Fabiano B; Mello, Carlos F; Marisco, Patricia C; Tonello, Raquel; Girardi, Bruna A; Ferreira, Juliano; Oliveira, Mauro S; Rubin, Maribel A
2012-06-05
Spermidine is an endogenous polyamine with a polycationic structure present in the central nervous system of mammals. Spermidine regulates biological processes, such as Ca(2+) influx by glutamatergic N-methyl-d-aspartate receptor (NMDA receptor), which has been associated with nitric oxide synthase (NOS) and cGMP/PKG pathway activation and a decrease of Na(+),K(+)-ATPase activity in rats' cerebral cortex synaptosomes. Na(+),K(+)-ATPase establishes Na(+) and K(+) gradients across membranes of excitable cells and by this means maintains membrane potential and controls intracellular pH and volume. However, it has not been defined whether spermidine modulates Na(+),K(+)-ATPase activity in the hippocampus. In this study we investigated whether spermidine alters Na(+),K(+)-ATPase activity in slices of hippocampus from rats, and possible underlying mechanisms. Hippocampal slices and homogenates were incubated with spermidine (0.05-10 μM) for 30 min. Spermidine (0.5 and 1 μM) decreased Na(+),K(+)-ATPase activity in slices, but not in homogenates. MK-801 (100 and 10 μM), a non-competitive antagonist of NMDA receptor, arcaine (0.5μM), an antagonist of the polyamine binding site at the NMDA receptor, and L-NAME (100μM), a NOS inhibitor, prevented the inhibitory effect of spermidine (0.5 μM). ODQ (10 μM), a guanylate cyclase inhibitor, and KT5823 (2 μM), a protein kinase G inhibitor, also prevented the inhibitory effect of spermidine on Na(+),K(+)-ATPase activity. Spermidine (0.5 and 1.0 μM) increased NO(2) plus NO(3) (NOx) levels in slices, and MK-801 (100 μM) and arcaine (0.5 μM) prevented the effect of spermidine (0.5 μM) on the NOx content. These results suggest that spermidine-induced decrease of Na(+),K(+)-ATPase activity involves NMDA receptor/NOS/cGMP/PKG pathway. Copyright © 2012 Elsevier B.V. All rights reserved.
Ferrari, Luiz Fernando; Lotufo, Celina Monteiro; Araldi, Dionéia; Rodrigues, Marcos A; Macedo, Larissa P; Ferreira, Sérgio H; Parada, Carlos Amilcar
2014-12-23
The present study evaluated the role of N-methyl-D-aspartate receptors (NMDARs) expressed in the dorsal root ganglia (DRG) in the inflammatory sensitization of peripheral nociceptor terminals to mechanical stimulation. Injection of NMDA into the fifth lumbar (L5)-DRG induced hyperalgesia in the rat hind paw with a profile similar to that of intraplantar injection of prostaglandin E2 (PGE2), which was significantly attenuated by injection of the NMDAR antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP-5) in the L5-DRG. Moreover, blockade of DRG AMPA receptors by the antagonist 6,7-dinitroquinoxaline-2,3-dione had no effect in the PGE2-induced hyperalgesia in the paw, showing specific involvement of NMDARs in this modulatory effect and suggesting that activation of NMDAR in the DRG plays an important role in the peripheral inflammatory hyperalgesia. In following experiments we observed attenuation of PGE2-induced hyperalgesia in the paw by the knockdown of NMDAR subunits NR1, NR2B, NR2D, and NR3A with antisense-oligodeoxynucleotide treatment in the DRG. Also, in vitro experiments showed that the NMDA-induced sensitization of cultured DRG neurons depends on satellite cell activation and on those same NMDAR subunits, suggesting their importance for the PGE2-induced hyperalgesia. In addition, fluorescent calcium imaging experiments in cultures of DRG cells showed induction of calcium transients by glutamate or NMDA only in satellite cells, but not in neurons. Together, the present results suggest that the mechanical inflammatory nociceptor sensitization is dependent on glutamate release at the DRG and subsequent NMDAR activation in satellite glial cells, supporting the idea that the peripheral hyperalgesia is an event modulated by a glutamatergic system in the DRG.
Glycine transporter 1 is a target for the treatment of epilepsy
Shen, Hai-Ying; van Vliet, Erwin A.; Bright, Kerry-Ann; Hanthorn, Marissa; Lytle, Nikki K.; Gorter, Jan; Aronica, Eleonora; Boison, Detlev
2015-01-01
Glycine is the major inhibitory neurotransmitter in brainstem and spinal cord, whereas in hippocampus glycine exerts dual modulatory roles on strychnine-sensitive glycine receptors and on the strychnine-insensitive glycineB site of the N-methyl-D-aspartate receptor (NMDAR). In hippocampus, the
Glycine transporter 1 is a target for the treatment of epilepsy
Shen, H-Y; van Vliet, E.A.; Bright, K-A.; Hanthorn, M.; Lytle, N.K.; Gorter, J.; Aronica, E.; Boison, D.
2015-01-01
Glycine is the major inhibitory neurotransmitter in brainstem and spinal cord, whereas in hippocampus glycine exerts dual modulatory roles on strychnine-sensitive glycine receptors and on the strychnine-insensitive glycineB site of the N-methyl-d-aspartate receptor (NMDAR). In hippocampus, the
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Kai Yang
2014-02-01
Full Text Available G Protein Coupled Receptors (GPCRs are the largest family of receptors whose ligands constitute nearly a third of prescription drugs in the market. They are widely involved in diverse physiological functions including learning and memory. NMDA receptors (NMDARs, which belong to the ionotropic glutamate receptor family, are likewise ubiquitously expressed in the central nervous system (CNS and play a pivotal role in learning and memory. Despite its critical contribution to physiological and pathophysiological processes, few pharmacological interventions aimed directly at regulating NMDAR function have been developed to date. However, it is well established that NMDAR function is precisely regulated by cellular signalling cascades recruited downstream of G protein coupled receptor (GPCR stimulation. Accordingly, the downstream regulation of NMDARs likely represents an important determinant of outcome following treatment with neuropsychiatric agents that target selected GPCRs. Importantly, the functional consequence of such regulation on NMDAR function varies, based not only on the identity of the GPCR, but also on the cell type in which relevant receptors are expressed. Indeed, the mechanisms responsible for regulating NMDARs by GPCRs involve numerous intracellular signalling molecules and regulatory proteins that vary from one cell type to another. In the present article, we highlight recent findings from studies that have uncovered novel mechanisms by which selected GPCRs regulate NMDAR function and consequently NMDAR-dependent plasticity.
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Bartlett, S.E.; Smith, M.T. (Department of Pharmacy, The University of Queensland (Australia)); Dood, P.R. (Clinical Research Centre, Royal Brisbane Hospital Foundation, Brisbane (Australia))
1994-07-01
Morphine in high doses and its major metabolite, morphine-3-glucuronide, cause CNS excitation following intrathecal and intracerebroventricular administration by an unknown mechanism. This study investigated whether morphine and morphine-3-glucuronide interact at major excitatory (glutamate), major inhibitory (GABA or glycine), or opioid binding sites. Homogenate binding assays were performed using specific radioligands. At opioid receptors, morphine-3-glucuronide and morphine caused an equipotent sodium shift, consistent with morphine-3-glucuronide behaving as an agonist. This suggests that morphine-3-glucuronide-mediated excitation is not caused by an interaction at opioid receptors. Morphine-3-glucuronide and morphine caused a weak inhibition of the binding of [sup 3]H-MK801 (non-competitive antagonist) and [sup 125]I-ifenprodil (polyamine site antagonist), but at unphysiologically high concentrations. This suggests that CNS excitation would not result from an interaction of morphine-3-glucuronide and high-dose morphine with these sites on the NMDA receptor. Morphine-3-glucuronide and morphine inhibited the binding of [sup 3]H-muscimol (GABA receptor agonist), [sup 3]H-diazepam and [sup 3]H-flunitraxepam (benzodiazepine agonists) binding very weakly, suggesting the excitatory effects of morphine-3-glucuronide and high-dose morphine are not elicited through GABA[sub A] receptors. Morphine-3-glucuronide and high-dose morphine did not prevent re-uptake of glutamate into presynaptic nerve terminals. In addition, morphine-3-glucuronide and morphine did not inhibit the binding of [sup 3]H-strychnine (glycine receptor antagonist) to synaptic membranes prepared from bovine spinal cord. It is concluded that excitation caused by high-dose morphine and morphine-3-glucuronide is not mediated by an interaction with postsynaptic amino acid receptors. (au) (30 refs.).
Gupta-Agarwal, Swati; Jarome, Timothy J.; Fernandez, Jordan; Lubin, Farah D.
2014-01-01
It is well established that fear memory formation requires de novo gene transcription in the amygdala. We provide evidence that epigenetic mechanisms in the form of histone lysine methylation in the lateral amygdala (LA) are regulated by NMDA receptor (NMDAR) signaling and involved in gene transcription changes necessary for fear memory…
Tian, Meng; Xu, Jian; Lei, Gang; Lombroso, Paul J.; Jackson, Michael F.; MacDonald, John F.
2016-01-01
N-methyl-D-aspartate receptors (NMDARs) are necessary for the induction of synaptic plasticity and for the consolidation of learning and memory. NMDAR function is tightly regulated by functionally opposed families of kinases and phosphatases. Herein we show that the striatal-enriched protein tyrosine phosphatase (STEP) is recruited by Gαq-coupled receptors, including the M1 muscarinic acetylcholine receptor (M1R), and opposes the Src tyrosine kinase-mediated increase in the function of NMDARs composed of GluN2A. STEP activation by M1R stimulation requires IP3Rs and can depress NMDA-evoked currents with modest intracellular Ca2+ buffering. Src recruitment by M1R stimulation requires coincident NMDAR activation and can augment NMDA-evoked currents with high intracellular Ca2+ buffering. Our findings suggest that Src and STEP recruitment is contingent on differing intracellular Ca2+ dynamics that dictate whether NMDAR function is augmented or depressed following M1R stimulation. PMID:27857196
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Gregory R Rompala
Full Text Available Pharmacological and genetic studies support a role for NMDA receptor (NMDAR hypofunction in the etiology of schizophrenia. We have previously demonstrated that NMDAR obligatory subunit 1 (GluN1 deletion in corticolimbic interneurons during early postnatal development is sufficient to confer schizophrenia-like phenotypes in mice. However, the consequence of NMDAR hypofunction in cortical excitatory neurons is not well delineated. Here, we characterize a conditional knockout mouse strain (CtxGluN1 KO mice, in which postnatal GluN1 deletion is largely confined to the excitatory neurons in layer II/III of the medial prefrontal cortex and sensory cortices, as evidenced by the lack of GluN1 mRNA expression in in situ hybridization immunocytochemistry as well as the lack of NMDA currents with in vitro recordings. Mutants were impaired in prepulse inhibition of the auditory startle reflex as well as object-based short-term memory. However, they did not exhibit impairments in additional hallmarks of schizophrenia-like phenotypes (e.g. spatial working memory, social behavior, saccharine preference, novelty and amphetamine-induced hyperlocomotion, and anxiety-related behavior. Furthermore, upon administration of the NMDA receptor antagonist, MK-801, there were no differences in locomotor activity versus controls. The mutant mice also showed negligible levels of reactive oxygen species production following chronic social isolation, and recording of miniature-EPSC/IPSCs from layer II/III excitatory neurons in medial prefrontal cortex suggested no alteration in GABAergic activity. All together, the mutant mice displayed cognitive deficits in the absence of additional behavioral or cellular phenotypes reflecting schizophrenia pathophysiology. Thus, NMDAR hypofunction in prefrontal and cortical excitatory neurons may recapitulate only a cognitive aspect of human schizophrenia symptoms.
Rompala, Gregory R; Zsiros, Veronika; Zhang, Shuqin; Kolata, Stefan M; Nakazawa, Kazu
2013-01-01
Pharmacological and genetic studies support a role for NMDA receptor (NMDAR) hypofunction in the etiology of schizophrenia. We have previously demonstrated that NMDAR obligatory subunit 1 (GluN1) deletion in corticolimbic interneurons during early postnatal development is sufficient to confer schizophrenia-like phenotypes in mice. However, the consequence of NMDAR hypofunction in cortical excitatory neurons is not well delineated. Here, we characterize a conditional knockout mouse strain (CtxGluN1 KO mice), in which postnatal GluN1 deletion is largely confined to the excitatory neurons in layer II/III of the medial prefrontal cortex and sensory cortices, as evidenced by the lack of GluN1 mRNA expression in in situ hybridization immunocytochemistry as well as the lack of NMDA currents with in vitro recordings. Mutants were impaired in prepulse inhibition of the auditory startle reflex as well as object-based short-term memory. However, they did not exhibit impairments in additional hallmarks of schizophrenia-like phenotypes (e.g. spatial working memory, social behavior, saccharine preference, novelty and amphetamine-induced hyperlocomotion, and anxiety-related behavior). Furthermore, upon administration of the NMDA receptor antagonist, MK-801, there were no differences in locomotor activity versus controls. The mutant mice also showed negligible levels of reactive oxygen species production following chronic social isolation, and recording of miniature-EPSC/IPSCs from layer II/III excitatory neurons in medial prefrontal cortex suggested no alteration in GABAergic activity. All together, the mutant mice displayed cognitive deficits in the absence of additional behavioral or cellular phenotypes reflecting schizophrenia pathophysiology. Thus, NMDAR hypofunction in prefrontal and cortical excitatory neurons may recapitulate only a cognitive aspect of human schizophrenia symptoms.
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Yan He
2011-01-01
Full Text Available Excessive production of Aβ (amyloid β-peptide has been shown to play an important role in the pathogenesis of AD (Alzheimer's disease. Although not yet well understood, aggregation of Aβ is known to cause toxicity to neurons. Our recent study demonstrated the ability for oligomeric Aβ to stimulate the production of ROS (reactive oxygen species in neurons through an NMDA (N-methyl-D-aspartate-dependent pathway. However, whether prolonged exposure of neurons to aggregated Aβ is associated with impairment of NMDA receptor function has not been extensively investigated. In the present study, we show that prolonged exposure of primary cortical neurons to Aβ oligomers caused mitochondrial dysfunction, an attenuation of NMDA receptor-mediated Ca2+ influx and inhibition of NMDA-induced AA (arachidonic acid release. Mitochondrial dysfunction and the decrease in NMDA receptor activity due to oligomeric Aβ are associated with an increase in ROS production. Gp91ds-tat, a specific peptide inhibitor of NADPH oxidase, and Mn(III-tetrakis(4-benzoic acid-porphyrin chloride, an ROS scavenger, effectively abrogated Aβ-induced ROS production. Furthermore, Aβ-induced mitochondrial dysfunction, impairment of NMDA Ca2+ influx and ROS production were prevented by pretreatment of neurons with EGCG [(–-epigallocatechin-3-gallate], a major polyphenolic component of green tea. Taken together, these results support a role for NADPH oxidase-mediated ROS production in the cytotoxic effects of Aβ, and demonstrate the therapeutic potential of EGCG and other dietary polyphenols in delaying onset or retarding the progression of AD.
Czech Academy of Sciences Publication Activity Database
Palygin, O.; Lalo, U.; Verkhratsky, Alexei; Pankratov, Y.
2010-01-01
Roč. 48, č. 4 (2010), s. 225-231 ISSN 0143-4160 R&D Projects: GA ČR GA305/08/1384 Institutional research plan: CEZ:AV0Z50390703 Keywords : Astroglia * Ca2+ signalling * NMDA receptors Subject RIV: FH - Neurology Impact factor: 3.553, year: 2010
Varju, P; Schlett, K; Eisel, U; Madarasz, E
NE-7C2 neuroectodermal cells derived from forebrain vesicles of p53-deficient mouse embryos (E9) produce neurons and astrocytes in vitro if induced by all-trans retinoic acid. The reproducible morphological stages of neurogenesis were correlated with the expression of various NMDA receptor subunits.
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Marco Pedrazzi
Full Text Available BACKGROUND: Extracellular high mobility group box 1 (HMGB1 protein can operate in a synergistic fashion with different signal molecules promoting an increase of cell Ca(2+ influx. However, the mechanisms responsible for this effect of HMGB1 are still unknown. PRINCIPAL FINDINGS: Here we demonstrate that, at concentrations of agonist per se ineffective, HMGB1 potentiates the activation of the ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR in isolated hippocampal nerve terminals and in a neuroblastoma cell line. This effect was abolished by the NMDA channel blocker MK-801. The HMGB1-facilitated NMDAR opening was followed by activation of the Ca(2+-dependent enzymes calpain and nitric oxide synthase in neuroblastoma cells, resulting in an increased production of NO, a consequent enhanced cell motility, and onset of morphological differentiation. We have also identified NMDAR as the mediator of HMGB1-stimulated murine erythroleukemia cell differentiation, induced by hexamethylenebisacetamide. The potentiation of NMDAR activation involved a peptide of HMGB1 located in the B box at the amino acids 130-139. This HMGB1 fragment did not overlap with binding sites for other cell surface receptors of HMGB1, such as the advanced glycation end products or the Toll-like receptor 4. Moreover, in a competition assay, the HMGB1((130-139 peptide displaced the NMDAR/HMGB1 interaction, suggesting that it comprised the molecular and functional site of HMGB1 regulating the NMDA receptor complex. CONCLUSION: We propose that the multifunctional cytokine-like molecule HMGB1 released by activated, stressed, and damaged or necrotic cells can facilitate NMDAR-mediated cell responses, both in the central nervous system and in peripheral tissues, independently of other known cell surface receptors for HMGB1.
Backpropagating Action Potentials Enable Detection of Extrasynaptic Glutamate by NMDA Receptors
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Yu-Wei Wu
2012-05-01
Full Text Available Synaptic NMDA receptors (NMDARs are crucial for neural coding and plasticity. However, little is known about the adaptive function of extrasynaptic NMDARs occurring mainly on dendritic shafts. Here, we find that in CA1 pyramidal neurons, backpropagating action potentials (bAPs recruit shaft NMDARs exposed to ambient glutamate. In contrast, spine NMDARs are “protected,” under baseline conditions, from such glutamate influences by perisynaptic transporters: we detect bAP-evoked Ca2+ entry through these receptors upon local synaptic or photolytic glutamate release. During theta-burst firing, NMDAR-dependent Ca2+ entry either downregulates or upregulates an h-channel conductance (Gh of the cell depending on whether synaptic glutamate release is intact or blocked. Thus, the balance between activation of synaptic and extrasynaptic NMDARs can determine the sign of Gh plasticity. Gh plasticity in turn regulates dendritic input probed by local glutamate uncaging. These results uncover a metaplasticity mechanism potentially important for neural coding and memory formation.
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Don A Davies
2013-12-01
Full Text Available Working memory is a type of short-term memory involved in the maintenance and manipulation of information essential for complex cognition. While memory span capacity has been extensively studied in humans as a measure of working memory, it has received considerably less attention in rodents. Our aim was to examine the role of the NMDA and AMPA glutamate receptors in odor span capacity using systemic injections or infusions of receptor antagonists into the medial prefrontal cortex. Long Evans rats were trained on a well-characterized odor span task. Initially, rats were trained to dig for a food reward in sand followed by training on a non-match to sample discrimination using sand scented with household spices. The rats were then required to perform a serial delayed non-match to sample procedure which was their odor span. Systemic injection of the broad spectrum NMDA receptor antagonist CPP (10 mg/kg or the GluN2B-selective antagonist Ro25-6981 (10 mg/kg but not 6 mg/kg significantly reduced odor span capacity. Infusions of the GluN2B- selective antagonist Ro25-6981 (2.5 µg/hemisphere into medial prefrontal cortex reduced span capacity, an effect that was nearly significant (p = 0.069. Infusions of the AMPA receptor antagonist CNQX (1.25 µg/hemisphere into medial prefrontal cortex reduced span capacity and latency for the rats to make a choice in the task. These results demonstrate span capacity in rats depends on ionotropic glutamate receptor activation in the medial prefrontal cortex. Further understanding of the circuitry underlying span capacity may aid in the novel therapeutic drug development for persons with working memory impairments as a result of disorders such as schizophrenia and Alzheimer’s disease.
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Tamás eKiss
2011-04-01
Full Text Available NMDA receptor (NMDAR antagonists, such as phencyclidine, ketamine or dizocilpine (MK-801 are commonly used in psychiatric drug discovery in order to model several symptoms of schizophrenia, including psychosis and impairments in working memory. In spite of the widespread use of NMDAR antagonists in preclinical and clinical studies, our understanding of the mode of action of these drugs on brain circuits and neuronal networks is still limited. In the present study spontaneous local field potential (LFP, multi- (MUA and single unit activity, and evoked potential, including paired-pulse facilitation (PPF in response to electrical stimulation of the ipsilateral subiculum were carried out in the medial prefrontal cortex (mPFC in urethane anesthetized rats. Systemic administration of MK-801 (0.05~mg/kg, i.v. decreased overall MUA, with a diverse effect on single unit activity, including increased, decreased or unchanged firing, and in line with our previous findings shifted delta frequency power of the LFP and disrupted PPF (Kiss et al., Int J Neuropsychopharmacol. 2010. In order to provide further insight to the mechanisms of action of NMDAR antagonists, MK-801 was administered intracranially into the mPFC and mediodorsal nucleus of the thalamus (MD. Microinjections of MK-801, but not physiological saline, localized into the MD evoked changes in both LFP parameters and PPF similar to the effects of systemically administered MK-801. Local microinjection of MK-801 into the mPFC was without effect on these parameters. Our findings indicate that the primary site of the action of systemic administration of NMDA receptor antagonists is unlikely to be the cortex. We presume that multiple neuronal networks, involving thalamic nuclei contribute to disrupted behavior and cognition following NMDA receptor blockade.
Banerjee, A.; Meredith, R.M.; Rodriguez-Moreno, A.; Mierau, S.B.; Auberson, Y.P.; Paulsen, O.
2009-01-01
Spike timing-dependent plasticity (STDP) is a strong candidate for an N-methyl-D-aspartate (NMDA) receptor-dependent form of synaptic plasticity that could underlie the development of receptive field properties in sensory neocortices. Whilst induction of timing-dependent long-term potentiation
Capocchi, G; Della Torre, G; Grassi, S; Pettorossi, V E; Zampolini, M
1992-01-01
The effect of high frequency stimulation (HFS) of the primary vestibular afferents on field potentials recorded in the ipsilateral Medial Vestibular Nuclei (MVN) was studied. Our results show that potentiation and depression can be induced in different portions of MVN, which are distinguishable by their anatomical organization. HFS induces potentiation of the monosynaptic component in the ventral portion of the MVN, whereas it provokes depression of the polysynaptic component in the dorsal portion of the same nucleus. The induction of both potentiation and depression was blocked under AP5 perfusion, thus demonstrating that NMDA receptor activation mediates both phenomena. Furthermore, the finding that the field potentials were not modified during perfusion with DL-AP5, as previously reported, supports the hypothesis that NMDA receptors are not involved in the normal synaptic transmission from the primary vestibular afferent fibres, but are only activated following hyperstimulation of this afferent system. Our results suggest that the mechanisms of long term modification of synaptic efficacy observed in MVN may underlie the plasticity phenomena occurring in vestibular nuclei.
NMDA or 5-HT receptor antagonists impair memory reconsolidation and induce various types of amnesia.
Nikitin, V P; Solntseva, S V; Kozyrev, S A; Nikitin, P V; Shevelkin, A V
2018-06-01
Elucidation of amnesia mechanisms is one of the central problems in neuroscience with immense practical application. Previously, we found that conditioned food presentation combined with injection of a neurotransmitter receptor antagonist or protein synthesis inhibitor led to amnesia induction. In the present study, we investigated the time course and features of two amnesias: induced by impairment of memory reconsolidation using an NMDA glutamate receptor antagonist (MK-801) and a serotonin receptor antagonist (methiothepin, MET) on snails trained with food aversion conditioning. During the early period of amnesia (types of amnesia. Retraining an on 1st or 3rd day of amnesia induction facilitated memory formation, i.e. the number of CS + US pairings was lower than at initial training. On the 10th or 30th day after the MET/reminder, the number of CS + US pairings did not change between initial training and retraining. Retraining on the 10th or 30th day following the MK-801/reminder in the same or a new context of learning resulted in short, but not long-term, memory, and the number of CS + US pairings was higher than at the initial training. This type of amnesia was specific to the CS we used at initial training, since long-term memory for another kind of CS could be formed in the same snails. The attained results suggest that disruption of memory reconsolidation using antagonists of serotonin or NMDA glutamate receptors induced amnesias with different abilities to form long-term memory during the late period of development. Copyright © 2018 Elsevier B.V. All rights reserved.
Del Arco, Alberto; Ronzoni, Giacomo; Mora, Francisco
2015-07-01
A dysfunction of prefrontal cortex has been associated with the exacerbated response to stress observed in schizophrenic patients and high-risk individuals to develop psychosis. The hypofunction of NMDA glutamatergic receptors induced by NMDA antagonists produces cortico-limbic hyperactivity, and this is used as an experimental model to resemble behavioural abnormalities observed in schizophrenia. The aim of the present study was to investigate whether injections of NMDA antagonists into the medial prefrontal cortex of the rat change (1) the increases of dopamine, noradrenaline and corticosterone concentrations produced by acute stress in amygdala, and (2) the acquisition of aversive memory related to a stressful event. Male Wistar rats were implanted with guide cannulae to perform microdialysis and bilateral microinjections (0.5 μl/side) of the NMDA antagonist 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phophonic acid (CPP) (25 and 100 ng). Prefrontal injections were performed 60 min before restraint stress in microdialysis experiments, or training (footshock; 0.6 mA, 2 s) in inhibitory avoidance test. Retention latency was evaluated 24 h after training as an index of aversive memory. Acute stress increased amygdala dialysate concentrations of dopamine (160% of baseline), noradrenaline (145% of baseline) and corticosterone (170% of baseline). Prefrontal injections of CPP did not change the increases of dopamine, noradrenaline or corticosterone produced by stress. In contrast, CPP significantly reduced the retention latency in the inhibitory avoidance test. These results suggest that the hypofunction of prefrontal NMDA receptors does not change the sensitivity to acute stress of dopamine and noradrenaline projections to amygdala but impairs the acquisition of aversive memory.
Kaminsky, Yury; Kosenko, Elena
2009-10-19
In hyperammonemia, a decrease in brain ATP can be a result of adenine nucleotide catabolism. Xanthine dehydrogenase (XD) and xanthine oxidase (XO) are the end steps in the purine catabolic pathway and directly involved in depletion of the adenylate pool in the cell. Besides, XD can easily be converted to XO to produce reactive oxygen species in the cell. In this study, the effects of acute ammonia intoxication in vivo on brain adenine nucleotide pool and xanthine and hypoxanthine, the end degradation products of adenine nucleotides, during the conversion of XD to XO were studied. Injection of rats with ammonium acetate was shown to lead to the dramatic decrease in the ATP level, adenine nucleotide pool size and adenylate energy charge and to the great increase in hypoxanthine and xanthine 11 min after the lethal dose indicating rapid degradation of adenylates. Conversion of XD to XO in hyperammonemic rat brain was evidenced by elevated XO/XD activity ratio. Injection of MK-801, a NMDA receptor blocker, prevented ammonia-induced catabolism of adenine nucleotides and conversion of XD to XO suggesting that in vivo these processes are mediated by activation of NMDA receptors. The in vitro dose-dependent effects of sodium nitroprusside, a NO donor, on XD and XO activities are indicative of the direct modification of the enzymes by nitric oxide. This is the first report evidencing the increase in brain xanthine and hypoxanthine levels and adenine nucleotide breakdown in acute ammonia intoxication and NMDA receptor-mediated prevention of these alterations.
International Nuclear Information System (INIS)
Kim, Sang Eun; Hong, Seung Bong; Yoon, Byung Woo
1995-01-01
There has recently been increasing interest in the use of NMDA receptor antagonists as potential neuroprotective agents for the treatment of ischemic stroke. To evaluate the neuroprotective effect of the selective non-competitive NMDA receptor antagonist MK-801 in focal cerebral ischemia, local cerebral glucose utilization (1CGU) was examined in 15 neuroanatomically discrete regions of the conscious rat brain using the 2-deoxy-D[14C]glucose quantitative autoradiographic technique 24 hr after left middle cerebral artery occlusion (MCAO). Animals received MK-801 (5 mg/kg i.v.) or saline vehicle before (20-30 min) or after (30 min) MCAO. Both pretreatment and posttreatment of MK-801 increased occluded/non-occluded 1CGU ratio in 7 and 5 of the 15 regions measured, respectively(most notably in cortical structures). Following MK-801 pretreatment, there was evidence of widespread increases in 1CCPU not only in the non-occluded hemisphere (12 of the 15 areas studied) but also in the occluded hemisphere (13 of the 15 areas studied), while MK-801 posttreatment did not significantly increase 1CGU both in the normal and occluded hemispheres. These data indicate that MK-801 has a neuroprotective effect in focal cerebral ischemia and demonstrate that MK-801 provides widespread alterations of glucose utilization in conscious animals.
Villmann, Carmen; Hoffmann, Jutta; Werner, Markus; Kott, Sabine; Strutz-Seebohm, Nathalie; Nilsson, Tanja; Hollmann, Michael
2008-10-01
Although considerable progress has been made in characterizing the physiological function of the high-affinity kainate (KA) receptor subunits KA1 and KA2, no homomeric ion channel function has been shown. An ion channel transplantation approach was employed in this study to directly test if homomerically expressed KA1 and KA2 pore domains are capable of conducting currents. Transplantation of the ion pore of KA1 or KA2 into GluR6 generated perfectly functional ion channels that allowed characterization of those electrophysiological and pharmacological properties that are determined exclusively by the ion pore of KA1 or KA2. This demonstrates for the first time that KA1 and KA2 ion pore domains are intrinsically capable of conducting ions even in homomeric pore assemblies. NMDA receptors, similar to KA1- or KA2-containing receptors, function only as heteromeric complexes. They are composed of NR1 and NR2 subunits, which both are non-functional when expressed homomerically. In contrast to NR1, the homomeric NR2B ion pore failed to translate ligand binding into pore opening when transplanted into GluR6. Similarly, heteromeric coexpression of the ion channel domains of both NR1 and NR2 inserted into GluR6 failed to produce functional channels. Therefore, we conclude that the mechanism underlying the ion channel opening in the obligatorily heterotetrameric NMDA receptors differs significantly from that in the facultatively heterotetrameric alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate and KA receptors.
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Fuchigami, Takeshi [Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582 (Japan); Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu 431-3192 (Japan); Haradahira, Terushi [Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555 (Japan)], E-mail: terushi@niu.ac.jp; Fujimoto, Noriko [Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582 (Japan); Okauchi, Takashi; Maeda, Jun; Suzuki, Kazutoshi; Suhara, Tetsuya [Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555 (Japan); Yamamoto, Fumihiko; Sasaki, Shigeki; Mukai, Takahiro [Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582 (Japan); Yamaguchi, Hiroshi [Molecular Imaging Frontier Research Center, Hamamatsu University School of Medicine, Hamamatsu 431-3192 (Japan); Ogawa, Mikako [Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu 431-3192 (Japan); Magata, Yasuhiro [Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu 431-3192 (Japan); Molecular Imaging Frontier Research Center, Hamamatsu University School of Medicine, Hamamatsu 431-3192 (Japan); Maeda, Minoru [Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582 (Japan)
2008-02-15
High-affinity iodine- and ethyl-C-5 substituted analogs of 4-hydroxy-3-(3-[{sup 11}C]methoxyphenyl)-2(1H)-quinolone ([{sup 11}C]4HQ) were synthesized as new positron emission tomography radioligands for the glycine-binding sites of the N-methyl-D-aspartate (NMDA) ion channel. Although both radioligands showed high in vitro specific binding to rat brain slices, their binding characteristics were quite different from each other. 5-Ethyl-[{sup 11}C]4HQ (5Et-[{sup 11}C]4HQ) showed higher in vitro binding in the forebrain regions than in the cerebellum, bindings that were strongly inhibited by both glycine-site agonists and antagonists. In contrast, 5-iodo-[{sup 11}C]4HQ (5I-[{sup 11}C]4HQ) showed a homogeneous in vitro binding throughout the brain, which was inhibited by antagonists but not by agonists. This difference in in vitro binding between 5Et-[{sup 11}C]4HQ and 5I-[{sup 11}C]4HQ was quite similar to that previously observed between [{sup 11}C]L-703,717 and [{sup 11}C]4HQ, both glycine-site antagonists. In vivo brain uptakes of these {sup 11}C-labeled 4-hydroxyquinolones were examined in mice. Initial brain uptakes of 5Et- and 5I-[{sup 11}C]4HQ at 1 min after intravenous injections were comparable to that of [{sup 11}C]4HQ, but they were 1.3-2.1 times higher than that of [{sup 11}C]L-703,717. The treatment with an anticoagulant, warfarin, only slightly increased the initial uptakes of [{sup 11}C]4HQ and 5Et-[{sup 11}C]4HQ in contrast to [{sup 11}C]L-703,717. The in vivo regional brain distributions were slightly different between the two radioligands. Pretreatment with nonradioactive ligand (2 mg/kg) slightly inhibited the binding of 5Et-[{sup 11}C]4HQ (16-36% inhibition) but not that of 5I-[{sup 11}C]4HQ. In this study, it was found that a small structural change in [{sup 11}C]4HQ resulted in a major change in binding characteristics and distributions, suggesting the existence of two binding sites for [{sup 11}C]4-hydroxyquinolones on the NMDA ion channel
International Nuclear Information System (INIS)
Ponchant, M.; Crouzel, C.
1992-01-01
In an attempt to visualize the NMDA glutamatergic receptors and after checking the biological activity of the cold 3-fluoromethyl-TCP, 3-[ 18 F]-fluoro-methyl-TCP was synthesized by a nucleophilic substitution of 3-bromomethyl-TCP with [ 18 F - ]. (author)
Varju, P; Schlett, K; Eisel, U; Madarász, E
2001-06-01
NE-7C2 neuroectodermal cells derived from forebrain vesicles of p53-deficient mouse embryos (E9) produce neurons and astrocytes in vitro if induced by all-trans retinoic acid. The reproducible morphological stages of neurogenesis were correlated with the expression of various NMDA receptor subunits. RT-PCR studies revealed that GluRepsilon1 and GluRepsilon4 subunit mRNAs were transcribed by both non-induced and neuronally differentiated cells. GluRepsilon3 subunit mRNAs were not synthesized by NE-7C2 cells and increased numbers of messages from the GluRepsilon2 gene were detected only after neural network formation. The presence of the GluRzeta1 protein was detected throughout neural induction, whereas retinoic acid-induced neuron formation elevated the amount of exon 21 (C1)- and exon 22 (C2)-containing GluRzeta1 mRNAs and resulted in the appearance of exon 5 (N1)-containing transcripts. NMDA-elicited Ca(2+)-signals were detected only in cells displaying neuronal morphology, but preceding the appearance of synapsin-I immunoreactivity. Our findings demonstrated that, in spite of the presence of subunits necessary for channel formation, functional channels were formed by NE-7C2 cells no sooner than the time of neurite maturation. The data show that the cell line provides a suitable model to analyse the mechanisms involved in NMDA receptor gene expression before the appearance of synaptic communication.
International Nuclear Information System (INIS)
Shakarjian, Michael P.; Velíšková, Jana; Stanton, Patric K.; Velíšek, Libor
2012-01-01
Tetramethylenedisulfotetramine (TMDT) is a highly lethal neuroactive rodenticide responsible for many accidental and intentional poisonings in mainland China. Ease of synthesis, water solubility, potency, and difficulty to treat make TMDT a potential weapon for terrorist activity. We characterized TMDT-induced convulsions and mortality in male C57BL/6 mice. TMDT (ip) produced a continuum of twitches, clonic, and tonic–clonic seizures decreasing in onset latency and increasing in severity with increasing dose; 0.4 mg/kg was 100% lethal. The NMDA antagonist, ketamine (35 mg/kg) injected ip immediately after the first TMDT-induced seizure, did not change number of tonic–clonic seizures or lethality, but increased the number of clonic seizures. Doubling the ketamine dose decreased tonic–clonic seizures and eliminated lethality through a 60 min observation period. Treating mice with another NMDA antagonist, MK-801, 0.5 or 1 mg/kg ip, showed similar effects as low and high doses of ketamine, respectively, and prevented lethality, converting status epilepticus EEG activity to isolated interictal discharges. Treatment with these agents 15 min prior to TMDT administration did not increase their effectiveness. Post-treatment with the GABA A receptor allosteric enhancer diazepam (5 mg/kg) greatly reduced seizure manifestations and prevented lethality 60 min post-TMDT, but ictal events were evident in EEG recordings and, hours post-treatment, mice experienced status epilepticus and died. Thus, TMDT is a highly potent and lethal convulsant for which single-dose benzodiazepine treatment is inadequate in managing electrographic seizures or lethality. Repeated benzodiazepine dosing or combined application of benzodiazepines and NMDA receptor antagonists is more likely to be effective in treating TMDT poisoning. -- Highlights: ► TMDT produces convulsions and lethality at low doses in mice. ► Diazepam pre- or post-treatments inhibit TMDT-induced convulsions and death.
Postnikova, T Y; Zubareva, O E; Kovalenko, A A; Kim, K K; Magazanik, L G; Zaitsev, A V
2017-03-01
Cognitive deficits and memory loss are frequent in patients with temporal lobe epilepsy. Persistent changes in synaptic efficacy are considered as a cellular substrate underlying memory processes. Electrophysiological studies have shown that the properties of short-term and long-term synaptic plasticity in the cortex and hippocampus may undergo substantial changes after seizures. However, the neural mechanisms responsible for these changes are not clear. In this study, we investigated the properties of short-term and long-term synaptic plasticity in rat hippocampal slices 24 h after pentylenetetrazole (PTZ)-induced status epilepticus. We found that the induction of long-term potentiation (LTP) in CA1 pyramidal cells is reduced compared to the control, while short-term facilitation is increased. The experimental results do not support the hypothesis that status epilepticus leads to background potentiation of hippocampal synapses and further LTP induction becomes weaker due to occlusion, as the dependence of synaptic responses on the strength of input stimulation was not different in the control and experimental animals. The decrease in LTP can be caused by impairment of molecular mechanisms of neuronal plasticity, including those associated with NMDA receptors and/or changes in their subunit composition. Real-time PCR demonstrated significant increases in the expression of GluN1 and GluN2A subunits 3 h after PTZ-induced status epilepticus. The overexpression of obligate GluN1 subunit suggests an increase in the total number of NMDA receptors in the hippocampus. A 3-fold increase in the expression of the GluN2B subunit observed 24 h after PTZ-induced status epilepticus might be indicative of an increase in the proportion of GluN2B-containing NMDA receptors. Increased expression of the GluN2B subunit may be a cause for reducing the magnitude of LTP at hippocampal synapses after status epilepticus.
Sequerra, Eduardo B; Goyal, Raman; Castro, Patricio A; Levin, Jacqueline B; Borodinsky, Laura N
2018-05-16
Failure of neural tube closure leads to neural tube defects (NTDs), which can have serious neurological consequences or be lethal. Use of antiepileptic drugs (AEDs) during pregnancy increases the incidence of NTDs in offspring by unknown mechanisms. Here we show that during Xenopus laevis neural tube formation, neural plate cells exhibit spontaneous calcium dynamics that are partially mediated by glutamate signaling. We demonstrate that NMDA receptors are important for the formation of the neural tube and that the loss of their function induces an increase in neural plate cell proliferation and impairs neural cell migration, which result in NTDs. We present evidence that the AED valproic acid perturbs glutamate signaling, leading to NTDs that are rescued with varied efficacy by preventing DNA synthesis, activating NMDA receptors, or recruiting the NMDA receptor target ERK1/2. These findings may prompt mechanistic identification of AEDs that do not interfere with neural tube formation. SIGNIFICANCE STATEMENT Neural tube defects are one of the most common birth defects. Clinical investigations have determined that the use of antiepileptic drugs during pregnancy increases the incidence of these defects in the offspring by unknown mechanisms. This study discovers that glutamate signaling regulates neural plate cell proliferation and oriented migration and is necessary for neural tube formation. We demonstrate that the widely used antiepileptic drug valproic acid interferes with glutamate signaling and consequently induces neural tube defects, challenging the current hypotheses arguing that they are side effects of this antiepileptic drug that cause the increased incidence of these defects. Understanding the mechanisms of neurotransmitter signaling during neural tube formation may contribute to the identification and development of antiepileptic drugs that are safer during pregnancy. Copyright © 2018 the authors 0270-6474/18/384762-12$15.00/0.
DEFF Research Database (Denmark)
Ring, Avi; Tanso, Rita; Noraberg, Jens
2010-01-01
There is a wide interest in testing neuroprotectants which inhibit the neurodegeneration that results from excessive activation of brain NMDA receptors. As an alternative to in vivo testing in animal models we demonstrate here the use of a complex in vitro model to compare the efficacy and toxic...
Czech Academy of Sciences Publication Activity Database
Adla, Santosh Kumar; Slavíková, Barbora; Šmídková, Markéta; Tloušťová, Eva; Svoboda, Martin; Vyklický, Vojtěch; Krausová, Barbora; Hubálková, Pavla; Nekardová, Michaela; Holubová, Kristína; Valeš, Karel; Buděšínský, Miloš; Vyklický ml., Ladislav; Chodounská, Hana; Kudová, Eva
2017-01-01
Roč. 117, Jan (2017), s. 52-61 ISSN 0039-128X. [Conference on Isoprenoids /23./. Minsk, 04.09.2016-07.09.2016] R&D Projects: GA TA ČR(CZ) TE01020028; GA ČR(CZ) GAP303/12/1464; GA MŠk LO1302; GA MZd(CZ) NV15-29370A; GA ČR(CZ) GBP208/12/G016 Institutional support: RVO:61388963 ; RVO:67985823 Keywords : neurosteroid * NMDA receptor * structure-activity relationship * amide * blood-brain-barrier permeability * Caco-2 assay Subject RIV: CC - Organic Chemistry OBOR OECD: Organic chemistry; Organic chemistry (FGU-C) Impact factor: 2.282, year: 2016
Moody, Teena D.; Watabe, Ayako M.; Indersmitten, Tim; Komiyama, Noboru H.; Grant, Seth G. N.; O'Dell, Thomas J.
2011-01-01
Through protein interactions mediated by their cytoplasmic C termini the GluN2A and GluN2B subunits of NMDA receptors (NMDARs) have a key role in the formation of NMDAR signaling complexes at excitatory synapses. Although these signaling complexes are thought to have a crucial role in NMDAR-dependent forms of synaptic plasticity such as long-term…
In Vivo Protection against Strychnine Toxicity in Mice by the Glycine Receptor Agonist Ivermectin
Directory of Open Access Journals (Sweden)
Ahmed Maher
2014-01-01
Full Text Available The inhibitory glycine receptor, a ligand-gated ion channel that mediates fast synaptic inhibition in mammalian spinal cord and brainstem, is potently and selectively inhibited by the alkaloid strychnine. The anthelminthic and anticonvulsant ivermectin is a strychnine-independent agonist of spinal glycine receptors. Here we show that ivermectin is an effective antidote of strychnine toxicity in vivo and determine time course and extent of ivermectin protection. Mice received doses of 1 mg/kg and 5 mg/kg ivermectin orally or intraperitoneally, followed by an intraperitoneal strychnine challenge (2 mg/kg. Ivermectin, through both routes of application, protected mice against strychnine toxicity. Maximum protection was observed 14 hours after ivermectin administration. Combining intraperitoneal and oral dosage of ivermectin further improved protection, resulting in survival rates of up to 80% of animals and a significant delay of strychnine effects in up to 100% of tested animals. Strychnine action developed within minutes, much faster than ivermectin, which acted on a time scale of hours. The data agree with a two-compartment distribution of ivermectin, with fat deposits acting as storage compartment. The data demonstrate that toxic effects of strychnine in mice can be prevented if a basal level of glycinergic signalling is maintained through receptor activation by ivermectin.
Zhou, Junfei; Wang, Fang; Zhang, Jun; Li, Jianfeng; Ma, Li; Dong, Tieli; Zhuang, Zhigang
2018-04-05
The aim of the present study was to verify whether propofol impaired learning and memory through the interplay of N-methyl-D-aspartate (NMDA) receptor with brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling pathway. 120 Sprague-Dawley (SD) rats were randomly assigned into eight groups. Experimental drugs including saline, intralipid, propofol, N-methyl-D-aspartate (NMDA), 7,8-dihydroxyflavone (7,8-DHF), K252a and MK-801. Spatial learning and memory of rats were tested by the Morris water maze (MWM) test. The mRNA and protein expression were determined by immunohistochemistry, RT-PCR and western blot. Finally, hippocampus cells proliferation and apoptosis were examined by PCNA immunohistochemistry and TUNEL respectively. The memory and learning was diminished in the propofol exposure group, however, the impaired memory and learning of rats were improved with the addition of NMDA and 7,8-DHF, while the improvement of memory and learning of rats were reversed with the addition of K252a and MK-801. In addition, the mRNA and protein expression levels and hippocampus cells proliferation were the same trend with the results of the MWM test, while apoptosis in hippocampus was reversed. The propofol can impair memory and learning of rats and induce cognition dysfunction through the interplay of NMDA receptor and BDNF-TrkB-CREB signaling pathway.
Collins, Stuart A; Gudelsky, Gary A; Yamamoto, Bryan K
2015-08-15
MDMA is a widely abused psychostimulant which causes a rapid and robust release of the monoaminergic neurotransmitters dopamine and serotonin. Recently, it was shown that MDMA increases extracellular glutamate concentrations in the dorsal hippocampus, which is dependent on serotonin release and 5HT2A/2C receptor activation. The increased extracellular glutamate concentration coincides with a loss of parvalbumin-immunoreactive (PV-IR) interneurons of the dentate gyrus region. Given the known susceptibility of PV interneurons to excitotoxicity, we examined whether MDMA-induced increases in extracellular glutamate in the dentate gyrus are necessary for the loss of PV cells in rats. Extracellular glutamate concentrations increased in the dentate gyrus during systemic and local administration of MDMA. Administration of the NMDA receptor antagonist, MK-801, during systemic injections of MDMA, prevented the loss of PV-IR interneurons seen 10 days after MDMA exposure. Local administration of MDL100907, a selective 5HT2A receptor antagonist, prevented the increases in glutamate caused by reverse dialysis of MDMA directly into the dentate gyrus and prevented the reduction of PV-IR. These findings provide evidence that MDMA causes decreases in PV within the dentate gyrus through a 5HT2A receptor-mediated increase in glutamate and subsequent NMDA receptor activation. Copyright © 2015 Elsevier B.V. All rights reserved.
Czech Academy of Sciences Publication Activity Database
Vrajová, M.; Šťastný, František; Horáček, J.; Lochman, J.; Šerý, O.; Peková, S.; Klaschka, Jan; Höschl, C.
2010-01-01
Roč. 35, č. 7 (2010), s. 994-1002 ISSN 0364-3190 Grant - others:GA MZd(CZ) NR9324 Institutional research plan: CEZ:AV0Z50110509; CEZ:AV0Z10300504 Keywords : schizophrenia * hippocampus * GluN1 subunit of NMDA receptor * splice variants * laterality Subject RIV: FL - Psychiatry, Sexuology Impact factor: 2.608, year: 2010
Analysis of NR3A receptor subunits in human native NMDA receptors
DEFF Research Database (Denmark)
Nilsson, Anna; Eriksson, Maria; Muly, E Chris
2007-01-01
NR3A, representing the third class of NMDA receptor subunits, was first studied in rats, demonstrating ubiquitous expression in the developing central nervous system (CNS), but in the adult mainly expressed in spinal cord and some forebrain nuclei. Subsequent studies showed that rodent and non-human...... primate NR3A expression differs. We have studied the distribution of NR3A in the human CNS and show a widespread distribution of NR3A protein in adult human brain. NR3A mRNA and protein were found in all regions of the cerebral cortex, and also in the subcortical forebrain, midbrain and hindbrain. Only...... very low levels of NR3A mRNA and protein could be detected in homogenized adult human spinal cord, and in situ hybridization showed that expression was limited to ventral motoneurons. We found that NR3A is associated with NR1, NR2A and NR2B in adult human CNS, suggesting the existence of native NR1-NR2...
Sugita, Manami; Yamada, Kazuo; Iguchi, Natsumi; Ichitani, Yukio
2015-10-22
The possible involvement of hippocampal N-methyl-D-aspartate (NMDA) receptors in spontaneous object recognition was investigated in rats under different memory load conditions. We first estimated rats' object memory span using 3-5 objects in "Different Objects Task (DOT)" in order to confirm the highest memory load condition in object recognition memory. Rats were allowed to explore a field in which 3 (3-DOT), 4 (4-DOT), or 5 (5-DOT) different objects were presented. After a delay period, they were placed again in the same field in which one of the sample objects was replaced by another object, and their object exploration behavior was analyzed. Rats could differentiate the novel object from the familiar ones in 3-DOT and 4-DOT but not in 5-DOT, suggesting that rats' object memory span was about 4. Then, we examined the effects of hippocampal AP5 infusion on performance in both 2-DOT (2 different objects were used) and 4-DOT. The drug treatment before the sample phase impaired performance only in 4-DOT. These results suggest that hippocampal NMDA receptors play a critical role in spontaneous object recognition only when the memory load is high. Copyright © 2015 Elsevier B.V. All rights reserved.
Enhanced Polyubiquitination of Shank3 and NMDA receptor in a mouse model of Autism
Bangash, M Ali; Park, Joo Min; Melnikova, Tatiana; Wang, Dehua; Jeon, Soo Kyeong; Lee, Deidre; Syeda, Sbaa; Kim, Juno; Kouser, Mehreen; Schwartz, Joshua; Cui, Yiyuan; Zhao, Xia; Speed, Haley E.; Kee, Sara E.; Tu, Jian Cheng
2011-01-01
We have created a mouse genetic model that mimics a human mutation of Shank3 that deletes the C-terminus and is associated with autism. Expressed as a single copy [Shank3(+/ΔC) mice], Shank3ΔC protein interacts with the WT gene product and results in >90 % reduction of Shank3 at synapses. This “gain of function” phenotype is linked to increased polyubiquitination of WT Shank3 and its redistribution into proteasomes. Similarly, the NR1 subunit of the NMDA receptor is reduced at synapses with i...
Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids.
Directory of Open Access Journals (Sweden)
Gonzalo E Yévenes
Full Text Available Glycine receptors (GlyRs are transmitter-gated anion channels of the Cys-loop superfamily which mediate synaptic inhibition at spinal and selected supraspinal sites. Although they serve pivotal functions in motor control and sensory processing, they have yet to be exploited as drug targets partly because of hitherto limited possibilities for allosteric control. Endocannabinoids (ECs have recently been characterized as direct allosteric GlyR modulators, but the underlying molecular sites have remained unknown. Here, we show that chemically neutral ECs (e.g. anandamide, AEA are positive modulators of α(1, α(2 and α(3 GlyRs, whereas acidic ECs (e.g. N-arachidonoyl-glycine; NA-Gly potentiate α(1 GlyRs but inhibit α(2 and α(3. This subunit-specificity allowed us to identify the underlying molecular sites through analysis of chimeric and mutant receptors. We found that alanine 52 in extracellular loop 2, glycine 254 in transmembrane (TM region 2 and intracellular lysine 385 determine the positive modulation of α(1 GlyRs by NA-Gly. Successive substitution of non-conserved extracellular and TM residues in α(2 converted NA-Gly-mediated inhibition into potentiation. Conversely, mutation of the conserved lysine within the intracellular loop between TM3 and TM4 attenuated NA-Gly-mediated potentiation of α(1 GlyRs, without affecting inhibition of α(2 and α(3. Notably, this mutation reduced modulation by AEA of all three GlyRs. These results define molecular sites for allosteric control of GlyRs by ECs and reveal an unrecognized function for the TM3-4 intracellular loop in the allosteric modulation of Cys-loop ion channels. The identification of these sites may help to understand the physiological role of this modulation and facilitate the development of novel therapeutic approaches to diseases such as spasticity, startle disease and possibly chronic pain.
Preparation of 99mTc-PQQE and preliminary biological evaluation for the NMDA receptor
International Nuclear Information System (INIS)
Zhou Xingqin; Kong Yanyan; Zou Meifen; Zhang Jiankang; Cao Guoxian
2013-01-01
The 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo(2, 3-f)quinoline-2, 7, 9-tricarboxylic acid 2-ethyl ester 7, 9-dimethyl ester (PQQE) was synthesized on the basis of Pyrroloquinoline quinine (PQQ). 99m Tc-PQQE was prepared using stannous fluoride (SnF 2 ) as reducing agent. Biological characteristics of 99m Tc-PQQE include lipophilic and the charge properties were compared to 99m Tc-PQQ. The biodistributions of 99m Tc-PQQE in mice and brain regional distribution were performed. In vivo distribution of 99m Tc-PQQE in mice indicates that the concentration ratio of drug and blood increases steadily over time. The major radioactivity may be metabolized by the hepatic and renal system. The elimination-phase half-time (t1/2 β) results indicate that the residence time of 99m Tc-PQQE (203.92) in the body is twice as long as 99m Tc-PQQ (100.45)., The uptake of 99n Tc- P QQE in brain was improved due to the ameliorating of charge and lipophilicity. The highest total regional brain uptake of 99m Tc-PQQE was in the frontal lobe and hippocampus, where the NMDA receptor is very abundant. 99m Tc-PQQE had a good target to nontarget ratio (hippocampus/cerebellum) which preserved a higher value (peak 4.0 at 120 min) from 60 min to 180 min after injection. In vitro autoradiographic results are in close agreement with the regional brain map. The enrichment can be blocked by N-methyl-D-aspartate receptor (NMDAR) redox modulatory site antagonists-ebselen (EB). This work suggests that 99m Tc-PQQE has some specific targeting to the NMDA receptor. (authors)
Storozheva, Z I; Solntseva, S V; Nikitin, V P; Proshin, A T; Sherstnev, V V
2011-01-01
The effect of MK-801, an antagonist to NMDA-glutamate receptors, on reconsolidation of olfactory discrimination task in rats and taste discrimination in edible snails was examined. Twenty-four hours after conditioning, the animals received a single systemic injection of MK-801 followed by a reminding conditional stimulus. Disturbances in retrieval of the acquired task were observed 10 days after injection followed by a reminding procedure. Repeated conditioning of these animals did not restore the task. Injection of MK-801 without reminding stimulation had no effect on task retention. Thus, disturbances of NMDA-dependent reconsolidation of the associative memory in animals of different taxonomic groups irreversibly eliminated long-term memory.
Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line
Directory of Open Access Journals (Sweden)
Ayako Kumagai
2014-12-01
Full Text Available Memantine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA receptor, and is an approved drug for the treatment of moderate-to-severe Alzheimer’s disease. We identified a mouse strain with a naturally occurring mutation and an ataxic phenotype that presents with severe leg cramps. To investigate the phenotypes of these mutant mice, we screened several phenotype-modulating drugs and found that memantine (10 mg/kg disrupted the sense of balance in the mutants. Moreover, the mutant mice showed an attenuated optokinetic response (OKR and impaired OKR learning, which was also observed in wild-type mice treated with memantine. Microsatellite analyses indicated that the Grid2 gene-deletion is responsible for these phenotypes. Patch-clamp analysis showed a relatively small change in NMDA-dependent current in cultured granule cells from Grid2 gene-deleted mice, suggesting that GRID2 is important for correct NMDA receptor function. In general, NMDA receptors are activated after the activation of non-NMDA receptors, such as AMPA receptors, and AMPA receptor dysregulation also occurs in Grid2 mutant mice. Indeed, the AMPA treatment enhanced memantine susceptibility in wild-type mice, which was indicated by balance sense and OKR impairments. The present study explores a new role for GRID2 and highlights the adverse effects of memantine in different genetic backgrounds.
Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line
Kumagai, Ayako; Fujita, Akira; Yokoyama, Tomoki; Nonobe, Yuki; Hasaba, Yasuhiro; Sasaki, Tsutomu; Itoh, Yumi; Koura, Minako; Suzuki, Osamu; Adachi, Shigeki; Ryo, Haruko; Kohara, Arihiro; Tripathi, Lokesh P.; Sanosaka, Masato; Fukushima, Toshiki; Takahashi, Hiroyuki; Kitagawa, Kazuo; Nagaoka, Yasuo; Kawahara, Hidehisa; Mizuguchi, Kenji; Nomura, Taisei; Matsuda, Junichiro; Tabata, Toshihide; Takemori, Hiroshi
2014-01-01
Memantine is a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, and is an approved drug for the treatment of moderate-to-severe Alzheimer’s disease. We identified a mouse strain with a naturally occurring mutation and an ataxic phenotype that presents with severe leg cramps. To investigate the phenotypes of these mutant mice, we screened several phenotype-modulating drugs and found that memantine (10 mg/kg) disrupted the sense of balance in the mutants. Moreover, the mutant mice showed an attenuated optokinetic response (OKR) and impaired OKR learning, which was also observed in wild-type mice treated with memantine. Microsatellite analyses indicated that the Grid2 gene-deletion is responsible for these phenotypes. Patch-clamp analysis showed a relatively small change in NMDA-dependent current in cultured granule cells from Grid2 gene-deleted mice, suggesting that GRID2 is important for correct NMDA receptor function. In general, NMDA receptors are activated after the activation of non-NMDA receptors, such as AMPA receptors, and AMPA receptor dysregulation also occurs in Grid2 mutant mice. Indeed, the AMPA treatment enhanced memantine susceptibility in wild-type mice, which was indicated by balance sense and OKR impairments. The present study explores a new role for GRID2 and highlights the adverse effects of memantine in different genetic backgrounds. PMID:25513882
Mohseni, Gholmreza; Ostadhadi, Sattar; Imran-Khan, Muhammad; Norouzi-Javidan, Abbas; Zolfaghari, Samira; Haddadi, Nazgol-Sadat; Dehpour, Ahmad-Reza
2017-04-01
Depression is one the world leading global burdens leading to various comorbidities. Lithium as a mainstay in the treatment of depression is still considered gold standard treatment. Similar to lithium another agent agmatine has also central protective role against depression. Since, both agmatine and lithium modulate various effects through interaction with NMDA receptor, therefore, in current study we aimed to investigate the synergistic antidepressant-like effect of agmatine with lithium in mouse force swimming test. Also to know whether if such effect is due to interaction with NMDA receptor. In our present study we found that when potent dose of lithium (30mg/kg) was administered, it significantly decreased the immobility time. Also, when subeffective dose of agmatine (0.01mg/kg) was coadministered with subeffective dose of lithium (3mg/kg), it potentiated the antidepressant-like effect of subeffective dose of lithium. For the involvement of NMDA receptor in such effect, we administered NMDA receptor antagonist MK-801 (0.05mg/kg) with a combination of subeffective dose of lithium (3mg/kg) and agmatine (0.001mg/kg). A significant antidepressant-like effect was observed. Furthermore, when subeffective dose (50 and 75mg/kg) of NMDA was given it inhibited the synergistic effect of agmatine (0.01mg/kg) with lithium (3mg/kg). Hence, our finding demonstrate that agmatine have synergistic effect with lithium which is mediated by NMDA receptor pathway. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
Kenny, Nathan J; Dearden, Peter K
2013-12-01
The C termini of N-methyl-D-aspartate (NMDA) receptor NR2 subunits are thought to play a major role in the molecular establishment of memory across the Bilateria, via the phenomenon known as long-term potentiation (LTP). Despite their long history of use as models in the study of memory, the expression and structure of the NR2 subunit in the Lophotrochozoa has remained uncategorized. Here, we report the phylogenic relationships of NR subunits across the Bilateria, and the cloning and in situ analysis of expression of NMDA NR1 and NR2 subunits in the monogont rotifer Brachionus plicatilis. RNA in situ hybridization suggests expression of NMDA receptor subunits in B. plicatilis is neural, consistent with expression observed in other species, and ours is the first report confirming NR2 expression in the lophotrochozoan clade. However, the single NR2 subunit identified in B. plicatilis was found to lack the long C terminal domain found in vertebrates, which is believed to modulate LTP. Further investigation revealed that mollusc and annelid NR2 subunits possess long intracellular C terminal domains. As data from molluscs (and particularly Aplysia californica) are the basis for much of our understanding of LTP, understanding how these diverse lophotrochozoan C termini function in vivo will have many implications for how we consider the evolution of the molecular control of learning and memory across the Metazoa as a whole and interpret the results of experiments into this vital component of cognition.
Bravo-Oro, Antonio; Abud-Mendoza, Carlos; Quezada-Corona, Arturo; Dalmau, Josep; Campos-Guevara, Verónica
2016-01-01
Introducción La encefalitis por anticuerpos contra el receptor de N-metil-D-aspartato (NMDA) es una entidad cada vez más diagnosticada en edad pediátrica. A diferencia de los adultos, en muchos casos no se asocia a tumores y las manifestaciones iniciales en niños más frecuentes son crisis convulsivas y trastornos del movimiento, mientras que en los adultos predominan las alteraciones psiquiátricas. Casos clínicos Presentamos seis casos pediátricos confirmados con anticuerpos contra la subunidad NR1 del receptor de NMDA en suero y líquido cefalorraquídeo. Cinco de los casos comenzaron con crisis convulsivas como manifestación clínica inicial antes de desarrollar el cuadro clásico de esta entidad. En todos los casos se utilizaron esteroides como primera línea de tratamiento, con los que sólo se observó control de las manifestaciones en uno, por lo que el resto de los pacientes requirió inmunomoduladores de segunda línea. Todos los pacientes recibieron metotrexato como tratamiento inmunomodulador para evitar recaídas y la evolución fue a la mejoría en todos ellos. Conclusiones En nuestra serie de pacientes con encefalitis por anticuerpos contra el receptor de NMDA, ninguno se asoció a tumores. Todos los casos recibieron metotrexato por lo menos durante un año, no observamos eventos adversos clínicos ni por laboratorio, ni hubo secuelas neurológicas ni recaídas durante el tratamiento. Aunque es una serie pequeña y es deseable incrementar el número y tiempo de evolución, consideramos el metotrexato una excelente alternativa como tratamiento inmunomodulador para esta patología. PMID:24150952
Abekawa, Tomohiro; Ito, Koki; Nakagawa, Shin; Koyama, Tsukasa
2007-06-01
Neurodevelopmental deficits of parvalbumin-immunoreactive gamma-aminobutyric acid (GABA)ergic interneurons in prefrontal cortex have been reported in schizophrenia. Glutamate influences the proliferation of this type of interneuron by an N-methyl-D-aspartate (NMDA)-receptor-mediated mechanism. The present study hypothesized that prenatal blockade of NMDA receptors would disrupt GABAergic neurodevelopment, resulting in differences in effects on behavioral responses to a noncompetitive NMDA antagonist, phencyclidine (PCP), and a dopamine releaser, methamphetamine (METH). GABAergic neurons were immunohistochemically stained with parvalbumin antibody. Psychostimulant-induced hyperlocomotion was measured using an infrared sensor. Prenatal exposure (E15-E18) to the NMDA receptor antagonist MK-801 reduced the density of parvalbumin-immunoreactive neurons in rat medial prefrontal cortex on postnatal day 63 (P63) and enhanced PCP-induced hyperlocomotion but not the acute effects of METH on P63 or the development of behavioral sensitization. Prenatal exposure to MK-801 reduced the number of parvalbumin-immunoreactive neurons even on postnatal day 35 (P35) and did not enhance PCP-induced hyperlocomotion, the acute effects of METH on P35, or the development of behavioral sensitization to METH. These findings suggest that prenatal blockade of NMDA receptors disrupts GABAergic neurodevelopment in medial prefrontal cortex, and that this disruption of GABAergic development may be related to the enhancement of the locomotion-inducing effect of PCP in postpubertal but not juvenile offspring. GABAergic deficit is unrelated to the effects of METH. This GABAergic neurodevelopmental disruption and the enhanced PCP-induced hyperlocomotion in adult offspring prenatally exposed to MK-801 may prove useful as a new model of the neurodevelopmental process of pathogenesis of treatment-resistant schizophrenia via an NMDA-receptor-mediated hypoglutamatergic mechanism.
Carlson, G C; Lin, R E; Chen, Y; Brookshire, B R; White, R S; Lucki, I; Siegel, S J; Kim, S F
2016-05-13
Dexras1 is a novel GTPase that acts at a confluence of signaling mechanisms associated with psychiatric and neurological disease including NMDA receptors, NOS1AP and nNOS. Recent work has shown that Dexras1 mediates iron trafficking and NMDA-dependent neurodegeneration but a role for Dexras1 in normal brain function or psychiatric disease has not been studied. To test for such a role, mice with germline knockout (KO) of Dexras1 were assayed for behavioral abnormalities as well as changes in NMDA receptor subunit protein expression. Because Dexras1 is up-regulated during stress or by dexamethasone treatment, we included measures associated with emotion including anxiety and depression. Baseline anxiety-like measures (open field and zero maze) were not altered, nor were depression-like behavior (tail suspension). Measures of memory function yielded mixed results, with no changes in episodic memory (novel object recognition) but a significant decrement on working memory (T-maze). Alternatively, there was an increase in pre-pulse inhibition (PPI), without concomitant changes in either startle amplitude or locomotor activity. PPI data are consistent with the direction of change seen following exposure to dopamine D2 antagonists. An examination of NMDA subunit expression levels revealed an increased expression of the NR2A subunit, contrary to previous studies demonstrating down-regulation of the receptor following antipsychotic exposure (Schmitt et al., 2003) and up-regulation after exposure to isolation rearing (Turnock-Jones et al., 2009). These findings suggest a potential role for Dexras1 in modulating a selective subset of psychiatric symptoms, possibly via its interaction with NMDARs and/or other disease-related binding-partners. Furthermore, data suggest that modulating Dexras1 activity has contrasting effects on emotional, sensory and cognitive domains. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
Ortega, Felipe; Pérez-Sen, Raquel; Morente, Verónica; Delicado, Esmerilda G; Miras-Portugal, Maria Teresa
2010-05-01
Glycogen synthase kinase-3 (GSK3) is a key player in the regulation of neuronal survival. Herein, we report evidence of an interaction between P2X7 receptors with NMDA and BDNF receptors at the level of GSK3 signalling and neuroprotection. The activation of these receptors in granule neurons led to a sustained pattern of GSK3 phosphorylation that was mainly PKC-dependent. BDNF was the most potent at inducing GSK3 phosphorylation, which was also dependent on PI3K. The P2X7 agonist, BzATP, exhibited additive effects with both NMDA and BDNF to rescue granule neurons from cell death induced by PI3K inhibition. This survival effect was mediated by the PKC-dependent GSK3 pathway. In addition, ERK1/2 proteins were also involved in BDNF protective effect. These results show the function of ATP in amplifying neuroprotective actions of glutamate and neurotrophins, and support the role of GSK3 as an important convergence point for these survival promoting factors in granule neurons.
Dawson, Neil; Xiao, Xiaolin; McDonald, Martin; Higham, Desmond J; Morris, Brian J; Pratt, Judith A
2014-02-01
Compromised functional integration between cerebral subsystems and dysfunctional brain network organization may underlie the neurocognitive deficits seen in psychiatric disorders. Applying topological measures from network science to brain imaging data allows the quantification of complex brain network connectivity. While this approach has recently been used to further elucidate the nature of brain dysfunction in schizophrenia, the value of applying this approach in preclinical models of psychiatric disease has not been recognized. For the first time, we apply both established and recently derived algorithms from network science (graph theory) to functional brain imaging data from rats treated subchronically with the N-methyl-D-aspartic acid (NMDA) receptor antagonist phencyclidine (PCP). We show that subchronic PCP treatment induces alterations in the global properties of functional brain networks akin to those reported in schizophrenia. Furthermore, we show that subchronic PCP treatment induces compromised functional integration between distributed neural systems, including between the prefrontal cortex and hippocampus, that have established roles in cognition through, in part, the promotion of thalamic dysconnectivity. We also show that subchronic PCP treatment promotes the functional disintegration of discrete cerebral subsystems and also alters the connectivity of neurotransmitter systems strongly implicated in schizophrenia. Therefore, we propose that sustained NMDA receptor hypofunction contributes to the pathophysiology of dysfunctional brain network organization in schizophrenia.
DEFF Research Database (Denmark)
Jensen, Anders A.; Kristiansen, Uffe
2004-01-01
In the present study, we have created a stable HEK293 cell line expressing the human homomeric alpha1 glycine receptor (GlyR) and characterised its functional pharmacology in a conventional patch-clamp assay and in the FLIPR Membrane Potential (FMP) assay, a fluorescence-based high throughput scr...... not be suited for sophisticated studies of GlyR pharmacology and kinetics. However, the assay offers several advantages in studies of ligand-receptor interactions. Furthermore, the assay could be highly useful in the search for structurally novel ligands acting at GlyRs.......In the present study, we have created a stable HEK293 cell line expressing the human homomeric alpha1 glycine receptor (GlyR) and characterised its functional pharmacology in a conventional patch-clamp assay and in the FLIPR Membrane Potential (FMP) assay, a fluorescence-based high throughput...... ion did not appear to potentiate GlyR function at lower concentrations. Analogously, whereas pregnenolone sulphate inhibited alpha1 GlyR function, the potentiation of alpha1 GlyR by pregnenolone in electrophysiological studies could not be reproduced in the assay. In conclusion, the FMP assay may...
Directory of Open Access Journals (Sweden)
Täuber Martin G
2003-09-01
Full Text Available Abstract Background Excitotoxic neuronal injury by action of the glutamate receptors of the N-methyl-d-aspartate (NMDA subtype have been implicated in the pathogenesis of brain damage as a consequence of bacterial meningitis. The most potent and selective blocker of NMDA receptors containing the NR2B subunit is (R,S-alpha-(4-hydroxyphenyl-beta-methyl-4-(phenylmethyl-1-piperid inepropanol (RO 25-6981. Here we evaluated the effect of RO 25-6981 on hippocampal neuronal apoptosis in an infant rat model of meningitis due to Streptococcus pneumoniae. Animals were randomized for treatment with RO 25-6981 at a dosage of either 0.375 mg (15 mg/kg; n = 28 or 3.75 mg (150 mg/kg; n = 15 every 3 h or an equal volume of sterile saline (250 μl; n = 40 starting at 12 h after infection. Eighteen hours after infection, animals were assessed clinically and seizures were observed for a period of 2 h. At 24 h after infection animals were sacrificed and brains were examined for apoptotic injury to the dentate granule cell layer of the hippocampus. Results Treatment with RO 25-6981 had no effect on clinical scores, but the incidence of seizures was reduced (P Conclusions Treatment with a highly selective blocker of NMDA receptors containing the NR2B subunit failed to protect hippocampal neurons from injury in this model of pneumococcal meningitis, while it had some beneficial effect on the incidence of seizures.
Characterisation of the expression of NMDA receptors in human astrocytes.
Directory of Open Access Journals (Sweden)
Ming-Chak Lee
Full Text Available Astrocytes have long been perceived only as structural and supporting cells within the central nervous system (CNS. However, the discovery that these glial cells may potentially express receptors capable of responding to endogenous neurotransmitters has resulted in the need to reassess astrocytic physiology. The aim of the current study was to characterise the expression of NMDA receptors (NMDARs in primary human astrocytes, and investigate their response to physiological and excitotoxic concentrations of the known endogenous NMDAR agonists, glutamate and quinolinic acid (QUIN. Primary cultures of human astrocytes were used to examine expression of these receptors at the mRNA level using RT-PCR and qPCR, and at the protein level using immunocytochemistry. The functionality role of the receptors was assessed using intracellular calcium influx experiments and measuring extracellular lactate dehydrogenase (LDH activity in primary cultures of human astrocytes treated with glutamate and QUIN. We found that all seven currently known NMDAR subunits (NR1, NR2A, NR2B, NR2C, NR2D, NR3A and NR3B are expressed in astrocytes, but at different levels. Calcium influx studies revealed that both glutamate and QUIN could activate astrocytic NMDARs, which stimulates Ca2+ influx into the cell and can result in dysfunction and death of astrocytes. Our data also show that the NMDAR ion channel blockers, MK801, and memantine can attenuate glutamate and QUIN mediated cell excitotoxicity. This suggests that the mechanism of glutamate and QUIN gliotoxicity is at least partially mediated by excessive stimulation of NMDARs. The present study is the first to provide definitive evidence for the existence of functional NMDAR expression in human primary astrocytes. This discovery has significant implications for redefining the cellular interaction between glia and neurons in both physiological processes and pathological conditions.
MARK/Par1 Kinase Is Activated Downstream of NMDA Receptors through a PKA-Dependent Mechanism.
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Laura P Bernard
Full Text Available The Par1 kinases, also known as microtubule affinity-regulating kinases (MARKs, are important for the establishment of cell polarity from worms to mammals. Dysregulation of these kinases has been implicated in autism, Alzheimer's disease and cancer. Despite their important function in health and disease, it has been unclear how the activity of MARK/Par1 is regulated by signals from cell surface receptors. Here we show that MARK/Par1 is activated downstream of NMDA receptors in primary hippocampal neurons. Further, we show that this activation is dependent on protein kinase A (PKA, through the phosphorylation of Ser431 of Par4/LKB1, the major upstream kinase of MARK/Par1. Together, our data reveal a novel mechanism by which MARK/Par1 is activated at the neuronal synapse.
Directory of Open Access Journals (Sweden)
Zhao Han
Full Text Available Excessive activation of the N-methyl-D-aspartic acid (NMDA type glutamate receptors (NMDARs causes excitotoxicity, a process important in stroke-induced neuronal death. Drugs that inhibit NMDA receptor-mediated [Ca(2+]i influx are potential leads for development to treat excitotoxicity-induced brain damage. Our previous studies showed that 2-(2-benzofu-ranyl-2-imidazoline (2-BFI, an immidazoline receptor ligand, dose-dependently protects rodent brains from cerebral ischemia injury. However, the molecular mechanisms remain unclear. In this study, we found that 2-BFI transiently and reversibly inhibits NMDA, but not AMPA currents, in a dose-dependent manner in cultured rat cortical neurons. The mechanism of 2-BFI inhibition of NMDAR is through a noncompetitive fashion with a faster on (Kon = 2.19±0.33×10(-9 M(-1 sec(-1 and off rate (Koff = 0.67±0.02 sec(-1 than those of memantine, a gold standard for therapeutic inhibition NMDAR-induced excitotoxicity. 2-BFI also transiently and reversibly blocked NMDA receptor-mediated calcium entry to cultured neurons and provided long-term neuroprotection against NMDA toxicity in vitro. Collectively, these studies demonstrated a potential mechanism of 2-BFI-mediated neuroprotection and indicated that 2-BFI is an excellent candidate for repositioning as a drug for stroke treatment.
Sutcu, Murat; Akturk, Hacer; Somer, Ayper; Tatli, Burak; Torun, Selda Hancerli; Yıldız, Edibe Pembegul; Şık, Guntulu; Citak, Agop; Agacfidan, Ali; Salman, Nuran
2016-03-01
Post-herpes simplex virus encephalitis relapses have been recently associated with autoimmunity driven by autoantibodies against N-methyl-d-aspartate (NMDA) receptors. Because it offers different treatment options, determination of this condition is important. Between 2011 and 2014, 7 children with proven diagnosis of herpes simplex virus encephalitis were identified in a university hospital of Istanbul. Two patients had neurologic relapse characterized mainly by movement disorders 2 to 3 weeks after initial encephalitis. The first patient received a second 14 days of acyclovir treatment together with antiepileptic drugs and left with severe neurologic sequelae. The second patient was found to be NMDA receptors antibody positive in the cerebrospinal fluid. She was treated with intravenous immunoglobulin and prednisolone. She showed substantial improvement, gradually regaining lost neurologic abilities. Post-herpes simplex virus encephalitis relapses may frequently be immune-mediated rather than a viral reactivation, particularly in children displaying movement disorders like choreoathetosis. Immunotherapy may provide benefit for this potentially devastating condition, like the case described in this report. © The Author(s) 2015.
Kubota, Akihiro; Tajima, Takashi; Narukawa, Shinya; Yamazato, Masamizu; Fukaura, Hikoaki; Takahashi, Yukitoshi; Tanaka, Keiko; Shimizu, Jun; Nomura, Kyoichi
2012-01-01
A 36-year-old man presented with cognitive impairment and disturbance of short-term memory functions with character change. Cerebrospinal fluid analysis revealed no abnormalities; however, brain MRI revealed high-signal intensity from bilateral hippocampus lesions on fluid attenuated inversion recovery (FLAIR) images and T(2) weighted images. The 18F-fluorodeoxyglucose PET demonstrated high glucose uptake in the bilateral hippocampus lesions. He was diagnosed as limbic encephalitis, and was administered high-dose intravenous methylprednisolone and immune adsorption plasma therapy followed by intravenous immunoglobulin therapy. MRI abnormalities improved after treatment but recent memory disturbance remained. Ma2 antibody, NMDA-receptor antibody, and GluRε2 antibody were positive. Eleven months atter the onset of disease, the tumor was identified in left testicle by ultrasound and removed the tumor. The pathological findings were seminoma. We experienced a case of paraneoplastic limbic encephalitis associated with seminoma with short-term memory disturbance. The occurrence of paraneoplastic limbic encephalitis with antibodies against cell membrane (NMDA-receptor antibody and GluRε2 antibody) and intracellular (Ma2 antibody) is rare even in the literature.
Contributions of conserved residues at the gating interface of glycine receptors
DEFF Research Database (Denmark)
Pless, Stephan Alexander; Leung, Ada W Y; Galpin, Jason D
2011-01-01
and the in vivo nonsense suppression method to incorporate unnatural amino acids to probe the electrostatic and hydrophobic contributions of five highly conserved side chains near the interface, Glu-53, Phe-145, Asp-148, Phe-187, and Arg-218. Our results suggest a salt bridge between Asp-148 in loop 7 and Arg-218......Glycine receptors (GlyRs) are chloride channels that mediate fast inhibitory neurotransmission and are members of the pentameric ligand-gated ion channel (pLGIC) family. The interface between the ligand binding domain and the transmembrane domain of pLGICs has been proposed to be crucial...
Chan, D W S; Thomas, T; Lim, M; Ling, S; Woodhall, M; Vincent, A
2017-03-01
Antibody-associated disorders of the central nervous system are increasingly recognised in adults and children. Some are known to be paraneoplastic, whereas in others an infective trigger is postulated. They include disorders associated with antibodies to N-methyl-d-aspartate receptor (NMDAR), voltage-gated potassium channel-complexes (VGKC-complex), GABA B receptor or glycine receptor (GlyR). With antibodies to NMDAR or VGKC-complexes, distinct clinical patterns are well characterised, but as more antibodies are discovered, the spectra of associated disorders are evolving. GlyR antibodies have been detected in patients with progressive encephalopathy with rigidity and myoclonus (PERM), or stiff man syndrome, both rare but disabling conditions. We report a case of a young child with focal seizures and progressive dyskinesia in whom GlyR antibodies were detected. Anticonvulsants and immunotherapy were effective in treating both the seizures and movement disorder with good neurological outcome and with a decline in the patient's serum GlyR-Ab titres. Glycine receptor antibodies are associated with focal status epilepticus and seizures, encephalopathy and progressive dyskinesia and should be evaluated in autoimmune encephalitis. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Zeng, Zhiwen; Wang, Dejun; Gaur, Uma; Rifang, Liao; Wang, Haitao; Zheng, Wenhua
2017-09-12
Impairment of insulin-like growth factor I (IGF-I) signaling plays an important role in the development of neurodegeneration. In the present study, we investigated the effect of H 2 O 2 on the survival signaling of IGF-1 and its underlying mechanisms in human neuronal cells SH-SY5Y. Our results showed that IGF-1 promoted cell survival and stimulated phosphorylation of IGF-1R as well as its downstream targets like AKT and ERK1/2 in these cells. Meanwhile, these effects of IGF-1 were abolished by H 2 O 2 at 200μM concentration which did not cause any significant toxicity to cells itself in our experiments. Moreover, studies using various glutamate receptor subtype antagonists displayed that N-methyl-D -aspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801) blocked the effects of H 2 O 2 , whereas other glutamate receptor subtype antagonists, such as non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX), metabolic glutamate receptor antagonists LY341495 and CPCCOEt, had no effect. Further studies revealed that NR2B-containing NMDARs are responsible for these effects as its effects were blocked by pharmacological inhibitor Ro25-698 or specific siRNA for NR2B, but not NR2A. Finally, our data also showed that Ca 2+ influx contributes to the effects of H 2 O 2 . Similar results were obtained in primary cultured cortical neurons. Taken together, the results from the present study suggested that H 2 O 2 attenuated IGF-1R tyrosine phosphorylation and its survival signaling properties via NR2B containing NMDA receptors and Ca 2+ influx in SH-SY5Y cells. Therefore, NMDAR antagonists, especially NR2B-selective ones, combined with IGF-1 may serve as an alternative therapeutic agent for oxidative stress related neurodegenerative disease.
NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin
Alagarsamy, Sudar; Saugstad, Julie; Warren, Lee; Mansuy, Isabelle M.; Gereau, Robert W.; Conn, P. Jeffrey
2010-01-01
Previous reports have shown that activation of N-methyl-D-aspartate (NMDA) receptors potentiates responses to activation of the group I metabotropic glutamate receptor mGluR5 by reversing PKC-mediated desensitization of this receptor. NMDA-induced reversal of mGluR5 desensitization is dependent on activation of protein phosphatases. However, the specific protein phosphatase involved and the precise mechanism by which NMDA receptor activation reduces mGluR desensitization are not known. We have performed a series of molecular, biochemical, and genetic studies to show that NMDA-induced regulation of mGluR5 is dependent on activation of calcium-dependent protein phosphatase 2B/calcineurin (PP2B/CaN). Furthermore, we report that purified calcineurin directly dephosphorylates the C-terminal tail of mGluR5 at sites that are phosphorylated by PKC. Finally, immunoprecipitation and GST fusion protein pull-down experiments reveal that calcineurin interacts with mGluR5, suggesting that these proteins could be colocalized in a signaling complex. Taken together with previous studies, these data suggest that activation of NMDA receptors leads to activation of calcineurin and that calcineurin modulates mGluR5 function by directly dephosphorylating mGluR5 at PKC sites that are involved in desensitization of this receptor. 2005 Elsevier Ltd. All rights reserved. PMID:16005030
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Shakarjian, Michael P., E-mail: michael_shakarjian@nymc.edu [Department of Environmental Health Science, School of Health Sciences and Practice, Institute of Public Health, New York Medical College, Valhalla, NY, 10595 (United States); Department of Medicine, Division of Pulmonary and Critical Care Medicine, UMDNJ–Robert Wood Johnson Medical School, Piscataway, NJ 08854 (United States); Velíšková, Jana [Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595 (United States); Department of Obstetrics and Gynecology, New York Medical College, Valhalla, NY 10595 (United States); Department of Neurology, New York Medical College, Valhalla, NY 10595 (United States); Stanton, Patric K., E-mail: patric_stanton@nymc.edu [Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595 (United States); Department of Neurology, New York Medical College, Valhalla, NY 10595 (United States); Velíšek, Libor [Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595 (United States); Department of Neurology, New York Medical College, Valhalla, NY 10595 (United States); Department of Pediatrics, New York Medical College, Valhalla, NY 10595 (United States)
2012-11-15
Tetramethylenedisulfotetramine (TMDT) is a highly lethal neuroactive rodenticide responsible for many accidental and intentional poisonings in mainland China. Ease of synthesis, water solubility, potency, and difficulty to treat make TMDT a potential weapon for terrorist activity. We characterized TMDT-induced convulsions and mortality in male C57BL/6 mice. TMDT (ip) produced a continuum of twitches, clonic, and tonic–clonic seizures decreasing in onset latency and increasing in severity with increasing dose; 0.4 mg/kg was 100% lethal. The NMDA antagonist, ketamine (35 mg/kg) injected ip immediately after the first TMDT-induced seizure, did not change number of tonic–clonic seizures or lethality, but increased the number of clonic seizures. Doubling the ketamine dose decreased tonic–clonic seizures and eliminated lethality through a 60 min observation period. Treating mice with another NMDA antagonist, MK-801, 0.5 or 1 mg/kg ip, showed similar effects as low and high doses of ketamine, respectively, and prevented lethality, converting status epilepticus EEG activity to isolated interictal discharges. Treatment with these agents 15 min prior to TMDT administration did not increase their effectiveness. Post-treatment with the GABA{sub A} receptor allosteric enhancer diazepam (5 mg/kg) greatly reduced seizure manifestations and prevented lethality 60 min post-TMDT, but ictal events were evident in EEG recordings and, hours post-treatment, mice experienced status epilepticus and died. Thus, TMDT is a highly potent and lethal convulsant for which single-dose benzodiazepine treatment is inadequate in managing electrographic seizures or lethality. Repeated benzodiazepine dosing or combined application of benzodiazepines and NMDA receptor antagonists is more likely to be effective in treating TMDT poisoning. -- Highlights: ► TMDT produces convulsions and lethality at low doses in mice. ► Diazepam pre- or post-treatments inhibit TMDT-induced convulsions and death
Agmatine protects against cell damage induced by NMDA and glutamate in cultured hippocampal neurons
Wang, Wei-Ping; Iyo, Abiye H.; Miguel-Hidalgo, Javier; Regunathan, Soundar; Zhu, Meng-Yang
2010-01-01
Agmatine is a polyamine and has been considered as a novel neurotransmitter or neuromodulator in the central nervous system. In the present study, the neuroprotective effect of agmatine against cell damage caused by N-methyl-d-aspartate (NMDA) and glutamate was investigated in cultured rat hippocampal neurons. Lactate dehydrogenase (LDH) activity assay, β-tubulin III immunocytochemical staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL) assay were conducted to detect cell damage. Exposure of 12-day neuronal cultures of rat hippocampus to NMDA or glutamate for 1 h caused a concentration-dependent neurotoxicity, as indicated by the significant increase in released LDH activities. Addition of 100 µM agmatine into media ablated the neurotoxicity induced by NMDA or glutamate, an effect also produced by the specific NMDA receptor antagonist dizocilpine hydrogen maleate (MK801). Arcaine, an analog of agmatine with similar structure as agmatine, fully prevented the NMDA- or glutamate-induced neuronal damage. Spermine and putrescine, the endogenous polyamine and metabolic products of agmatine without the guanidine moiety of agmatine, failed to show this effect, indicating a structural relevance for this neuroprotection. Immunocytochemical staining and TUNEL assay confirmed the findings in the LDH measurement. That is, agmatine and MK801 markedly attenuated NMDA-induced neuronal death and significantly reduced TUNEL-positive cell numbers induced by exposure of cultured hippocampal neurons to NMDA. Taken together, these results demonstrate that agmatine can protect cultured hippocampal neurons from NMDA- or glutamate-induced excitotoxicity, through a possible blockade of the NMDA receptor channels or a potential anti-apoptotic property. PMID:16546145
MacQueen, David A.; Dalrymple, Savannah R.; Drobes, David J.; Diamond, David M.
2016-01-01
Developed as a tool to assess working memory capacity in rodents, the odor span task (OST) has significant potential to advance drug discovery in animal models of psychiatric disorders. Prior investigations indicate OST performance is impaired by systemic administration of N-methyl-D-aspartate receptor (NMDA-r) antagonists and is sensitive to…
Zoladz, Phillip R; Campbell, Adam M; Park, Collin R; Schaefer, Daniela; Danysz, Wojciech; Diamond, David M
2006-10-01
Memantine and neramexane are noncompetitive NMDA receptor antagonists which have been investigated for their promising effects in aiding memory in people with dementia. Memantine is approved for the treatment of Alzheimer's disease, and neramexane is currently under development for this indication. Therefore, the present study provided a comparative assessment of the effects of equimolar doses of memantine and neramexane on spatial (hippocampus-dependent) memory. Adult male rats were given only 3 training trials to learn the location of a hidden platform in a water maze. In control (vehicle-injected) rats, this minimal amount of training produced intact short-term (15 min), but poor long-term (24 h), memory. Pre-training administration of memantine or neramexane produced a dose-dependent enhancement of long-term memory. Pharmacokinetic experiments with equimolar doses of both agents indicated that lower plasma levels of neramexane were more effective than memantine at enhancing memory. The effective doses of both agents in the current study produced plasma levels (and extrapolated brain CSF levels) within a range of activity at NMDA receptors and plasma levels seen in patients with Alzheimer's disease. These findings provide support for the use of neramexane as a pharmacological intervention in the treatment of dementia.
Marcus, Monica M; Jardemark, Kent; Malmerfelt, Anna; Björkholm, Carl; Svensson, Torgny H
2010-01-01
Preclinical data have shown that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine increases the antipsychotic-like effect of the D2/3 antagonist raclopride and, in parallel, enhances cortical dopamine output. Subsequent clinical results suggested that adding reboxetine to stable treatments with various antipsychotic drugs (APDs) may improve positive, negative and depressive symptoms in schizophrenia. In this study, we investigated in rats the effects of adding reboxetine to the second-generation APD olanzapine on: (i) antipsychotic efficacy, using the conditioned avoidance response (CAR) test, (ii) extrapyramidal side effect (EPS) liability, using a catalepsy test, (iii) dopamine efflux in the medial prefrontal cortex and the nucleus accumbens, using in vivo microdialysis in freely moving animals and (iv) cortical N-methyl--aspartate (NMDA) receptor-mediated transmission, using intracellular electrophysiological recording in vitro. Reboxetine (6 mg/kg) enhanced the suppression of CAR induced by a suboptimal dose (1.25 mg/kg), but not an optimal (2.5 mg/kg) dose of olanzapine without any concomitant catalepsy. Addition of reboxetine to the low dose of olanzapine also markedly increased cortical dopamine outflow and facilitated prefrontal NMDA receptor-mediated transmission. Our data suggest that adjunctive treatment with a NET inhibitor may enhance the therapeutic effect of low-dose olanzapine in schizophrenia without increasing EPS liability and add an antidepressant action, thus in principle allowing for a dose reduction of olanzapine with a concomitant reduction of dose-related side effects, such as EPS and weight gain. PMID:20463659
Ostadhadi, Sattar; Khan, Muhammad Imran; Norouzi-Javidan, Abbas; Chamanara, Mohsen; Jazaeri, Farahnaz; Zolfaghari, Samira; Dehpour, Ahmad-Reza
2016-04-01
Topiramate (TPM) is an agent primarily used in the treatment of epilepsy. Using mice model of forced swimming test (FST) the current study was basically aimed to investigate the influence of TPM on depression by inhibiting NMDA receptor and nitric oxide-cGMP production. When TPM was administered in a dose of 20 and 30 mg/kg by i.p. route it reduced the immobility time during FST. However this effect of TPM (30 mg/kg, i.p.) in the FST was abolished when the mice were pretreated either with NMDA (75 mg/kg, i.p.), or l-arginine (750 mg/kg, i.p. NO precursor), or sildenafil (5mg/kg, i.p. Phosphodiesterase 5 inhibitor). The immobility time in the FST was reduced after administration of L-NAME (10mg/kg, i.p, a non-specific NOS inhibitor), 7-nitoinidazol (30 mg/kg, i.p. a nNOS inhibitor) or MK-801 (0.05 mg/kg, i.p, a NMDA receptor antagonist) in combination with a subeffective dose of TPM (10mg/kg, i.p.) as compared with single use of either drug. Co-administrated of lower doses of MK-801 (0.01 mg/kg) or L-NAME (1mg/kg) failed to effect immobility time. However, simultaneous administration of these two agents in the same doses with subeffective dose of TPM (10mg/kg, i.p.), reduced the immobility time during FST. None of these drugs were found to have a profound effect on the locomotor activity per se during the open field test. Taken together, our data demonstrates that TPM exhibit antidepressant-like effect which is accomplished either due to inhibition of NMDA receptors or NO-cGMP production. Copyright © 2016 Elsevier Inc. All rights reserved.
Kinetic modelling of [123I]CNS 1261--a potential SPET tracer for the NMDA receptor
International Nuclear Information System (INIS)
Erlandsson, Kjell; Bressan, Rodrigo A.; Mulligan, Rachel S.; Gunn, Roger N; Cunningham, Vincent J.; Owens, Jonathan; Wyper, David; Ell, Peter J.; Pilowsky, Lyn S.
2003-01-01
N-(1-napthyl)-N'-(3-[ 123 I]-iodophenyl)-N-methylguanidine ([ 123 I]CNS 1261) is a novel SPET ligand developed for imaging the NMDA receptor intra-channel MK 801/PCP/ketamine site. Data was acquired in 7 healthy volunteers after bolus injection of [ 123 I]CNS 1261. Kinetic modeling showed reversible tracer binding. Arterial and venous time-activity curves overlapped after 90 min. The rank order of binding was: Thalamus > striatum > cortical regions > white matter. This distribution concurs with [ 11 C]-ketamine and [ 18 F]-memantine PET studies . These data provide a methodological basis for further direct in vivo challenge studies
DEFF Research Database (Denmark)
Rinaldi, Tania; Kulangara, Karina; Antoniello, Katia
2007-01-01
as the commonly linked kinase calcium/calmodulin-dependent protein kinase II. Synaptic plasticity experiments between pairs of pyramidal neurons revealed an augmented postsynaptic form of long-term potentiation. These results indicate that VPA significantly enhances NMDA receptor-mediated transmission and causes......Valproic acid (VPA) is a powerful teratogen causing birth defects in humans, including autism spectrum disorder (ASD), if exposure occurs during the first trimester of embryogenesis. Learning and memory alterations are common symptoms of ASD, but underlying molecular and synaptic alterations remain...
Directory of Open Access Journals (Sweden)
Yoko Hagino
Full Text Available Phencyclidine (PCP, a noncompetitive N-methyl-D-aspartate (NMDA receptor antagonist, increases locomotor activity in rodents and causes schizophrenia-like symptoms in humans. Although activation of the dopamine (DA pathway is hypothesized to mediate these effects of PCP, the precise mechanisms by which PCP induces its effects remain to be elucidated. The present study investigated the effect of PCP on extracellular levels of DA (DA(ex in the striatum and prefrontal cortex (PFC using in vivo microdialysis in mice lacking the NMDA receptor channel ε1 or ε4 subunit (GluRε1 [GluN2A] or GluRε4 [GluN2D] and locomotor activity. PCP significantly increased DA(ex in wildtype and GluRε1 knockout mice, but not in GluRε4 knockout mice, in the striatum and PFC. Acute and repeated administration of PCP did not increase locomotor activity in GluRε4 knockout mice. The present results suggest that PCP enhances dopaminergic transmission and increases locomotor activity by acting at GluRε4.
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Karel eVales
2014-04-01
Full Text Available A number of studies demonstrated a rapid onset of an antidepressant effect of non-competitive NMDA receptor antagonists. Nonetheless, its therapeutic potential is rather limited, due to a high coincidence of negative side-effects. Therefore, the challenge seems to be in the development of NMDA receptor (NMDAR antagonists displaying antidepressant properties, and at the same time maintaining regular physiological function of the NMDAR. Previous results demonstrated that naturally occurring neurosteroid 3α5β-pregnanolone sulfate shows pronounced inhibitory action by a use-dependent mechanism on the tonically active NMDAR. The aim of the present experiments is to find out whether the treatment with pregnanolone 3αC derivatives affects behavioral response to chronic and acute stress in an animal model of depression. Adult male mice were used throughout the study. Repeated social defeat and forced swimming tests were used as animal models of depression. The effect of the drugs on the locomotor/exploratory activity in the open-field test was also tested together with an effect on anxiety in the elevated plus maze. Results showed that pregnanolone glutamate (PG did not induce hyperlocomotion, whereas both dizocilpine and ketamine significantly increased spontaneous locomotor activity in the open field. In the elevated plus maze PG displayed anxiolytic-like properties. In forced swimming PG prolonged time to the first floating. Acute treatment of PG disinhibited suppressed locomotor activity in the repeatedly defeated group-housed mice. Aggressive behavior of isolated mice was reduced after the chronic 30-day administration of PG. PG showed antidepressant-like and anxiolytic-like properties in the used tests, with minimal side-effects. Since PG combines GABAA receptor potentiation and use-dependent NMDAR inhibition, synthetic derivatives of neuroactive steroids present a promising strategy for the treatment of mood disorders.
Adamec, R E
1998-01-01
The anxiogenic beta-carboline, FG-7142, produces intense anxiety in humans and anxiety-like behavior in animals. FG-7142 also mimics the effects of exogenous stressors. In cats, FG-7142 lastingly changes defensive and aggressive behavior. Long-term potentiation (LTP) of neural transmission between limbic structures known to modulate feline defensive response to threat accompany behavioral changes. A series of three reports describes experiments designed to test the hypothesis that behavioral changes depend upon an N-methyl-D-aspartate (NMDA) receptor-based LTP of efferent transmission from the amygdala. This first study characterizes the dose and time effects of injection of the NMDA receptor blocker 7-amino-phosphono-heptanoic acid (AP7) on efferent transmission from the cat amygdala to the ventromedial hypothalamus (VMH). Effects of doses of 0.5-10mg/kg (i.v.) of AP7 on potentials evoked in the VMH by single pulse stimulation of the basal amygdala were examined. In order to localize the action of the drug, concurrent measurements were taken of potentials evoked in the VMH by stimulation of the efferent fibers from the amygdala to the VMH (ventral amygdalofugal pathway, VAF). There was a dose-dependent reduction in the amygdalo-VMH evoked potential. The greatest reduction occurred at 5 mg/kg. Effects peaked at 10 min, and persisted for at least 1 h after injection. In contrast, AP7 increased the VAF-VMH-evoked potential at 10 min after injection, with a maximal increase at 5mg/kg. The data suggest that NMDA receptors intrinsic to the amygdala modulate excitatory efferent transmission from amygdala to VMH in the cat. It is speculated that a glutamatergic projection to gamma-aminobutyric acid tonic inhibitory systems in the VMH accounts for the VAF-VMH results.
Energy Technology Data Exchange (ETDEWEB)
Beart, P M; Mercer, L D; Jarrott, B [University of Melbourne, Clinical Pharmacology and Therapeutics Unit, Austin Hospital, Heidelberg, Vic (Australia)
1991-04-01
Iodination of ifenprodil, a non-competitive NMDA antagonist, with Na{sup 125}I/Chloramin-T gave a radioligand which bound rapidly and saturably to a single population of sites (dissociation constant 145 nM) in membranes of rat cerebral cortex. In competition studies, specific binding of ({sup 125}I)-ifenprodil was inhibited by analogues of ifenprodil, as well as by spermine and spermidine. Binding was sensitive to Ca{sup 2+}, Mg{sup 2+} and Zn{sup 2+}. ({sup 125}I)-Ifenprodil labelled a population of binding sites, which was topographically distributed in rat forebrain, as shown by autoradiography. ({sup 125}I)-Ifenprodil is a useful radioligand for the investigation of the polyamine site of the N-methyl-D-aspartate (NMDA) receptor-complex. (author).
Toxic acrolein production due to Ca(2+) influx by the NMDA receptor during stroke.
Nakamura, Mizuho; Uemura, Takeshi; Saiki, Ryotaro; Sakamoto, Akihiko; Park, Hyerim; Nishimura, Kazuhiro; Terui, Yusuke; Toida, Toshihiko; Kashiwagi, Keiko; Igarashi, Kazuei
2016-01-01
N-Methyl-d-aspartate (NMDA) receptors have a high permeability to Ca(2+), contributing to neuronal cell death after stroke. We recently found that acrolein produced from polyamines is a major toxic compound during stroke. Thus, it was determined whether over-accumulation of Ca(2+) increases the production of acrolein from polyamines in a photochemically-induced thrombosis mouse model of stroke and in cell culture systems. A unilateral infarction was induced in mouse brain by photoinduction after injection of Rose Bengal. The volume of the infarction was analyzed using the public domain National Institutes of Health image program. Protein-conjugated acrolein levels at the locus of infarction and in cells were measured by Western blotting. Levels of polyamines were measured by high-performance liquid chromatography. When the size of brain infarction was decreased by N(1), N(4), N(8)-tribenzylspermidine, a channel blocker of the NMDA receptors, levels of Ca(2+) and protein-conjugated acrolein (PC-Acro) were reduced, while levels of polyamines were increased at the locus of infarction. When cell growth of mouse mammary carcinoma FM3A cells and neuroblastoma Neuro2a cells was inhibited by Ca(2+), the level of polyamines decreased, while that of PC-Acro increased. It was also shown that Ca(2+) toxicity was decreased in an acrolein toxicity decreasing FM3A mutant cells recently isolated. In addition, 20-40 μM Ca(2+) caused the release of polyamines from ribosomes. The results indicate that acrolein is produced from polyamines released from ribosomes through Ca(2+) increase. The results indicate that toxicity of Ca(2+) during brain infarction is correlated with the increase of acrolein. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Ramadan, Epolia; Basselin, Mireille; Rao, Jagadeesh S.; Chang, Lisa; Chen, Mei; Ma, Kaizong; Rapoport, Stanley I.
2011-01-01
An upregulated brain arachidonic acid (AA) cascade and a hyperglutamatergic state characterize bipolar disorder (BD). Lamotrigine (LTG), a mood stabilizer approved for treating BD, is reported to interfere with glutamatergic neurotransmission involving N-methyl-D-aspartate receptors (NMDARs). NMDARs allow extracellular calcium into the cell, thereby stimulating calcium-dependent cytosolic phospholipase A2 (cPLA2) to release arachidonic acid (AA) from membrane phospholipid. We hypothesized that LTG, like other approved mood stabilizers, would reduce NMDAR-mediated AA signaling in rat brain. An acute subconvulsant dose of NMDA (25 mg/kg) or saline was administered intraperitoneally to unanesthetized rats that had been treated p.o. daily for 42 days with vehicle or a therapeutically relevant dose of LTG (10 mg/kg/.d). Regional brain AA incorporation coefficients k* and rates Jin, AA signals, were measured using quantitative autoradiography after intravenous [1-14C]AA infusion, as were other AA cascade markers. In chronic vehicle-treated rats, acute NMDA compared to saline increased k* and Jin in widespread regions of the brain, as well as prostaglandin (PG)E2 and thromboxane B2 concentrations. Chronic LTG treatment compared to vehicle reduced brain cyclooxygenase (COX) activity, PGE2 concentration, and DNA binding activity of the COX-2 transcription factor, NF-κB. Pretreatment with chronic LTG blocked the acute NMDA effects on AA cascade markers. In summary, chronic LTG like other mood stabilizers blocks NMDA-mediated signaling involving the AA metabolic cascade. Since markers of the AA cascade and of NMDAR signaling are up-regulated in the postmortem BD brain, mood stabilizers generally may be effective in BD by dampening NMDAR signalling and the AA cascade. PMID:21733229
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Sinem eAtak
2015-12-01
Full Text Available Ligand-binding of Cys-loop receptors is determined by N-terminal extracellular loop structures from the plus as well as from the minus side of two adjacent subunits in the pentameric receptor complex. An aromatic residue in loop B of the glycine receptor (GlyR undergoes direct interaction with the incoming ligand via cation-π interactions. Recently we showed that mutated residues in loop B identified from human patients suffering from hyperekplexia disturb ligand-binding. Here, we exchanged the affected human residues by amino acids found in related members of the Cys-loop receptor family to determine the effects of side chain volume for ion channel properties. GlyR variants were characterized in vitro following transfection into cell lines in order to analyze protein expression, trafficking, degradation and ion channel function. GlyR α1 G160 mutations significantly decrease glycine potency arguing for a positional effect on neighboring aromatic residues and consequently glycine-binding within the ligand-binding pocket. Disturbed glycinergic inhibition due to T162 α1 mutations is an additive effect of affected biogenesis and structural changes within the ligand-binding site. Protein trafficking from the ER towards ER-Golgi intermediate compartment, the secretory Golgi pathways and finally the cell surface is largely diminished, but still sufficient to deliver ion channels that are functional at least at high glycine concentrations. The majority of T162 mutant protein accumulates in the ER and is conducted to ER-associated proteasomal degradation. Hence, G160 is an important determinant during glycine binding. In contrast, T162 assigns primarily receptor biogenesis whereas exchanges in functionality are secondary effects thereof.
Energy Technology Data Exchange (ETDEWEB)
Labas, R
2007-07-01
The aim of this thesis was to develop new radioactive tracers for imaging NR2B subtype NMDA receptors with positron emission tomography. Several compounds including 4-(4-fluoro-benzyl)piperidine and presenting interesting in vivo biological properties were the object of a labelling with a positrons emitter atom ({sup 11}C or {sup 18}F)
International Nuclear Information System (INIS)
Eng, W.S.; Burns, H.D.; Gibson, R.E.; Ransom, R.W.; Thorpe, H.; Fioravanit, C.; Britcher, S.F.; Magill, C.A.; Solomon, H.F.; Dannals, R.F.; Wilson, A.A.; Ravert, H.T.; Wagner, H.N.
1989-01-01
MK-801 is a potent, non-competitive antagonist for the N-methyl-D-asspartate (NMDA) receptor-ion channel complex. This complex is though to be involved in nerve cell damage in stroke patients when excess calcium is released through the activated channel. A thorough understanding of drug interactions with the NMDA receptor complex could lead to improved therapy for reducing hypoxic-ischemic neuronal injuries in stroke patients. Based on the results of extensive structure-activity studies, the authors have developed several enantiomerically enriched, radiolabeled analogs of MK-801, including: 3-1231-MK-801 for Single Photon Emission Computed tomography (SPECT); 3-1251-MK-801 for in-vivo and in-vitro autoradiography; 8-11C-MeO-MK-801 for Positron Emission Tomography (PET). Details of the synthesis of these radiotracers and their application to both in-vitro and in-vivo studies are described
Ostadhadi, Sattar; Ahangari, Mohammad; Nikoui, Vahid; Norouzi-Javidan, Abbas; Zolfaghari, Samira; Jazaeri, Farahnaz; Chamanara, Mohsen; Akbarian, Reyhaneh; Dehpour, Ahmad-Reza
2016-08-01
Lamotrigine is an anticonvulsant agent that shows clinical antidepressant properties. The aim of the present study was to investigate the involvement of N-methyl-d-aspartate (NMDA) receptors and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) synthesis in possible antidepressant-like effect of lamotrigine in forced swimming test (FST) in mice. Intraperitoneal administration of lamotrigine (10mg/kg) decreased the immobility time in the FST (P<0.01) without any effect on locomotor activity in the open-field test (OFT), while higher dose of lamotrigine (30mg/kg) reduced the immobility time in the FST (P<0.001) as well as the number of crossings in the OFT. Pretreatment of animals with NMDA (75mg/kg), l-arginine (750mg/kg, a substrate for nitric oxide synthase [NOS]) or sildenafil (5mg/kg, a phosphodiesterase [PDE] 5 inhibitor) reversed the antidepressant-like effect of lamotrigine (10mg/kg) in the FST. Injection of l-nitroarginine methyl ester (l-NAME, 10mg/kg, a non-specific NOS inhibitor), 7-nitroindazole (30mg/kg, a neuronal NOS inhibitor), methylene blue (20mg/kg, an inhibitor of both NOS and soluble guanylate cyclase [sGC]), or MK-801 (0.05mg/kg), ketamine (1mg/kg), and magnesium sulfate (10mg/kg) as NMDA receptor antagonists in combination with a sub-effective dose of lamotrigine (5mg/kg) diminished the immobility time of animals in the FST compared with either drug alone. None of the drugs produced significant effects on the locomotor activity in the OFT. Based on our findings, it is suggested that the antidepressant-like effect of lamotrigine might mediated through inhibition of either NMDA receptors or NO-cGMP synthesis. Copyright © 2016. Published by Elsevier Masson SAS.
DEFF Research Database (Denmark)
Bode, Anna; Wood, Sian-Elin; Mullins, Jonathan G L
2013-01-01
Hyperekplexia is a syndrome of readily provoked startle responses, alongside episodic and generalized hypertonia, that presents within the first month of life. Inhibitory glycine receptors are pentameric ligand-gated ion channels with a definitive and clinically well stratified linkage...... a structural mechanism for channel activation. Receptors incorporating p.P230S (which is heterozygous with p.R65W) desensitized much faster than wild type receptors and represent a new TM1 site capable of modulating desensitization. The recessive mutations p.R72C, p.R218W, p.L291P, p.D388A, and p.E375X...... precluded cell surface expression unless co-expressed with α1 wild type subunits. The recessive p.E375X mutation resulted in subunit truncation upstream of the TM4 domain. Surprisingly, on the basis of three independent assays, we were able to infer that p.E375X truncated subunits are incorporated...
Calon, Frédéric; Lim, Giselle P; Morihara, Takashi; Yang, Fusheng; Ubeda, Oliver; Salem, Norman; Frautschy, Sally A; Cole, Greg M
2005-08-01
Epidemiological data indicate that low n-3 polyunsaturated fatty acids (PFA) intake is a readily manipulated dietary risk factor for Alzheimer's disease (AD). Studies in animals confirm the deleterious effect of n-3 PFA depletion on cognition and on dendritic scaffold proteins. Here, we show that in transgenic mice overexpressing the human AD gene APPswe (Tg2576), safflower oil-induced n-3 PFA deficiency caused a decrease in N-methyl-D-aspartate (NMDA) receptor subunits, NR2A and NR2B, in the cortex and hippocampus with no loss of the presynaptic markers, synaptophysin and synaptosomal-associated protein 25 (SNAP-25). n-3 PFA depletion also decreased the NR1 subunit in the hippocampus and Ca2+/calmodulin-dependent protein kinase (CaMKII) in the cortex of Tg2576 mice. These effects of dietary n-3 PFA deficiency were greatly amplified in Tg2576 mice compared to nontransgenic mice. Loss of the NR2B receptor subunit was not explained by changes in mRNA expression, but correlated with p85alpha phosphatidylinositol 3-kinase levels. Most interestingly, n-3 PFA deficiency dramatically increased levels of protein fragments, corresponding to caspase/calpain-cleaved fodrin and gelsolin in Tg2576 mice. This effect was minimal in nontransgenic mice suggesting that n-3 PFA depletion potentiated caspase activation in the Tg2576 mouse model of AD. Dietary supplementation with docosahexaenoic acid (DHA; 22 : 6n-3) partly protected from NMDA receptor subunit loss and accumulation of fodrin and gelsolin fragments but fully prevented CaMKII decrease. The marked effect of dietary n-3 PFA on NMDA receptors and caspase/calpain activation in the cortex of an animal model of AD provide new insights into how dietary essential fatty acids may influence cognition and AD risk.
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Mengwen Qi
2018-02-01
Full Text Available Background/Aims: Glycine plays an important role in regulating hippocampal inhibitory/ excitatory neurotransmission through activating glycine receptors (GlyRs and acting as a co-agonist of N-methyl-d-aspartate-type glutamate receptors. Activation of transient receptor potential vanilloid 4 (TRPV4 is reported to inhibit hippocampal A-type γ-aminobutyric acid receptor, a ligand-gated chloride ion channel. GlyRs are also ligand-gated chloride ion channels and this paper aimed to explore whether activation of TRPV4 could modulate GlyRs. Methods: Whole-cell patch clamp recording was employed to record glycine-activated current (IGly and Western blot was conducted to assess GlyRs subunits protein expression. Results: Application of TRPV4 agonist (GSK1016790A or 5,6-EET increased IGly in mouse hippocampal CA1 pyramidal neurons. This action was blocked by specific antagonists of TRPV4 (RN-1734 or HC-067047 and GlyR (strychnine, indicating that activation of TRPV4 increases strychnine-sensitive GlyR function in mouse hippocampal pyramidal neurons. GSK1016790A-induced increase in IGly was significantly attenuated by protein kinase C (PKC (BIM II or D-sphingosine or calcium/calmodulin-dependent protein kinase II (CaMKII (KN-62 or KN-93 antagonists but was unaffected by protein kinase A or protein tyrosine kinase antagonists. Finally, hippocampal protein levels of GlyR α1 α2, α3 and β subunits were not changed by treatment with GSK1016790A for 30 min or 1 h, but GlyR α2, α3 and β subunits protein levels increased in mice that were intracerebroventricularly (icv. injected with GSK1016790A for 5 d. Conclusion: Activation of TRPV4 increases GlyR function and expression, and PKC and CaMKII signaling pathways are involved in TRPV4 activation-induced increase in IGly. This study indicates that GlyRs may be effective targets for TRPV4-induced modulation of hippocampal inhibitory neurotransmission.
Activity-dependent control of NMDA receptor subunit composition at hippocampal mossy fibre synapses.
Carta, Mario; Srikumar, Bettadapura N; Gorlewicz, Adam; Rebola, Nelson; Mulle, Christophe
2018-02-15
CA3 pyramidal cells display input-specific differences in the subunit composition of synaptic NMDA receptors (NMDARs). Although at low density, GluN2B contributes significantly to NMDAR-mediated EPSCs at mossy fibre synapses. Long-term potentiation (LTP) of NMDARs triggers a modification in the subunit composition of synaptic NMDARs by insertion of GluN2B. GluN2B subunits are essential for the expression of LTP of NMDARs at mossy fibre synapses. Single neurons express NMDA receptors (NMDARs) with distinct subunit composition and biophysical properties that can be segregated in an input-specific manner. The dynamic control of the heterogeneous distribution of synaptic NMDARs is crucial to control input-dependent synaptic integration and plasticity. In hippocampal CA3 pyramidal cells from mice of both sexes, we found that mossy fibre (MF) synapses display a markedly lower proportion of GluN2B-containing NMDARs than associative/commissural synapses. The mechanism involved in such heterogeneous distribution of GluN2B subunits is not known. Here we show that long-term potentiation (LTP) of NMDARs, which is selectively expressed at MF-CA3 pyramidal cell synapses, triggers a modification in the subunit composition of synaptic NMDARs by insertion of GluN2B. This activity-dependent recruitment of GluN2B at mature MF-CA3 pyramidal cell synapses contrasts with the removal of GluN2B subunits at other glutamatergic synapses during development and in response to activity. Furthermore, although expressed at low levels, GluN2B is necessary for the expression of LTP of NMDARs at MF-CA3 pyramidal cell synapses. Altogether, we reveal a previously unknown activity-dependent regulation and function of GluN2B subunits that may contribute to the heterogeneous plasticity induction rules in CA3 pyramidal cells. © 2017 Centre Nationnal de la Recherche Scientifique. The Journal of Physiology © 2017 The Physiological Society.
Levite, Mia
2014-08-01
Glutamate is the major excitatory neurotransmitter of the Central Nervous System (CNS), and it is crucially needed for numerous key neuronal functions. Yet, excess glutamate causes massive neuronal death and brain damage by excitotoxicity--detrimental over activation of glutamate receptors. Glutamate-mediated excitotoxicity is the main pathological process taking place in many types of acute and chronic CNS diseases and injuries. In recent years, it became clear that not only excess glutamate can cause massive brain damage, but that several types of anti-glutamate receptor antibodies, that are present in the serum and CSF of subpopulations of patients with a kaleidoscope of human neurological diseases, can undoubtedly do so too, by inducing several very potent pathological effects in the CNS. Collectively, the family of anti-glutamate receptor autoimmune antibodies seem to be the most widespread, potent, dangerous and interesting anti-brain autoimmune antibodies discovered up to now. This impression stems from taking together the presence of various types of anti-glutamate receptor antibodies in a kaleidoscope of human neurological and autoimmune diseases, their high levels in the CNS due to intrathecal production, their multiple pathological effects in the brain, and the unique and diverse mechanisms of action by which they can affect glutamate receptors, signaling and effects, and subsequently impair neuronal signaling and induce brain damage. The two main families of autoimmune anti-glutamate receptor antibodies that were already found in patients with neurological and/or autoimmune diseases, and that were already shown to be detrimental to the CNS, include the antibodies directed against ionotorpic glutamate receptors: the anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies and anti-NMDA-NR2 antibodies, and the antibodies directed against Metabotropic glutamate receptors: the anti-mGluR1 antibodies and the anti-mGluR5 antibodies. Each type of these anti
DEFF Research Database (Denmark)
Kucharz, Krzysztof; Søndergaard Rasmussen, Ida; Bach, Anders
2017-01-01
during the first hour after i.v. injection. The Tat-N-dimer suppressed stimulation-evoked synaptic activity by 2-20%, while cortical blood flow and cerebral oxygen metabolic (CMRO2) responses were preserved. During cortical spreading depression, the Tat-N-dimer reduced the average amplitude...... depression on cortical blood flow and CMRO2 We suggest that uncoupling of PSD-95 from NMDA receptors reduces overall neuronal excitability and the amplitude of the spreading depolarisation wave. These findings may be of interest for understanding the neuroprotective effects of the nNOS/PSD-95 uncoupling...
Directory of Open Access Journals (Sweden)
Shan-xue Jin
Full Text Available BACKGROUND: NMDA-type glutamate receptors (NMDARs are major contributors to long-term potentiation (LTP, a form of synaptic plasticity implicated in the process of learning and memory. These receptors consist of calcium-permeating NR1 and multiple regulatory NR2 subunits. A majority of studies show that both NR2A and NR2B-containing NMDARs can contribute to LTP, but their unique contributions to this form of synaptic plasticity remain poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we show that NR2A and NR2B-containing receptors promote LTP differently in the CA1 hippocampus of 1-month old mice, with the NR2A receptors functioning through Ras-GRF2 and its downstream effector, Erk Map kinase, and NR2B receptors functioning independently of these signaling molecules. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that NR2A-, but not NR2B, containing NMDA receptors induce LTP in pyramidal neurons of the CA1 hippocampus from 1 month old mice through Ras-GRF2 and Erk. This difference add new significance to the observation that the relative levels of these NMDAR subtypes is regulated in neurons, such that NR2A-containing receptors become more prominent late in postnatal development, after sensory experience and synaptic activity.
Early history of glycine receptor biology in mammalian spinal cord circuits
Directory of Open Access Journals (Sweden)
Robert J Callister
2010-05-01
Full Text Available In this review we provide an overview of key in vivo experiments, undertaken in the cat spinal cord in the 1950s and 1960s, and point out their contributions to our present understanding of glycine receptor (GlyR function. Importantly, some of these discoveries were made well before an inhibitory receptor, or its agonist, was identified. These contributions include the universal acceptance of a chemical mode of synaptic transmission, that GlyRs are chloride channels, are involved in reciprocal and recurrent spinal inhibition, are selectively blocked by strychnine, and can be distinguished from the GABAA receptor by their insensitivity to bicuculline. The early in vivo work on inhibitory mechanisms in spinal neurons also contributed to several enduring principles on synaptic function, such as the time associated with synaptic delay, the extension of Dale’s hypothesis (regarding the chemical unity of nerve cells and their terminals to neurons within the central nervous system, and the importance of inhibition for synaptic integration in motor and sensory circuits. We hope the work presented here will encourage those interested in GlyR biology and inhibitory mechanisms to seek out and read some of the “classic” articles that document the above discoveries.
International Nuclear Information System (INIS)
Gillberg, P.-G.; Aquilonius, S.-M.
1985-01-01
Binding sites for the receptor ligands 3 H-quinuclidinylbenzilate, 3 H-alpha-bungarotoxin ( 3 H-alpha-Btx), 3 H-etorphine and 3 H-strychnine were localized autoradiographically at cervical, thoracic and lumbar levels of spinal cords from post-mortem human control subjects and subjects with amyotrophic lateral sclerosis (ALS). The highest densities of muscarinic binding sites were found in the motor neuron areas and in the substantia gelatinosa, while the grey matter binding was very low within Clarke's column. Both 3 H-alpha-Btx and opioid receptor binding sites were numerous within the substantia gelatinosa, while glycine receptor binding sites were more uniformly distribute within the spinal grey matter. In ALS cases, muscarinic receptor binding sites were markedly reduced in motor neuron areas and slightly reduced in the dorsal horn, while the other binding sites studied were relatively unchanged. (author)
Featherstone, Robert E; Shin, Rick; Kogan, Jeffrey H; Liang, Yuling; Matsumoto, Mitsuyuki; Siegel, Steven J
2015-01-01
Reductions in glutamate function are regarded as an important contributory factor in schizophrenia. However, there is a paucity of animal models characterized by developmental and sustained reductions in glutamate function. Pharmacological models using NMDA antagonists have been widely used but these typically produce only transient changes in behavior and brain function. Likewise, mice with homozygous constitutive reductions in glutamate receptor expression show stable brain and behavioral changes, but many of these phenotypes are more severe than the human disease. The current study examines a variety of schizophrenia-related EEG measures in mice with a heterozygous alteration of the NMDA receptor NR1 subunit gene (NR1) that is known to result in reduced NR1 receptor expression in the homozygous mouse (NR1-/-). (NR1+/-) mice showed a 30% reduction in NR1 receptor expression and were reared after weaning in either group or isolated conditions. Outcome measures include the response to paired white noise stimuli, escalating inter-stimulus intervals (ISIs) and deviance-related mismatch negativity (MMN). In contrast to what has been reported in (NR1-/-) mice and mice treated with NMDA antagonists, (NR1+/-) mice showed no change on obligatory Event Related Potential (ERP) measures including the murine P50 and N100 equivalents (P20 and N40), or measures of baseline or evoked gamma power. Alternatively, (NR1+/-) mice showed a marked reduction in response to a deviant auditory tone during MMN task. Data suggest that EEG response to deviant, rather than static, stimuli may be more sensitive for detecting subtle changes in glutamate function. Deficits in these heterozygous NR1 knockdown mice are consistent with data demonstrating MMN deficits among family members of schizophrenia patients and among prodromal patients. Therefore, the current study suggests that (NR1+/-) mice may be among the most sensitive models for increased vulnerability to schizophrenia. Copyright
DEFF Research Database (Denmark)
Blaabjerg, M; Kristensen, Bjarne Winther; Bonde, C
2001-01-01
the PI uptake in both CA1 and CA3, compared to cultures exposed to 10 microM NMDA only. Adding the 300 microM ACPD as pretreatment for 30 min followed by a 30 min wash in normal medium before the ACPD/NMDA co-exposure, eliminated the potentiation of NMDA toxicity. The potentiation was also blocked...
Institute of Scientific and Technical Information of China (English)
王增贤; 王晓亚; 王怀经; 李振中; 王越; 邢子英
2007-01-01
目的 研究音乐对大鼠空间学习和记忆的影响及对大鼠海马内NMDA受体的表达的影响.方法 用Morris水迷宫中,位置非匹配任务行为检测方法,检测音乐刺激后,大鼠学习和记忆行为能力的变化,并用免疫组织化学、PCR技术,检测大鼠海马NMDA受体及编码NMDA受体的mRNA表达的变化.结果 音乐刺激后,大鼠空间记忆能力改善,信息游泳逃和选择游泳逃避潜伏期缩短,选择游泳选择正确率提高;海马神经元NMDA受体及其mRNA表达增加.这些变化以持续音乐刺激组变化最明显,生后音乐组次之,对照组变化最小.结论 音乐刺激能提高大鼠空间记忆能力,能增强大鼠海马神经元NMDA受体表达,增强海马组织编码NMDA受体的mRNA表达.%Objective: To study the effect of music on spatial learning and memory and the expression of the NMDA receptor in rat hippocampus. Methods:The no-matched position task in the Morris's water maze was used to examine the behavior changes on learning and memory , and immunohistochemistry and PCR technique were carried out to measure the expression of NMDA receptor and mRNA coding the receptor on hippocampus from Wistar rats after music stimulation. Results:After music exposure the spatial memory of rats improved; the avoiding latency of information swim and choice swim shortened, and choice accuration in choice swim increased; the expression of NMDA receptor and the mRNA coding the NMDA receptor on hippocampus was strengthened. All these effects were the strongest in the persistent music treated group, moderate in the postnatal music treated group, and least in the control groups. Conclusion:Music can improve the spatial memory of rats and increase the expression of the NMDA receptor and the mRNA coding the NMDA receptor in hippocampus.
Ketamine Infusion Associated with Improved Neurology in a Patient with NMDA Receptor Encephalitis
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Michael MacMahon
2013-01-01
Full Text Available A young lady was ventilated on intensive care for a prolonged period with NMDA receptor encephalitis. She had undergone steroid, immunoglobulin, and plasmapheresis with no evidence of recovery. Her main management issue was the control of severe orofacial and limb dyskinesia. Large doses of sedating agents had been used to control the dystonia but were ineffective, unless she was fully anaesthetised. The introduction of a ketamine infusion was associated with a dramatic improvement in her symptoms such that it was possible to remove her tracheostomy two days after commencement. She was discharged shortly after that and is making a good recovery. The successful use of ketamine has not previously been described in this context, and we hope this case report will provide some insight into the management of this rare but serious condition.
Srivastava, Pranay; Dhuriya, Yogesh K; Kumar, Vivek; Srivastava, Akriti; Gupta, Richa; Shukla, Rajendra K; Yadav, Rajesh S; Dwivedi, Hari N; Pant, Aditya B; Khanna, Vinay K
2018-04-30
Protective efficacy of curcumin in arsenic induced NMDA receptor dysfunctions and PI3K/Akt/ GSK3β signalling in hippocampus has been investigated in vivo and in vitro. Exposure to sodium arsenite (in vivo - 20 mg/kg, body weight p.o. for 28 days; in vitro - 10 μM for 24 h) and curcumin (in vivo - 100 mg/kg body weight p.o. for 28 days; in vitro - 20 μM for 24 h) was carried out alone or simultaneously. Treatment with curcumin ameliorated sodium arsenite induced alterations in the levels of NMDA receptors, its receptor subunits and synaptic proteins - pCaMKIIα, PSD-95 and SynGAP both in vivo and in vitro. Decreased levels of BDNF, pAkt, pERK1/2, pGSK3β and pCREB on sodium arsenite exposure were also protected by curcumin. Curcumin was found to decrease sodium arsenite induced changes in hippocampus by modulating PI3K/Akt/GSK3β neuronal survival pathway, known to regulate various cellular events. Treatment of hippocampal cultures with pharmacological inhibitors for ERK1/2, GSK3β and Akt individually inhibited levels of CREB and proteins associated with PI3K/Akt/GSK3β pathway. Simultaneous treatment with curcumin was found to improve sodium arsenite induced learning and memory deficits in rats assessed by water maze and Y-maze. The results provide evidence that curcumin exercises its neuroprotective effect involving PI3K/Akt pathway which may affect NMDA receptors and downstream signalling through TrKβ and BDNF in arsenic induced cognitive deficits in hippocampus. Copyright © 2018 Elsevier B.V. All rights reserved.
Schaefer, Natascha; Kluck, Christoph J; Price, Kerry L; Meiselbach, Heike; Vornberger, Nadine; Schwarzinger, Stephan; Hartmann, Stephanie; Langlhofer, Georg; Schulz, Solveig; Schlegel, Nadja; Brockmann, Knut; Lynch, Bryan; Becker, Cord-Michael; Lummis, Sarah C R; Villmann, Carmen
2015-01-07
Recent studies on the pathogenic mechanisms of recessive hyperekplexia indicate disturbances in glycine receptor (GlyR) α1 biogenesis. Here, we examine the properties of a range of novel glycine receptor mutants identified in human hyperekplexia patients using expression in transfected cell lines and primary neurons. All of the novel mutants localized in the large extracellular domain of the GlyR α1 have reduced cell surface expression with a high proportion of receptors being retained in the ER, although there is forward trafficking of glycosylated subpopulations into the ER-Golgi intermediate compartment and cis-Golgi compartment. CD spectroscopy revealed that the mutant receptors have proportions of secondary structural elements similar to wild-type receptors. Two mutants in loop B (G160R, T162M) were functional, but none of those in loop D/β2-3 were. One nonfunctional truncated mutant (R316X) could be rescued by coexpression with the lacking C-terminal domain. We conclude that a proportion of GlyR α1 mutants can be transported to the plasma membrane but do not necessarily form functional ion channels. We suggest that loop D/β2-3 is an important determinant for GlyR trafficking and functionality, whereas alterations to loop B alter agonist potencies, indicating that residues here are critical elements in ligand binding. Copyright © 2015 the authors 0270-6474/15/350422-16$15.00/0.
Kinetic modelling of [{sup 123}I]CNS 1261--a potential SPET tracer for the NMDA receptor
Energy Technology Data Exchange (ETDEWEB)
Erlandsson, Kjell E-mail: k.erlandsson@nucmed.ucl.ac.uk; Bressan, Rodrigo A.; Mulligan, Rachel S.; Gunn, Roger N; Cunningham, Vincent J.; Owens, Jonathan; Wyper, David; Ell, Peter J.; Pilowsky, Lyn S
2003-05-01
N-(1-napthyl)-N'-(3-[{sup 123}I]-iodophenyl)-N-methylguanidine ([{sup 123}I]CNS 1261) is a novel SPET ligand developed for imaging the NMDA receptor intra-channel MK 801/PCP/ketamine site. Data was acquired in 7 healthy volunteers after bolus injection of [{sup 123}I]CNS 1261. Kinetic modeling showed reversible tracer binding. Arterial and venous time-activity curves overlapped after 90 min. The rank order of binding was: Thalamus > striatum > cortical regions > white matter. This distribution concurs with [{sup 11}C]-ketamine and [{sup 18}F]-memantine PET studies . These data provide a methodological basis for further direct in vivo challenge studies.
DEFF Research Database (Denmark)
Harvey, Brian H; Oosthuizen, Frasia; Brand, Linda
2004-01-01
. The NOS isoform involved, and the role of stress-mediated corticosterone release in NOS activation, was verified with the administration of selective iNOS and nNOS inhibitors, aminoguanidine (50 mg/kg/day i.p.) and 7-nitroindazole (12.5 mg/kg/day i.p.), and the steroid synthesis inhibitor, ketoconazole...... (24 mg/kg/day i.p.), administered for 21 days prior to and during the stress procedure. RESULTS: Stress evoked a sustained increase in NOS activity, but reduced NMDA receptor density and total GABA levels. Aminoguanidine or ketoconazole, but not 7-nitroindazole or saline, blocked stress-induced NOS...
N-Methyl-D-aspartic Acid (NMDA in the nervous system of the amphioxus Branchiostoma lanceolatum
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Garcia-Fernàndez Jordi
2007-12-01
Full Text Available Abstract Background NMDA (N-methyl-D-aspartic acid is a widely known agonist for a class of glutamate receptors, the NMDA type. Synthetic NMDA elicits very strong activity for the induction of hypothalamic factors and hypophyseal hormones in mammals. Moreover, endogenous NMDA has been found in rat, where it has a role in the induction of GnRH (Gonadotropin Releasing Hormone in the hypothalamus, and of LH (Luteinizing Hormone and PRL (Prolactin in the pituitary gland. Results In this study we show evidence for the occurrence of endogenous NMDA in the amphioxus Branchiostoma lanceolatum. A relatively high concentration of NMDA occurs in the nervous system of this species (3.08 ± 0.37 nmol/g tissue in the nerve cord and 10.52 ± 1.41 nmol/g tissue in the cephalic vesicle. As in rat, in amphioxus NMDA is also biosynthesized from D-aspartic acid (D-Asp by a NMDA synthase (also called D-aspartate methyl transferase. Conclusion Given the simplicity of the amphioxus nervous and endocrine systems compared to mammalian, the discovery of NMDA in this protochordate is important to gain insights into the role of endogenous NMDA in the nervous and endocrine systems of metazoans and particularly in the chordate lineage.
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Zhe eJin
2014-01-01
Full Text Available Glutamate is the main excitatory transmitter in the human brain. Drugs that affect the glutamatergic signaling will alter neuronal excitability. Ethanol inhibits glutamate receptors. We examined the expression level of glutamate receptor subunit mRNAs in human post-mortem samples from alcoholics and compared the results to brain samples from control subjects. RNA from hippocampal dentate gyrus (HP-DG, orbitofrontal cortex (OFC, and dorso-lateral prefrontal cortex (DL-PFC samples from 21 controls and 19 individuals with chronic alcohol dependence were included in the study. Total RNA was assayed using quantitative RT-PCR. Out of the 16 glutamate receptor subunits, mRNAs encoding two AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-ylpropanoic acid receptor subunits GluA2 and GluA3; three kainate receptor subunits GluK2, GluK3 and GluK5 and five NMDA (N-methyl-D-aspartate receptor subunits GluN1, GluN2A, GluN2C, GluN2D and GluN3A were significantly increased in the HP-DG region in alcoholics. In the OFC, mRNA encoding the NMDA receptor subunit GluN3A was increased, whereas in the DL-PFC, no differences in mRNA levels were observed. Our laboratory has previously shown that the expression of genes encoding inhibitory GABA-A receptors is altered in the HP-DG and OFC of alcoholics (Jin et al., 2011. Whether the changes in one neurotransmitter system drives changes in the other or if they change independently is currently not known. The results demonstrate that excessive long-term alcohol consumption is associated with altered expression of genes encoding glutamate receptors in a brain region-specific manner. It is an intriguing possibility that genetic predisposition to alcoholism may contribute to these gene expression changes.
Hepp, Yanil; Salles, Angeles; Carbo-Tano, Martin
2016-01-01
The aim of the present study was to analyze the surface expression of the NMDA-like receptors during the consolidation of contextual learning in the crab Neohelice granulata. Memory storage is based on alterations in the strength of synaptic connections between neurons. The glutamatergic synapses undergo various forms of N-methyl-D aspartate receptor (NMDAR)-dependent changes in strength, a process that affects the abundance of other receptors at the synapse and underlies some forms of learning and memory. Here we propose a direct regulation of the NMDAR. Changes in NMDAR's functionality might be induced by the modification of the subunit's expression or cellular trafficking. This trafficking does not only include NMDAR's movement between synaptic and extra-synaptic localizations but also the cycling between intracellular compartments and the plasma membrane, a process called surface expression. Consolidation of contextual learning affects the surface expression of the receptor without affecting its general expression. The surface expression of the GluN1 subunit of the NMDAR is down-regulated immediately after training, up-regulated 3 h after training and returns to naïve and control levels 24 h after training. The changes in NMDAR surface expression observed in the central brain are not seen in the thoracic ganglion. A similar increment in surface expression of GluN1 in the central brain is observed 3 h after administration of the competitive GABAA receptor antagonist, bicuculline. These consolidation changes are part of a plasticity event that first, during the down-regulation, stabilizes the trace and later, at 3-h post-training, changes the threshold for synapse activation. PMID:27421895
Czech Academy of Sciences Publication Activity Database
Lichnerová, Katarina; Kaniaková, Martina; Park, S. P.; Skřenková, Kristýna; Wang, Y.- X.; Petralia, R. S.; Suh, Y. H.; Horák, Martin
2015-01-01
Roč. 290, č. 30 (2015), s. 18379-18390 ISSN 0021-9258 R&D Projects: GA ČR(CZ) GA14-02219S; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:67985823 Keywords : peptide-N-glycosidase * NMDAR * NMDA receptor * endoplasmic reticulum Subject RIV: FH - Neurology Impact factor: 4.258, year: 2015
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Carolina R den Hartog
Full Text Available Ethanol's action on the brain likely reflects altered function of key ion channels such as glutamatergic N-methyl-D-aspartate receptors (NMDARs. In this study, we determined how expression of a mutant GluN1 subunit (F639A that reduces ethanol inhibition of NMDARs affects ethanol-induced behaviors in mice. Mice homozygous for the F639A allele died prematurely while heterozygous knock-in mice grew and bred normally. Ethanol (44 mM; ∼0.2 g/dl significantly inhibited NMDA-mediated EPSCs in wild-type mice but had little effect on responses in knock-in mice. Knock-in mice had normal expression of GluN1 and GluN2B protein across different brain regions and a small reduction in levels of GluN2A in medial prefrontal cortex. Ethanol (0.75-2.0 g/kg; i.p. increased locomotor activity in wild-type mice but had no effect on knock-in mice while MK-801 enhanced activity to the same extent in both groups. Ethanol (2.0 g/kg reduced rotarod performance equally in both groups but knock-in mice recovered faster following a higher dose (2.5 g/kg. In the elevated zero maze, knock-in mice had a blunted anxiolytic response to ethanol (1.25 g/kg as compared to wild-type animals. No differences were noted between wild-type and knock-in mice for ethanol-induced loss of righting reflex, sleep time, hypothermia or ethanol metabolism. Knock-in mice consumed less ethanol than wild-type mice during daily limited-access sessions but drank more in an intermittent 24 h access paradigm with no change in taste reactivity or conditioned taste aversion. Overall, these data support the hypothesis that NMDA receptors are important in regulating a specific constellation of effects following exposure to ethanol.
den Hartog, Carolina R; Beckley, Jacob T; Smothers, Thetford C; Lench, Daniel H; Holseberg, Zack L; Fedarovich, Hleb; Gilstrap, Meghin J; Homanics, Gregg E; Woodward, John J
2013-01-01
Ethanol's action on the brain likely reflects altered function of key ion channels such as glutamatergic N-methyl-D-aspartate receptors (NMDARs). In this study, we determined how expression of a mutant GluN1 subunit (F639A) that reduces ethanol inhibition of NMDARs affects ethanol-induced behaviors in mice. Mice homozygous for the F639A allele died prematurely while heterozygous knock-in mice grew and bred normally. Ethanol (44 mM; ∼0.2 g/dl) significantly inhibited NMDA-mediated EPSCs in wild-type mice but had little effect on responses in knock-in mice. Knock-in mice had normal expression of GluN1 and GluN2B protein across different brain regions and a small reduction in levels of GluN2A in medial prefrontal cortex. Ethanol (0.75-2.0 g/kg; i.p.) increased locomotor activity in wild-type mice but had no effect on knock-in mice while MK-801 enhanced activity to the same extent in both groups. Ethanol (2.0 g/kg) reduced rotarod performance equally in both groups but knock-in mice recovered faster following a higher dose (2.5 g/kg). In the elevated zero maze, knock-in mice had a blunted anxiolytic response to ethanol (1.25 g/kg) as compared to wild-type animals. No differences were noted between wild-type and knock-in mice for ethanol-induced loss of righting reflex, sleep time, hypothermia or ethanol metabolism. Knock-in mice consumed less ethanol than wild-type mice during daily limited-access sessions but drank more in an intermittent 24 h access paradigm with no change in taste reactivity or conditioned taste aversion. Overall, these data support the hypothesis that NMDA receptors are important in regulating a specific constellation of effects following exposure to ethanol.
Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons
Yang, Jiangyan; Ruchti, Evelyne; Petit, Jean Marie; Jourdain, Pascal; Grenningloh, Gabriele; Allaman, Igor; Magistretti, Pierre J.
2014-01-01
L-lactate is a product of aerobic glycolysis that can be used by neurons as an energy substrate. Here we report that in neurons L-lactate stimulates the expression of synaptic plasticity-related genes such as Arc, c-Fos, and Zif268 through a mechanism involving NMDA receptor activity and its downstream signaling cascade Erk1/2. L-lactate potentiates NMDA receptor-mediated currents and the ensuing increase in intracellular calcium. In parallel to this, L-lactate increases intracellular levels of NADH, thereby modulating the redox state of neurons. NADH mimics all of the effects of L-lactate on NMDA signaling, pointing to NADH increase as a primary mediator of L-lactate effects. The induction of plasticity genes is observed both in mouse primary neurons in culture and in vivo in the mouse sensory-motor cortex. These results provide insights for the understanding of the molecular mechanisms underlying the critical role of astrocyte-derived L-lactate in long-term memory and long-term potentiation in vivo. This set of data reveals a previously unidentified action of L-lactate as a signaling molecule for neuronal plasticity.
Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons
Yang, Jiangyan
2014-07-28
L-lactate is a product of aerobic glycolysis that can be used by neurons as an energy substrate. Here we report that in neurons L-lactate stimulates the expression of synaptic plasticity-related genes such as Arc, c-Fos, and Zif268 through a mechanism involving NMDA receptor activity and its downstream signaling cascade Erk1/2. L-lactate potentiates NMDA receptor-mediated currents and the ensuing increase in intracellular calcium. In parallel to this, L-lactate increases intracellular levels of NADH, thereby modulating the redox state of neurons. NADH mimics all of the effects of L-lactate on NMDA signaling, pointing to NADH increase as a primary mediator of L-lactate effects. The induction of plasticity genes is observed both in mouse primary neurons in culture and in vivo in the mouse sensory-motor cortex. These results provide insights for the understanding of the molecular mechanisms underlying the critical role of astrocyte-derived L-lactate in long-term memory and long-term potentiation in vivo. This set of data reveals a previously unidentified action of L-lactate as a signaling molecule for neuronal plasticity.
Dysfunctional synapse in Alzheimer's disease - A focus on NMDA receptors.
Mota, Sandra I; Ferreira, Ildete L; Rego, A Cristina
2014-01-01
Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly. Alterations capable of causing brain circuitry dysfunctions in AD may take several years to develop. Oligomeric amyloid-beta peptide (Aβ) plays a complex role in the molecular events that lead to progressive loss of function and eventually to neurodegeneration in this devastating disease. Moreover, N-methyl-D-aspartate (NMDA) receptors (NMDARs) activation has been recently implicated in AD-related synaptic dysfunction. Thus, in this review we focus on glutamatergic neurotransmission impairment and the changes in NMDAR regulation in AD, following the description on the role and location of NMDARs at pre- and post-synaptic sites under physiological conditions. In addition, considering that there is currently no effective ways to cure AD or stop its progression, we further discuss the relevance of NMDARs antagonists to prevent AD symptomatology. This review posits additional information on the role played by Aβ in AD and the importance of targeting the tripartite glutamatergic synapse in early asymptomatic and possible reversible stages of the disease through preventive and/or disease-modifying therapeutic strategies. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'. Copyright © 2013 Elsevier Ltd. All rights reserved.
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Edgar Antonio Reyes Montaño
2011-12-01
Full Text Available Producing polyclonal antibodies (IgY inchickens has advantages over those obtainedin other animal models, since theyhave been used as a tool for studyingdifferent proteins (NMDA glutamate receptorin our case, specifically the NR1subunit. We produced specific antibodiesagainst expression products by thealternative splicing of the gene encodingNMDA receptor NR1 subunit in adult ratbrain. Three peptides corresponding tothe splicing sites (N1, C1 and C2’ cassetteswere designed, synthesised and usedindividually as antigens in hens. Specificimmunoglobulins were purified fromyolks. The antibodies were then used forpurifying the NMDA receptor NR1 subunitusing affinity chromatography couplingthe three antibodies to the support.R
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Aykut Üner
2015-10-01
Conclusions: GluN2B-containing NMDA receptors in AgRP neurons play a critical role in central control of body weight homeostasis and blood glucose balance via mechanisms that likely involve regulation of AgRP neuronal survival and structure, and modulation of hypothalamic leptin action.
Kolarova, Anna; Ringer, Ralph; Täuber, Martin G; Leib, Stephen L
2003-01-01
Background Excitotoxic neuronal injury by action of the glutamate receptors of the N-methyl-d-aspartate (NMDA) subtype have been implicated in the pathogenesis of brain damage as a consequence of bacterial meningitis. The most potent and selective blocker of NMDA receptors containing the NR2B subunit is (R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperid inepropanol (RO 25-6981). Here we evaluated the effect of RO 25-6981 on hippocampal neuronal apoptosis in an infant rat model of meningitis due to Streptococcus pneumoniae. Animals were randomized for treatment with RO 25-6981 at a dosage of either 0.375 mg (15 mg/kg; n = 28) or 3.75 mg (150 mg/kg; n = 15) every 3 h or an equal volume of sterile saline (250 μl; n = 40) starting at 12 h after infection. Eighteen hours after infection, animals were assessed clinically and seizures were observed for a period of 2 h. At 24 h after infection animals were sacrificed and brains were examined for apoptotic injury to the dentate granule cell layer of the hippocampus. Results Treatment with RO 25-6981 had no effect on clinical scores, but the incidence of seizures was reduced (P < 0.05 for all RO 25-6981 treated animals combined). The extent of apoptosis was not affected by low or high doses of RO 25-6981. Number of apoptotic cells (median [range]) was 12.76 [3.16–25.3] in animals treated with low dose RO 25-6981 (control animals 13.8 [2.60–31.8]; (P = NS) and 9.8 [1.7–27.3] (controls: 10.5 [2.4–21.75]) in animals treated with high dose RO 25-6981 (P = NS). Conclusions Treatment with a highly selective blocker of NMDA receptors containing the NR2B subunit failed to protect hippocampal neurons from injury in this model of pneumococcal meningitis, while it had some beneficial effect on the incidence of seizures. PMID:13129439
Cysteine regulation of protein function--as exemplified by NMDA-receptor modulation.
Lipton, Stuart A; Choi, Yun-Beom; Takahashi, Hiroto; Zhang, Dongxian; Li, Weizhong; Godzik, Adam; Bankston, Laurie A
2002-09-01
Until recently cysteine residues, especially those located extracellularly, were thought to be important for metal coordination, catalysis and protein structure by forming disulfide bonds - but they were not thought to regulate protein function. However, this is not the case. Crucial cysteine residues can be involved in modulation of protein activity and signaling events via other reactions of their thiol (sulfhydryl; -SH) groups. These reactions can take several forms, such as redox events (chemical reduction or oxidation), chelation of transition metals (chiefly Zn(2+), Mn(2+) and Cu(2+)) or S-nitrosylation [the catalyzed transfer of a nitric oxide (NO) group to a thiol group]. In several cases, these disparate reactions can compete with one another for the same thiol group on a single cysteine residue, forming a molecular switch composed of a latticework of possible redox, NO or Zn(2+) modifications to control protein function. Thiol-mediated regulation of protein function can also involve reactions of cysteine residues that affect ligand binding allosterically. This article reviews the basis for these molecular cysteine switches, drawing on the NMDA receptor as an exemplary protein, and proposes a molecular model for the action of S-nitrosylation based on recently derived crystal structures.
Li, De-Pei; Zhou, Jing-Jing; Zhang, Jixiang; Pan, Hui-Lin
2017-11-01
NMDAR activity in the hypothalamic paraventricular nucleus (PVN) is increased and critically involved in heightened sympathetic vasomotor tone in hypertension. Calcium/calmodulin-dependent protein kinase II (CaMKII) binds to and modulates NMDAR activity. In this study, we determined the role of CaMKII in regulating NMDAR activity of PVN presympathetic neurons in male spontaneously hypertensive rats (SHRs). NMDAR-mediated EPSCs and puff NMDA-elicited currents were recorded in spinally projecting PVN neurons in SHRs and male Wistar-Kyoto (WKY) rats. The basal amplitude of evoked NMDAR-EPSCs and puff NMDA currents in retrogradely labeled PVN neurons were significantly higher in SHRs than in WKY rats. The CaMKII inhibitor autocamtide-2-related inhibitory peptide (AIP) normalized the increased amplitude of NMDAR-EPSCs and puff NMDA currents in labeled PVN neurons in SHRs but had no effect in WKY rats. Treatment with AIP also normalized the higher frequency of NMDAR-mediated miniature EPSCs of PVN neurons in SHRs. CaMKII-mediated phosphorylation level of GluN2B serine 1303 (S1303) in the PVN, but not in the hippocampus and frontal cortex, was significantly higher in SHRs than in WKY rats. Lowering blood pressure with celiac ganglionectomy in SHRs did not alter the increased level of phosphorylated GluN2B S1303 in the PVN. In addition, microinjection of AIP into the PVN significantly reduced arterial blood pressure and lumbar sympathetic nerve discharges in SHRs. Our findings suggest that CaMKII activity is increased in the PVN and contributes to potentiated presynaptic and postsynaptic NMDAR activity to elevate sympathetic vasomotor tone in hypertension. SIGNIFICANCE STATEMENT Heightened sympathetic vasomotor tone is a major contributor to the development of hypertension. Although glutamate NMDA receptor (NMDAR)-mediated excitatory drive in the hypothalamus plays a critical role in increased sympathetic output in hypertension, the molecular mechanism involved in
DEFF Research Database (Denmark)
Kostenis, Evi; Martini, Lene; Ellis, James
2004-01-01
Numerous studies have attested to the importance of the extreme C terminus of G protein alpha subunits in determining their selectivity of receptor recognition. We have previously reported that a highly conserved glycine residue within linker I is important for constraining the fidelity of receptor...... recognition by Galpha(q) proteins. Herein, we explored whether both modules (linker I and extreme C terminus) interact cooperatively in switching G protein-coupled receptor (GPCR)-to-effector specificity and created as models mutant Galpha(q) proteins in which glycine was replaced with various amino acids...... and the C-terminal five Galpha(q) residues with the corresponding Galpha(i) or Galpha(s) sequence. Coupling properties of the mutated Galpha(q) proteins were determined after coexpression with a panel of 13 G(i)-and G(s) -selective receptors and compared with those of Galpha proteins modified in only one...
GABA and glycine as neurotransmitters: a brief history.
Bowery, N G; Smart, T G
2006-01-01
gamma-Aminobutyric acid (GABA) emerged as a potentially important brain chemical just over 50 years ago, but its significance as a neurotransmitter was not fully realized until over 16 years later. We now know that at least 40% of inhibitory synaptic processing in the mammalian brain uses GABA. Establishing its role as a transmitter was a lengthy process and it seems hard to believe with our current knowledge that there was ever any dispute about its role in the mammalian brain. The detailed information that we now have about the receptors for GABA together with the wealth of agents which facilitate or reduce GABA receptor mechanisms make the prospects for further research very exciting. The emergence of glycine as a transmitter seems relatively painless by comparison to GABA. Perhaps this is appropriate for the simplest of transmitter structures! Its discovery within the spinal cord and brainstem approximately 40 years ago was followed only 2 years later by the proposal that it be conferred with 'neurotransmitter' status. It was another 16 years before the receptor was biochemically isolated. Now it is readily accepted as a vital spinal and supraspinal inhibitory transmitter and we know many details regarding its molecular structure and trafficking around neurones. The pharmacology of these receptors has lagged behind that of GABA. There is not the rich variety of allosteric modulators that we have come to readily associate with GABA receptors and which has provided us with a virtual treasure trove of important drugs used in anxiety, insomnia, epilepsy, anaesthesia, and spasticity, all stemming from the actions of the simple neutral amino acid GABA. Nevertheless, the realization that glycine receptors are involved in motor reflexes and nociceptive pathways together with the more recent advent of drugs that exhibit some subtype selectivity make the goal of designing selective therapeutic ligands for the glycine receptor that much closer.
Synthesis of n.c.a. 18F-fluorinated NMDA- and D4-receptor ligands via [18F]fluorobenzenes
International Nuclear Information System (INIS)
Ludwig, T.
2005-11-01
In this thesis new strategies were developed and evaluated for the no-carrier-added (n.c.a.) 18 F-labelling of receptor ligands as radiodiagnostics for characterization of brain receptors using positron-emission-tomography (PET). Special emphasis was placed on the synthesis of n.c.a. (±)-3-(4-hydroxy-4-(4-[ 18 F]fluorophenyl)-piperidin-l-yl)chroman-4,7-diol, a ligand with high affinity for the NR2B subtype of NMDA receptors and n.c.a. (3-(4-[ 18 F]fluorphenoxy)propyl)-(2-(4-tolylphenoxy)ethyl)amine ([ 18 F]FPTEA) a dopamine D 4 receptor ligand. In order to synthesize n.c.a. (±)-3-(4-hydroxy-4-(4-[ 18 F]fluorophenyl)-piperidin-l-yl)chroman-4,7-diol the 18 F-fluoroarylation method via metallorganic intermediates was modified and improved. The suitability of the organometallic 18 F-fluoroarylation agents was proven with several model compounds. High radiochemical yields of 20-30% were obtained also with piperidinone-derivatives. The preparation of a suitable precursor for the synthesis of the NMDA receptor ligand, however, could not be achieved by synthesis of appropriate 1,3-dioxolane protected piperidinone derivatives. Further, the synthesis of n.c.a. ([ 18 F]fluoroaryloxy)alkylamines via n.c.a. 4-[ 18 F]fluorophenol was developed and evaluated. The synthesis of n.c.a. [ 18 F]fluoroarylethers with corresponding model compounds was optimized and led to a radiochemical yield of 25-60%, depending on the alkylhalide used. The preparation of n.c.a. 1-(3-bromopropoxy)-4-[ 18 F]fluorobenzene proved advantageous in comparison to direct use of 4-[ 18 ]fluorophenol for coupling with a corresponding N-protected precursor for the synthesis of n.c.a. [ 18 F]FPTEA. With regard to the radiochemical yields and the loss of activity during the synthesis and isolation of n.c.a. 4-[ 18 F]fluorophenol and n.c.a. 1-(3-bromopropoxy)-4-[ 18 F]fluorobenzene, [ 18 F]FPTEA was obtained by reaction with 2-(4-tolyloxy)ethylamine in radiochemical yields of about 25-30% in ethanol or 2-butanone
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María Verónica Baez
2018-01-01
Full Text Available NMDA ionotropic glutamate receptors (NMDARs are crucial in activity-dependent synaptic changes and in learning and memory. NMDARs are composed of two GluN1 essential subunits and two regulatory subunits which define their pharmacological and physiological profile. In CNS structures involved in cognitive functions as the hippocampus and prefrontal cortex, GluN2A and GluN2B are major regulatory subunits; their expression is dynamic and tightly regulated, but little is known about specific changes after plasticity induction or memory acquisition. Data strongly suggest that following appropriate stimulation, there is a rapid increase in surface GluN2A-NMDAR at the postsynapses, attributed to lateral receptor mobilization from adjacent locations. Whenever synaptic plasticity is induced or memory is consolidated, more GluN2A-NMDARs are assembled likely using GluN2A from a local translation and GluN1 from local ER. Later on, NMDARs are mobilized from other pools, and there are de novo syntheses at the neuron soma. Changes in GluN1 or NMDAR levels induced by synaptic plasticity and by spatial memory formation seem to occur in different waves of NMDAR transport/expression/degradation, with a net increase at the postsynaptic side and a rise in expression at both the spine and neuronal soma. This review aims to put together that information and the proposed hypotheses.
Glycine receptors in the human substantia nigra as defined by (3H)strychnine binding
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de Montis, G; Beaumont, K; Javoy-Agid, F; Agid, Y; Constandinidis, J; Lowenthal, A; Lloyd, K G
1982-03-01
Specific (3H)strychnine binding was used to identify the glycine receptor macromolecular complex in human spinal cord, substantia nigra, inferior olivary nucleus, and cerebral cortex. In material from control patients a high-affinity KD (3--8 nM) was observed in the spinal cord and the substantia nigra, both the pars compacta and the pars reticulata. This is very similar to the values observed in the rat and bovine spinal cord (8 and 3 nM, respectively) and rat substantia nigra (12 nM). In the human brain the distribution of (3H)strychnine binding (at 10 nM) was: spinal cord . substantia nigra, pars compacta greater than substantia nigra, pars reticulata . inferior olivary nucleus greater than cerebral cortex. The binding capacity (Bmax) of the rat brain (substantia nigra or spinal cord) was approximately 10-fold that of the human brain. (3H)Strychnine binding was significantly decreased in the substantia nigra from Parkinson's disease patients, both in the pars compacta (67% of control) and the pars reticulata (50% of control), but not in the inferior olivary nucleus. The results were reproduced in preliminary experiment in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. In the substantia nigra from patients who died with Huntington's disease, (3H)strychnine binding tended to be high (150% of control, NS) in both the pars compacta and the reticulata. (3H)Strychnine binding was unaltered in the substantia nigra of patients with senile dementia. Together with previous neurophysiological and neuropharmacological findings, those results support the hypothesis of glycine receptors occurring on dopamine cell bodies and/or dendrites in the substantia nigra.
Voltage-Dependent Inhibition of Glycine Receptor Channels by Niflumic Acid
Directory of Open Access Journals (Sweden)
Galyna Maleeva
2017-05-01
Full Text Available Niflumic acid (NFA is a member of the fenamate class of nonsteroidal anti-inflammatory drugs. This compound and its derivatives are used worldwide clinically for the relief of chronic and acute pain. NFA is also a commonly used blocker of voltage-gated chloride channels. Here we present evidence that NFA is an efficient blocker of chloride-permeable glycine receptors (GlyRs with subunit heterogeneity of action. Using the whole-cell configuration of patch-clamp recordings and molecular modeling, we analyzed the action of NFA on homomeric α1ΔIns, α2B, α3L, and heteromeric α1β and α2β GlyRs expressed in CHO cells. NFA inhibited glycine-induced currents in a voltage-dependent manner and its blocking potency in α2 and α3 GlyRs was higher than that in α1 GlyR. The Woodhull analysis suggests that NFA blocks α1 and α2 GlyRs at the fractional electrical distances of 0.16 and 0.65 from the external membrane surface, respectively. Thus, NFA binding site in α1 GlyR is closer to the external part of the membrane, while in α2 GlyR it is significantly deeper in the pore. Mutation G254A at the cytoplasmic part of the α1 GlyR pore-lining TM2 helix (level 2′ increased the NFA blocking potency, while incorporation of the β subunit did not have a significant effect. The Hill plot analysis suggests that α1 and α2 GlyRs are preferably blocked by two and one NFA molecules, respectively. Molecular modeling using Monte Carlo energy minimizations provides the structural rationale for the experimental data and proposes more than one interaction site along the pore where NFA can suppress the ion permeation.
James, Alex S; Pennington, Zachary T; Tran, Phu; Jentsch, James David
2015-01-01
Two theories regarding the role for dopamine neurons in learning include the concepts that their activity serves as a (1) mechanism that confers incentive salience onto rewards and associated cues and/or (2) contingency teaching signal reflecting reward prediction error. While both theories are provocative, the causal role for dopamine cell activity in either mechanism remains controversial. In this study mice that either fully or partially lacked NMDARs in dopamine neurons exclusively, as well as appropriate controls, were evaluated for reward-related learning; this experimental design allowed for a test of the premise that NMDA/glutamate receptor (NMDAR)-mediated mechanisms in dopamine neurons, including NMDA-dependent regulation of phasic discharge activity of these cells, modulate either the instrumental learning processes or the likelihood of pavlovian cues to become highly motivating incentive stimuli that directly attract behavior. Loss of NMDARs in dopamine neurons did not significantly affect baseline dopamine utilization in the striatum, novelty evoked locomotor behavior, or consumption of a freely available, palatable food solution. On the other hand, animals lacking NMDARs in dopamine cells exhibited a selective reduction in reinforced lever responses that emerged over the course of instrumental learning. Loss of receptor expression did not, however, influence the likelihood of an animal acquiring a pavlovian conditional response associated with attribution of incentive salience to reward-paired cues (sign tracking). These data support the view that reductions in NMDAR signaling in dopamine neurons affect instrumental reward-related learning but do not lend support to hypotheses that suggest that the behavioral significance of this signaling includes incentive salience attribution.
Cunha, Andréia S; Matheus, Filipe C; Moretti, Morgana; Sampaio, Tuane B; Poli, Anicleto; Santos, Danúbia B; Colle, Dirleise; Cunha, Mauricio P; Blum-Silva, Carlos H; Sandjo, Louis P; Reginatto, Flávio H; Rodrigues, Ana Lúcia S; Farina, Marcelo; Prediger, Rui D
2016-10-01
Dyskinesia consists in a series of trunk, limbs and orofacial involuntary movements that can be observed following long-term pharmacological treatment in some psychotic and neurological disorders such as schizophrenia and Parkinson's disease, respectively. Agmatine is an endogenous arginine metabolite that emerges as neuromodulator and a promising agent to manage diverse central nervous system disorders by modulating nitric oxide (NO) pathway, glutamate NMDA receptors and oxidative stress. Herein, we investigated the effects of a single intraperitoneal (i.p.) administration of different agmatine doses (10, 30 or 100mg/kg) against the orofacial dyskinesia induced by reserpine (1mg/kg,s.c.) in mice by measuring the vacuous chewing movements and tongue protusion frequencies, and the duration of facial twitching. The results showed an orofacial antidyskinetic effect of agmatine (30mg/kg, i.p.) or the combined administration of sub-effective doses of agmatine (10mg/kg, i.p.) with the NMDA receptor antagonists amantadine (1mg/kg, i.p.) and MK801 (0.01mg/kg, i.p.) or the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI; 0.1mg/kg, i.p.). Reserpine-treated mice displayed locomotor activity deficits in the open field and agmatine had no effect on this response. Reserpine increased nitrite and nitrate levels in cerebral cortex, but agmatine did not reverse it. Remarkably, agmatine reversed the decrease of dopamine and non-protein thiols (NPSH) levels caused by reserpine in the striatum. However, no changes were observed in striatal immunocontent of proteins related to the dopaminergic system including tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter type 2, pDARPP-32[Thr75], dopamine D1 and D2 receptors. These results indicate that the blockade of NO pathway, NMDAR and oxidative stress are possible mechanisms associated with the protective effects of agmatine against the orofacial dyskinesia induced by reserpine in mice
Novel Fluorine-Containing NMDA Antagonists for Brain Imaging: In Vitro Evaluation
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Alvarado, M.; Biegon, A.
2001-01-01
The NMDA receptor has been implicated in neuronal death following stroke, brain injury and neurodegenerative disorders (e.g. Alzheimer's, Parkinson's and Huntington's disease) and in physiological functions (e.g. memory and cognition). Non-competitive antagonists, such as MK- 801 and CNS-1102, that block the action of glutamate at the NMDA receptor have been shown to be neuroprotective by blocking the influx of calcium into the cells. As a result, they are being considered as therapeutic agents for the above mentioned diseases. Several Fluorine-containing novel analogs of NMDA channel blockers have been synthesized and evaluated in search of a compound suitable for 18F labeling and Positron Emission Tomography (PET). Based on in vitro binding assay studies on rat brain membranes, the novel compounds examined displayed a range of affinities. Preliminary analyses indicated that chlorine is the best halogen on the ring, and that ethyl fluoro derivatives are more potent than methyl-fluoro compounds. Further analysis based on autoradiography will be needed to examine the regional binding characteristics of the novel compounds examined in this study. Labeling with 18F will allow the use of these compounds in humans, generating new insights into mechanisms and treatment of diseases involving malfunction of the glutamatergic system in the brain.
Nations, Kari R; Smits, Jasper A J; Tolin, David F; Rothbaum, Barbara O; Hofmann, Stefan G; Tart, Candyce D; Lee, Allen; Schipper, Jacques; Sjogren, Magnus; Xue, Dixi; Szegedi, Armin; Otto, Michael W
2012-05-01
A growing body of evidence supports the efficacy of D-cycloserine (DCS), a partial agonist at the N-methyl-D-aspartate (NMDA) glutamate receptor, as augmentation to cognitive-behavioral therapy (CBT) in the treatment of anxiety disorders. Org 25935 is a glycine transporter 1 inhibitor that acts to increase synaptic glycine levels and enhance NMDA-mediated glutamatergic activity. The aim of this study was to examine the efficacy of a glutamatergic compound other than DCS in a CBT augmentation paradigm. This was a randomized, double-blind, placebo-controlled, parallel-group clinical trial for which participants were recruited from November 2008 through February 2010. Eligible adult patients diagnosed (DSM-IV) with panic disorder with or without agoraphobia (N = 40) were scheduled to receive 5 manualized CBT treatment sessions. Participants were randomly assigned to receive either a dose of Org 25935 (4 mg or 12 mg) or placebo 2 hours prior to the start of CBT sessions 3, 4, and 5. The primary endpoint was symptomatic change as measured by the Panic Disorder Severity Scale (PDSS) 1 week following the last CBT session. Although mean PDSS total scores decreased significantly from baseline to end of treatment in every group, no statistically significant benefit was observed for Org 25935 (4 or 12 mg) over placebo on the primary endpoint or on any secondary efficacy endpoint. Org 25935 showed no safety issues at either dose but was much better tolerated at the 4-mg dose level than at the 12-mg dose level. Org 25935 demonstrated no benefit over placebo in augmenting CBT for panic disorder. Study limitations and implications are discussed. clinicaltrials.gov Identifier: NCT00725725. © Copyright 2012 Physicians Postgraduate Press, Inc.
High throughput techniques for discovering new glycine receptor modulators and their binding sites
Directory of Open Access Journals (Sweden)
Daniel F Gilbert
2009-10-01
Full Text Available The inhibitory glycine receptor (GlyR is a member of the Cys-loop receptor family that mediates inhibitory neurotransmission in the central nervous system. These receptors are emerging as potential drug targets for inflammatory pain, immunomodulation, spasticity and epilepsy. Antagonists that specifically inhibit particular GlyR isoforms are also required as pharmacological probes for elucidating the roles of particular GlyR isoforms in health and disease. Although a substantial number of both positive and negative GlyR modulators have been identified, very few of these are specific for the GlyR over other receptor types. Thus, the potential of known compounds as either therapeutic leads or pharmacological probes is limited. It is therefore surprising that there have been few published studies describing attempts to discover novel GlyR isoform-specific compounds. The first aim of this review is to consider various methods for efficiently screening compounds against these receptors. We conclude that an anion sensitive yellow fluorescent protein is optimal for primary screening and that automated electrophysiology of cells stably expressing GlyRs is useful for confirming hits and quantitating the actions of identified compounds. The second aim of this review is to demonstrate how these techniques are used in our laboratory for the purpose of both discovering novel GlyR-active compounds and characterizing their binding sites. We also describe a reliable, cost effective method for transfecting HEK293 cells in single wells of a 384 well plate using nanogram quantities of cDNA.
Inta, Ioana; Vogt, Miriam A; Vogel, Anne S; Bettendorf, Markus; Gass, Peter; Inta, Dragos
2016-10-01
NMDA receptor (NMDAR) antagonists induce in perinatal rodent cortical apoptosis and protracted schizophrenia-like alterations ameliorated by antipsychotic treatment. The broad-spectrum antibiotic minocycline elicits antipsychotic and neuroprotective effects. Here we tested, if minocycline protects also against apoptosis triggered by the NMDAR antagonist MK-801 at postnatal day 7. Surprisingly, minocycline induced widespread cortical apoptosis and exacerbated MK-801-triggered cell death. In some areas such as the subiculum, the pro-apoptotic effect of minocycline was even more pronounced than that elicited by MK-801. These data reveal among antipsychotics unique pro-apoptotic properties of minocycline, raising concerns regarding consequences for brain development and the use in children.
Selective cognitive impairments associated with NMDA receptor blockade in humans.
Rowland, Laura M; Astur, Robert S; Jung, Rex E; Bustillo, Juan R; Lauriello, John; Yeo, Ronald A
2005-03-01
Hypofunction of the N-methyl-D-aspartate receptor (NMDAR) may be involved in the pathophysiology of schizophrenia. NMDAR antagonists like ketamine induce schizophrenia-like features in humans. In rodent studies, NMDAR antagonism impairs learning by disrupting long-term potentiation (LTP) in the hippocampus. This study investigated the effects of ketamine on spatial learning (acquisition) vs retrieval in a virtual Morris water task in humans. Verbal fluency, working memory, and learning and memory of verbal information were also assessed. Healthy human subjects participated in this double-blinded, placebo-controlled study. On two separate occasions, ketamine/placebo was administered and cognitive tasks were assessed in association with behavioral ratings. Ketamine impaired learning of spatial and verbal information but retrieval of information learned prior to drug administration was preserved. Schizophrenia-like symptoms were significantly related to spatial and verbal learning performance. Ketamine did not significantly impair attention, verbal fluency, or verbal working memory task performance. Spatial working memory was slightly impaired. In conclusion, these results provide evidence for ketamine's differential impairment of verbal and spatial learning vs retrieval. By using the Morris water task, which is hippocampal-dependent, this study helps bridge the gap between nonhuman animal and human NMDAR antagonism research. Impaired cognition is a core feature of schizophrenia. A better understanding of NMDA antagonism, its physiological and cognitive consequences, may provide improved models of psychosis and cognitive therapeutics.
Excitatory amino acid receptors and disease.
Meldrum, B S
1992-08-01
Recent advances in the molecular biology of excitatory amino acid receptors are reviewed. Evidence that drugs blocking the excitatory action of glutamate at the N-methyl-D-aspartate (NMDA) and non-NMDA receptors may be of clinical use in epilepsy, Parkinson's disease, cerebral ischaemia and trauma, acquired immune deficiency syndrome (AIDS) encephalopathy and neuropathic pain is summarized.
O’Mahony, S.; Harkany, T.; Ábrahám, I.; Jong, G.I. de; Varga, J.L.; Zarándi, M.; Penke, B.; Nyakas, C.; Luiten, P.G.M.; Leonard, B.E.
1998-01-01
Ample experimental evidence indicates that acute beta-amyloid infusion into the nucleus basalis of rats elicits abrupt degeneration of the magnocellular cholinergic neurons projecting to the cerebral cortex, In fact, involvement of a permanent Ca2+ overload, partially via N-methyl-D-aspartate (NMDA)
Kolik, L G; Nadorova, A V; Seredenin, S B
2017-12-01
Activity of hemantane, an amino adamantane derivative, exhibiting the properties of lowaffinity non-competitive NMDA receptor antagonist, was evaluated in experimental in vivo models of alcoholism. Hemantane had no effects on the formation and manifestation of behavioral sensitization to ethanol in DBA/2 mice. Under conditions of free choice between 10% ethanol and water, hemantane (20 mg/kg/day for 14 days, intraperitoneally) significantly reduced the daily ethanol intake in random-bred male rats with formed alcohol motivation (>4 g/kg of ethanol). During modelling of withdrawal syndrome, hemantane administered intraperitoneally in doses of 5-20 mg/kg dose-dependently attenuated alcohol-deprivation effect after acute withdrawal with no effects on protracted abstinence. It was found that hemantane suppressed alcohol drinking behavior in long-term ethanol experienced rats and attenuated alcohol-seeking behavior after acute withdrawal.
Li, Yan-Hai; Han, Lei; Wu, Kenneth Lap Kei; Chan, Ying-Shing
2017-09-01
The medial vestibular nucleus (MVN) is a major output station for neurons that project to the vestibulo-spinal pathway. MVN neurons show capacity for long-term depression (LTD) during the juvenile period. We investigated LTD of MVN neurons using whole-cell patch-clamp recordings. High frequency stimulation (HFS) robustly induced LTD in 90% of type B neurons in the MVN, while only 10% of type A neurons were responsive, indicating that type B neurons are the major contributors to LTD in the MVN. The neuromodulator serotonin (5-HT) is known to modulate LTD in neural circuits of the cerebral cortex and the hippocampus. We therefore aim to determine the action of 5-HT on the LTD of type B MVN neurons and elucidate the relevant 5-HT receptor subtypes responsible for its action. Using specific agonists and antagonists of 5-HT receptors, we found that selective activation of 5-HT 7 receptor in type B neurons in the MVN of juvenile (P13-16) rats completely abolished NMDA-receptor-mediated LTD in a protein kinase A (PKA)-dependent manner. Our finding that 5-HT restricts plasticity of type B MVN neurons via 5-HT 7 receptors offers a mechanism whereby vestibular tuning contributes to the maturation of the vestibulo-spinal circuit and highlights the role of 5-HT in postural control. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Orita, Kazuhiro; Sasaki, Shigeki; Maeda, Minoru [Kyushu Univ., Fukuoka (Japan). Faculty of Pharmaceutical Sciences; Hashimoto, Atsushi; Nishikawa, Toru [National Inst. of Neuroscience, Tokyo (Japan); Yugami, Tomoko; Umezu, Kohei [Mitsubishi Kasei Corp., Yokohama (Japan). Research Center
1993-10-01
1-[l brace]1-[5-(2'-[[sup 18]F]Fluoroethyl)-2-thienyl]cyclohexyl[r brace]piperidine ([sup 18]FE-TCP) was prepared a fluorine-substituted analogue of the potent NMDA receptor channel blocker, 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), by the mesylate displacement with [[sup 18]F]fluoride ion with isolated radiochemical yields of 6-12%, and the synthesis time including a two step HPLC purification was 120 min. The regional distribution in rat brain after i.v. injection of [sup 18]FE-TCP was heterogeneous and similar to the known distribution of phencyclidine recognition sites, with hippocampus-cerebellum, striatum-cerebellum and cerebral cortex-cerebellum concentration ratios of 2.08, 1.7 and 1.54, respectively, 15 min post-injection. Furthermore, this localized regional cerebral distribution was blocked by co-injection with the unlabelled FE-TCP or pretreatment with cis-2-hydroxymethyl-r-1-(N-piperidyl)-1-(2-thienyl)cyclohexane, with the greatest reductions seen in the hippocampus followed by the striatum and cerebral cortex. However, relatively low receptor binding affinity and high non-specific binding due to its high lipophilicity suggest that [sup 18]FE-TCP may not be a suitable radioligand for in vivo PET investigations of the NMDA receptor-channel complex. (Author).
Synthesis and radiofluorination of putative NMDA receptor ligands
Energy Technology Data Exchange (ETDEWEB)
Kronenberg, U
2011-01-15
In the course of this work on the synthesis of radioligands for the NMDA receptor the authentic standards and labeling precursors of four compounds with an amidine structure was performed. Synthesis of the precursors followed reaction conditions given in the literature and was successful. The imidoesters used for the synthesis were obtained from their nitriles in a Pinner synthesis, while 2-hydroxybenzylamine was synthesized in a reduction of 2-hydroxybenzonitrile using borane as a reducing agent. After a coupling reaction of the amine and the imidoester in DMF using triethylamine as base the precursors were obtained in good yields and purified by crystallization from methanol. The cyclic standard compound was synthesized directly from 2-(bromomethyl)- benzonitrile and 2-hydroxybenzylamine in a ring closing reaction. Similar to the other precursors, crystallization from methanol produced a pure compound. The authentic standards were synthesized starting from salicylaldehyde. In a four step synthesis the desired ortho-fluoroethoxybenzylamine was obtained in good yield. Coupling of the amine with the respective imidoester or in the case of the cyclic compound 2-(bromomethyl)-benzonitrile gave the desired product which was then purified by column chromatography or by crystallization from ethanol and water. For the labeling procedure 1-bromo-2-[{sub 18}F]fluoroethane was synthesized following a previously published pathway starting from 1,2-dibromoethane. An alternative route of radiosynthesis for this prosthetic group was tested using ethyleneglycole- 1,2-ditosylate. The labeling reaction was performed on one of the precursors testing both DMF and DMSO as solvents and using NaOH as base. Yields of N-(2-fluoroethoxybenzyl)- cinnamamidine were about 78 % at 80 C after 30 minutes in DMSO. The desired product can now be synthesized in sufficient yields for in vitro and in vivo evaluation studies. Labeling on the cyclic precursor was attempted utilizing DMSO as solvent
Synthesis and radiofluorination of putative NMDA receptor ligands
International Nuclear Information System (INIS)
Kronenberg, U.
2011-01-01
In the course of this work on the synthesis of radioligands for the NMDA receptor the authentic standards and labeling precursors of four compounds with an amidine structure was performed. Synthesis of the precursors followed reaction conditions given in the literature and was successful. The imidoesters used for the synthesis were obtained from their nitriles in a Pinner synthesis, while 2-hydroxybenzylamine was synthesized in a reduction of 2-hydroxybenzonitrile using borane as a reducing agent. After a coupling reaction of the amine and the imidoester in DMF using triethylamine as base the precursors were obtained in good yields and purified by crystallization from methanol. The cyclic standard compound was synthesized directly from 2-(bromomethyl)- benzonitrile and 2-hydroxybenzylamine in a ring closing reaction. Similar to the other precursors, crystallization from methanol produced a pure compound. The authentic standards were synthesized starting from salicylaldehyde. In a four step synthesis the desired ortho-fluoroethoxybenzylamine was obtained in good yield. Coupling of the amine with the respective imidoester or in the case of the cyclic compound 2-(bromomethyl)-benzonitrile gave the desired product which was then purified by column chromatography or by crystallization from ethanol and water. For the labeling procedure 1-bromo-2-[ 18 F]fluoroethane was synthesized following a previously published pathway starting from 1,2-dibromoethane. An alternative route of radiosynthesis for this prosthetic group was tested using ethyleneglycole- 1,2-ditosylate. The labeling reaction was performed on one of the precursors testing both DMF and DMSO as solvents and using NaOH as base. Yields of N-(2-fluoroethoxybenzyl)- cinnamamidine were about 78 % at 80 C after 30 minutes in DMSO. The desired product can now be synthesized in sufficient yields for in vitro and in vivo evaluation studies. Labeling on the cyclic precursor was attempted utilizing DMSO as solvent, but no
Dela Cruz, J A D; Coke, T; Icaza-Cukali, D; Khalifa, N; Bodnar, R J
2014-10-01
Animals learn to prefer flavors associated with the intake of sugar (sucrose, fructose, glucose) and fat (corn oil: CO) solutions. Conditioned flavor preferences (CFP) have been elicited for sugars based on orosensory (flavor-flavor: e.g., fructose-CFP) and post-ingestive (flavor-nutrient: e.g., intragastric (IG) glucose-CFP) processes. Dopamine (DA) D1, DA D2 and NMDA receptor antagonism differentially eliminate the acquisition and expression of fructose-CFP and IG glucose-CFP. However, pharmacological analysis of fat (CO)-CFP, mediated by both flavor-flavor and flavor-nutrient processes, indicated that acquisition and expression of fat-CFP were minimally affected by systemic DA D1 and D2 antagonists, and were reduced by NMDA antagonism. Therefore, the present study examined whether systemic DA D1 (SCH23390), DA D2 (raclopride) or NMDA (MK-801) receptor antagonists altered acquisition and/or expression of CFP induced by oral glucose that should be mediated by both flavor-flavor and flavor-nutrient processes. Oral glucose-CFP was elicited following by training rats to drink one novel flavor (CS+, e.g., cherry) mixed in 8% glucose and another flavor (CS-, e.g., grape) mixed in 2% glucose. In expression studies, food-restricted rats drank these solutions in one-bottle sessions (2 h) over 10 days. Subsequent two-bottle tests with the CS+ and CS- flavors mixed in 2% glucose occurred 0.5 h after systemic administration of vehicle (VEH), SCH23390 (50-800 nmol/kg), raclopride (50-800 nmol/kg) or MK-801 (50-200 μg/kg). Rats displayed a robust CS+ preference following VEH treatment (94-95%) which was significantly though marginally attenuated by SCH23390 (67-70%), raclopride (77%) or MK-801 (70%) at doses that also markedly reduced overall CS intake. In separate acquisition studies, rats received VEH, SCH23390 (50-400 nmol/kg), raclopride (50-400 nmol/kg) or MK-801 (100 μg/kg) 0.5 h prior to ten 1-bottle training trials with CS+/8%G and CS-/2%G training solutions that was
International Nuclear Information System (INIS)
Dekundy, Andrzej; Kaminski, Rafal M.; Zielinska, Elzbieta; Turski, Waldemar A.
2007-01-01
Organophosphate (OP) and carbamate acetylcholinesterase (AChE) inhibitors produce seizures and lethality in mammals. Anticonvulsant and neuroprotective properties of N-methyl-D-aspartate (NMDA) antagonists encourage the investigation of their effects in AChE inhibitor-induced poisonings. In the present study, the effects of dizocilpine (MK-801, 1 mg/kg) or 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 10 mg/kg), alone or combined with muscarinic antagonist atropine (1.8 mg/kg), on convulsant and lethal properties of an OP pesticide dichlorvos or a carbamate drug physostigmine, were studied in mice. Both dichlorvos and physostigmine induced dose-dependent seizure activity and lethality. Atropine did not prevent the occurrence of convulsions but decreased the lethal effects of both dichlorvos and physostigmine. MK-801 or CPP blocked or attenuated, respectively, dichlorvos-induced convulsions. Contrariwise, NMDA antagonists had no effect in physostigmine-induced seizures or lethality produced by dichlorvos or physostigmine. Concurrent pretreatment with atropine and either MK-801 or CPP blocked or alleviated seizures produced by dichlorvos, but not by physostigmine. Both MK-801 and CPP co-administered with atropine enhanced its antilethal effects in both dichlorvos and physostigmine poisoning. In both saline- and AChE inhibitor-treated mice, no interaction of the investigated antidotes with brain cholinesterase was found. The data indicate that both muscarinic ACh and NMDA receptor-mediated mechanisms contribute to the acute toxicity of AChE inhibitors, and NMDA receptors seem critical to OP-induced seizures
[Contributions of neuropsychology to anti-NMDA receptor antibody encephalitis: a literature review].
Luna-Lario, P; Hernaez-Goni, P; Tirapu-Ustarroz, J
2016-05-01
Limbic encephalitis generated by anti-N-methyl-D-aspartate (NMDA) receptor antibodies is an acute and severe neurological entity, which is more prevalent in young females and is associated to an underlying tumour. Since it leads to severe cognitive impairment, thought needs to be given to the contributions of neuropsychology to the diagnosis, development and treatment of the disease, which have received little attention from researchers to date. A review is conducted of the prior literature, evaluating the measurement of the cognitive symptoms (predominantly mnemonic and executive) associated to this disease. Valid, reliable neuropsychological instruments are proposed, and it is suggested that neuropsychological measures may be used as parameters to follow up these patients which help monitor their functionality in daily living once they have recovered from the acute phase. Similarly they can become a basis on which to assemble rehabilitation programmes that favour the accomplishment of personal autonomy and the patients' reintegration in the community. Nevertheless, we stress the need to include neuropsychologists and neuropsychiatrists in not only the detection but also the treatment of these patients so as to enable them to recover their personal independence and re-adapt to their natural settings.
Vulnerability to omega-3 deprivation in a mouse model of NMDA receptor hypofunction.
Islam, Rehnuma; Trépanier, Marc-Olivier; Milenkovic, Marija; Horsfall, Wendy; Salahpour, Ali; Bazinet, Richard P; Ramsey, Amy J
2017-01-01
Several studies have found decreased levels of ω-3 polyunsaturated fatty acids in the brain and blood of schizophrenia patients. Furthermore, dietary ω-3 supplements may improve schizophrenia symptoms and delay the onset of first-episode psychosis. We used an animal model of NMDA receptor hypofunction, NR1KD mice, to understand whether changes in glutamate neurotransmission could lead to changes in brain and serum fatty acids. We further asked whether dietary manipulations of ω-3, either depletion or supplementation, would affect schizophrenia-relevant behaviors of NR1KD mice. We discovered that NR1KD mice have elevated brain levels of ω-6 fatty acids regardless of their diet. While ω-3 supplementation did not improve any of the NR1KD behavioral abnormalities, ω-3 depletion exacerbated their deficits in executive function. Omega-3 depletion also caused extreme mortality among male mutant mice, with 75% mortality rate by 12 weeks of age. Our studies show that alterations in NMDAR function alter serum and brain lipid composition and make the brain more vulnerable to dietary ω-3 deprivation.
DEFF Research Database (Denmark)
Hansen, Kasper Bø; Mullasseril, Praseeda; Dawit, Sara
2010-01-01
N-Methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels that mediate a slow, Ca(2+)-permeable component of excitatory synaptic transmission in the central nervous system and play a pivotal role in synaptic plasticity, neuronal development, and several neurological diseases. We describe...... a fluorescence-based assay that measures NMDA receptor-mediated changes in intracellular calcium in a BHK-21 cell line stably expressing NMDA receptor NR2D with NR1 under the control of a tetracycline-inducible promoter (Tet-On). The assay selectively identifies allosteric modulators by using supramaximal...
Moriguchi, Shigeki; Tanaka, Tomoya; Narahashi, Toshio; Fukunaga, Kohji
2013-10-01
Sunifiram is a novel pyrrolidone nootropic drug structurally related to piracetam, which was developed for neurodegenerative disorder like Alzheimer's disease. Sunifiram is known to enhance cognitive function in some behavioral experiments such as Morris water maze task. To address question whether sunifiram affects N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic function in the hippocampal CA1 region, we assessed the effects of sunifiram on NMDAR-dependent long-term potentiation (LTP) by electrophysiology and on phosphorylation of synaptic proteins by immunoblotting analysis. In mouse hippocampal slices, sunifiram at 10-100 nM significantly enhanced LTP in a bell-shaped dose-response relationship which peaked at 10 nM. The enhancement of LTP by sunifiram treatment was inhibited by 7-chloro-kynurenic acid (7-ClKN), an antagonist for glycine-binding site of NMDAR, but not by ifenprodil, an inhibitor for polyamine site of NMDAR. The enhancement of LTP by sunifilam was associated with an increase in phosphorylation of α-amino-3-hydroxy-5-methylisozazole-4-propionate receptor (AMPAR) through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and an increase in phosphorylation of NMDAR through activation of protein kinase Cα (PKCα). Sunifiram treatments at 1-1000 nM increased the slope of field excitatory postsynaptic potentials (fEPSPs) in a dose-dependent manner. The enhancement was associated with an increase in phosphorylation of AMPAR receptor through activation of CaMKII. Interestingly, under the basal condition, sunifiram treatments increased PKCα (Ser-657) and Src family (Tyr-416) activities with the same bell-shaped dose-response curve as that of LTP peaking at 10 nM. The increase in phosphorylation of PKCα (Ser-657) and Src (Tyr-416) induced by sunifiram was inhibited by 7-ClKN treatment. The LTP enhancement by sunifiram was significantly inhibited by PP2, a Src family inhibitor. Finally, when pretreated with a high
Czech Academy of Sciences Publication Activity Database
Vrajová, M.; Bubeníková-Valešová, V.; Klaschka, Jan
2010-01-01
Roč. 9, Suppl.1 (2010), S147 ISSN 1744-859X. [International Congress on Neurobiology and Clinical Psychopharmacology and European Psychiatric Association Conference on Treatment Guidance /1./. 19.11.2009-22.11.2009, Thessaloniki] R&D Projects: GA ČR GD309/09/H072; GA MŠk(CZ) 1M0517 Institutional research plan: CEZ:AV0Z10300504 Keywords : schizophrenia * animal model * NMDA receptor * aODN-NR1/NR2 * PPI Subject RIV: FL - Psychiatry, Sexuology
Cheng, Jing; Liu, Xiaoqing; Cao, Longhui; Zhang, Tianhua; Li, Huiting; Lin, Wenqian
2017-01-10
Whether Neo-adjuvant chemotherapy can affect patients' postoperative brain function is not clear. In this study, we investigated the effect of preoperative cisplatin treatment on postoperative cognitive function and its possible mechanism in rats. Moreover, we also tested whether the NMDAR inhibitor memantine could attenuate cisplatin-induced alterations. 12-month-oldSprague-Dawley rats randomly received an intraperitoneal injection of either cisplatin once a week at a dose of 3mg/kg for three consecutive weeks or an equivalent volume of normal saline. After the injections, the normal saline injection group was divided into 3 groups (n=5 each): a normal saline group (group S), normal saline+pentobarbital group (group SP), and normal saline+pentobarbital+operation group (group SPO).The cisplatin injection group was divided into 3 groups: a cisplatin group (group C), cisplatin+pentobarbital group (group CP), and cisplatin+pentobarbital+operation group (group CPO).Rats in the group SP, SPO,CP and CPO were anaesthetized with sodium pentobarbital and then the SPO and CPO groups underwent a simple laparotomy operation. The effects of memantine were tested through two additional groups of rats (cisplatin+memantine group (group CM) and cisplatin+pentobarbital+operation+memantine group (group CPOM)). A Morris water maze test was performed to evaluate the spatial learning and memory ability five days after anesthesia or operation. After the test, the hippocampi were removed for detection of the expression of NMDAR by western bloting. The relevant protein expression levels of PSD95 and ERK1/2 were detected by western blot analysis. Rats treated with cisplatin had a longer mean escape latency and spent a shorter amount of time in the target quadrant than did the normal saline injection rats. Furthermore, the protein expression levels of NMDA receptors, PSD95 and ERK1/2 were decreased in cisplatin group and memantine could up-regulate their expression. These results suggest
Yadav, Rajeev; Lu, H Peter
2018-03-28
The N-methyl-d-aspartate (NMDA) receptor ion-channel is activated by the binding of ligands, along with the application of action potential, important for synaptic transmission and memory functions. Despite substantial knowledge of the structure and function, the gating mechanism of the NMDA receptor ion channel for electric on-off signals is still a topic of debate. We investigate the NMDA receptor partition distribution and the associated channel's open-close electric signal trajectories using a combined approach of correlating single-molecule fluorescence photo-bleaching, single-molecule super-resolution imaging, and single-channel electric patch-clamp recording. Identifying the compositions of NMDA receptors, their spatial organization and distributions over live cell membranes, we observe that NMDA receptors are organized inhomogeneously: nearly half of the receptor proteins are individually dispersed; whereas others exist in heterogeneous clusters of around 50 nm in size as well as co-localized within the diffraction limited imaging area. We demonstrate that inhomogeneous interactions and partitions of the NMDA receptors can be a cause of the heterogeneous gating mechanism of NMDA receptors in living cells. Furthermore, comparing the imaging results with the ion-channel electric current recording, we propose that the clustered NMDA receptors may be responsible for the variation in the current amplitude observed in the on-off two-state ion-channel electric signal trajectories. Our findings shed new light on the fundamental structure-function mechanism of NMDA receptors and present a conceptual advancement of the ion-channel mechanism in living cells.
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Xinyan Gao
2012-01-01
Full Text Available Previous studies have demonstrated the efficacy of electroacupuncture at ST36 for patients with gastrointestinal motility disorders. While several lines of evidence suggest that the effect may involve vagal reflex, the precise molecular mechanism underlying this process still remains unclear. Here we report that the intragastric pressure increase induced by low frequency electric stimulation at ST36 was blocked by AP-5, an antagonist of N-methyl-D-aspartate receptors (NMDARs. Indeed, stimulating ST36 enhanced NMDAR-mediated, but not 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-ylpropanoic-acid-(AMPA- receptor-(AMPAR- mediated synaptic transmission in gastric-projecting neurons of the dorsal motor nucleus of the vagus (DMV. We also identified that suppression of presynaptic μ-opioid receptors may contribute to upregulation of NMDAR-mediated synaptic transmission induced by electroacupuncture at ST36. Furthermore, we determined that the glutamate-receptor-2a-(NR2A- containing NMDARs are essential for NMDAR-mediated enhancement of gastric motility caused by stimulating ST36. Taken together, our results reveal an important role of NMDA receptors in mediating enhancement of gastric motility induced by stimulating ST36.
Glufosinate ammonium induces convulsion through N-methyl-D-aspartate receptors in mice.
Matsumura, N; Takeuchi, C; Hishikawa, K; Fujii, T; Nakaki, T
2001-05-18
Glufosinate ammonium, a broad-spectrum herbicide, causes convulsion in rodents and humans. Because of the structural similarities between glufosinate and glutamate, the convulsion induced by glufosinate ammonium may be ascribed to glutamate receptor activation. Three N-methyl-D-asparate (NMDA) receptor antagonists, dizocilpine, LY235959, and Compound 40, and an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor antagonist, NBQX, were coadministrated with glufosinate ammonium (80 mg/kg, intraperitoneally) in mice. Statistical analyses showed that the NMDA receptor antagonists markedly inhibited the convulsions, while the AMPA/kainate receptor antagonist had no effect on the convulsion. These results suggest that the convulsion caused by glufosinate ammonium is mediated through NMDA receptors.
Paquette, Melanie A.; Martinez, Alex A.; Macheda, Teresa; Meshul, Charles K.; Johnson, Steven W.; Berger, S. Paul; Giuffrida, Andrea
2013-01-01
Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinson’s disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6-hydroxydopamine (6-OHDA) rat model. These effects have been attributed to N-methyl-d-aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5-HT) uptake and cause 5-HT overflow, leading to stimulation of 5-HT1A receptors, which has been shown to reduce LID. We undertook a study in 6-OHDA rats to determine whether the anti-dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5-HT1A agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae-Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM-suppressing effect of amantadine was not affected by the 5-HT1A antagonist WAY-100635, but was partially reversed by the NMDA agonist d-cycloserine. Conversely, the AIM-suppressing effect of dextromethorphan was prevented by WAY-100635 but not by d-cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L-DOPA in sensorimotor tests. We conclude that the anti-dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5-HT1A agonism. Combined with previous work from our group, our results support the investigation of 5-HT1A agonists as pharmacotherapies for LID in PD patients. PMID:22861201
Hida, Hirotake; Mouri, Akihiro; Mori, Kentaro; Matsumoto, Yurie; Seki, Takeshi; Taniguchi, Masayuki; Yamada, Kiyofumi; Iwamoto, Kunihiro; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro
2015-01-01
Blonanserin differs from currently used serotonin 5-HT2A/dopamine-D2 receptor antagonists in that it exhibits higher affinity for dopamine-D2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT2A receptor agonist) and 7-OH-DPAT (a dopamine-D3 receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D1 receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr197 and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser897 by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser896 by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D1-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D3 and serotonin 5-HT2A receptors in the mPFC. PMID:25120077
Paquette, Melanie A; Martinez, Alex A; Macheda, Teresa; Meshul, Charles K; Johnson, Steven W; Berger, S Paul; Giuffrida, Andrea
2012-11-01
Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinson's disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6-hydroxydopamine (6-OHDA) rat model. These effects have been attributed to N-methyl-d-aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5-HT) uptake and cause 5-HT overflow, leading to stimulation of 5-HT(1A) receptors, which has been shown to reduce LID. We undertook a study in 6-OHDA rats to determine whether the anti-dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5-HT(1A) agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae-Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM-suppressing effect of amantadine was not affected by the 5-HT(1A) antagonist WAY-100635, but was partially reversed by the NMDA agonist d-cycloserine. Conversely, the AIM-suppressing effect of dextromethorphan was prevented by WAY-100635 but not by d-cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L-DOPA in sensorimotor tests. We conclude that the anti-dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5-HT(1A) agonism. Combined with previous work from our group, our results support the investigation of 5-HT(1A) agonists as pharmacotherapies for LID in PD patients. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.
DEFF Research Database (Denmark)
Christensen, Thomas; Bruhn, T; Frank, L
1996-01-01
treated with either saline, MK-801 (5 mg/kg i.p.) or NBQX (30 mg/kg i.p. x 3) were subjected to permanent MCAO. Regional CPSR and volumes of gray matter structures displaying normal CPSR were measured in coronal cryosections of the brain by quantitative autoradiography following an i.v. bolus injection....... Treatment with MK-801 significantly increased the volume of tissue with normal CPSR in the ischemic hemisphere compared to controls, whereas this was not seen with NBQX treatment. The results suggest that MK-801 and NBQX have different effects on peri-infarct protein synthesis after MCAO. Since both......We investigated whether the known neuroprotective effects of two selective glutamate receptor antagonists, the NMDA antagonist MK-801 and the AMPA antagonist NBQX, are reflected in the regional cerebral protein synthesis rates (CPSR) in rats with middle cerebral artery occlusion (MCAO). Rats...
Anti-NMDA receptor encephalitis and nonencephalitic HSV-1 infection.
Salovin, Amy; Glanzman, Jason; Roslin, Kylie; Armangue, Thais; Lynch, David R; Panzer, Jessica A
2018-07-01
To determine whether there is an association between nonencephalitic herpes simplex virus 1 (HSV-1) infection and anti-NMDA receptor encephalitis (anti-NMDARE). Antibody testing was performed using samples from 2 cohorts in a case-control observational study. The cohort "Philadelphia" included 16 serum samples of pediatric anti-NMDARE cases and 42 age-matched controls with other neuroinflammatory disorders studied at the Children's Hospital of Philadelphia and University of Pennsylvania. The cohort "Barcelona" contained 23 anti-NMDARE patient samples and 26 age-matched participants with other neuroinflammatory disorders studied at IDIBAPS-Hospital Clinic, University of Barcelona. The presence of HSV-1 IgG antibodies was examined by ELISA. As an additional control, IgG antibodies to cytomegalovirus (CMV) and Epstein-Barr virus viral capsid antigen (EBV-VCA) were determined. In each cohort, more participants with anti-NMDARE than controls had anti-HSV-1 IgG antibodies. In the Philadelphia cohort (58 participants), 44% of anti-NMDARE cases had antibodies to HSV-1 compared with 14% controls (OR 4.67, 95% CI 1.3-17.3, p = 0.031). In the Barcelona cohort (49 participants), 52% of participants with anti-NMDARE had antibodies to HSV-1 compared with 31% of controls (OR 2.45, 95% CI 0.7-7.9, p = 0.155). Overall, 49% of anti-NMDARE cases have antibodies to HSV-1 in these 2 combined cohorts compared with 21% of controls (Mantel-Haenszel OR 3.21, 95% CI 1.3-7.7, p = 0.007). Past HSV-1 infection was found in significantly more anti-NMDARE cases than controls. This suggests a meaningful association between nonencephalitic HSV-1 infection and development of anti-NMDARE.
NMDA receptor content of synapses in stratum radiatum of the hippocampal CA1 area.
Racca, C; Stephenson, F A; Streit, P; Roberts, J D; Somogyi, P
2000-04-01
Glutamate receptors activated by NMDA (NMDARs) or AMPA (AMPARs) are clustered on dendritic spines of pyramidal cells. Both the AMPAR-mediated postsynaptic responses and the synaptic AMPAR immunoreactivity show a large intersynapse variability. Postsynaptic responses mediated by NMDARs show less variability. To assess the variability in NMDAR content and the extent of their coexistence with AMPARs in Schaffer collateral-commissural synapses of adult rat CA1 pyramidal cells, electron microscopic immunogold localization of receptors has been used. Immunoreactivity of NMDARs was detected in virtually all synapses on spines, but AMPARs were undetectable, on average, in 12% of synapses. A proportion of synapses had a very high AMPAR content relative to the mean content, resulting in a distribution more skewed toward larger values than that of NMDARs. The variability of synaptic NMDAR content [coefficient of variation (CV), 0.64-0.70] was much lower than that of the AMPAR content (CV, 1.17-1.45). Unlike the AMPAR content, the NMDAR content showed only a weak correlation with synapse size. As reported previously for AMPARs, the immunoreactivity of NMDARs was also associated with the spine apparatus within spines. The results demonstrate that the majority of the synapses made by CA3 pyramidal cells onto spines of CA1 pyramids express both NMDARs and AMPARs, but with variable ratios. A less-variable NMDAR content is accompanied by a wide variability of AMPAR content, indicating that the regulation of expression of the two receptors is not closely linked. These findings support reports that fast excitatory transmission at some of these synapses is mediated by activation mainly of NMDARs.
Anti-N-Methyl-D-Aspartate Receptor Encephalitis and Rasmussen-like Syndrome: An Association?
Gurcharran, Kevin; Karkare, Shefali
2017-01-01
N-methyl-D-aspartate (NMDA) receptor encephalitis is an immune-mediated condition that has a broad spectrum of manifestations, including seizures, coma, psychosis, and focal neurological deficits. Although usually a diffuse process, unihemispheric involvement mimicking early stages of Rasmussen encephalitis can occur. Rasmussen's encephalitis is a unique syndrome characterized by progressive hemiplegia, drug-resistant focal epilepsy, cognitive decline, and hemispheric brain atrophy contralateral to the hemiplegia. We describe a two-year-old girl with progressive right weakness and epilepsia partialis continua, concerning for early Rasmussen's encephalitis, who tested positive for anti-NMDA receptor antibodies. She experienced complete clinical recovery after immunotherapy. Anti-NMDA receptor antibodies were absent at three weeks and again at one year after the first treatment of intravenous immunoglobulin. There are few reports of Rasmussen-like encephalitis in individuals with anti-NMDA receptor antibody positivity. Thus the clinical significance of this association is yet to be determined. In addition, several other antibodies have been documented in individuals with Rasmussen encephalitis. The lack of a consistently reported antibody in Rasmussen encephalitis patients and the temporary nature of the anti-NMDA receptor antibody in our patient raise the following question: Is the presence of anti-NMDA receptor antibodies the cause of the symptoms or secondary to the pathogenic process? Copyright © 2016 Elsevier Inc. All rights reserved.
Role of NMDA receptor GluN2D subunit in the antidepressant effects of enantiomers of ketamine
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Soichiro Ide
2017-11-01
Full Text Available We investigated the rapid and sustained antidepressant effects of enantiomers of ketamine in N-methyl-d-aspartate (NMDA receptor GluN2D subunit knockout (GluN2D-KO mice. Intraperitoneal administration of ketamine or its enantiomers 10 min before the tail-suspension test exerted significant antidepressant effects on restraint stress-induced depression in both wildtype and GluN2D-KO mice. The antidepressant effects of (RS-ketamine and (S-ketamine were sustained 96 h after the injection in both wildtype and GluN2D-KO mice, but such sustained antidepressant effects of (R-ketamine were only observed in wildtype mice. These data suggest that the GluN2D subunit is critical for the sustained antidepressant effects of (R-ketamine.
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Kelli Lauderdale
2015-09-01
Full Text Available Cellular edema (cell swelling is a principal component of numerous brain disorders including ischemia, cortical spreading depression, hyponatremia, and epilepsy. Cellular edema increases seizure-like activity in vitro and in vivo, largely through nonsynaptic mechanisms attributable to reduction of the extracellular space. However, the types of excitability changes occurring in individual neurons during the acute phase of cell volume increase remain unclear. Using whole-cell patch clamp techniques, we report that one of the first effects of osmotic edema on excitability of CA1 pyramidal cells is the generation of slow inward currents (SICs, which initiate after approximately 1 min. Frequency of SICs increased as osmolarity decreased in a dose-dependent manner. Imaging of real-time volume changes in astrocytes revealed that neuronal SICs occurred while astrocytes were still in the process of swelling. SICs evoked by cell swelling were mainly nonsynaptic in origin and NMDA receptor-dependent. To better understand the relationship between SICs and changes in neuronal excitability, recordings were performed in increasingly physiological conditions. In the absence of any added pharmacological reagents or imposed voltage clamp, osmotic edema induced excitatory postsynaptic potentials and burst firing over the same timecourse as SICs. Like SICs, action potentials were blocked by NMDAR antagonists. Effects were more pronounced in adult (8–20 weeks old compared with juvenile (P15–P21 mice. Together, our results indicate that cell swelling triggered by reduced osmolarity rapidly increases neuronal excitability through activation of NMDA receptors. Our findings have important implications for understanding nonsynaptic mechanisms of epilepsy in relation to cell swelling and reduction of the extracellular space.
Shimazu, S; Katsuki, H; Takenaka, C; Tomita, M; Kume, T; Kaneko, S; Akaike, A
2000-01-28
We investigated the potential neuroprotective effects of several sigma receptor ligands in organotypic midbrain slice cultures as an excitotoxicity model system. When challenged with 100-microM N-methyl-D-aspartate (NMDA) for 24 h, dopaminergic neurons in midbrain slice cultures degenerated, and this was prevented by (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]-cyclohepten-5, 10-imine (MK-801; 1-10 microM). Concomitant application of ifenprodil (1-10 microM) or haloperidol (1-10 microM), both of which are high-affinity sigma receptor ligands, significantly attenuated the neurotoxicity of 100 microM NMDA. The sigma(1) receptor-selective ligand (+)-N-allylnormetazocine ((+)-SKF 10047; 1-10 microM) was also effective in attenuating the toxicity of NMDA. The effect of R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane hydrochloride ((-)-PPAP), a sigma receptor ligand with negligible affinity for the phencyclidine site of NMDA receptors, was also examined. (-)-PPAP (3-100 microM) caused a concentration-dependent reduction of NMDA cytotoxicity, with significant protection at concentrations of 30 and 100 microM. In contrast, (+)-SKF 10047 (10 microM) and (-)-PPAP (100 microM) showed no protective effects against cell death induced by the Ca(2+) ionophore ionomycin (1-3 microM). These results indicate that sigma receptor ligands attenuate the cytotoxic effects of NMDA on midbrain dopaminergic neurons, possibly via inhibition of NMDA receptor functions.
Takahashi, Eiki; Niimi, Kimie; Itakura, Chitoshi
2010-10-25
Ca(V)2.1 is highly expressed in the nervous system and plays an essential role in the presynaptic modulation of neurotransmitter release machinery. Recently, the antiepileptic drug levetiracetam was reported to inhibit presynaptic Ca(V)2.1 functions, reducing glutamate release in the hippocampus, although the precise physiological role of Ca(V)2.1-regulated synaptic functions in cognitive performance at the system level remains unknown. This study examined whether Ca(V)2.1 mediates hippocampus-dependent spatial short-term memory using the object location and Y-maze tests, and perirhinal cortex-dependent nonspatial short-term memory using the object recognition test, via a combined pharmacological and genetic approach. Heterozygous rolling Nagoya (rol/+) mice carrying the Ca(V)2.1alpha(1) mutation had normal spatial and nonspatial short-term memory. A 100mg/kg dose of levetiracetam, which is ineffective in wild-type controls, blocked spatial short-term memory in rol/+ mice. At 5mg/kg, the N-methyl-D-aspartate (NMDA) receptor blocker (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), which is ineffective in wild-type controls, also blocked the spatial short-term memory in rol/+ mice. Furthermore, a combination of subthreshold doses of levetiracetam (25 mg/kg) and CPP (2.5mg/kg) triggered a spatial short-term memory deficit in rol/+ mice, but not in wild-type controls. Similar patterns of nonspatial short-term memory were observed in wild-type and rol/+ mice when injected with levetiracetam (0-300 mg/kg). These results indicate that Ca(V)2.1-mediated NMDA receptor signaling is critical in hippocampus-dependent spatial short-term memory and differs in various regions. The combination subthreshold pharmacological and genetic approach presented here is easily performed and can be used to study functional signaling pathways in neuronal circuits. Copyright © 2010 Elsevier B.V. All rights reserved.
Karasawa, Jun-ichi; Yamamoto, Hideko; Yamamoto, Toshifumi; Sagi, Naoki; Horikomi, Kazutoshi; Sora, Ichiro
2002-02-22
MS-377 ((R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate) is a antipsychotic agent that binds to sigma-1 receptor. MS-377 showed anti-dopaminergic and anti-serotonergic activities and antagonistic action against phencyclidine (PCP)-induced behaviors in an animal model. These anti-psychotic activities of MS-377 are attributable to association with sigma-1 receptor. However, the mechanism by which the sigma-1 receptor ligands exact those numerous effects remains to be elucidated. In the present study, we evaluated the effect of MS-377 on N-methyl-D-aspartate (NMDA) receptor ion-channel complex in primary cultured rat neuronal cells. First, we examined the effect of MS-377 on NMDA-induced Ca2+ influx with fura-2/ AM loaded cells. MS-377 showed no effects on the basal Ca2+ concentration and NMDA-induced Ca2+ influx by itself PCP and SKF-10047 reduced the NMDA-induced increase in intracellular Ca2+ concentration. Pre-incubation of 1 microM MS-377 was found to significantly block the reduction by PCP or SKF-10047 of the NMDA-induced Ca2+ influx. Second, the effect of MS-377 on [3H]MK-801 intact cell binding was examined. PCP, haloperidol and (+)-pentazocine inhibited [3H]MK-801 binding, although MS-377 showed no effect by itself Pre-treatment of MS-377 markedly reversed the inhibition of [3H]MK-801 binding by PCP in a dose-dependent manner. These effects of MS-377 may depend on its affinity for the sigma-1 receptor, because MS-377 is a selective sigma-1 receptor ligand without any affinity for NMDA receptor ion-channel complex. These observations suggest that the MS-377 indirectly modulated the NMDA receptor ion-channel complex, and the anti-psychotic activities of MS-377, in part, are attributable to such on action via sigma-1 receptor.
Glycine Receptor Activation Impairs ATP-Induced Calcium Transients in Cultured Cortical Astrocytes
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Tatiana P. Morais
2018-01-01
Full Text Available In central nervous system, glycine receptor (GlyR is mostly expressed in the spinal cord and brainstem, but glycinergic transmission related elements have also been identified in the brain. Astrocytes are active elements at the tripartite synapse, being responsible for the maintenance of brain homeostasis and for the fine-tuning of synaptic activity. These cells communicate, spontaneously or in response to a stimulus, by elevations in their cytosolic calcium (calcium transients, Ca2+T that can be propagated to other cells. How these Ca2+T are negatively modulated is yet poorly understood. In this work, we evaluated GlyR expression and its role on calcium signaling modulation in rat brain astrocytes. We first proved that GlyR, predominantly subunits α2 and β, was expressed in brain astrocytes and its localization was confirmed in the cytoplasm and astrocytic processes by immunohistochemistry assays. Calcium imaging experiments in cultured astrocytes showed that glycine (500 μM, a GlyR agonist, caused a concentration-dependent reduction in ATP-induced Ca2+T, an effect abolished by the GlyR antagonist, strychnine (0.8 μM, as well as by nocodazole (1 μM, known to impair GlyR anchorage to the plasma membrane. This effect was mimicked by activation of GABAAR, another Cl--permeable channel. In summary, we demonstrated that GlyR activation in astrocytes mediates an inhibitory effect upon ATP induced Ca2+T, which most probably involves changes in membrane permeability to Cl- and requires GlyR anchorage at the plasma membrane. GlyR in astrocytes may thus be part of a mechanism to modulate astrocyte-to-neuron communication.
Novel Functional Properties of Drosophila CNS Glutamate Receptors
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Li, Yan; Dharkar, Poorva; Han, Tae-Hee; Serpe, Mihaela; Lee, Chi-Hon; Mayer, Mark L.
2016-12-01
Phylogenetic analysis reveals AMPA, kainate, and NMDA receptor families in insect genomes, suggesting conserved functional properties corresponding to their vertebrate counterparts. However, heterologous expression of the Drosophila kainate receptor DKaiR1D and the AMPA receptor DGluR1A revealed novel ligand selectivity at odds with the classification used for vertebrate glutamate receptor ion channels (iGluRs). DKaiR1D forms a rapidly activating and desensitizing receptor that is inhibited by both NMDA and the NMDA receptor antagonist AP5; crystallization of the KaiR1D ligand-binding domain reveals that these ligands stabilize open cleft conformations, explaining their action as antagonists. Surprisingly, the AMPA receptor DGluR1A shows weak activation by its namesake agonist AMPA and also by quisqualate. Crystallization of the DGluR1A ligand-binding domain reveals amino acid exchanges that interfere with binding of these ligands. The unexpected ligand-binding profiles of insect iGluRs allows classical tools to be used in novel approaches for the study of synaptic regulation.
Moraga-Amaro, Rodrigo; González, Hugo; Ugalde, Valentina; Donoso-Ramos, Juan Pablo; Quintana-Donoso, Daisy; Lara, Marcelo; Morales, Bernardo; Rojas, Patricio; Pacheco, Rodrigo; Stehberg, Jimmy
2016-04-01
Pharmacological evidence associates type I dopamine receptors, including subtypes D1 and D5, with learning and memory. Analyses using genetic approaches have determined the relative contribution of dopamine receptor D1 (D1R) in cognitive tasks. However, the lack of drugs that can discriminate between D1R and D5R has made the pharmacological distinction between the two receptors difficult. Here, we aimed to determine the role of D5R in learning and memory. In this study we tested D5R knockout mice and wild-type littermates in a battery of behavioral tests, including memory, attention, locomotion, anxiety and motivational evaluations. Our results show that genetic deficiency of D5R significantly impairs performance in the Morris water maze paradigm, object location and object recognition memory, indicating a relevant role for D5R in spatial memory and recognition memory. Moreover, the lack of D5R resulted in decreased exploration and locomotion. In contrast, D5R deficiency had no impact on working memory, anxiety and depressive-like behavior, measured using the spontaneous alternation, open-field, tail suspension test, and forced swimming test. Electrophysiological analyses performed on hippocampal slices showed impairment in long-term-potentiation in mice lacking D5R. Further analyses at the molecular level showed that genetic deficiency of D5R results in a strong and selective reduction in the expression of the NMDA receptor subunit NR2B in the hippocampus. These findings demonstrate the relevant contribution of D5R in memory and suggest a functional interaction of D5R with hippocampal glutamatergic pathways. Copyright © 2015 Elsevier Ltd. All rights reserved.
Czech Academy of Sciences Publication Activity Database
Šťastná, Eva; Chodounská, Hana; Pouzar, Vladimír; Kapras, Vojtěch; Borovská, Jiřina; Cais, Ondřej; Vyklický ml., Ladislav
2009-01-01
Roč. 74, č. 2 (2009), s. 256-263 ISSN 0039-128X R&D Projects: GA ČR(CZ) GA309/07/0271; GA ČR(CZ) GA203/08/1498 Grant - others:GA MŠk(CZ) LC554; FP6 Photolysis(XE) LSHM-CT-2007-037765 Program:LC Institutional research plan: CEZ:AV0Z40550506; CEZ:AV0Z50110509 Keywords : pregnane derivatives * NMDA receptor * structure-activity relationship * patch-clamp recording Subject RIV: CC - Organic Chemistry Impact factor: 2.905, year: 2009
Ligand-specific conformational changes in the alpha1 glycine receptor ligand-binding domain
DEFF Research Database (Denmark)
Pless, Stephan Alexander; Lynch, Joseph W
2009-01-01
, and by the antagonist, strychnine. Voltage-clamp fluorometry involves labeling introduced cysteines with environmentally sensitive fluorophores and inferring structural rearrangements from ligand-induced fluorescence changes. In the inner beta-sheet, we labeled residues in loop 2 and in binding domain loops D and E....... At each position, strychnine and glycine induced distinct maximal fluorescence responses. The pre-M1 domain responded similarly; at each of four labeled positions glycine produced a strong fluorescence signal, whereas strychnine did not. This suggests that glycine induces conformational changes...... in the inner beta-sheet and pre-M1 domain that may be important for activation, desensitization, or both. In contrast, most labeled residues in loops C and F yielded fluorescence changes identical in magnitude for glycine and strychnine. A notable exception was H201C in loop C. This labeled residue responded...
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Cui A
2017-04-01
Full Text Available Ai-Ling Cui,1 Ying-Hua Zhang,2 Jian-Zhong Li,3 Tianbin Song,4 Xue-Min Liu,1 Hui Wang,2 Ce Zhang,5 Guo-Lin Ma,6 Hui Zhang,7 Kefeng Li8 1Anatomy Department, Changzhi Medical College, Changzhi, Shanxi, 2Key Laboratory of Tissue Regeneration of Henan Province, Xinxiang Medical University, Xinxiang, Henan, 3Clinical Laboratory of Heji Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, 4Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, 5Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, 6Department of Radiology, China-Japan Friendship Hospital, Beijing, 7Department of Radiology, First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 8School of Medicine, University of California – San Diego, San Diego, CA, USA Abstract: N-methyl-D-aspartate (NDMA receptor-mediated excitotoxicity has been implicated in a variety of pathological situations such as Alzheimer’s disease (AD and Parkinson’s disease. However, no effective treatments for the same have been developed so far. Humanin (HN is a 24-amino acid peptide originally cloned from the brain of patients with AD and it prevents stress-induced cell death in many cells/tissues. In our previous study, HN was found to effectively rescue rat cortical neurons. It is still not clear whether HN protects the neurons through the attenuation of mitochondrial dysfunction. In this study, excitatory toxicity was induced by NMDA, which binds the NMDA receptor in primarily cultured rat cortical neurons. We found that NMDA (100 µmol/L dramatically induced the decrease of cell viability and caused mitochondrial dysfunction. Pretreatment of the neurons with HN (1 µmol/L led to significant increases of mitochondrial succinate dehydrogenase (SDH activity and membrane potential. In addition, HN pretreatment significantly reduced the excessive production of both reactive oxygen species (ROS and nitric
Zhao, Wen-Jie; Zhang, Min; Miao, Yanying; Yang, Xiong-Li; Wang, Zhongfeng
2010-07-15
In vertebrate retina, melatonin regulates various physiological functions. In this work we investigated the mechanisms underlying melatonin-induced potentiation of glycine currents in rat retinal ganglion cells (RGCs). Immunofluorescence double labelling showed that rat RGCs were solely immunoreactive to melatonin MT(2) receptors. Melatonin potentiated glycine currents of RGCs, which was reversed by the MT(2) receptor antagonist 4-P-PDOT. The melatonin effect was blocked by intracellular dialysis of GDP-beta-S. Either preincubation with pertussis toxin or application of the phosphatidylcholine (PC)-specific phospholipase C (PLC) inhibitor D609, but not the phosphatidylinositol (PI)-PLC inhibitor U73122, blocked the melatonin effect. The protein kinase C (PKC) activator PMA potentiated the glycine currents and in the presence of PMA melatonin failed to cause further potentiation of the currents, whereas application of the PKC inhibitor bisindolylmaleimide IV abolished the melatonin-induced potentiation. The melatonin effect persisted when [Ca(2+)](i) was chelated by BAPTA, and melatonin induced no increase in [Ca(2+)](i). Neither cAMP-PKA nor cGMP-PKG signalling pathways seemed to be involved because 8-Br-cAMP or 8-Br-cGMP failed to cause potentiation of the glycine currents and both the PKA inhibitor H-89 and the PKG inhibitor KT5823 did not block the melatonin-induced potentiation. In consequence, a distinct PC-PLC/PKC signalling pathway, following the activation of G(i/o)-coupled MT(2) receptors, is most likely responsible for the melatonin-induced potentiation of glycine currents of rat RGCs. Furthermore, in rat retinal slices melatonin potentiated light-evoked glycine receptor-mediated inhibitory postsynaptic currents in RGCs. These results suggest that melatonin, being at higher levels at night, may help animals to detect positive or negative contrast in night vision by modulating inhibitory signals largely mediated by glycinergic amacrine cells in the inner
Modulation of extrasynaptic NMDA receptors by synaptic and tonic zinc.
Anderson, Charles T; Radford, Robert J; Zastrow, Melissa L; Zhang, Daniel Y; Apfel, Ulf-Peter; Lippard, Stephen J; Tzounopoulos, Thanos
2015-05-19
Many excitatory synapses contain high levels of mobile zinc within glutamatergic vesicles. Although synaptic zinc and glutamate are coreleased, it is controversial whether zinc diffuses away from the release site or whether it remains bound to presynaptic membranes or proteins after its release. To study zinc transmission and quantify zinc levels, we required a high-affinity rapid zinc chelator as well as an extracellular ratiometric fluorescent zinc sensor. We demonstrate that tricine, considered a preferred chelator for studying the role of synaptic zinc, is unable to efficiently prevent zinc from binding low-nanomolar zinc-binding sites, such as the high-affinity zinc-binding site found in NMDA receptors (NMDARs). Here, we used ZX1, which has a 1 nM zinc dissociation constant and second-order rate constant for binding zinc that is 200-fold higher than those for tricine and CaEDTA. We find that synaptic zinc is phasically released during action potentials. In response to short trains of presynaptic stimulation, synaptic zinc diffuses beyond the synaptic cleft where it inhibits extrasynaptic NMDARs. During higher rates of presynaptic stimulation, released glutamate activates additional extrasynaptic NMDARs that are not reached by synaptically released zinc, but which are inhibited by ambient, tonic levels of nonsynaptic zinc. By performing a ratiometric evaluation of extracellular zinc levels in the dorsal cochlear nucleus, we determined the tonic zinc levels to be low nanomolar. These results demonstrate a physiological role for endogenous synaptic as well as tonic zinc in inhibiting extrasynaptic NMDARs and thereby fine tuning neuronal excitability and signaling.
Modulation of extrasynaptic NMDA receptors by synaptic and tonic zinc
Anderson, Charles T.; Radford, Robert J.; Zastrow, Melissa L.; Zhang, Daniel Y.; Apfel, Ulf-Peter; Lippard, Stephen J.; Tzounopoulos, Thanos
2015-01-01
Many excitatory synapses contain high levels of mobile zinc within glutamatergic vesicles. Although synaptic zinc and glutamate are coreleased, it is controversial whether zinc diffuses away from the release site or whether it remains bound to presynaptic membranes or proteins after its release. To study zinc transmission and quantify zinc levels, we required a high-affinity rapid zinc chelator as well as an extracellular ratiometric fluorescent zinc sensor. We demonstrate that tricine, considered a preferred chelator for studying the role of synaptic zinc, is unable to efficiently prevent zinc from binding low-nanomolar zinc-binding sites, such as the high-affinity zinc-binding site found in NMDA receptors (NMDARs). Here, we used ZX1, which has a 1 nM zinc dissociation constant and second-order rate constant for binding zinc that is 200-fold higher than those for tricine and CaEDTA. We find that synaptic zinc is phasically released during action potentials. In response to short trains of presynaptic stimulation, synaptic zinc diffuses beyond the synaptic cleft where it inhibits extrasynaptic NMDARs. During higher rates of presynaptic stimulation, released glutamate activates additional extrasynaptic NMDARs that are not reached by synaptically released zinc, but which are inhibited by ambient, tonic levels of nonsynaptic zinc. By performing a ratiometric evaluation of extracellular zinc levels in the dorsal cochlear nucleus, we determined the tonic zinc levels to be low nanomolar. These results demonstrate a physiological role for endogenous synaptic as well as tonic zinc in inhibiting extrasynaptic NMDARs and thereby fine tuning neuronal excitability and signaling. PMID:25947151
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Jelte A Wouda
2010-11-01
Full Text Available Disrupting reconsolidation of drug-related memories may be effective in reducing the incidence of relapse. In the current study we examine whether alcohol- related memories are prone to disruption by the β -adrenergicreceptor antagonist propranolol (10 mg/kg and the NMDA receptor antagonist MK801 (0.1 mg/kg following their reactivation. In operant chambers, male Wistar rats were trained to self-administer a 12% alcohol solution. After 3 weeks of abstinence, the animals were placed in the self-administration cages and were reexposed to the alcohol-associated cues for a 20-min retrieval period, immediately followed by a systemic injection of either propranolol, MK801 or saline. Rats were tested for cue-induced alcohol seeking on the following day. Retrieval session, injection and test were repeated on 2 further occasions at weekly intervals. Both propranolol and MK801 administration upon reactivation did not reduce alcohol seeking after the first reactivation test. However, a significant reduction of alcohol seeking was observed over three post-training tests in propranolol treated animals, and MK801 treated animals showed a strong tendency towards reduced alcohol seeking (p=0.06. Our data indicate that reconsolidation of alcohol-related memories can be disrupted after a long post-training interval and that particularly β-adrenergic receptors may represent novel targets for pharmacotherapy of alcoholism, in combination with cue-exposure therapies.
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Ioana Neagoe
2018-04-01
Full Text Available Abnormal signaling pathways mediated by N-methyl-d-aspartate receptors (NMDARs have been implicated in the pathogenesis of various CNS disorders and have been long considered as promising points of therapeutic intervention. However, few efforts have been previously described concerning evaluation of therapeutic modulators of NMDARs and their downstream pathways in human neurons with endogenous expression of NMDARs. In the present study, we assessed expression, functionality, and subunit composition of endogenous NMDARs in human induced pluripotent stem cell (hiPSC-derived cortical neurons (iCell Neurons and iCell GlutaNeurons. We initially confirmed the expected pharmacological response of iCell Neurons and iCell GlutaNeurons to NMDA by patch-clamp recordings. Subsequent pharmacological interrogation using GluN2 subunit-selective antagonists revealed the predominance of GluN2B in both iCell Neurons and iCell GlutaNeurons. This observation was also supported by qRT-PCR and Western blot analyses of GluN2 subunit expression as well as pharmacological experiments using positive allosteric modulators with distinct GluN2 subunit selectivity. We conclude that iCell Neurons and iCell GlutaNeurons express functional GluN2B-containing NMDARs and could serve as a valuable system for development and validation of GluN2B-modulating pharmaceutical agents. Keywords: Human induced pluripotent stem cell-derived neurons, iCell Neurons, iCell GlutaNeurons, NMDA receptors, GluN2B, Positive allosteric modulators
Rodríguez-Ruiz, Mar; Moreno, Estefanía; Moreno-Delgado, David; Navarro, Gemma; Mallol, Josefa; Cortés, Antonio; Lluís, Carme; Canela, Enric I; Casadó, Vicent; McCormick, Peter J; Franco, Rafael
2017-08-01
Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive memory loss and cognitive dysfunction. Anti-AD strategies targeting cell receptors consider them as isolated units. However, many cell surface receptors cooperate and physically contact each other forming complexes having different biochemical properties than individual receptors. We here report the discovery of dopamine D 1 , histamine H 3 , and N-methyl-D-aspartate (NMDA) glutamate receptor heteromers in heterologous systems and in rodent brain cortex. Heteromers were detected by co-immunoprecipitation and in situ proximity ligation assays (PLA) in the rat cortex where H 3 receptor agonists, via negative cross-talk, and H 3 receptor antagonists, via cross-antagonism, decreased D 1 receptor agonist signaling determined by ERK1/2 or Akt phosphorylation, and counteracted D 1 receptor-mediated excitotoxic cell death. Both D 1 and H 3 receptor antagonists also counteracted NMDA toxicity suggesting a complex interaction between NMDA receptors and D 1 -H 3 receptor heteromer function. Likely due to heteromerization, H 3 receptors act as allosteric regulator for D 1 and NMDA receptors. By bioluminescence resonance energy transfer (BRET), we demonstrated that D 1 or H 3 receptors form heteromers with NR1A/NR2B NMDA receptor subunits. D 1 -H 3 -NMDA receptor complexes were confirmed by BRET combined with fluorescence complementation. The endogenous expression of complexes in mouse cortex was determined by PLA and similar expression was observed in wild-type and APP/PS1 mice. Consistent with allosteric receptor-receptor interactions within the complex, H 3 receptor antagonists reduced NMDA or D 1 receptor-mediated excitotoxic cell death in cortical organotypic cultures. Moreover, H 3 receptor antagonists reverted the toxicity induced by ß 1-42 -amyloid peptide. Thus, histamine H 3 receptors in D 1 -H 3 -NMDA heteroreceptor complexes arise as promising targets to prevent neurodegeneration.
Role of NMDA receptor GluN2D subunit in the antidepressant effects of enantiomers of ketamine.
Ide, Soichiro; Ikekubo, Yuiko; Mishina, Masayoshi; Hashimoto, Kenji; Ikeda, Kazutaka
2017-11-01
We investigated the rapid and sustained antidepressant effects of enantiomers of ketamine in N-methyl-d-aspartate (NMDA) receptor GluN2D subunit knockout (GluN2D-KO) mice. Intraperitoneal administration of ketamine or its enantiomers 10 min before the tail-suspension test exerted significant antidepressant effects on restraint stress-induced depression in both wildtype and GluN2D-KO mice. The antidepressant effects of (RS)-ketamine and (S)-ketamine were sustained 96 h after the injection in both wildtype and GluN2D-KO mice, but such sustained antidepressant effects of (R)-ketamine were only observed in wildtype mice. These data suggest that the GluN2D subunit is critical for the sustained antidepressant effects of (R)-ketamine. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.
Guo, Xiaoli; Chronis, Demosthenis; De La Torre, Carola M; Smeda, John; Wang, Xiaohong; Mitchum, Melissa G
2015-08-01
CLE peptides are small extracellular proteins important in regulating plant meristematic activity through the CLE-receptor kinase-WOX signalling module. Stem cell pools in the SAM (shoot apical meristem), RAM (root apical meristem) and vascular cambium are controlled by CLE signalling pathways. Interestingly, plant-parasitic cyst nematodes secrete CLE-like effector proteins, which act as ligand mimics of plant CLE peptides and are required for successful parasitism. Recently, we demonstrated that Arabidopsis CLE receptors CLAVATA1 (CLV1), the CLAVATA2 (CLV2)/CORYNE (CRN) heterodimer receptor complex and RECEPTOR-LIKE PROTEIN KINASE 2 (RPK2), which transmit the CLV3 signal in the SAM, are required for perception of beet cyst nematode Heterodera schachtii CLEs. Reduction in nematode infection was observed in clv1, clv2, crn, rpk2 and combined double and triple mutants. In an effort to develop nematode resistance in an agriculturally important crop, orthologues of Arabidopsis receptors including CLV1, CLV2, CRN and RPK2 were identified from soybean, a host for the soybean cyst nematode Heterodera glycines. For each of the receptors, there are at least two paralogues in the soybean genome. Localization studies showed that most receptors are expressed in the root, but vary in their level of expression and spatial expression patterns. Expression in nematode-induced feeding cells was also confirmed. In vitro direct binding of the soybean receptors with the HgCLE peptide was analysed. Knock-down of the receptors in soybean hairy roots showed enhanced resistance to SCN. Our findings suggest that targeted disruption of nematode CLE signalling may be a potential means to engineer nematode resistance in crop plants. © 2015 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.
Kishi, Taro; Iwata, Nakao
2013-09-01
We examined whether N-methyl d-aspartate (NMDA) receptor antagonists as adjunctive therapy have therapeutic potential for schizophrenia treatment. Systematic review of PubMed, Cochrane Library, PsycINFO and Google Scholar up until October 2012 and meta-analysis of randomized placebo-controlled trials were performed. Risk ratio (RR), 95% confidence intervals (CI), numbers-needed-to-harm (NNH), and standardized mean difference (SMD) were calculated. Results were across 8 studies and 406 patients (85.5% schizophrenia related disorder and 14.5% bipolar disorder) were included (amantadine: 5 trials and 220 patients, memantine: 3 trials and 186 patients). NMDA receptor antagonists (NMDAR-ANTs) as adjunctive therapy were not superior to placebo in overall (SMD = -0.25, CI = -0.72, 0.23, p = 0.31, N = 6, n = 347), positive symptoms (SMD = -0.20, CI = -0.70, 0.31, p = 0.44, N = 4, n = 205), and negative symptoms (SMD = -0.69, CI = -1.65, 0.27, p = 0.16, N = 4, n = 205), and Clinical Global Impression Severity scale (SMD = -0.27, CI = -1.20, 0.65, p = 0.56, N = 3, n = 177). There was also no significant difference in discontinuation rate between NMDAR-ANTs and placebo treatments (all cause: RR = 1.23, CI = 0.89-1.70, p = 0.20, N = 8, n = 396, side effects: RR = 1.86, CI = 0.84-4.13, p = 0.13, N = 6, n = 359, inefficacy/worsening psychosis: RR = 0.70, CI = 0.20-2.38, p = 0.56, N = 7, n = 380). However, memantine was favorable compared with placebo in Mini-Mental State Examination in schizophrenia (SMD = -0.77, CI = -1.27, -0.28, p = 0.002, N = 3, n = 71). While NMDAR-ANTs caused weight loss compared with placebo (SMD = -0.42, CI = -0.73, -0.11, p = 0.008, N = 3, n = 165), amantadine caused more frequent insomnia than placebo (RR = 3.83, CI = 1.41-10.38, p = 0.008, NNH = 9, p = 0.002, N = 2, n = 147). Our results indicate that NMDAR-ANTs as adjunctive therapy may improve
International Nuclear Information System (INIS)
Petzke, K.J.; Albrecht, V.; Przybilski, H.
1986-01-01
Male albino rats were adapted to isocaloric purified diets that differed mainly in their glycine and casein contents. Controls received a 30% casein diet. In experimental diets gelatin or gelatin hydrolysate was substituted for half of the 30% casein. An additional group was fed a glycine-supplemented diet, which corresponded in glycine level to the gelatin diet but in which the protein level was nearly the same as that of the casein control diet. Another group received a 15% casein diet. Rat liver glycine cleavage system, serine hydroxymethyltransferase and serine dehydratase activities were measured. 14 CO 2 production from the catabolism of 14 C-labeled glycine was measured in vivo and in vitro (from isolated hepatocytes). Serine dehydratase and glycine cleavage system activities were higher in animals fed 30% casein diets than in those fed 15% casein diets. Serine hydroxymethyltransferase activity of the cytosolic and mitochondrial fractions was highest when a high glycine diet (glycine administered as pure, protein bound in gelatin or peptide bound in gelatin hydrolysate) was fed. 14 CO 2 formation from [1- 14 C]- and [2- 14 C]glycine both in vivo and in isolated hepatocytes was higher when a high glycine diet was fed than when a casein diet was fed. These results suggest that glycine catabolism is dependent on and adaptable to the glycine content of the diet. Serine hydroxymethyltransferase appears to play a major role in the regulation of glycine degradation via serine and pyruvate
Haj-Mirzaian, Arya; Kordjazy, Nastaran; Ostadhadi, Sattar; Amiri, Shayan; Haj-Mirzaian, Arvin; Dehpour, AhmadReza
2016-06-01
Opioid and N-methyl-d-aspartate (NMDA) receptors mediate different effects of fluoxetine. We investigated whether opioid and NMDA receptors are involved in the protective effect of fluoxetine against the behavioral despair induced by acute physical stress in male mice. We used the forced swimming test (FST), tail suspension test (TST), and open-field test (OFT) for behavioral evaluation. We used fluoxetine, naltrexone (opioid receptor antagonist), MK-801 (NMDA receptor antagonist), morphine (opioid receptor agonist), and NMDA (NMDA receptor agonist). Acute foot-shock stress (FSS) significantly induced behavioral despair (depressive-like) and anxiety-like behaviors in tests. Fluoxetine (5 mg/kg) reversed the depressant-like effect of FSS, but it did not alter the locomotion and anxiety-like behavior in animals. Acute administration of subeffective doses of naltrexone (0.3 mg/kg) or MK-801 (0.01 mg/kg) potentiated the antidepressant-like effect of fluoxetine, while subeffective doses of morphine (1 mg/kg) and NMDA (75 mg/kg) abolished this effect of fluoxetine. Also, co-administration of subeffective doses of naltrexone (0.05 mg/kg) and MK-801 (0.003 mg/kg) with fluoxetine (1 mg/kg) induced a significant decrease in the immobility time in FST and TST. Our results showed that opioid and NMDA receptors (alone or in combination) are involved in the antidepressant-like effect of fluoxetine against physical stress.
Falck, Evamaria; Begrow, Frank; Verspohl, Eugen J; Wünsch, Bernhard
2014-06-01
Structural modification of the GluN2B selective NMDA receptor antagonist ifenprodil led to the 3-benzazepine WMS-1410 with similar GluN2B affinity but higher receptor selectivity. Herein the in vitro and in vivo biotransformation of WMS-1410 is reported. Incubation of WMS-1410 with rat liver microsomes and different cofactors resulted in four hydroxylated phase I metabolites, two phase II metabolites and five combined phase I/II metabolites. With exception of catechol 4, these metabolites were also identified in the urine of a rat treated with WMS-1410. However the metabolites 7, 8 and 12 clearly show that the catechol metabolite 4 was also formed in vivo. As shown for ifenprodil the phenol of WMS-1410 represents the metabolically most reactive structural element. The biotransformation of WMS-1410 is considerably slower than the biotransformation of ifenprodil indicating a higher metabolic stability. From the viewpoint of metabolic stability the bioisosteric replacement of the phenol of WMS-1410 by a metabolically more stable moiety should be favourable. Copyright © 2014 Elsevier B.V. All rights reserved.
Faber, E S L; Chambers, J P; Evans, R H
1998-01-01
α2-Adrenoceptor agonists have a spinal site of analgesic action. In the current study the synaptic depressant actions of xylazine, detomidine, romifidine and dexmedetomidine have been compared on segmental reflexes containing NMDA receptor-mediated components in the neonatal rat hemisected spinal cord preparation in vitro.Reflexes were evoked in the ventral root following either supramaximal electrical stimulation of the corresponding ipsilateral lumbar dorsal root to evoke the high intensity excitatory postsynaptic potential (e.p.s.p.) involving all primary afferent fibres, or low intensity stimulation to evoke the solely A fibre-mediated low intensity e.p.s.p. The high intensity e.p.s.p. contains a greater NMDA receptor-mediated component.Xylazine, romifidine, detomidine and dexmedetomidine all depressed both the high intensity e.p.s.p. and the low intensity e.p.s.p. giving respective EC50 values of 0.91±0.2 μM (n=12), 23.4±3 nM (n=12), 37.7±7 nM (n=8) and 0.84±0.1 nM (n=4) for depression of the high intensity e.p.s.p. and 0.76±0.1 μM (n=12), 22.0±3 nM (n=12), 24.9±6 nM (n=4) and 2.7±0.6 nM (n=4) for depression of the low intensity e.p.s.p., respectively. Unlike the other three drugs, the two values for dexmedetomidine, showing a greater selectivity for the high intensity e.p.s.p., are significantly different.Each of these depressant actions was reversed by the selective α2-adrenoceptor antagonist atipamezole (1 μM).In contrast to previous reports of the actions of α2-adrenoceptor agonists on the in vitro spinal cord preparation, at concentrations ten fold higher than the above EC50 values xylazine, romifidine, detomidine and dexmedetomidine depressed the initial population spike of motoneurons (MSR). This depression was not reversed by atipamezole.Comparison of the rank order of the present EC50 values for depression of the high intensity e.p.s.p. with potency ratios from in vivo analgesic tests in previous studies show a close
N-Methyl-d-Aspartate (NMDA Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection
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Vivian V. Costa
2017-04-01
Full Text Available Zika virus (ZIKV infection is a global health emergency that causes significant neurodegeneration. Neurodegenerative processes may be exacerbated by N-methyl-d-aspartate receptor (NMDAR-dependent neuronal excitoxicity. Here, we have exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking NMDA overstimulation with memantine. Our results show that ZIKV actively replicates in primary neurons and that virus replication is directly associated with massive neuronal cell death. Interestingly, treatment with memantine or other NMDAR blockers, including dizocilpine (MK-801, agmatine sulfate, or ifenprodil, prevents neuronal death without interfering with the ability of ZIKV to replicate in these cells. Moreover, in vivo experiments demonstrate that therapeutic memantine treatment prevents the increase of intraocular pressure (IOP induced by infection and massively reduces neurodegeneration and microgliosis in the brain of infected mice. Our results indicate that the blockade of NMDARs by memantine provides potent neuroprotective effects against ZIKV-induced neuronal damage, suggesting it could be a viable treatment for patients at risk for ZIKV infection-induced neurodegeneration.
Diagnóstico diferencial en la encefalitis por anticuerpos contra el receptor NMDA
González-Valcárcel, J.; Rosenfeld, M.R.; Dalmau, J.
2011-01-01
Resumen Introducción La encefalitis por anticuerpos contra el receptor de NMDA (NMDAR) suele desarrollarse como un síndrome característico de evolución multifásica y diagnóstico diferencial amplio. Pacientes Presentamos a 2 pacientes diagnosticadas de encefalitis por anticuerpos NMDAR con un cuadro clínico típico, pero que inicialmente señaló otras etiologías. Discusión La afectación frecuente de pacientes jóvenes con manifestaciones psiquiátricas prominentes indica frecuentemente otras consideraciones diagnósticas; las más frecuentes son las encefalitis virales, los procesos psiquiátricos y el síndrome neuroléptico maligno. Varios síndromes previamente definidos de manera parcial o descriptiva en adultos y pacientes pediátricos probablemente eran casos de encefalitis anti-NMDAR. Conclusiones La encefalitis anti-NMDAR debe considerarse en pacientes jóvenes con manifestaciones psiquiátricas subagudas, movimientos anormales y alteraciones autonómicas. La caracterización clínica e inmunológica de esta enfermedad ha llevado a la identificación de nuevos anticuerpos que afectan a procesos de memoria, aprendizaje, conducta y psicosis. PMID:20964986
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Shi, Wen-Zhu [Anesthesia and Operation Center, Hainan Branch of Chinese PLA General Hospital, Hainan 572013 (China); Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853 (China); Miao, Yu-Liang [Department of Anesthesiology, PLA No. 306 Hospital, Beijing 100101 (China); Guo, Wen-Zhi [Department of Anesthesiology, Beijing Military General Hospital of Chinese People’s Liberation Army, Beijing 100700 (China); Wu, Wei, E-mail: wwzwgk@163.com [Department of Head and Neck Surgery of Otolaryngology, PLA No. 306 Hospital, Beijing 100101 (China); Li, Bao-Wei [Department of Head and Neck Surgery of Otolaryngology, PLA No. 306 Hospital, Beijing 100101 (China); An, Li-Na [Department of Anesthesiology, Armed Police General Hospital, Beijing 100039 (China); Fang, Wei-Wu [Department of Anesthesiology, PLA No. 306 Hospital, Beijing 100101 (China); Mi, Wei-Dong, E-mail: elite2005gg@163.com [Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853 (China)
2014-04-25
Highlights: • Leptin promotes the proliferation of neural stem cells isolated from embryonic mouse hippocampus. • Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation. • The effects of leptin are partially mediated by upregulating NR2B subunits. - Abstract: Corticosterone inhibits the proliferation of hippocampal neural stem cells (NSCs). The removal of corticosterone-induced inhibition of NSCs proliferation has been reported to contribute to neural regeneration. Leptin has been shown to regulate brain development, improve angiogenesis, and promote neural regeneration; however, its effects on corticosterone-induced inhibition of NSCs proliferation remain unclear. Here we reported that leptin significantly promoted the proliferation of hippocampal NSCs in a concentration-dependent pattern. Also, leptin efficiently reversed the inhibition of NSCs proliferation induced by corticosterone. Interestingly, pre-treatment with non-specific NMDA antagonist MK-801, specific NR2B antagonist Ro 25-6981, or small interfering RNA (siRNA) targeting NR2B, significantly blocked the effect of leptin on corticosterone-induced inhibition of NSCs proliferation. Furthermore, corticosterone significantly reduced the protein expression of NR2B, whereas pre-treatment with leptin greatly reversed the attenuation of NR2B expression caused by corticosterone in cultured hippocampal NSCs. Our findings demonstrate that leptin reverses the corticosterone-induced inhibition of NSCs proliferation. This process is, at least partially mediated by increased expression of NR2B subunits of NMDA receptors.
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Marion Rodier
Full Text Available Brain-derived neurotrophic factor (BDNF through TrkB activation is central for brain functioning. Since the demonstration that plasmin is able to process pro-BDNF to mature BDNF and that these two forms have opposite effects on neuronal survival and plasticity, a particular attention has been paid to the link between tissue plasminogen activator (tPA/plasmin system and BDNF metabolism. However, t-PA via its action on different N-methyl-D-aspartate (NMDA receptor subunits is also considered as a neuromodulator of glutamatergic transmission. In this context, the aim of our study was to investigate the effect of recombinant (rt-PA administration on brain BDNF metabolism in rats. In the hippocampus, we found that rt-PA (10 mg/kg administration induced a progressive increase in mature BDNF levels associated with TrkB activation. In order to delineate the mechanistic involved, plasmin activity was assessed and its inhibition was attempted using tranexamic acid (30 or 300 mg/kg, i.v. while NMDA receptors were antagonized with MK801 (0.3 or 3 mg/kg, i.p. in combination with rt-PA treatment. Our results showed that despite a rise in rt-PA activity, rt-PA administration failed to increase hippocampal plasmin activity suggesting that the plasminogen/plasmin system is not involved whereas MK801 abrogated the augmentation in mature BDNF levels observed after rt-PA administration. All together, our results show that rt-PA administration induces increase in hippocampal mature BDNF expression and suggests that rt-PA contributes to the control of brain BDNF synthesis through a plasmin-independent potentiation of NMDA receptors signaling.
Liu, Shui-Bing; Ma, Lan; Guo, Hong-Ju; Feng, Bin; Guo, Yan-Yan; Li, Xiao-Qiang; Sun, Wen-Ji; Zheng, Lian-He; Zhao, Ming-Gao
2012-08-01
Gentiopicroside (Gent) is one of the secoiridoid compound isolated from Gentiana lutea. This compound exhibits analgesic activities and inhibits the expression of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the anterior cingulate cortex in mice. Nucleus accumbens (NAc) is a forebrain structure known for its role in drug addiction. However, little is known about the role of Gent on morphine dependence and synaptic transmission changes in the NAc. Conditioned place preference (CPP) test and behavioral sensitization of locomotor activity were used to investigate drug-seeking related behaviors. Brain slices containing NAc were prepared, and whole-cell patch-clamp recordings were performed to record the excitatory postsynaptic currents (EPSCs). Expression of proteins was detected by Western blot analysis. Systemic administration of Gent attenuated the CPP effect induced by morphine, but had no effect on morphine-induced behavioral sensitization. Gent significantly reversed overexpression of GluN2B-containing NMDA receptors and dopamine D2 receptors in NAc during the first week of morphine withdrawal. However, the compound did not affect the overexpression of GluN2A-containing NMDA receptors, GluA1, and dopamine D1 receptors. Lastly, Gent significantly reduced NMDA receptors-mediated EPSCs in the NAc. Our study provides strong evidence that Gent inhibits morphine dependence through downregulation of GluN2B-containing NMDA receptors in the NAc. © 2012 Blackwell Publishing Ltd.
Excitatory amino acid receptor antagonists
DEFF Research Database (Denmark)
Johansen, T N; Frydenvang, Karla Andrea; Ebert, B
1997-01-01
We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation......)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 microM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments......, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 +/- 5 microM and 57 +/- 1 microM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation...
Pelissier, Teresa; Infante, Claudio; Constandil, Luis; Espinosa, Jeannette; Lapeyra, Carolina De; Hernández, Alejandro
2008-01-01
We assessed whether intrathecal administration of the uncompetitive and competitive NMDA receptor antagonists ketamine and (+/-)CPP, respectively, could produce differential modulation on chemical and mechanical nociception in normal and monoarthritic rats. In addition, the antinociceptive interaction of ketamine and (+/-)CPP on monoarthritic pain was also studied using isobolographic analysis. Monoarthritis was produced by intra-articular injection of complete Freund's adjuvant into the tibio-tarsal joint. Four weeks later, the antinociceptive effect of intrathecal administration of the drugs alone or combined was evaluated by using the intraplantar capsaicin and the paw pressure tests. Ketamine (0.1, 1, 10, 30, 100, 300 and 1000 microg i.t.) and (+/-)CPP (0.125, 2.5, 7.5, 12.5, 25 and 50 microg i.t.) produced significantly greater dose-dependent antinociception in the capsaicin than in the paw pressure test. Irrespective of the nociceptive test employed, both antagonists showed greater antinociceptive activity in monoarthritic than in healthy rats. Combinations produced synergy of a supra-additive nature in the capsaicin test, but only additive antinociception in paw pressure testing. The efficacy of the drugs, alone or combined, is likely to depend on the differential sensitivity of tonic versus phasic pain and/or chemical versus mechanical pain to NMDA antagonists.
Directory of Open Access Journals (Sweden)
Yu Omori
2015-03-01
Full Text Available This study was conducted to identify the characteristic pharmacological features of GT-0198 that is phenoxymethylbenzamide derivatives. GT-0198 inhibited the function of glycine transporter 2 (GlyT2 in human GlyT2-expressing HEK293 cells and did not bind various major transporters or receptors of neurotransmitters in a competitive manner. Thus, GT-0198 is considered to be a comparatively selective GlyT2 inhibitor. Intravenous, oral, and intrathecal injections of GT-0198 decreased the pain-related response in a model of neuropathic pain with partial sciatic nerve ligation. This result suggests that GT-0198 has an analgesic effect. The analgesic effect of GT-0198 was abolished by the intrathecal injection of strychnine, a glycine receptor antagonist. Therefore, GT-0198 is considered to exhibit its analgesic effect via the activation of a glycine receptor by glycine following presynaptic GlyT2 inhibition in the spinal cord. In summary, GT-0198 is a structurally novel GlyT2 inhibitor bearing a phenoxymethylbenzamide moiety with in vivo efficacy in behavioral models of neuropathic pain.
Synthesis and receptor binding studies of (+/-)1-iodo-MK-801
International Nuclear Information System (INIS)
Yang, D.J.; Ciliax, B.J.; Van Dort, M.E.; Gildersleeve, D.; Pirat, J.L.; Young, A.B.; Wieland, D.M.
1989-01-01
The glutamate analogue N-methyl-D-aspartate (NMDA) binds to a subset of glutamate receptors that are coupled to a voltage-sensitive cation channel. This NMDA-linked channel is the likely binding locus of the potent anticonvulsant MK-801. To develop single-photon emission computed tomography (SPECT) probes of this brain channel, we synthesized (+/)1-iodo-MK-801 and (+/-)1-[ 125 I]iodo-MK-801. The effect of (+/-)1-iodo-MK-801 on ligand binding to the NMDA-linked glutamate receptor site was assessed using a rat brain homogenate assay. (+/-)1-Iodo-MK-801 displaced the dissociative anesthetic ligand [ 3 H]N-[1-(2-thienyl)cyclohexyl]piperidine ([ 3 H]TCP) binding with an IC50 of 1 microM, which is a 10-fold lower binding affinity than that of (+/-)MK-801. In in vivo autoradiographic studies, (+/-)MK-801 failed to block selective uptake of (+/-)1-iodo-MK-801 in rat brain. These results suggest that (+/-)1-iodo-MK-801 may not be a suitable ligand for mapping NMDA-linked glutamate receptor channels
Yamazaki, Yuu; Ishioka, Miwa; Matsubayashi, Hiroaki; Amano, Taku; Sasa, Masashi
2002-04-01
MS-377 [( R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl) piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate] is a novel anti-psychotic drug candidate with high affinity for sigma receptors but devoid of binding affinity for PCP binding site of NMDA receptor/ion channel complex. The effects of MS-377 on NMDA receptor and/or its ion channel complex were examined to elucidate the antipsychotic properties of MS-377. We examined the effect of MS-377 on NMDA ( N-methyl- D-aspartate)-induced current in acutely dissociated dopamine neurons of rat ventral tegmental area (VTA) using patch clamp whole cell recording. MS-377 applied in a bath inhibited the peak current evoked by NMDA applied via the U-tube method for 2 s in a concentration-dependent manner. Other sigma receptor ligands, BD-1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine), NE-100 ( N, N-dipropyl-2-[4-methoxy-3-(2-phenylenoxy)-phenyl]-ethylamine monohydrochloride) and haloperidol also inhibited NMDA-induced current in a concentration-dependent manner. Interestingly, concomitant application of MS-377 with BD-1063, NE-100 or haloperidol at concentrations that had no effects on NMDA-induced current, potentiated the MS-377-induced inhibition. The results suggest that MS-377, as well as other sigma receptor ligands, indirectly acts on the sigma receptor to inhibit glutaminergic transmission mediated by NMDA receptor/ion channel complex in VTA dopamine neurons, thereby inhibiting dopamine release in target VTA areas.
International Nuclear Information System (INIS)
Haradahira, Terushi; Zhang, Ming-Rong; Maeda, Jun; Okauchi, Takashi; Kawabe, Kouichi; Kida, Takayo; Suzuki, Kazutoshi; Suhara, Tetsuya
2000-01-01
A positron-emitter labeled radioligand for the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor, [ 11 C]L-703,717, was examined for its ability to penetrate the brain in animals by simultaneous use with drugs having high-affinity separate binding sites on human serum albumin. [ 11 C]L-703,717 has poor blood-brain barrier (BBB) permeability because it binds tightly to plasma proteins. Co-injection of warfarin (50-200 mg/kg), a drug that binds to albumin and resembles L-703,717 in structure, dose-dependently enhanced the penetration by [ 11 C]L-703,717 in mice, resulting in a five-fold increase in the brain radioactivity at 1 min after the injection. Drugs structurally unrelated to L-703,717, salicylate, phenol red, and L-tryptophan, were less effective or ineffective in increasing the uptake of [ 11 C]L-703,717. These results suggest that the simultaneous use of a drug that inhibits the binding of a radioligand to plasma proteins is a useful way to overcome the poor BBB permeability of the radioligand triggered by its tight binding to plasma proteins. In brain distribution studies in rodents, it was found that, after the increase in brain uptake with warfarin, much of the glycine site antagonist accumulates in the cerebellum but its pharmacological specificity did not match the glycine site of NMDA receptors
Directory of Open Access Journals (Sweden)
Christine Laura Dixon
2015-12-01
Full Text Available Fast inhibitory neurotransmission in the brain is mediated by wide range of GABAA receptor (GABAAR and glycine receptor (GlyR isoforms, each with different physiological and pharmacological properties. Because multiple isoforms are expressed simultaneously in most neurons, it is difficult to define the properties of inhibitory postsynaptic currents mediated by individual isoforms in vivo. Although recombinant expression systems permit the expression of individual isoforms in isolation, they require exogenous agonist application which cannot mimic the dynamic neurotransmitter profile characteristic of native synapses. We describe a neuron-HEK293 cell co-culture technique for generating inhibitory synapses incorporating defined combinations of GABAAR or GlyR subunits. Primary neuronal cultures, prepared from embryonic rat cerebral cortex or spinal cord, are used to provide presynaptic GABAergic and glycinergic terminals, respectively. When the cultures are mature, HEK293 cells expressing the subunits of interest plus neuroligin 2A are plated onto the neurons, which rapidly form synapses onto HEK293 cells. Patch clamp electrophysiology is then used to analyze the physiological and pharmacological properties of the inhibitory postsynaptic currents mediated by the recombinant receptors. The method is suitable for investigating the kinetic properties or the effects of drugs on inhibitory postsynaptic currents mediated by defined GABAAR or GlyR isoforms of interest, the effects of hereditary disease mutations on the formation and function of both types of synapses, and synaptogenesis and synaptic clustering mechanisms. The entire cell preparation procedure takes 2 – 5 weeks.
Directory of Open Access Journals (Sweden)
Maria Veronica Baez
Full Text Available NMDA receptor subunits change during development and their synaptic expression is modified rapidly after synaptic plasticity induction in hippocampal slices. However, there is scarce information on subunits expression after synaptic plasticity induction or memory acquisition, particularly in adults. GluN1, GluN2A and GluN2B NMDA receptor subunits were assessed by western blot in 1 adult rats that had explored an open field (OF for 5 minutes, a time sufficient to induce habituation, 2 mature rat hippocampal neuron cultures depolarized by KCl and 3 hippocampal slices from adult rats where long term potentiation (LTP was induced by theta-burst stimulation (TBS. GluN1 and GluN2A, though not GluN2B, were significantly higher 70 minutes--but not 30 minutes--after a 5 minutes session in an OF. GluN1 and GluN2A total immunofluorescence and puncta in neurites increased in cultures, as evaluated 70 minutes after KCl stimulation. Similar changes were found in hippocampal slices 70 minutes after LTP induction. To start to explore underlying mechanisms, hippocampal slices were treated either with cycloheximide (a translation inhibitor or actinomycin D (a transcription inhibitor during electrophysiological assays. It was corroborated that translation was necessary for LTP induction and expression. The rise in GluN1 depends on transcription and translation, while the increase in GluN2A appears to mainly depend on translation, though a contribution of some remaining transcriptional activity during actinomycin D treatment could not be rouled out. LTP effective induction was required for the subunits to increase. Although in the three models same subunits suffered modifications in the same direction, within an apparently similar temporal course, further investigation is required to reveal if they are related processes and to find out whether they are causally related with synaptic plasticity, learning and memory.
A critical role for glycine transporters in hyperexcitability disorders
Directory of Open Access Journals (Sweden)
Robert J Harvey
2008-03-01
Full Text Available Defects in mammalian glycinergic neurotransmission result in a complex motor disorder characterized by neonatal hypertonia and an exaggerated startle refl ex, known as hyperekplexia (OMIM 149400. This affects newborn children and is characterized by noise or touch-induced seizures that result in muscle stiffness and breath-holding episodes. Although rare, this disorder can have serious consequences, including brain damage and/or sudden infant death. The primary cause of hyperekplexia is missense and nonsense mutations in the glycine receptor (GlyR α1 subunit gene (GLRA1 on chromosome 5q33.1, although we have also discovered rare mutations in the genes encoding the GlyR β subunit (GLRB and the GlyR clustering proteins gephyrin (GPNH and collybistin (ARHGEF9. Recent studies of the Na+ /Cl--dependent glycine transporters GlyT1 and GlyT2 using mouse knockout models and human genetics have revealed that mutations in GlyT2 are a second major cause of hyperekplexia, while the phenotype of the GlyT1 knockout mouse resembles a devastating neurological disorder known as glycine encephalopathy (OMIM 605899. These findings highlight the importance of these transporters in regulating the levels of synaptic glycine.
Lipsky, Robert H
2015-01-01
For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-d-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis. PMID:25245072
Xu, Ke; Lipsky, Robert H
2015-02-01
For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis. © 2014 by the Society for Experimental Biology and Medicine.
Lee, Kuo-Wei; Liou, Li-Min; Wu, Meng-Ni
2018-04-01
Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune disorder that can be controlled and reversed by immunotherapy. The presentation of NMDA receptor encephalitis varies, but NMDA receptor encephalitis is seldom reported in patients with both bilateral teratomas and preexisting brain injury. A 28-year-old female with a history of traumatic intracranial hemorrhage presented acute psychosis, seizure, involuntary movement, and conscious disturbance with a fulminant course. Anti-NMDA receptor antibody was identified in both serum and cerebrospinal fluid, confirming the diagnosis of anti-NMDA receptor encephalitis. Bilateral teratomas were also identified during tumor survey. DIAGNOSES:: anti-N-methyl-D-aspartate receptor encephalitis. Tumor resection and immunotherapy were performed early during the course. The patient responded well to tumor resection and immunotherapy. Compared with other reports in the literature, her symptoms rapidly improved without further relapse. This case report demonstrates that bilateral teratomas may be related to high anybody titers and that the preexisting head injury may be responsible for lowering the threshold of neurological deficits. Early diagnosis and therapy are crucial for a good prognosis in such patients.
Kristofikova, Zdena; Ricny, Jan; Sirova, Jana; Ripova, Daniela; Lubitz, Irit; Schnaider-Beeri, Michal
2015-08-01
It has been suggested that advanced glycation end (AGE) products, via cognate receptor activation, are implicated in several diseases, including Alzheimer's disease. The NMDA receptor-nitric oxide pathway appears to be influenced by AGE products and involved in the pathogenesis of this type of dementia. In this study, C57BL/6J (WT) and transgenic (Tg2576) mice expressing human mutant amyloid precursor protein were kept on prolonged (8 months) diets containing regular or high amounts of AGE products. After the decapitation of 11-months old mice, brain tissue analyses were performed [expressions of the NR1, NR2A and NR2B subunits of NMDA receptors, activities of neuronal, endothelial and inducible nitric oxide synthase (nNOS, eNOS and iNOS)]. Moreover, levels of malondialdehyde and of human amyloid β 1-42 were estimated. We found increased activity of nNOS in WT mice maintained on a high compared to regular AGE diet; however, no similar differences were found in Tg2576 mice. In addition, we observed an increase in NR1 expression in Tg2576 compared to WT mice, both kept on a diet high in AGE products. Correlation analyses performed on mice kept on the regular AGE diet supported close links between particular subunits (NR2A-NR2B, in WT as well as in Tg2576 mice), between subunits and synthase (NR2A/NR2B-nNOS, only in WT mice) or between particular synthases (nNOS-iNOS, only in WT). Correlation analysis also revealed differences between WT mice kept on both diets (changed correlations between NR2A/NR2B-nNOS, between nNOS-eNOS and between eNOS-iNOS). Malondialdehyde levels were increased in both Tg2576 groups when compared to the corresponding WT mice, but no effects of the diets were observed. Analogously, no significant effects of diets were found in the levels of soluble or insoluble amyloid β 1-42 in Tg2576 mice. Our results demonstrate that prolonged ingestion of AGE products can influence the NMDA receptor-nitric oxide pathway in the brain and that only WT mice
The effect of hippocampal NMDA receptor blockade by MK-801 on cued fear extinction.
Zhang, Bo; Li, Chuan-Yu; Wang, Xiu-Song
2017-08-14
Extinction of conditioned fear has been suggested to be a new form of learning instead of erasure of what was originally learned, and the process is NMDA (N-methyl d-aspartate) receptor (NMDAR) dependent. Most of studies have so far revealed the important roles of NMDARs in the amygdala and medial prefrontal cortex (mPFC) in cued fear extinction. Although the ventral hippocampus has intimately reciprocal connections with the amygdala and mPFC, the role of its NMDARs in cued fear extinction remains unclear. The present experiment explored the issue by bilateral pre-extinction microinjection of the noncompetitive NMDAR antagonist MK-801 into the ventral hippocampus. Four groups of rats were given habituation, tone cued fear conditioning, fear extinction training and extinction test. Prior to extinction training, rats received bilateral infusions of either MK-801 (1.5, 3, or 6μg/0.5μl) or saline. Our results showed that MK-801 reduced freezing on the first trial of extinction training with no impact on within-session acquisition of extinction, and that the lower doses of MK-801 resulted in increased freezing on the extinction retrieval test. These findings suggest that ventral hippocampal NMDARs are necessary for the consolidation of tone cued fear extinction. Copyright © 2017 Elsevier B.V. All rights reserved.
The relation of Cx43 and NMDA to visceral sensitization in rats with irritable bowel syndrome
Directory of Open Access Journals (Sweden)
Jing-yu ZHANG
2016-01-01
Full Text Available Objective To study the relationship between connexin 43 (Cx43 and N-methyl-D-aspartate (NMDA receptors and visceral sensitization in the rats with irritable bowel syndrome (IBS. Methods Thirty rats were gavaged with Triehinella spiralis to reproduce the IBS model. These rats were randomly divided into IBS group, IBS+colon distension group, and IBS+STI-571+colon distension group, and other groups of normal rats were randomized into normal group and normal+colon distension group, with 10 rats in each group. Immunofluorescent double staining were used to observe the expressions of intestine Cx43 and sacral NMDA re ceptors of rats in all the groups. Results The Cx43 and sacral NMDA expressions in the normal group, normal+colon distension group and IBS group showed no significant changes (P>0.05, however, Cx43 and sacral NMDA expressions were significantly higher in IBS rats with colon distension as compared with those in normal group, normal+colon distension group, and IBS group (P<0.05, while they were significantly lower in the IBS+STI-571+colon distension group after STI-571 intervention (P<0.05. Conclusion Cx43 and sacral NMDA may be the most important factor of visceral sensitization in IBS rats. DOI: 10.11855/j.issn.0577-7402.2015.12.02
DEFF Research Database (Denmark)
Jensen, J B; Schousboe, A; Pickering, D S
1999-01-01
) toxicity mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, and (3) toxicity that can be mediated by kainate receptors when desensitization of the receptors is blocked. The indirect action at NMDA receptors was discovered because (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H...... nedioxy-5H-2,3-benzodiazepine (GYKI 53655), a selective AMPA receptor antagonist, abolished the remaining toxicity. These results indicated that kainate- and domoate-mediated toxicity involves both the NMDA and the AMPA receptors. Pretreatment of the cultures with concanavalin A to prevent desensitization...
Energy Technology Data Exchange (ETDEWEB)
Ludwig, T
2005-11-01
In this thesis new strategies were developed and evaluated for the no-carrier-added (n.c.a.) {sup 18}F-labelling of receptor ligands as radiodiagnostics for characterization of brain receptors using positron-emission-tomography (PET). Special emphasis was placed on the synthesis of n.c.a. ({+-})-3-(4-hydroxy-4-(4-[{sup 18}F]fluorophenyl)-piperidin-l-yl)chroman-4,7-diol, a ligand with high affinity for the NR2B subtype of NMDA receptors and n.c.a. (3-(4-[{sup 18}F]fluorphenoxy)propyl)-(2-(4-tolylphenoxy)ethyl)amine ([{sup 18}F]FPTEA) a dopamine D{sub 4} receptor ligand. In order to synthesize n.c.a. ({+-})-3-(4-hydroxy-4-(4-[{sup 18}F]fluorophenyl)-piperidin-l-yl)chroman-4,7-diol the {sup 18}F-fluoroarylation method via metallorganic intermediates was modified and improved. The suitability of the organometallic {sup 18}F-fluoroarylation agents was proven with several model compounds. High radiochemical yields of 20-30% were obtained also with piperidinone-derivatives. The preparation of a suitable precursor for the synthesis of the NMDA receptor ligand, however, could not be achieved by synthesis of appropriate 1,3-dioxolane protected piperidinone derivatives. Further, the synthesis of n.c.a. ([{sup 18}F]fluoroaryloxy)alkylamines via n.c.a. 4-[{sup 18}F]fluorophenol was developed and evaluated. The synthesis of n.c.a. [{sup 18}F]fluoroarylethers with corresponding model compounds was optimized and led to a radiochemical yield of 25-60%, depending on the alkylhalide used. The preparation of n.c.a. 1-(3-bromopropoxy)-4-[{sup 18}F]fluorobenzene proved advantageous in comparison to direct use of 4-[{sup 18}]fluorophenol for coupling with a corresponding N-protected precursor for the synthesis of n.c.a. [{sup 18}F]FPTEA. With regard to the radiochemical yields and the loss of activity during the synthesis and isolation of n.c.a. 4-[{sup 18}F]fluorophenol and n.c.a. 1-(3-bromopropoxy)-4-[{sup 18}F]fluorobenzene, [{sup 18}F]FPTEA was obtained by reaction with 2-(4-tolyloxy
Thalamocortical NMDA conductances and intracortical inhibition can explain cortical temporal tuning
Krukowski, A. E.; Miller, K. D.
2001-01-01
Cells in cerebral cortex fail to respond to fast-moving stimuli that evoke strong responses in the thalamic nuclei innervating the cortex. The reason for this behavior has remained a mystery. We study an experimentally motivated model of the thalamic input-recipient layer of cat primary visual cortex that accounts for many aspects of cortical orientation tuning. In this circuit, inhibition dominates over excitation, but temporal modulations of excitation and inhibition occur out of phase with one another, allowing excitation to transiently drive cells. We show that this circuit provides a natural explanation of cortical low-pass temporal frequency tuning, provided N-methyl-D-aspartate (NMDA) receptors are present in thalamocortical synapses in proportions measured experimentally. This suggests a new and unanticipated role for NMDA conductances in shaping the temporal response properties of cortical cells, and suggests that common cortical circuit mechanisms underlie both spatial and temporal response tuning.
Glutamate in schizophrenia: clinical and research implications.
Goff, D C; Wine, L
1997-10-30
The excitatory amino acids, glutamate and aspartate, are of interest to schizophrenia research because of their roles in neurodevelopment, neurotoxicity and neurotransmission. Recent evidence suggests that densities of glutamatergic receptors and the ratios of subunits composing these receptors may be altered in schizophrenia, although it is unclear whether these changes are primary or compensatory. Agents acting at the phencyclidine binding site of the NMDA receptor produce symptoms of schizophrenia in normal subjects, and precipitate relapse in patients with schizophrenia. The improvement of negative symptoms with agents acting at the glycine modulatory site of the NMDA receptor, as well as preliminary evidence that clozapine may differ from conventional neuroleptic agents in its effects on glutamatergic systems, suggest that clinical implications may follow from this model. While geriatric patients may be at increased risk for glutamate-mediated neurotoxicity, very little is known about the specific relevance of this model to geriatric patients with schizophrenia.
Directory of Open Access Journals (Sweden)
Douglas Bledsoe
2017-05-01
Full Text Available N-methyl D-aspartate receptors (NMDAR play crucial role in normal brain function and pathogenesis of neurodegenerative and psychiatric disorders. Functional tetra-heteromeric NMDAR contains two obligatory GluN1 subunits and two identical or different non-GluN1 subunits that include six different gene products; four GluN2 (A–D and two GluN3 (A–B subunits. The heterogeneity of subunit combination facilities the distinct function of NMDARs. All GluN subunits contain an extracellular N-terminal Domain (NTD and ligand binding domain (LBD, transmembrane domain (TMD and an intracellular C-terminal domain (CTD. Interaction between the GluN1 and co-assembling GluN2/3 subunits through the LBD has been proven crucial for defining receptor deactivation mechanisms that are unique for each combination of NMDAR. Modulating the LBD interactions has great therapeutic potential. In the present work, by amino acid point mutations and electrophysiology techniques, we have studied the role of LBD interactions in determining the effect of well-characterized pharmacological agents including agonists, competitive antagonists, and allosteric modulators. The results reveal that agonists (glycine and glutamate potency was altered based on mutant amino acid sidechain chemistry and/or mutation site. Most antagonists inhibited mutant receptors with higher potency; interestingly, clinically used NMDAR channel blocker memantine was about three-fold more potent on mutated receptors (N521A, N521D, and K531A than wild type receptors. These results provide novel insights on the clinical pharmacology of memantine, which is used for the treatment of mild to moderate Alzheimer's disease. In addition, these findings demonstrate the central role of LBD interactions that can be exploited to develop novel NMDAR based therapeutics.
Directory of Open Access Journals (Sweden)
Michael T McCarville
Full Text Available Heterodera glycines is a cyst nematode that causes significant lost soybean yield in the U.S. Recent studies observed the aphid Aphis glycines and H. glycines interacting via their shared host, soybean, Glycine max. A greenhouse experiment was conducted to discern the effect of A. glycines feeding on H. glycines reproduction. An H. glycines-susceptible cultivar, Kenwood 94, and a resistant cultivar, Dekalb 27-52, were grown in H. glycines-infested soil for 30 and 60 d. Ten days after planting, plants were infested with either zero, five, or ten aphids. At 30 and 60 d, the number of H. glycines females and cysts (dead females and the number of eggs within were counted. In general, H. glycines were less abundant on the resistant than the susceptible cultivar, and H. glycines abundance increased from 30 to 60 d. At 30 d, 33% more H. glycines females and eggs were produced on the resistant cultivar in the ten-aphid treatment compared to the zero-aphid treatment. However, at 30 d the susceptible cultivar had 50% fewer H. glycines females and eggs when infested with ten aphids. At 60 d, numbers of H. glycines females and cysts and numbers of eggs on the resistant cultivar were unaffected by A. glycines feeding, while numbers of both were decreased by A. glycines on the susceptible cultivar. These results indicate that A. glycines feeding improves the quality of soybean as a host for H. glycines, but at higher herbivore population densities, this effect is offset by a decrease in resource quantity.
DEFF Research Database (Denmark)
Kristensen, Bjarne Winther; Noraberg, J; Zimmer, J
2001-01-01
) values was found after 2 days of exposure: AMPA (3.7 mM)>NMDA (11 mM)=KA (13 mM)>ATPA (33 mM). Exposed to 30 microM ATPA, 3 microM AMPA and 10 microM NMDA, CA1 was the most susceptible subfield followed by fascia dentata and CA3. Using 8 microM KA, CA3 was the most susceptible subfield, followed...... by fascia dentata and CA1. In 100 microM concentrations, all four agonists induced the same, maximal PI uptake in all hippocampal subfields, corresponding to total neuronal degeneration. Using glutamate receptor antagonists, like GYKI 52466, NBQX and MK-801, inhibition data revealed that AMPA excitotoxicity...
Lin, Hui-Ching; Mao, Sheng-Chun; Su, Chun-Lin; Gean, Po-Wu
2010-04-01
Understanding the neurophysiology of fear extinction has important implications for the treatment of post-traumatic stress disorders. Here we report that fear conditioning resulted in an increase in AMPA/NMDA ratio as well as depression of paired-pulse facilitation (PPF) in neurons of the lateral nucleus of amygdala. These conditioning-induced changes in synaptic transmission were not affected by extinction training. D-cycloserine (DCS), a partial agonist at the glycine-binding site of the NMDA receptor, facilitated extinction and reversed the increase in AMPA/NMDA ratio without altering the depression of PPF when administered before extinction training. Extinction training, however, significantly increased the frequency and amplitude of miniature inhibitory post-synaptic currents and these effects were unaffected by the DCS treatment. Disruption of AMPA receptor endocytosis with a synthetic peptide containing a short C-terminal sequence of GluR2 (869YKEGYNVYG877, GluR23Y) specifically blocked DCS-induced reversal of AMPA/NMDA ratio and the facilitation of extinction. These results suggest that extinction training mainly increases inhibitory transmission leaving conditioning-induced excitatory association unaltered. DCS does not affect inhibitory transmission but reverses the conditioning-induced post-synaptic memory trace when administered before extinction training.
Institute of Scientific and Technical Information of China (English)
无
2001-01-01
Objective: To investigate the relationship between the changes of N-methyl-D-aspartate (NMDA) receptor activity and brain edema after injury in rats. Methods: The brain injury models were made by using a free-falling body. The treatment model was induced by means of injecting AP5 into lateral ventricle before brain injury; water contents in brain cortex were measured with dry-wet method; and NMDA receptor activity was detected with a radio ligand binding assay. Results: The water contents began to increase at 30 minutes and reached the peak at 6 hours after brain injury. The maximal binding (Bmax) of NMDA receptor increased significantly at 15 minutes and reached the peak at 30 minutes, then decreased gradually and had the lowest value 6 hours after brain injury. Followed the treatment with AP5, NMDA receptor activity in the injured brain showed a normal value; and the water contents were lower than that of AP5-free injury group 24 hours after brain injury. Conclusions: It suggests that excessive activation of NMDA receptor may be one of the most important factors to induce the secondary cerebral impairments, and AP5 may protect the brain from edema after brain injury.
Schmidt, André; Kometer, Michael; Bachmann, Rosilla; Seifritz, Erich; Vollenweider, Franz
2013-01-01
Both glutamate and serotonin (5-HT) play a key role in the pathophysiology of emotional biases. Recent studies indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine and the 5-HT receptor agonist psilocybin are implicated in emotion processing. However, as yet, no study has systematically compared their contribution to emotional biases. This study used event-related potentials (ERPs) and signal detection theory to compare the effects of the NMDA (via S-ketamine) and 5-HT (via psilocybin) receptor system on non-conscious or conscious emotional face processing biases. S-ketamine or psilocybin was administrated to two groups of healthy subjects in a double-blind within-subject placebo-controlled design. We behaviorally assessed objective thresholds for non-conscious discrimination in all drug conditions. Electrophysiological responses to fearful, happy, and neutral faces were subsequently recorded with the face-specific P100 and N170 ERP. Both S-ketamine and psilocybin impaired the encoding of fearful faces as expressed by a reduced N170 over parieto-occipital brain regions. In contrast, while S-ketamine also impaired the encoding of happy facial expressions, psilocybin had no effect on the N170 in response to happy faces. This study demonstrates that the NMDA and 5-HT receptor systems differentially contribute to the structural encoding of emotional face expressions as expressed by the N170. These findings suggest that the assessment of early visual evoked responses might allow detecting pharmacologically induced changes in emotional processing biases and thus provides a framework to study the pathophysiology of dysfunctional emotional biases.
Ginkgolides and glycine receptors
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Jaracz, Stanislav; Nakanishi, Koji; Jensen, Anders A.
2004-01-01
Ginkgolides from the Ginkgo biloba tree are diterpenes with a cage structure consisting of six five-membered rings and a unique tBu group. They exert a variety of biological properties. In addition to being antagonists of the platelet activating factor receptor (PAFR), it has recently been shown ...
Gurd, J W; Bissoon, N
1997-08-01
The NMDA receptor has recently been found to be phosphorylated on tyrosine. To assess the possible connection between tyrosine phosphorylation of the NMDA receptor and signaling pathways in the postsynaptic cell, we have investigated the relationship between tyrosine phosphorylation and the binding of NMDA receptor subunits to the SH2 domains of phospholipase C-gamma (PLC-gamma). A glutathione S-transferase (GST) fusion protein containing both the N- and the C-proximal SH2 domains of PLC-gamma was bound to glutathione-agarose and reacted with synaptic junctional proteins and glycoproteins. Tyrosine-phosphorylated PSD-GP180, which has been identified as the NR2B subunit of the NMDA receptor, bound to the SH2-agarose beads in a phosphorylation-dependent fashion. Immunoblot analysis with antibodies specific for individual NMDA receptor subunits showed that both NR2A and NR2B subunits bound to the SH2-agarose. No binding occurred to GST-agarose lacking an associated SH2 domain, indicating that binding was specific for the SH2 domains. The binding of receptor subunits increased after the incubation of synaptic junctions with ATP and decreased after treatment of synaptic junctions with exogenous protein tyrosine phosphatase. Immunoprecipitation experiments confirmed that NR2A and NR2B were phosphorylated on tyrosine and further that tyrosine phosphorylation of each of the subunits was increased after incubation with ATP. The results demonstrate that NMDA receptor subunits NR2A and NR2B will bind to the SH2 domains of PLC-gamma and that isolated synaptic junctions contain endogenous protein tyrosine kinase(s) that can phosphorylate both NR2A and NR2B receptor subunits, and suggest that interaction of the tyrosine-phosphorylated NMDA receptor with proteins that contain SH2 domains may serve to link it to signaling pathways in the postsynaptic cell.
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V. Baptista
2005-01-01
Full Text Available The nucleus tractus solitarius (NTS plays an important role in the control of autonomic reflex functions. Glutamate, acting on N-methyl-D-aspartate (NMDA and non-NMDA ionotropic receptors, is the major neurotransmitter in this nucleus, and the relative contribution of each receptor to signal transmission is unclear. We have examined NMDA excitatory postsynaptic currents (NMDA-EPSCs in the subpostremal NTS using the whole cell patch clamp technique on a transverse brainstem slice preparation. The NMDA-EPSCs were evoked by stimulation of the solitary tract over a range of membrane potentials. The NMDA-EPSCs, isolated pharmacologically, presented the characteristic outward rectification and were completely blocked by 50 µM DL-2-amino-5-phosphonopentanoic acid. The I-V relationship of the NMDA response shows that current, with a mean (± SEM amplitude of -41.2 ± 5.5 pA, is present even at a holding potential of -60 mV, suggesting that the NMDA receptors are weakly blocked by extracellular Mg2+ at near resting membrane potentials. This weak block can also be inferred from the value of 0.67 ± 0.17 for parameter delta obtained from a fit of the Woodhull equation to the I-V relationship. The maximal inward current measured on the I-V relationship was at -38.7 ± 4.2 mV. The decay phase of the NMDA currents was fitted with one exponential function with a decay time constant of 239 ± 51 and 418 ± 80 ms at a holding potential of -60 and +50 mV, respectively, which became slower with depolarization (e-fold per 145 mV. The biophysical properties of the NMDA receptors observed in the present study suggest that these receptors in the NTS contain NR2C subunits and may contribute to the synaptic signal integration.
Cui, Zhenzhong; Lindl, Kathryn A; Mei, Bing; Zhang, Shuqing; Tsien, Joe Z
2005-08-01
We employed an inducible, reversible and region-specific gene knockout technique to investigate the requirements for cortical NMDA receptors (NMDAR) during the various stages (acquisition, consolidation and storage, and retrieval) of nondeclarative, hippocampal-independent memory in mice using a conditioned taste aversion memory paradigm. Here we show that temporary knockout of the cortical NMDAR during either the learning or postlearning consolidation stage, but not during the retrieval stage, causes severe performance deficits in the 1-month taste memory retention tests. More importantly, we found that the consolidation and storage of the long-term nondeclarative taste memories requires cortical NMDAR reactivation. Thus, the dynamic engagement of the NMDAR during the postlearning stage leads us to postulate that NMDAR reactivation-mediated synaptic re-entry reinforcement is crucial for overcoming the destabilizing effects intrinsic to synaptic protein turnover and for achieving consolidation and storage of nondeclarative memories in the brain.
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Dikopoltsev, Elena; Foltyn, Veronika N; Zehl, Martin
2014-01-01
d-Serine is a physiological activator of NMDA receptors (NMDARs) in the nervous system that mediates several NMDAR-mediated processes ranging from normal neurotransmission to neurodegeneration. d-Serine is synthesized from l-serine by serine racemase (SR), a brain-enriched enzyme. However, little......, SR interacts preferentially with free FBXO22 species. In vivo ubiquitination and SR half-life determination indicate that FBXO22 does not target SR to the proteasome system. FBXO22 primarily affects SR subcellular localization and seems to increase d-serine synthesis by preventing the association...... is known about the regulation of d-serine synthesis. We now demonstrate that the F-box only protein 22 (FBXO22) interacts with SR and is required for optimal d-serine synthesis in cells. Although FBXO22 is classically associated with the ubiquitin system and is recruited to the Skip1-Cul1-F-box E3 complex...
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Cushla R. McCarthny
2018-01-01
Full Text Available Sex steroid hormones have neuroprotective properties which may be mediated by brain-derived neurotrophic factor (BDNF. This study sought to determine the interactive effects of preadolescent hormone manipulation and BDNF heterozygosity (+/− on hippocampal NMDA-R expression. Wild-type and BDNF+/− mice were gonadectomised, and females received either 17β-estradiol or progesterone treatment, while males received either testosterone or dihydrotestosterone (DHT treatment. Dorsal (DHP and ventral hippocampus (VHP were dissected, and protein expression of GluN1, GluN2A, GluN2B, and PSD-95 was assessed by Western blot analysis. Significant genotype × OVX interactions were found for GluN1 and GluN2 expression within the DHP of female mice, suggesting modulation of select NMDA-R levels by female sex hormones is mediated by BDNF. Furthermore, within the DHP BDNF+/− mice show a hypersensitive response to hormone treatment on GluN2 expression which may result from upstream alterations in TrkB phosphorylation. In contrast to the DHP, the VHP showed no effects of hormone manipulation but significant effects of genotype on NMDA-R expression. Castration had no effect on NMDA-R expression; however, androgen treatment had selective effects on GluN2B. These data show case distinct, interactive roles for sex steroid hormones and BDNF in the regulation of NMDA-R expression that are dependent on dorsal versus ventral hippocampal region.
Li, Shijia; Gu, Yiran; Meng, Bo; Mei, Bing; Li, Fei
2010-09-10
The glutamate transmission system and the N-methyl-D-aspartate receptor (NMDA-R), in particular its 2B subunit (NR2B), have been reported to be possibly related to taste memory as a result of treatment with NMDA antagonists and agonists. In order to further study the role of the NR2B subunit in gustation memory, we applied four different taste aversive tasks to observe the behavior of a transgenic mice model in which the NR2B subunit was specifically over-expressed in the forebrain. We found that in both short- and long-term conditioned taste aversion (CTA) experiments, mice with forebrain expression of the NR2B transgene (Tg) showed significantly enhanced CTA 2 days after training. However, both the Tg and the wild-type (Wt) mice shared the same level of aversive memory on the 30th day after training. In both fast and slow extinction experiments, Tg mice maintained a higher CTA memory than that of control mice in most extinction trials. The third experiment, which involved testing the memory for familiar taste, demonstrated that NR2B augmentation had no benefit on the latent inhibition (LI) of CTA. In addition, the last experiment (two-taste LI) showed a suppression of enhanced CTA in Tg mice when the mice were exposed to both novel and familiar tastes. These data suggested that forebrain NR2B over-expression had different effects on gustatory learning and memory. The transgenic animals were only sensitive to novel but not familiar tastes, and up-regulation of NR2B resulted in enhanced CTA function for only a short period of time. 2010 Elsevier B.V. All rights reserved.
Glycine receptor mutants of the mouse: what are possible routes of inhibitory compensation?
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Natascha eSchaefer
2012-10-01
Full Text Available Defects in glycinergic inhibition result in a complex neuromotor disorder in humans known as hyperekplexia (OMIM 149400 with similar phenotypes in rodents characterized by an exaggerated startle reflex and hypertonia. Analogous to genetic defects in humans, single point mutations, microdeletions, or insertions in the Glra1 gene but also in the Glrb gene underlie the pathology in mice. The mutations either localized in the α (spasmodic, oscillator, cincinnati, Nmf11 or the β (spastic subunit of the GlyR are much less tolerated in mice than in humans, leaving the question for the existence of different regulatory elements of the pathomechanisms in humans and rodents. In addition to the spontaneous mutations, new insights into understanding of the regulatory pathways in hyperekplexia or glycine encephalopathy arose from the constantly increasing number of knock-out as well as knock-in mutants of GlyRs. Over the last five years, various efforts using in vivo whole cell recordings provided a detailed analysis of the kinetic parameters underlying glycinergic dysfunction. Presynaptic compensation as well as postsynaptic compensatory mechanisms in these mice by other GlyR subunits or GABAA receptors, and the role of extra-synaptic GlyRs is still a matter of debate. A recent study on the mouse mutant oscillator, displayed a novel aspect for compensation of functionality by complementation of receptor domains that fold independently. This review focuses on defects in glycinergic neurotransmission in mice discussed with the background of human hyperekplexia en route to strategies of compensation.
Kuiken, S. D.; Lei, A.; Tytgat, G. N. J.; Holman, R.; Boeckxstaens, G. E. E.
2002-01-01
Background: The use of N-methyl-d-aspartate (NMDA) receptor antagonists may hold promise for the treatment of pain of visceral origin, in particular in conditions characterized by visceral hypersensitivity. Aim: To study the effect of dextromethorphan, a low affinity, non-competitive NMDA receptor
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Cao Xiaoyan
2007-04-01
Full Text Available Abstract NMDA receptors (NMDARs are involved in excitatory synaptic transmission and plasticity associated with a variety of brain functions, from memory formation to chronic pain. Subunit-selective antagonists for NMDARs provide powerful tools to dissect NMDAR functions in neuronal activities. Recently developed antagonist for NR2A-containing receptors, NVP-AAM007, triggered debates on its selectivity and involvement of the NMDAR subunits in bi-directional synaptic plasticity. Here, we re-examined the pharmacological properties of NMDARs in the anterior cingulate cortex (ACC using NVP-AAM007 as well as ifenprodil, a selective antagonist for NR2B-containing NMDARs. By alternating sequence of drug application and examining different concentrations of NVP-AAM007, we found that the presence of NVP-AAM007 did not significantly affect the effect of ifenprodil on NMDAR-mediated EPSCs. These results suggest that NVP-AAM007 shows great preference for NR2A subunit and could be used as a selective antagonist for NR2A-containing NMDARs in the ACC.
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Walailuk Kerdsan
2009-01-01
Full Text Available Methamphetamine (METH is a psychostimulant drug of abuse that produces long-term behavioral changes including behavioral sensitization, tolerance, and dependence. METH has been reported to induce neurotoxic effects in several areas of the brain via the dopaminergic system. Changes of dopamine function can induce malfunction of the glutamatergic system. Therefore, the aim of the present study was to examine the effects of METH administration on the expression of glutamate N-methyl-D-aspartate receptor subunit 1 (NMDAR1 in frontal cortex, striatum, and hippocampal formation after acute and subacute exposure to METH by western blotting. Male Sprague-Dawley rats were injected intraperitoneally with a single dose of 8 mg/kg METH, 4 mg/kg/day METH for 14 days and saline in acute, subacute, and control groups, respectively. A significant increase in NMDAR1 immunoreactive protein was found in frontal cortex in the subacute group (P=.036 but not in the acute group (P=.580. Moreover, a significant increase in NMDAR1 was also observed in striatum in both acute (P=.025 and subacute groups (P=.023. However, no significant differences in NMDAR1 in hippocampal formation were observed in either acute or subacute group. The results suggest that an upregulation of NMDA receptor expression may be a consequence of glutamatergic dysfunction induced by METH.
Kim, Chea-Ha; Park, Soo-Hyun; Sim, Yun-Beom; Kim, Sung-Su; Jung, Jun-Sub; Sharma, Naveen; Suh, Hong-Won
2017-02-28
Kainic acid (KA) is a well-known excitatory neurotoxic substance. In the present study, effects of KA-injected intraperitoneally (i.p.), intracerebroventricularly (i.c.v.) or intrathecally (i.t.) on the blood glucose level were investigated in ICR mice. We found that KA administered intraperitoneally (i.p.), intracerebroventricularly (i.c.v.) or intrathecally (i.t.) increased the blood glucose and corticosterone levels, suggesting that KA-induced hyperglycemia appeared to be due to increased blood corticosterone level. In support of this finding, adrenalectomy causes a reduction of KA-induced hyperglycemia and neuronal cell death in CA3 regions of the hippocampus. In addition, pretreatment with i.c.v. or i.t. injection of CNQX (6-cyano-7-nitroquinoxaline-2, 3-dione; a non-NMDA receptor blocker) attenuated the i.p. and i.c.v. administered KA-induced hyperglycemia. KA administered i.c.v. caused an elevation of the blood corticosterone level whereas the plasma insulin level was reduced. Moreover, i.c.v. pretreatment with CNQX inhibited the decrease of plasma insulin level induced by KA i.c.v. injection, whereas the KA-induced plasma corticosterone level was further enhanced by CNQX pretreatment. Our results suggest that KA administered systemically or centrally produces hyperglycemia. A glucocorticoid system appears to be involved in KA-induced hyperglycemia. Furthermore, central non-N-methyl-D-aspartate receptors may be responsible for KA-induced hyperglycemia.
Aoshima, H; Tenpaku, Y
1997-12-01
To study the effects of 13-L-hydroxylinoleic acid (LOH) and food additives on gamma-aminobutyric acid (GABA) receptors, ionotropic GABA receptors were expressed in Xenopus oocytes by injecting mRNAs prepared from rat whole brain. LOH, which was prepared by reduction of 13-L-hydroperoxylinoleic acid (LOOH), inhibited the response of GABA receptors in the presence of high concentrations of GABA. LOH also inhibited nicotinic acetylcholine, glycine, and kainate receptors, while it had little effect on NMDA receptors expressed in Xenopus oocytes. However, LOH potentiated the response of GABA receptors as well as LOOH in the presence of low concentrations of GABA, possibly increasing the affinity of GABA for the receptors, while linoleic acid did not. Since some modification of the compounds seemed to change their effects on GABA receptors, the responses of GABA receptors elicited by 10 microM GABA were measured in the presence of compounds with various kinds of functional groups or the structural isomers of pentanol. Potentiation of GABA receptors depended strongly on the species of functional groups and also depended on the structure of the isomers. Then effects of various kinds of food additives on GABA receptors were also examined; perfumes such as alcohols or esters potentiated the responses strongly, while hexylamine, nicotinamide, or caffeine inhibited the responses, mainly in a competitive manner, and vanillin inhibited the responses noncompetitively. These results suggest the possibility that production of LOOH and LOH, or intake of much of some food additives, modulates the neural transmission in the brain, especially through ionotropic GABA receptors and changes the frame of the human mind, as alcohol or tobacco does.
Abo-Riziq, Ali; Grace, Louis; Crews, Bridgit; Callahan, Michael P,; van Mourik, Tanja; de Vries, Mattanjah S,
2011-01-01
We investigated the variation in conformation for the amino acid tyrosine (Y), alone and in the small peptides tyrosine-glycine (YC) and tyrosine-glycine-glycine (YGG), in the gas phase by using UV-UV and IR-UV double resonance spectroscopy and density functional theory calculations. For tyrosine we found seven different conformations, for YG we found four different conformations, and for YGG we found three different conformations. As the peptides get larger, we observe fewer stable conformers, despite the increasing complexity and number of degrees of freedom. We find structural trends similar to those in phenylalanine-glycine glycine (FGG) and tryptophan-glycine-glycine (WGG)j however) the effect of dispersive forces in FGG for stabilizing a folded structure is replaced by that of hydrogen bonding in YGG.
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Haradahira, Terushi E-mail: terushi@nirs.go.jp; Zhang, Ming-Rong; Maeda, Jun; Okauchi, Takashi; Kawabe, Kouichi; Kida, Takayo; Suzuki, Kazutoshi; Suhara, Tetsuya
2000-05-01
A positron-emitter labeled radioligand for the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor, [{sup 11}C]L-703,717, was examined for its ability to penetrate the brain in animals by simultaneous use with drugs having high-affinity separate binding sites on human serum albumin. [{sup 11}C]L-703,717 has poor blood-brain barrier (BBB) permeability because it binds tightly to plasma proteins. Co-injection of warfarin (50-200 mg/kg), a drug that binds to albumin and resembles L-703,717 in structure, dose-dependently enhanced the penetration by [{sup 11}C]L-703,717 in mice, resulting in a five-fold increase in the brain radioactivity at 1 min after the injection. Drugs structurally unrelated to L-703,717, salicylate, phenol red, and L-tryptophan, were less effective or ineffective in increasing the uptake of [{sup 11}C]L-703,717. These results suggest that the simultaneous use of a drug that inhibits the binding of a radioligand to plasma proteins is a useful way to overcome the poor BBB permeability of the radioligand triggered by its tight binding to plasma proteins. In brain distribution studies in rodents, it was found that, after the increase in brain uptake with warfarin, much of the glycine site antagonist accumulates in the cerebellum but its pharmacological specificity did not match the glycine site of NMDA receptors.
Cloning and expression of the human N-methyl-D-aspartate receptor subunit NR3A
DEFF Research Database (Denmark)
Eriksson, Maria; Nilsson, Anna; Froelich-Fabre, Susanne
2002-01-01
Native N-methyl-D-aspartate (NMDA) receptors are heteromeric assemblies of four or five subunits. The NMDA receptor subunits, NR1, NR2A, NR2B, NR2C, and NR2D have been cloned in several species, including man. The NR3A subunit, which in rodents is predominantly expressed during early development......, seems to function by reducing the NMDA receptor response. The human homologue to the rat NR3A, however, had not been cloned. In order to study the functions of the human NR3A (hNR3A), we have cloned and sequenced the hNR3A. It was found to share 88% of the DNA sequence with the rat gene, corresponding...
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Júlia Niehues da Cruz
2017-04-01
Full Text Available ABSTRACT Membrane/lipid rafts (MLRs are plasmalemmal microdomains that are essential for neuronal signaling and synaptic development/stabilization. Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (statins can disable the N-methyl-D-aspartate (NMDA receptor through disruption of MLRs and, in turn, decrease NMDA-mediated anxiety. This hypothesis will contribute to understanding the critical roles of simvastatin in treating anxiety via the NMDA receptor.
Bordji, Karim; Becerril-Ortega, Javier; Nicole, Olivier; Buisson, Alain
2010-11-24
Calcium is a key mediator controlling essential neuronal functions depending on electrical activity. Altered neuronal calcium homeostasis affects metabolism of amyloid precursor protein (APP), leading to increased production of β-amyloid (Aβ), and contributing to the initiation of Alzheimer's disease (AD). A linkage between excessive glutamate receptor activation and neuronal Aβ release was established, and recent reports suggest that synaptic and extrasynaptic NMDA receptor (NMDAR) activation may have distinct consequences in plasticity, gene regulation, and neuronal death. Here, we report for the first time that prolonged activation of extrasynaptic NMDAR, but not synaptic NMDAR, dramatically increased the neuronal production of Aβ. This effect was preceded by a shift from APP695 to Kunitz protease inhibitory domain (KPI) containing APPs (KPI-APPs), isoforms exhibiting an important amyloidogenic potential. Conversely, after synaptic NMDAR activation, we failed to detect any KPI-APP expression and neuronal Aβ production was not modified. Calcium imaging data showed that intracellular calcium concentration after extrasynaptic NMDAR stimulation was lower than after synaptic activation. This suggests distinct signaling pathways for each pool of receptors. We found that modification of neuronal APP expression pattern triggered by extrasynaptic NMDAR activation was regulated at an alternative splicing level involving calcium-/calmodulin-dependent protein kinase IV, but overall APP expression remained identical. Finally, memantine dose-dependently inhibited extrasynaptic NMDAR-induced KPI-APPs expression as well as neuronal Aβ release. Altogether, these data suggest that a chronic activation of extrasynaptic NMDAR promotes amyloidogenic KPI-APP expression leading to neuronal Aβ release, representing a causal risk factor for developing AD.
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Wong, E H; Knight, A R; Woodruff, G N
1988-01-01
The potent noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist (/sup 3/H)MK-801 bound with nanomolar affinity to rat brain membranes in a reversible, saturable, and stereospecific manner. The affinity of (/sup 3/H)MK-801 was considerably higher in 5 mM Tris-HCl (pH 7.4) than in previous studies using Krebs-Henseleit buffer. (/sup 3/H)MK-801 labels a homogeneous population of sites in rat cerebral cortical membranes with KD of 6.3 nM and Bmax of 2.37 pmol/mg of protein. This binding was unevenly distributed among brain regions, with hippocampus greater than cortex greater than olfactory bulb = striatum greater than medulla-pons, and the cerebellum failing to show significant binding. Detailed pharmacological characterization indicated (/sup 3/H)MK-801 binding to a site which was competitively and potently inhibited by known noncompetitive NMDA receptor antagonists, such as phencyclidine, thienylcyclohexylpiperidine (TCP), ketamine, N-allylnormetazocine (SKF 10,047), cyclazocine, and etoxadrol, a specificity similar to sites labelled by (/sup 3/H)TCP. These sites were distinct from the high-affinity sites labelled by the sigma receptor ligand (+)-(/sup 3/H)SKF 10,047. (/sup 3/H)MK-801 binding was allosterically modulated by the endogenous NMDA receptor antagonist Mg2+ and by other active divalent cations. These data suggest that (/sup 3/H)MK-801 labels a high-affinity site on the NMDA receptor channel complex, distinct from the NMDA recognition site, which is responsible for the blocking action of MK-801 and other noncompetitive NMDA receptor antagonists.
Maslinic acid ameliorates NMDA receptor blockade-induced schizophrenia-like behaviors in mice.
Jeon, Se Jin; Kim, Eunji; Lee, Jin Su; Oh, Hee Kyong; Zhang, Jiabao; Kwon, Yubeen; Jang, Dae Sik; Ryu, Jong Hoon
2017-11-01
Schizophrenia is a chronic psychotic disorder characterized by positive, negative, and cognitive symptoms. Primary treatments for schizophrenia relieve the positive symptoms but are less effective against the negative and cognitive symptoms. In the present study, we investigated whether maslinic acid, isolated from Syzygium aromaticum (clove), can ameliorate schizophrenia-like behaviors in mice induced by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. After maslinic acid treatment in the MK-801 model, we examined the behavioral alteration and signaling pathways in the prefrontal cortex. Mice were treated with maslinic acid (30 mg/kg), and their behaviors were evaluated through an array of behavioral tests. The effects of maslinic acid were also examined in the signaling pathways in the prefrontal cortex. A single administration of maslinic acid blocked the MK-801-induced hyperlocomotion and reversed the MK-801-induced sensorimotor gating deficit in the acoustic startle response test. In the social novelty preference test, maslinic acid ameliorated the social behavior deficits induced by MK-801. The MK-801-induced attention and recognition memory impairments were also alleviated by a single administration of maslinic acid. Furthermore, maslinic acid normalized the phosphorylation levels of Akt-GSK-3β and ERK-CREB in the prefrontal cortex. Overall, maslinic acid ameliorated the schizophrenia-like symptoms induced by MK-801, and these effects may be partly mediated through Akt-GSK-3β and ERK-CREB activation. These findings suggest that maslinic acid could be a candidate for the treatment of several symptoms of schizophrenia, including positive symptoms, sensorimotor gating disruption, social interaction deficits, and cognitive impairments. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Mohammed El-Hafidi
2018-01-01
Full Text Available Oxidative stress and redox status play a central role in the link between insulin resistance (IR and lipotoxicity in metabolic syndrome. This mechanistic link may involve alterations in the glutathione redox state. We examined the effect of glycine supplementation to diet on glutathione biosynthesis, oxidative stress, IR, and insulin cell signaling in liver from sucrose-fed (SF rats characterized by IR and oxidative stress. Our hypothesis is that the correction of glutathione levels by glycine treatment leads to reduced oxidative stress, a mechanism associated with improved insulin signaling and IR. Glycine treatment decreases the levels of oxidative stress markers in liver from SF rats and increases the concentrations of glutathione (GSH and γ-glutamylcysteine and the amount of γ-glutamylcysteine synthetase (γ-GCS, a key enzyme of GSH biosynthesis in liver from SF rats. In liver from SF rats, glycine also decreases the insulin-induced phosphorylation of insulin receptor substrate-1 (ISR-1 in serine residue and increases the phosphorylation of insulin receptor β-subunit (IR-β in tyrosine residue. Thus, supplementing diets with glycine to correct GSH deficiency and to reduce oxidative stress provides significant metabolic benefits to SF rats by improving insulin sensitivity.
Rouach, N.; Tencé, M.; Glowinski, J.; Giaume, C.
2002-01-01
Cocultures of neurons and astrocytes from the rat striatum were used to determine whether the stimulation of neuronal receptors could affect the level of intercellular communication mediated by gap junctions in astrocytes. The costimulation of N-methyl-D-asparte (NMDA) and muscarinic receptors led to a prominent reduction of astrocyte gap junctional communication (GJC) in coculture. This treatment was not effective in astrocyte cultures, these cells being devoid of NMDA receptors. Both types ...
Holubova, Kristina; Nekovarova, Tereza; Pistovcakova, Jana; Sulcova, Alexandra; Stuchlík, Ales; Vales, Karel
2014-01-01
-pregnanolone glutamate (PG) is a use-dependent antagonist of NMDA receptors.-We demonstrated that PG did not induce significant hyperlocomotion.-We showed that PG displayed anxiolytic-like and antidepressant-like properties.
International Nuclear Information System (INIS)
Christiaans, Johannes A.M.; Klein, Pieter J.; Metaxas, Athanasios; Kooijman, Esther J.M.; Schuit, Robert C.; Leysen, Josée E.; Lammertsma, Adriaan A.; Berckel, Bart N.M. van; Windhorst, Albert D.
2014-01-01
Introduction: The N-methyl-D-Aspartate (NMDA) receptor plays an important role in learning and memory. Overactivation is thought to play an important role in neurodegenerative disorders such as Alzheimer's disease. Currently, it is not possible to assess N-methyl-D-aspartate receptor (NMDAr) bio-availability in vivo. The purpose of this study was to develop a positron emission tomography (PET) ligand for the NR2B binding site of the NMDA receptor. Methods: N-((5-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was radiolabelled with carbon-11 in the phenyl moiety. Biodistribution and blocking studies were carried out in anaesthetized mice and in non-anaesthetized rats. Results: N-((5-(4-fluoro-2-[ 11 C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was prepared in 49 ± 3% (decay-corrected) yield, affording 4.1 ± 0.3 GBq of formulated product at the end of synthesis with a radiochemical purity of > 99% and with a specific activity of 78 ± 10 GBq/μmol. Conclusion: A new NR2B PET ligand was developed in high yield. [ 11 C]4 readily enters the brain and binds to the NR2B subunit-containing NMDAr in the rodent brain. High sigma-1 receptor binding may, however, limit its future application as a PET probe for imaging the NR2B subunit-containing NMDAr. Anaesthesia has an effect on NMDAr function and therefore can complicate interpretation of preclinical in vivo results. In addition, effects of endogenous compounds cannot be excluded. Despite these potential limitations, further studies are warranted to investigate the values of [ 11 C]4 as an NR2B PET ligand
Ando, Yoshihito; Shimazaki, Haruo; Shiota, Katsutoshi; Tetsuka, Syuichi; Nakao, Koichi; Shimada, Tatsuhiro; Kurata, Kazumi; Kuroda, Jinichi; Yamashita, Akihiro; Sato, Hayato; Sato, Mamoru; Eto, Shinkichi; Onishi, Yasunori; Tanaka, Keiko; Kato, Satoshi
2016-07-08
Increasing numbers of patients with elevated anti-N-methyl-D-aspartate (NMDA) receptor antibody titers presenting exclusively with psychiatric symptoms have been reported. The aim of the present study was to clarify the prevalence of elevated serum anti-NMDA receptor antibody titers in patients with new-onset or acute exacerbations of psychiatric symptoms. In addition, the present study aimed to investigate the association between elevated anti-NMDA receptor titers and psychiatric symptoms. The present collaborative study included 59 inpatients (23 male, 36 female) presenting with new-onset or exacerbations of schizophrenia-like symptoms at involved institutions from June 2012 to March 2014. Patient information was collected using questionnaires. Anti-NMDA receptor antibody titers were measured using NMDAR NR1 and NR2B co-transfected human embryonic kidney (HEK) 293 cells as an antigen (cell-based assay). Statistical analyses were performed for each questionnaire item. The mean age of participants was 42.0 ± 13.7 years. Six cases had elevated serum anti-NMDA antibody titers (10.2 %), four cases were first onset, and two cases with disease duration >10 years presented with third and fifth recurrences. No statistically significant difference in vital signs or major symptoms was observed between antibody-positive and antibody-negative groups. However, a trend toward an increased frequency of schizophrenia-like symptoms was observed in the antibody-positive group. Serum anti-NMDA receptor antibody titers may be associated with psychiatric conditions. However, an association with specific psychiatric symptoms was not observed in the present study. Further studies are required to validate the utility of serum anti-NMDA receptor antibody titer measurements at the time of symptom onset.
Synthesis and distribution of N-benzyloxycarbonyl-[14C]-glycine, a lipophilic derivative of glycine
International Nuclear Information System (INIS)
Lambert, D.M.; Gallez, Bernard; Poupaert, J.H.
1995-01-01
N-benzyloxycarbonyl[ 14 C]-glycine, a lipophilic derivative of glycine exhibiting anticonvulsant properties, was prepared in one step from [U- 14 C] glycine and benzyl chloroformate in alkali medium. a comparative study of biodistribution was carried on mice between this compound and the parent amino-acid after intravenous administration. Dimethylsulfoxide was used as injection vehicle for N-benzyloxycarbonylglycine. The influence of this injection vehicle was studied comparing glycine injected in a saline solution and glycine co-administered with dimethylsulfoxide. No significant difference was found between these two treatments. Compared to glycine, N-benzyloxycarbonylglycine reached quickly the central nervous system and exhibited an enhanced brain penetration index, 13-fold superior to the parent aminoacid value. (Author)
The GluR2 hypothesis: Ca(++)-permeable AMPA receptors in delayed neurodegeneration
Bennett, M. V.; Pellegrini-Giampietro, D. E.; Gorter, J. A.; Aronica, E.; Connor, J. A.; Zukin, R. S.
1996-01-01
Increased glutamate-receptor-mediated Ca++ influx is considered an important factor underlying delayed neurodegeneration following ischemia or seizures. Until recently, the NMDA receptor was the only glutamate receptor known to be Ca(++)-permeable. It is now well established that glutamate receptors
Coffey, M Justin; Cooper, Joseph J
2016-12-01
There is a growing scientific literature describing the neuropsychiatric symptoms of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, including the use of electroconvulsive therapy (ECT) to treat those symptoms. We sought to consolidate this literature into a review that highlights its relevance to ECT practitioners. We performed a PubMed search using the terms electroconvulsive therapy and encephalitis, autoimmune encephalitis, or anti-NMDA receptor encephalitis. We reviewed all relevant studies in detail, cross-referenced all bibliographies, and collected key clinical information related to the practice of ECT. We identified 6 studies offering patient-level descriptions of the use of ECT in patients with anti-NMDA receptor encephalitis. In all cases ECT was used to target symptoms of catatonia. Electroconvulsive therapy was delivered safely and effectively irrespective of the timing of diagnosis, tumor removal, or immunotherapy. There are no controlled data on the use of ECT in anti-NMDA receptor encephalitis. Further investigation is needed to determine whether ECT has a disease-modifying effect on this form of autoimmune encephalitis.
International Nuclear Information System (INIS)
Keana, J.F.W.; McBurney, R.N.; Scherz, M.W.
1989-01-01
Four diarylguanidine derivatives were synthesized. These compounds were found to displace, at submicromolar concentrations, 3 H-labeled 1-[1-(2-thienyl)cyclohexyl]piperidine and (+)-[ 3 H]MK-801 from phencyclidine receptors in brain membrane preparations. In electrophysiological experiments the diarylguanidines blocked N-methyl-D-aspartate (NMDA)-activated ion channels. These dairylguanidines also protected rat hippocampal neurons in vitro from glutamate-induced cell death. The results show that some diarylguanidines are noncompetitive antagonists of NMDA receptor-mediated responses and have the neuroprotective property that is commonly associated with blockers of the NMDA receptor-gated cation channel. Diarylguanidines are structurally unrelated to known blockers of NMDA channels and, therefore, represent a new compound series for the development of neuroprotective agents with therapeutic value in patients suffering from stroke, from brain or spinal cord trauma, from hypoglycemia, and possibly from brain ischemia due to heart attack
Adamec, R E
1998-01-01
The findings of this study support the hypothesis that N-methyl-D-aspartate (NMDA) receptors mediate the initiation of long-term potentiation (LTP) and behavioral changes induced by the anxiogenic beta-carboline, FG-7142. Unlike previous work, this study examined the effects of FG-7142 on LTP of amygdala efferents in both hemispheres. 7-amino-phosphono-heptanoic acid (AP7), a competitive NMDA receptor blocker, given prior to administration of FG-7142, prevented LTP in amygdala efferent transmission to the medial hypothalamus and periacqueductal gray (PAG). When given FG-7142 alone, cats showed lasting behavioral changes accompanied by LTP in all pathways studied. Duration of LTP, and its relationship to behavioral change, depended on the pathway and the hemisphere of the pathway. Correlation and covariance analyses indicate that LTP in the left amygdalo-ventromedial hypothalamic pathway mediates initiation, but not maintenance, of increased defensiveness. This finding replicates previous work. A new finding is that increased local excitability in the right basal amygdala (reduced threshold for evoked response), and LTP in the right amygdalo-PAG pathway, may be important for maintenance of increases in defensive behavior. Furthermore, the effects of flumazenil, a benzodiazepine receptor antagonist, on behavior and physiology single out the importance of right amygdalo-PAG LTP as a critical mediator of increased defensiveness. Flumazenil reversed the increase in defensiveness produced by FG-7142 in a drug-dependent manner as described in Adamec (1998a). Moreover, flumazenil reversed LTP only in the right amygdalo-PAG pathway. The findings of the present study suggest that response to FG-7142 may be a useful model of the effects of traumatic stressors on limbic system function in anxiety, especially in view of the recent data in humans implicating right hemispheric function in persisting negative affective states.
Priya, Anusha; Johar, Kaid; Wong-Riley, Margaret T T
2013-01-01
Neuronal activity and energy metabolism are tightly coupled processes. Previously, we found that nuclear respiratory factor 1 (NRF-1) transcriptionally co-regulates energy metabolism and neuronal activity by regulating all 13 subunits of the critical energy generating enzyme, cytochrome c oxidase (COX), as well as N-methyl-d-aspartate (NMDA) receptor subunits 1 and 2B, GluN1 (Grin1) and GluN2B (Grin2b). We also found that another transcription factor, nuclear respiratory factor 2 (NRF-2 or GA-binding protein) regulates all subunits of COX as well. The goal of the present study was to test our hypothesis that NRF-2 also regulates specific subunits of NMDA receptors, and that it functions with NRF-1 via one of three mechanisms: complementary, concurrent and parallel, or a combination of complementary and concurrent/parallel. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, in vivo chromatin immunoprecipitation of mouse neuroblastoma cells and rat visual cortical tissue, promoter mutations, real-time quantitative PCR, and western blot analysis, NRF-2 was found to functionally regulate Grin1 and Grin2b genes, but not any other NMDA subunit genes. Grin1 and Grin2b transcripts were up-regulated by depolarizing KCl, but silencing of NRF-2 prevented this up-regulation. On the other hand, over-expression of NRF-2 rescued the down-regulation of these subunits by the impulse blocker TTX. NRF-2 binding sites on Grin1 and Grin2b are conserved among species. Our data indicate that NRF-2 and NRF-1 operate in a concurrent and parallel manner in mediating the tight coupling between energy metabolism and neuronal activity at the molecular level. Copyright © 2012 Elsevier B.V. All rights reserved.
Preclinical anxiolytic profiles of 7189 and 8319, novel non-competitive NMDA antagonists
International Nuclear Information System (INIS)
Dunn, R.W.; Corbett, R.; Martin, L.L.; Payack, J.F.; Laws-Ricker, L.; Wilmot, C.A.; Rush, D.K.; Cornfeldt, M.L.; Fielding, S.
1990-01-01
Antagonists at excitatory amino acid receptors, especially the N-methyl-d-aspartate (NMDA) subtype, have been shown to possess anticonvulsant and anxiolytic properties. Two closely related benzeneethanamines, are potential novel anxiolytic agents which bind with high affinity to the NMDA receptor at the non-competitive site and are relatively non-toxic (LD50's-160 mg/kg, ip). 7189 and 8319 showed anxiolytic effects in schedule controlled conflict assays as well as in the social interaction (SI) and elevated plus maze (EPM) procedures in rats. Following intraperitoneal administration of 7189 at 20 to 60 mg/kg, conflict responding was increased from 2- to 7-fold in the modified Cook and Davidson and Geller conflict paradigms. 8319, at 2.5 to 5 mg/kg, produced a two fold increase in conflict responding. In the non-schedule controlled procedures, 7189 at 20 mg/kg increased SI time by 23% while in the EPM at 10 to 20 mg/kg, open arm exploration time increased by 41 to 77%. Likewise, 8319 at 2.5 and 5 mg/kg increased open arm exploration and SI time by 50 and 37%, respectively. In summary, 7189 and 8319 were efficacious in four behavioral procedures predictive of potential anxiolytic agents. Although these compounds have not been submitted for clinical evaluation, they may represent a new class of beneficial compounds for the treatment of anxiety
Olszewski, Maciej; Dolowa, Wioleta; Matulewicz, Pawel; Kasicki, Stefan; Hunt, Mark J
2013-12-01
Systemic administration of NMDA receptor antagonists, used to model schizophrenia, increase the power of high-frequency oscillations (130-180Hz, HFO) in a variety of neuroanatomical and functionally distinct brain regions. However, it is unclear whether HFO are independently and locally generated or instead spread from a distant source. To address this issue, we used local infusion of tetrodotoxin (TTX) to distinct brain areas to determine how accurately HFO recorded after injection of NMDAR antagonists reflect the activity actually generated at the electrode tip. Changes in power were evaluated in local field potentials (LFPs) recorded from the nucleus accumbens (NAc), prefrontal cortex and caudate and in electrocorticograms (ECoGs) from visual and frontal areas. HFO recorded in frontal and visual cortices (ECoGs) or in the prefrontal cortex, caudate (LFPs) co-varied in power and frequency with observed changes in the NAc. TTX infusion to the NAc immediately and profoundly reduced the power of accumbal HFO which correlated with changes in HFO recorded in distant cortical sites. In contrast, TTX infusion to the prefrontal cortex did not change HFO power recorded locally, although gamma power was reduced. A very similar result was found after TTX infusion to the caudate. These findings raise the possibility that the NAc is an important neural generator. Our data also support existing studies challenging the idea that high frequencies recorded in LFPs are necessarily generated at the recording site. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.
Kordjazy, Nastaran; Haj-Mirzaian, Arya; Amiri, Shayan; Ostadhadi, Sattar; Amini-Khoei, Hossein; Dehpour, Ahmad Reza
2016-02-01
Recent evidence indicates that 5-hydroxytryptamine 3 (5-HT3) antagonists such as ondansetron and tropisetron exert positive behavioral effects in animal models of depression. Due to the ionotropic nature of 5-HT3 and N-methyl-d-aspartate (NMDA) receptors, plus their contribution to the pathophysiology of depression, we investigated the possible role of NMDA receptors in the antidepressant-like effect of 5-HT3 receptor antagonists in male mice. In order to evaluate the animals' behavior in response to different treatments, we performed open-field test (OFT), forced swimming test (FST), and tail-suspension test (TST), which are considered as valid tasks for measuring locomotor activity and depressive-like behaviors in mice. Our data revealed that intraperitoneal (i.p.) administration of tropisetron (5, 10, and 30mg/kg) and ondansetron (0.01, and 0.1μg/kg) significantly decreased the immobility time in FST and TST. Also, co-administration of subeffective doses of tropisetron (1mg/kg, i.p.) or ondansetron (0.001μg/kg, i.p.) with subeffective doses of NMDA receptor antagonists, ketamine (1mg/kg, i.p.), MK-801 (0.05mg/kg, i.p.) and magnesium sulfate (10mg/kg, i.p.) resulted in a reduced immobility time both in FST and TST. The subeffective dose of NMDA (NMDA receptor agonist, 75mg/kg, i.p.) abolished the effects of 5-HT3 antagonists in FST and TST, further supporting the presumed interaction between 5-HT3 and NMDA receptors. These treatments did not affect the locomotor behavior of animals in OFT. Finally, the results of our study suggest that the positive effects of 5-HT3 antagonists on the coping behavior of mice in FST and TST are at least partly mediated through NMDA receptors participation. Copyright © 2015 Elsevier Inc. All rights reserved.
Calpain inhibition reduces NMDA receptor rundown in rat substantia nigra dopamine neurons.
Zhao, Jerry; Baudry, Michel; Jones, Susan
2018-05-04
Repeated activation of N-Methyl-d-aspartate receptors (NMDARs) causes a Ca 2+ -dependent reduction in NMDAR-mediated current in dopamine (DA) neurons of the substantia nigra pars compacta (SNc) in one week old rats; however, a Ca 2+ -dependent regulatory protein has not been identified. The role of the Ca 2+ -dependent cysteine protease, calpain, in mediating NMDAR current rundown was investigated. In brain slices from rats aged postnatal day 7-9 ('P7'), bath application of either of the membrane permeable calpain inhibitors, N-Acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN, 20 μM) or MDL-28170 (30 μM) significantly reduced whole-cell NMDAR current rundown. To investigate the role of the calpain-2 isoform, the membrane permeable calpain-2 inhibitor, Z-Leu-Abu-CONH-CH2-C6H3 (3, 5-(OMe)2 (C2I, 200 nM), was applied; C2I application significantly reduced whole cell NMDAR current rundown. Interestingly, ALLN but not C2I significantly reduced rundown of NMDA-EPSCs. These results suggest the calpain-2 isoform mediates Ca 2+ -dependent regulation of extrasynaptic NMDAR current in the first postnatal week, while calpain-1 might mediate rundown of synaptic NMDAR currents. One week later in postnatal development, at P12-P16 ('P14'), there was significantly less rundown in SNc-DA neurons, and no significant effect on rundown of either Ca 2+ chelation or treatment with the calpain inhibitor, ALLN, suggesting that the rundown observed in SNc-DA neurons from two week-old rats might be Ca 2+ -independent. In conclusion, Ca 2+ -dependent rundown of extrasynaptic NMDAR currents in SNc DA neurons involves calpain-2 activation, but Ca 2+ - and calpain-2-dependent NMDAR current rundown is developmentally regulated. Copyright © 2018 Elsevier Ltd. All rights reserved.
Energy Technology Data Exchange (ETDEWEB)
Lambert, D.M.; Gallez, Bernard; Poupaert, J.H. [Universite Catholique de Louvain, Brussels (Belgium). Dept. des Sciences Pharmaceutiques
1995-12-31
N-benzyloxycarbonyl[{sup 14}C]-glycine, a lipophilic derivative of glycine exhibiting anticonvulsant properties, was prepared in one step from [U-{sup 14}C] glycine and benzyl chloroformate in alkali medium. a comparative study of biodistribution was carried on mice between this compound and the parent amino-acid after intravenous administration. Dimethylsulfoxide was used as injection vehicle for N-benzyloxycarbonylglycine. The influence of this injection vehicle was studied comparing glycine injected in a saline solution and glycine co-administered with dimethylsulfoxide. No significant difference was found between these two treatments. Compared to glycine, N-benzyloxycarbonylglycine reached quickly the central nervous system and exhibited an enhanced brain penetration index, 13-fold superior to the parent aminoacid value. (Author).