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Sample records for mk-801 nmda receptor

  1. Competitive (AP7) and non-competitive (MK-801) NMDA receptor antagonists differentially alter glucose utilization in rat cortex

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    Clow, D.W.; Lee, S.J.; Hammer, R.P. Jr. (Department of Anatomy and Reproductive Biology, School of Medicine, University of Hawaii, Honolulu (USA))

    1991-04-01

    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 {sup 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.

  2. Knockout of NMDA-receptors from parvalbumin interneurons sensitizes to schizophrenia-related deficits induced by MK-801.

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    Bygrave, A M; Masiulis, S; Nicholson, E; Berkemann, M; Barkus, C; Sprengel, R; Harrison, P J; Kullmann, D M; Bannerman, D M; Kätzel, D

    2016-04-12

    It has been suggested that a functional deficit in NMDA-receptors (NMDARs) on parvalbumin (PV)-positive interneurons (PV-NMDARs) is central to the pathophysiology of schizophrenia. Supportive evidence come from examination of genetically modified mice where the obligatory NMDAR-subunit GluN1 (also known as NR1) has been deleted from PV interneurons by Cre-mediated knockout of the corresponding gene Grin1 (Grin1(ΔPV) mice). Notably, such PV-specific GluN1 ablation has been reported to blunt the induction of hyperlocomotion (a surrogate for psychosis) by pharmacological NMDAR blockade with the non-competitive antagonist MK-801. This suggests PV-NMDARs as the site of the psychosis-inducing action of MK-801. In contrast to this hypothesis, we show here that Grin1(ΔPV) mice are not protected against the effects of MK-801, but are in fact sensitized to many of them. Compared with control animals, Grin1(ΔPV)mice injected with MK-801 show increased stereotypy and pronounced catalepsy, which confound the locomotor readout. Furthermore, in Grin1(ΔPV)mice, MK-801 induced medial-prefrontal delta (4 Hz) oscillations, and impaired performance on tests of motor coordination, working memory and sucrose preference, even at lower doses than in wild-type controls. We also found that untreated Grin1(ΔPV)mice are largely normal across a wide range of cognitive functions, including attention, cognitive flexibility and various forms of short-term memory. Taken together these results argue against PV-specific NMDAR hypofunction as a key starting point of schizophrenia pathophysiology, but support a model where NMDAR hypofunction in multiple cell types contribute to the disease.

  3. A NMDA receptor antagonist, MK-801 impairs consolidating extinction of auditory conditioned fear responses in a Pavlovian model.

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    Jun-Li Liu

    Full Text Available BACKGROUND: In auditory fear conditioning, repeated presentation of the tone in the absence of shock leads to extinction of the acquired fear responses. The glutamate N-methyl-D-aspartate receptor (NMDAR is thought to be involved in the extinction of the conditioned fear responses, but its detailed role in initiating and consolidating or maintaining the fear extinction memory is unclear. Here we investigated this issue by using a NMDAR antagonist, MK-801. METHODS/MAIN FINDINGS: The effects of immediate (beginning at 10 min after the conditioning and delayed (beginning at 24 h after conditioning extinctions were first compared with the finding that delayed extinction caused a better and long-lasting (still significant on the 20(th day after extinction depression on the conditioned fear responses. In a second experiment, MK-801 was intraperitoneally (i.p. injected at 40 min before, 4 h or 12 h after the delayed extinction, corresponding to critical time points for initiating, consolidating or maintaining the fear extinction memory. i.p. injection of MK-801 at either 40 min before or 4 h after delayed extinction resulted in an impairment of initiating and consolidating fear extinction memory, which caused a long lasting increased freezing score that was still significant on the 7th day after extinction, compared with extinction group. However, MK-801 administered at 12 h after the delayed extinction, when robust consolidation has been occurred and stabilized, did not affect the established extinction memory. Furthermore, the changed freezing behaviors was not due to an alteration in general anxiety levels, since MK-801 treatment had no effect on the percentage of open-arm time or open-arm entries in an Elevated Plus Maze (EPM task. CONCLUSIONS/SIGNIFICANCE: Our data suggested that the activation of NMDARs plays important role in initiation and consolidation but not maintenance of fear extinction memory. Together with the fact that NMDA receptor is

  4. A neuroligin-1-derived peptide stimulates phosphorylation of the NMDA receptor NR1 subunit and rescues MK-801-induced decrease in long-term potentiation and memory impairment

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    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...

  5. Low doses of the NMDA receptor antagonists, MK-801, PEAQX, and ifenprodil, induces social facilitation in adolescent male rats.

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    Morales, Melissa; Varlinskaya, Elena I; Spear, Linda P

    2013-08-01

    Adolescents display high levels of interactions with peers relative to other age groups, with these interactions further enhanced by ethanol under some circumstances. Understanding of the neural mechanisms underlying these high levels of social interactions is important given that alcohol use is initiated during adolescence and adolescents tend to report drinking for social reasons. Given that ethanol's effects are associated in part with functional antagonism of the NMDA receptor system, the current experiment explored the role of NMDA antagonists for facilitating adolescent social behavior. Adolescent male Sprague-Dawley rats were challenged acutely with either the non-competitive NMDA antagonist, MK-801 (0.01, 0.03mg/kg), the NR2A antagonist, PEAQX (1.25, 3.75mg/kg) or the NR2B antagonist, ifenprodil (0.75, 2.25mg/kg) 30min prior to a 10-min social interaction test. All compounds generally increased overall social activity (i.e., sum of social investigation, contact behavior, and play), with ifenprodil also significantly enhancing play and social contact behaviors. Although the frequencies of peer-directed social behaviors were typically greater following administration with these NMDA antagonists, social preference, indexed via the number of crossovers to the side with the partner relative to crossovers away, was significantly reduced in MK-801 and PEAQX-treated rats. None of these changes were associated with concomitant alterations in overall locomotor activity under these test circumstances. These data support the suggestion that the increases in social interactions observed in adolescents following acute ethanol may be driven in part by NMDA receptor antagonism - particularly of the NR2B subunit - given that ifenprodil stimulated social behavior in a manner similar to that produced by low doses of ethanol. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. The nicotinic agonist RJR-2403 compensates the impairment of eyeblink conditioning produced by the noncompetitive NMDA-receptor antagonist MK-801.

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    Rodríguez-Moreno, Antonio; Carrión, Miriam; Delgado-García, José María

    2006-07-10

    The classical conditioning of eyelid responses using trace paradigms is a hippocampal-related model of associative learning, involving the activation of N-methyl-D-aspartate (NMDA) receptors. We have evaluated here the effects of NMDA-receptor blockage with the selective noncompetitive antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine, MK-801). Mice were implanted with stimulating electrodes on the supraorbitary nerve and with recording electrodes in the ipsilateral orbicularis oculi muscle. Animals were conditioned with a trace shock-SHOCK paradigm. MK-801-injected animals (0.02 mg/kg) seemed unable to acquire this type of associative learning task, but the latency and amplitude of their unconditioned eyelid responses was not affected by drug administration. The administration of the nicotinic agonist (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403; 2 mg/kg) was able to restore completely the acquisition of the conditioned response when administered both before and after MK-801. In vitro recordings of field excitatory postsynaptic potentials (fEPSPs) evoked in the hippocampal CA1 area by the electrical stimulation of the Schaffer collateral pathway indicates that RJR-2403 application to the bath enhance the release of glutamate by a presynaptic mechanism. These findings reveal that nicotinic acetylcholine receptors enhance glutamatergic transmission in hippocampal circuits involved in the acquisition of associative learning.

  7. NMDA Receptors as Potential Therapeutic Targets in Diabetic Nephropathy: Increased Renal NMDA Receptor Subunit Expression in Akita Mice and Reduced Nephropathy Following Sustained Treatment With Memantine or MK-801.

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    Roshanravan, Hila; Kim, Eun Young; Dryer, Stuart E

    2016-10-01

    N-methyl-d-aspartate (NMDA) receptors are expressed throughout the kidney, and the abundance of these receptors and some of their endogenous agonists are increased in diabetes. Moreover, sustained activation of podocyte NMDA receptors induces Ca(2+) influx, oxidative stress, loss of slit diaphragm proteins, and apoptosis. We observed that NMDA receptor subunits and their transcripts are increased in podocytes and mesangial cells cultured in elevated glucose compared with controls. A similar increase in NMDA subunits, especially NR1, NR2A, and NR2C, was observed in glomeruli and tubules of Akita mice. Sustained continuous treatment with the strong NMDA receptor antagonist dizocilpine (MK-801) for 28 days starting at 8 weeks of age reduced 24-h albumin excretion and mesangial matrix expansion and improved glomerular ultrastructure in Akita mice. MK-801 did not alleviate reduced Akita mouse body weight and had no effect on kidney histology or ultrastructure in DBA/2J controls. The structurally dissimilar NMDA antagonist memantine also reduced diabetic nephropathy, although it was less effective than MK-801. Inhibition of NMDA receptors may represent a valid therapeutic approach to reduce renal complications of diabetes, and it is possible to develop well-tolerated agents with minimal central nervous system effects. Two such agents, memantine and dextromethorphan, are already in widespread clinical use.

  8. Synthesis and receptor binding studies of (+/-)1-iodo-MK-801

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    Yang, D.J.; Ciliax, B.J.; Van Dort, M.E.; Gildersleeve, D.; Pirat, J.L.; Young, A.B.; Wieland, D.M. (Univ. of Michigan Medical School, Ann Arbor (USA))

    1989-06-01

    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-({sup 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 ({sup 3}H)N-(1-(2-thienyl)cyclohexyl)piperidine (({sup 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.

  9. Possible involvement of nitric oxide (NO) signaling pathway in the antidepressant-like effect of MK-801(dizocilpine), a NMDA receptor antagonist in mouse forced swim test.

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    Dhir, Ashish; Kulkarni, S K

    2008-03-01

    L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) is an important signaling pathway involved in depression. With this information, the present study aimed to study the involvement of this signaling pathway in the antidepressant-like action of MK-801 (dizocilpine; N-methyl-d-aspartate receptor antagonist) in the mouse forced-swim test. Total immobility period was recorded in mouse forced swim test for 6 min. MK-801 (5-25 microg/kg., ip) produced a U-shaped curve in reducing the immobility period. The antidepressant-like effect of MK-801 (10 microg/kg, ip) was prevented by pretreatment with L-arginine (750 mg/kg, ip) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (7-NI) (25 mg/kg, ip) [a specific neuronal nitric oxide synthase inhibitor] produced potentiation of the action of subeffective dose of MK-801 (5 microg/kg, ip). In addition, treatment of mice with methylene blue (10 mg/kg, ip) [direct inhibitor of both nitric oxide synthase and soluble guanylate cyclase] potentiated the effect of MK-801 (5 microg/kg, ip) in the forced-swim test. Further, the reduction in the immobility period elicited by MK-801 (10 microg/kg, ip) was also inhibited by pretreatment with sildenafil (5 mg/kg, ip) [phosphodiesterase 5 inhibitor]. The various modulators used in the study and their combination did not produce any changes in locomotor activity per se and in combination with MK-801. MK-801 however, at higher doses (25 microg/kg, ip) produced hyperlocomotion. The results demonstrated the involvement of nitric oxide signaling pathway in the antidepressant-like effect of MK-801 in mouse forced-swim test.

  10. Therapeutic effect of the NMDA antagonist MK-801 on low-level laser induced retinal injury

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    Yan, W.-H.; Wu, J.; Chen, P.; Dou, J.-T.; Pan, C.-Y.; Mu, Y.-M.; Lu, J.-M.

    2009-03-01

    The aim of this article was to explore the mechanism of injury in rat retina after constant low-level helium-neon (He-Ne) laser exposure and therapeutic effects of MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, on laser-induced retinal injury. He-Ne laser lesions were created in the central retina of adult Wistar Kyoto rats and were followed immediately by intraperitoneal injection of MK-801 (2 mg/kg) or saline, macroscopical and microscopical lesion were observed by funduscope and light microscope. Ultrastructural changes of the degenerating cells were examined by electron microscopy. Photoreceptor apoptosis was evaluated by TdT-mediated dUTP nick end-labeling (TUNEL). mRNA levels were measured by in situ hybridization and NMDA receptor expression was determined by immunohistochemistry. Laser induced damage was histologically quantified by image-analysis morphometry. Electroretinograms (ERGs) were recorded at different time point after the cessation of exposure to constant irradiation. There was no visible bleeding, exudation or necrosis under funduscope. TUNEL and electron microscopy showed photoreceptor apoptosis after irradiation. MK-801-treated animals had significantly fewer TUNEL-positive cells in the photoreceptors than saline-treated animals after exposure to laser. In situ hybridization (ISH) showed that the NMDAR mRNA level of MK-801-treated rats decreased in the inner plexiform layer 6 h after the cessation of exposure to constant irradiation when compared with that of saline-treated rats. So did Immunohistochemistry (IHC). Electroretinogram showed that b-wave amplitudes of MK-801-treated group were higher than that of saline-treated group after laser exposure. These findings suggest that Low level laser may cause the retinal pathological changes under given conditions. High expression of NMDAR is one of the possible mechanisms causing experimental retinal laser injury of rats. MK-801 exhibits the therapeutic effect due to promote the

  11. Pentamidine analogs as inhibitors of [(3)H]MK-801 and [(3)H]ifenprodil binding to rat brain NMDA receptors.

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    Berger, Michael L; Maciejewska, Dorota; Vanden Eynde, Jean Jacques; Mottamal, Madhusoodanan; Żabiński, Jerzy; Kaźmierczak, Paweł; Rezler, Mateusz; Jarak, Ivana; Piantanida, Ivo; Karminski-Zamola, Grace; Mayence, Annie; Rebernik, Patrick; Kumar, Arvind; Ismail, Mohamed A; Boykin, David W; Huang, Tien L

    2015-08-01

    The anti-protozoal drug pentamidine is active against opportunistic Pneumocystis pneumonia, but in addition has several other biological targets, including the NMDA receptor (NR). Here we describe the inhibitory potencies of 76 pentamidine analogs at 2 binding sites of the NR, the channel binding site labeled with [(3)H]MK-801 and the [(3)H]ifenprodil binding site. Most analogs acted weaker at the ifenprodil than at the channel site. The spermine-sensitivity of NR inhibition by the majority of the compounds was reminiscent of other long-chain dicationic NR blockers. The potency of the parent compound as NR blocker was increased by modifying the heteroatoms in the bridge connecting the 2 benzamidine moieties and also by integrating the bridge into a seven-membered ring. Docking of the 45 most spermine-sensitive bisbenzamidines to a recently described acidic interface between the N-terminal domains of GluN1 and GluN2B mediating polyamine stimulation of the NR revealed the domain contributed by GluN1 as the most relevant target.

  12. In vivo protection against NMDA-induced neurodegeneration by MK-801 and nimodipine : Combined therapy and temporal course of protection

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    Stuiver, BT; Douma, BRK; Bakker, R; Nyakas, C; Luiten, PGM

    1996-01-01

    Neuroprotection against excitotoxicity by a combined therapy with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the L-type Ca2+ channel blocker nimodipine was examined using an in vivo rat model of NMDA-induced neurodegeneration. Attention was focused on the neuroprotective potentia

  13. Effect of the NMDA antagonist MK-801 on latent inhibition of fear conditioning.

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    Traverso, Luis M; Ruiz, Gabriel; De la Casa, Luis G

    2012-10-01

    N-methyl-D-aspartate (NMDA) receptors seem to play a central role in learning and memory processes involved in Latent Inhibition (LI). In fact, MK-801, a non-competitive NMDA receptor antagonist, has proved its effectiveness as a drug for attenuating LI when administered before or after stimulus preexposure and conditioning stages. This paper presents three experiments designed to analyze the effect of MK-801 on LI when the drug is administered before (Experiment 1A) or after (Experiment 1B) preexposure and conditioning stages with a conditioned emotional response procedure. Additionally, we analyze the effect of the drug when it was administered before preexposure, before conditioning or before both phases (Experiment 2). The results show that the effect of the drug varied as a function of the dose (with only the highest dose being effective), the moment of administration (with only the drug administered before the experimental treatments being effective), and the phase of procedure (reducing LI when the drug was administered only at preexposure, and disrupting fear conditioning when administered at conditioning). These differences may be due to several factors ranging from the role played by NMDA receptors in the processing of stimuli of different sensorial modalities to the molecular processes triggered by drug administration.

  14. PCP and MK-801 Induced Behaviors Reduced by NAAG Peptidase Inhibition via Metabotropic Glutamate Receptors

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    Olszewski, Rafal T.; Wegorzewska, Marta M.; Monteiro, Ana C.; Krolikowski, Kristyn A.; Zhou, Jia; Kozikowski, Alan P.; Long, Katrice; Mastropaolo, John; Deutsch, Stephen I.; Neale, Joseph H.

    2007-01-01

    Background NMDA receptor open channel blockers phencyclidine (PCP) and dizocilpine (MK-801) elicit schizophrenia-like symptoms in humans and in animal models. Group II metabotropic glutamate receptor agonists reverse the behavioral effects of PCP and MK-801 in animal models. N-Acetylaspartylglutamate (NAAG), third most prevalent neurotransmitter in the mammalian nervous system, is a selective group II metabotropic glutamate receptor agonist. We previously reported that ZJ43, a potent inhibitor of the enzymes that inactivate synaptically released NAAG, reduced motor and stereotypic effects of PCP in the rat. Methods To confirm the efficacy of NAAG peptidase inhibition in decreasing motor behaviors induced by PCP and MK-801, ZJ43 was tested in additional schizophrenia models. Results ZJ43 reduced MK-801-induced motor activation in a mouse model that has been used to characterize the efficacy of a wide range of pharmacotherapies for this human disorder. In a second mouse strain, the peptidase inhibitor reduced PCP-induced stereotypic movements. ZJ43 also reduced PCP-induced negative symptoms in a resident-intruder assay. The group II metabotropic glutamate receptor antagonist, LY341495, blocked the effect of NAAG peptidase inhibition in these mouse models of positive and negative PCP- and MK-801-induced behaviors. Additionally, LY341495 alone increased some PCP-induced behaviors suggesting that normal levels of NAAG act to moderate the effect of PCP via a group II mGluR. Conclusion These data support the proposal that NAAG peptidase inhibition and elevation of synaptic NAAG levels represent a new therapeutic approach to treating the positive and negative symptoms of schizophrenia that are modeled by open channel NMDA receptor antagonists. PMID:17597589

  15. UCCB01-125, a dimeric inhibitor of PSD-95, reduces inflammatory pain without disrupting cognitive or motor performance: Comparison with the NMDA receptor antagonist MK-801

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    Andreasen, Jesper T.; Bach, Anders; Gynther, Mikko

    2013-01-01

    's adjuvant (CFA) model of inflammatory pain. To examine side-effect profiles we also compared the effects of UCCB01-125 and MK-801 in tests of attention, long-term memory, and motor performance. When administered concurrently with CFA, both MK-801 and UCCB01-125 prevented the development of CFA......-induced mechanical hypersensitivity 1 and 24 h after treatment. Moreover, UCCB01-125 was found to reverse CFA-induced hypersensitivity when administered 24 h after CFA treatment, an effect lasting for at least 3 days. At the dose reducing hypersensitivity, MK-801 disrupted attention, long-term memory, and motor...

  16. White matter injuries induced by MK-801 in a mouse model of schizophrenia based on NMDA antagonism.

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    Xiu, Yun; Kong, Xiang-Ru; Zhang, Lei; Qiu, Xuan; Chao, Feng-Lei; Peng, Chao; Gao, Yuan; Huang, Chun-Xia; Wang, San-Rong; Tang, Yong

    2014-08-01

    The etiology of schizophrenia (SZ) is complex and largely unknown. Neuroimaging and postmortem studies have suggested white matter disturbances in SZ. In the present study, we tested the white matter deficits hypothesis of SZ using a mouse model of SZ induced by NMDA receptor antagonist MK-801. We found that mice with repeated chronic MK-801 administration showed increased locomotor activity in the open field test, less exploration of a novel environment in the hole-board test, and increased anxiety in the elevated plus maze but no impairments were observed in coordination or motor function on accelerating rota-rod. The total white matter volume and corpus callosum volume in mice treated with MK-801 were significantly decreased compared to control mice treated with saline. Myelin basic protein and 2', 3'-cyclic nucleotide 3'-phosphodiesterase were also significantly decreased in the mouse model of SZ. Furthermore, we observed degenerative changes of myelin sheaths in the mouse model of SZ. These results provide further evidence of white matter deficits in SZ and indicate that the animal model of SZ induced by MK-801 is a useful model to investigate mechanisms underlying white matter abnormalities in SZ.

  17. (/sup 3/H)MK-801 labels a site on the N-methyl-D-aspartate receptor channel complex in rat brain membranes

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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.

  18. "Interaction of different doses of Aspartame with Morphine-induced antinociception in the presence of MK-801, a NMDA antagonist "

    Directory of Open Access Journals (Sweden)

    Abdollahi M

    2002-07-01

    Full Text Available This study was designed to investigate the relative role of sweetness and comparative effects of different taste sensation of the non - caloric sweetener , aspartame on pain and its interaction with MK - 80] as a non - selective MMDA antagonist by formalin - test in mice. The formalin - test was chosen because it measures the response to a long - lasting nociceptive stimulus and closely resembles to the clinical pain. Morphine induced a dose dependent antinociception in the early and late phases of formalin test. Twelve days pretreatment of animals by aspartame ( 0.08% , 0.16% , 0.32% significantly potentiated morphine - induced (1.5-9 mg/kg analgesia in the early phase but significantly antagonized its analgesic effect in the late phase, dose dependently. Aspartame (0.16% alone showed a reduction in pain response . Naloxone (0.4 mg/kg significantly antagonized the antinociceptive effect of morphine in the presence of aspartame (0-0.32% in the early phase. Increasing the dose of aspartame decreased effects of naloxone. MK-801 (0.1 mg/kg as an N- Methyl - D - Aspartate (NMDA antagonist significantly potentiated the effect of aspartame on morphine - induced antinociception in the early phase. In the late phase, naloxone (0.4 mg/kg increased pain response but MK- 801 (0.1 mg/kg induced anti-inflammatory effect significantly. Treatment of animals with MK- 801 alone, significantly induced analgesia in both phases of formalin - test. This effect was potentiated with aspartame dose - dependently. Possible interaction of aspartame with NMDA receptors and its role to facilitate endogenous opioid system are proposed mechanisms of aspartame in modulating morphine - induced antinociception. Furthermore, the resulting association between morphine and aspartame chronic consumption may be explained as an interactive action rather than simple dose combination of both drugs.

  19. Oxygen glucose deprivation causes mitochondrial dysfunction in cultivated rat hippocampal slices: protective effects of CsA, its immunosuppressive congener [D-Ser](8)CsA, the novel non-immunosuppressive cyclosporin derivative Cs9, and the NMDA receptor antagonist MK 801.

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    Trumbeckaite, Sonata; Gizatullina, Zemfira; Arandarcikaite, Odeta; Röhnert, Peter; Vielhaber, Stefan; Malesevic, Miroslav; Fischer, Gunter; Seppet, Enn; Striggow, Frank; Gellerich, Frank Norbert

    2013-09-01

    We have introduced a sensitive method for studying oxygen/glucose deprivation (OGD)-induced mitochondrial alterations in homogenates of organotypic hippocampal slice cultures (slices) by high-resolution respirometry. Using this approach, we tested the neuroprotective potential of the novel non-immunosuppressive cyclosporin (CsA) derivative Cs9 in comparison with CsA, the immunosuppressive CsA analog [D-Ser](8)CsA, and MK 801, a N-methyl-d-aspartate (NMDA) receptor antagonist. OGD/reperfusion reduced the glutamate/malate dependent (and protein-related) state 3 respiration to 30% of its value under control conditions. All of the above drugs reversed this effect, with an increase to >88% of the value for control slices not exposed to OGD. We conclude that Cs9, [D-Ser](8)CsA, and MK 801, despite their different modes of action, protect mitochondria from OGD-induced damage.

  20. Differential regulation by MK801 of immediate-early genes, brain-derived neurotrophic factor and trk receptor mRNA induced by a kindling after-discharge.

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    Hughes, P E; Young, D; Preston, K M; Yan, Q; Dragunow, M

    1998-01-01

    Transient changes in immediate-early genes and neurotrophin expression produced by kindling stimulation may mediate secondary downstream events involved in kindling development. Recent experiments have demonstrated conclusively that both kindling progression and mossy fibre sprouting are significantly impaired by administration of the N-methyl-D-aspartate (NMDA) receptor antagonist MK801. To further examine the link between kindling, changes in gene expression and the NMDA receptor, we examined the effects of MK801 on neuronal induction of immediate-early genes, brain-derived neurotrophic factor (BDNF) and trk receptor mRNA expression produced by a single electrically induced hippocampal after-discharge in rats. The after-discharge produced a rapid (after 1 h) increase in Fos, Jun-B, c-Jun, Krox-24 mRNA and protein and Krox-20 protein in dentate granule neurons and a delayed, selective expression of Fos, Jun-D and Krox-24 in hilar interneurons. MK801 pretreatment produced a very strong inhibition of Fos, Jun-D and Krox-20 increases in dentate neurons but had a much smaller effect on Jun-B and c-Jun expression. MK801 did not inhibit Krox-24 expression in granule neurons or the delayed expression of Fos, Jun-D and Krox-24 in hilar interneurons. BDNF protein and trk B and trk C mRNA expression were also strongly induced in dentate granule cells 4 h following an after-discharge. MK801 abolished the increase in BDNF protein and trk B, but not trk C mRNA in granule cells at 4 h. These results demonstrate that MK801 differentially regulates the AD-increased expression of a group of genes previously identified as being likely candidates for an involvement in kindling. Because MK801 significantly retards the development of kindling and mossy fibre sprouting, it can be argued that those genes whose induction is not significantly attenuated by MK801 are unlikely to play an important role in the MK801-sensitive component of kindling and the changes in neural connectivity

  1. NMDA antagonist MK 801 in nucleus accumbens core but not shell disrupts the restraint stress-induced reinstatement of extinguished cocaine-conditioned place preference in rats.

    Science.gov (United States)

    De Giovanni, Laura N; Guzman, Andrea S; Virgolini, Miriam B; Cancela, Liliana M

    2016-12-15

    Relapse is a common feature of cocaine addiction. In rodents, it can be elicited by cues, stress or the drug. Restraint stress-induced reinstatement of cocaine-conditioned place preference (CPP) is a useful model to study the mechanisms involved in stress-induced relapse of drug-seeking behavior. There is evidence that the glutamate NMDA receptors are critically involved in drug- and cue-induced reinstatement of seeking behavior and drug-CPP responses. The aim of this study was to investigate the contribution of NMDA receptors within core vs. shell nucleus accumbens (NAc) subregions to restraint stress-induced reinstatement of extinguished cocaine-CPP. After extinction of cocaine-conditioned preference, animals were administered MK 801 systemically or directly into intra-core or intra-shell, and restrained for 30min or left undisturbed in their home-cages. First, we demonstrated that restraint stress-induced reinstatement of extinguished cocaine-CPP depends on the duration of restraint as well as on the context in which it is applied. Second, this effect was blocked by systemic MK 801 administration either before or after restraint. Third, intra-core but not intra-shell administration abrogated the restraint stress-induced reinstatement. These findings show that NMDA receptors within NAc core, but not shell, play a critical role in restraint stress-induced reinstatement of cocaine-CPP.

  2. The role of 5-HT7 receptor antagonism in the amelioration of MK-801-induced learning and memory deficits by the novel atypical antipsychotic drug lurasidone.

    Science.gov (United States)

    Horisawa, Tomoko; Nishikawa, Hiroyuki; Toma, Satoko; Ikeda, Atsushi; Horiguchi, Masakuni; Ono, Michiko; Ishiyama, Takeo; Taiji, Mutsuo

    2013-05-01

    Lurasidone is a novel atypical antipsychotic with high affinity for dopamine D2, serotonin 5-HT7 and 5-HT2A receptors. We previously reported that lurasidone and the selective 5-HT7 receptor antagonist, SB-656104-A improved learning and memory deficits induced by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, in the rat passive avoidance test. In this study, we first examined the role of the 5-HT7 receptor antagonistic activity of lurasidone in its pro-cognitive effect to ameliorate MK-801-induced deficits in the rat passive avoidance test. The 5-HT7 receptor agonist, AS19, (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino) tetralin, (3 mg/kg, s.c.) completely blocked the attenuating effects of lurasidone (3 mg/kg, p.o.), highlighting the importance of 5-HT7 receptor antagonism in the pro-cognitive effect of lurasidone. AS19 (3 mg/kg, s.c.) also blocked the ameliorating effect of SB-656104-A (10 mg/kg, i.p.) in the same experimental paradigm. To further extend our observation, we next tested whether 5-HT7 receptor antagonism still led to the amelioration of MK-801-induced deficits when combined with D2 and 5-HT2A receptor antagonists, and found that SB-656104-A (10 mg/kg, i.p.) significantly ameliorated MK-801-induced deficits even in the presence of the D2 receptor antagonist raclopride (0.1 mg/kg, s.c.) and 5-HT2A receptor antagonist ketanserin (1 mg/kg, s.c.). Taken together, these results suggest that the 5-HT7 receptor antagonistic activity of lurasidone plays an important role in its effectiveness against MK-801-induced deficits, and may contribute to its pharmacological actions in patients with schizophrenia.

  3. Dizocilpine (MK-801) induces distinct changes of N-methyl-D-aspartic acid receptor subunits in parvalbumin-containing interneurons in young adult rat prefrontal cortex.

    Science.gov (United States)

    Xi, Dong; Zhang, Wentong; Wang, Huai-Xing; Stradtman, George G; Gao, Wen-Jun

    2009-11-01

    N-methyl-D-aspartic acid receptor (NMDAR) hypofunction has long been implicated in schizophrenia and NMDARs on gamma-aminobutyric acid (GABA)ergic interneurons are proposed to play an essential role in the pathogenesis. However, controversial results have been reported regarding the regulation of NMDAR expression, and direct evidence of how NMDAR antagonists act on specific subpopulations of prefrontal interneurons is missing. We investigated the effects of the NMDAR antagonist dizocilpine (MK-801) on the expression of NMDAR subtypes in the identified interneurons in young adult rat prefrontal cortex (PFC) by using laser microdissection and real-time polymerase chain reaction, combined with Western blotting and immunofluorescent staining. We found that MK-801 induced distinct changes of NMDAR subunits in the parvalbumin-immunoreactive (PV-ir) interneurons vs. pyramidal neurons in the PFC circuitry. The messenger RNA (mRNA) expression of all NMDAR subtypes, including NR1 and NR2A to 2D, exhibited inverted-U dose-dependent changes in response to MK-801 treatment in the PFC. In contrast, subunit mRNAs of NMDARs in PV-ir interneurons were significantly down-regulated at low doses, unaltered at medium doses, and significantly decreased again at high doses, suggesting a biphasic dose response to MK-801. The differential effects of MK-801 in mRNA expression of NMDAR subunits were consistent with the protein expression of NR2A and NR2B subunits revealed with Western blotting and double immunofluorescent staining. These results suggest that PV-containing interneurons in the PFC exhibit a distinct responsiveness to NMDAR antagonism and that NMDA antagonist can differentially and dose-dependently regulate the functions of pyramidal neurons and GABAergic interneurons in the prefrontal cortical circuitry.

  4. Effect of GNTI,a kappa opioid receptor antagonist, on MK-801-induced hyperlocomotion and stereotypy in mice

    Institute of Scientific and Technical Information of China (English)

    Chun-ting QI; Hong ZOU; Chen-hao ZHANG; Qing-lian XIE; Mei-lei JIN; Lei YU

    2006-01-01

    Aim:To examine the effect of GNTI[5'-guanidinyl-17-(cyclopropylmethyl)-6,7-dehydro-4,-5α-epoxy-3-14-dihydroxy-6,7-2',3'-indolomorphinan],a selective antagonist for the kappa opioid receptor,in the MK-801 (dizocilpine maleate)-induced behavioral model of psychosis in schizophrenia as a way to explore the involvement of the kappa opioid receptor in modulating psychotic symptoms of schizophrenia.Methods:Two doses 0f MK-801 (0.3 mg/kg and 0.6 mg/kg) were administered by systemic injection in mice to induce psychosis-like behavior as a rodent schizophrenia model, preceded by an injection of different doses of GNTI. Both locomotion and stereotypy were measured as the behavioral endpoints for quantitative analysis.Results:GNTI inhibited MK-801-induced hyperlocomotion and stereotypy.In particular,GNTI showed differential modulation of stereotypy induced by 0.3 mg/kg VS 0.6 mg/kg MK-801.Conclusion:Antagonism of kappa opioid receptors attenuates MK-801-induced behavior,suggesting a potential involvement of the kappa opioid receptor in psychosis-like symptoms of schizophrenia.GNTI aDpears to be a useful pharmacological tool to explore the kappa opioid receptor function in vivo.

  5. Altered 13C glucose metabolism in the cortico-striato-thalamo-cortical loop in the MK-801 rat model of schizophrenia

    DEFF Research Database (Denmark)

    Eyjolfsson, Elvar M; Nilsen, Linn Hege; Kondziella, Daniel;

    2011-01-01

    Using a modified MK-801 (dizocilpine) N-methyl-D-aspartic acid (NMDA) receptor hypofunction model for schizophrenia, we analyzed glycolysis, as well as glutamatergic, GABAergic, and monoaminergic neurotransmitter synthesis and degradation. Rats received an injection of MK-801 daily for 6 days...... in all regions. In conclusion, neurotransmitter metabolism in the cortico-striato-thalamo-cortical loop is severely impaired in the MK-801 (dizocilpine) NMDA receptor hypofunction animal model for schizophrenia....

  6. The combination of glutamate receptor antagonist MK-801 with tamoxifen and its active metabolites potentiates their antiproliferative activity in mouse melanoma K1735-M2 cells

    Energy Technology Data Exchange (ETDEWEB)

    Ribeiro, Mariana P.C. [Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra (Portugal); Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra (Portugal); Nunes-Correia, Isabel [Center for Neuroscience and Cell Biology, Flow Cytometry Unit, University of Coimbra, 3000-354 Coimbra (Portugal); Santos, Armanda E., E-mail: aesantos@ci.uc.pt [Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra (Portugal); Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra (Portugal); Custódio, José B.A. [Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra (Portugal); Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra (Portugal)

    2014-02-15

    Recent reports suggest that N-methyl-D-aspartate receptor (NMDAR) blockade by MK-801 decreases tumor growth. Thus, we investigated whether other ionotropic glutamate receptor (iGluR) antagonists were also able to modulate the proliferation of melanoma cells. On the other hand, the antiestrogen tamoxifen (TAM) decreases the proliferation of melanoma cells, and is included in combined therapies for melanoma. As the efficacy of TAM is limited by its metabolism, we investigated the effects of the NMDAR antagonist MK-801 in combination with TAM and its active metabolites, 4-hydroxytamoxifen (OHTAM) and endoxifen (EDX). The NMDAR blockers MK-801 and memantine decreased mouse melanoma K1735-M2 cell proliferation. In contrast, the NMDAR competitive antagonist APV and the AMPA and kainate receptor antagonist NBQX did not affect cell proliferation, suggesting that among the iGluR antagonists only the NMDAR channel blockers inhibit melanoma cell proliferation. The combination of antiestrogens with MK-801 potentiated their individual effects on cell biomass due to diminished cell proliferation, since it decreased the cell number and DNA synthesis without increasing cell death. Importantly, TAM metabolites combined with MK-801 promoted cell cycle arrest in G1. Therefore, the data obtained suggest that the activity of MK-801 and antiestrogens in K1735-M2 cells is greatly enhanced when used in combination. - Highlights: • MK-801 and memantine decrease melanoma cell proliferation. • The combination of MK-801 with antiestrogens inhibits melanoma cell proliferation. • These combinations greatly enhance the effects of the compounds individually. • MK-801 combined with tamoxifen active metabolites induces cell cycle arrest in G1. • The combination of MK-801 and antiestrogens is an innovative strategy for melanoma.

  7. Locomotor activity induced by MK-801 is enhanced in dopamine D3 receptor knockout mice but suppression by dopamine D3/D2 antagonists does not occur through the dopamine D3 receptor.

    Science.gov (United States)

    Yarkov, Alex V; Der, Terry C; Joyce, Jeffrey N

    2010-02-10

    There are contradictory data regarding the role of the dopamine D(3) receptor in regulating N-methyl-d-aspartate (NMDA) receptor antagonist (e.g., dizocilpine) induced hyperactivity. The purpose of the present study was to examine the interaction of dopamine D(3) receptor preferring antagonists U99194A (5,6-dimethoxy-2(dipropylamino)indan) and S33804 ((3aR,9bS)-N[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl] (4-phenyl)benzamide)) with dizocilpine (MK-801)-induced hyperactivity in wild type (WT) and dopamine D(3) receptor mutant (D(3)R KO) mice. D(3)R KO and WT mice were administered vehicle (saline, 1 ml/100g body weight, i.p.), or S33084 (1.0mg/kg.) and U99194A (0.1mg/kg or 0.01 mg/kg), and horizontal and vertical activity counts were recorded for 30 min. Mice were then treated with vehicle or MK-801 (0.12 mg/kg i.p.) and returned to the open field for an additional 55 min. D(3)R KO mice showed a significantly higher level of locomotor and rearing activity during the 1st 30 min after vehicle treatment compared to WT mice. MK-801-hyperactivity was significantly higher in D(3)R KO mice than WT mice. Dopamine D(3) receptor preferring antagonists suppressed the locomotor activity response to MK-801 to an equal extent in D(3)R KO and WT mice. The results confirm that MK-801-induced hyperactivity and novelty-induced behavioral activity and rearing are enhanced in D(3)R KO mice, but suppression by dopamine D(3) receptor preferring antagonists is not through dopamine D(3) receptor antagonism.

  8. Rolipram attenuates MK-801-induced deficits in latent inhibition.

    Science.gov (United States)

    Davis, Jennifer A; Gould, Thomas J

    2005-04-01

    Latent inhibition is used to examine attention and study cognitive deficits associated with schizophrenia. Research using MK-801, an N-methyl-D-aspartate (NMDA) open channel blocker, implicates glutamate receptors in acquisition of latent inhibition of cued fear conditioning. Evidence suggests an important relationship between NMDA-induced increases in cyclic adenosine monophosphate (cAMP) and learning and memory. The authors examine whether amplification of the cAMP signaling pathway by rolipram, a selective Type 4 cAMP phosphodiesterase inhibitor, reverses MK-801-induced impairments in latent inhibition. One day before training, mice were injected with MK-801, rolipram, MK-801 and rolipram, or vehicle and received 20 preexposures or no preexposures to an auditory conditioned stimulus (CS). Training consisted of 2 CS-footshock unconditioned stimulus pairings. Rolipram attenuated the disruptive effect of MK-801 on latent inhibition, which suggests a role for the cAMP signaling pathway in the task and implicates phosphodiesterase inhibition as a target for treating cognitive impairments associated with schizophrenia.

  9. Reactive Transformation and Increased BDNF Signaling by Hippocampal Astrocytes in Response to MK-801.

    Directory of Open Access Journals (Sweden)

    Wenjuan Yu

    Full Text Available MK-801, also known as dizocilpine, is a noncompetitive N-methyl-D-aspartic acid (NMDA receptor antagonist that induces schizophrenia-like symptoms. While astrocytes have been implicated in the pathophysiology of psychiatric disorders, including schizophrenia, astrocytic responses to MK-801 and their significance to schizotypic symptoms are unclear. Changes in the expression levels of glial fibrillary acid protein (GFAP, a marker of astrocyte activation in response to a variety of pathogenic stimuli, were examined in the hippocampus of rats treated with the repeated MK-801 injection (0.5 mg/10 ml/kg body weight for 6 days and in primary cultured hippocampal astrocytes incubated with MK-801 (5 or 20 μM for 24 h. Moreover, the expression levels of BDNF and its receptors TrkB and p75 were examined in MK-801-treated astrocyte cultures. MK-801 treatment enhanced GFAP expression in the rat hippocampus and also increased the levels of GFAP protein and mRNA in hippocampal astrocytes in vitro. Treatment of cultured hippocampal astrocytes with MK-801 enhanced protein and mRNA levels of BDNF, TrkB, and p75. Collectively, our results suggest that hippocampal astrocytes may contribute to the pathophysiology of schizophrenia symptoms associated with NMDA receptor hypofunction by reactive transformation and altered BDNF signaling.

  10. Associative learning performance is impaired in zebrafish (Danio rerio) by the NMDA-R antagonist MK-801.

    Science.gov (United States)

    Sison, Margarette; Gerlai, Robert

    2011-09-01

    The zebrafish is gaining popularity in behavioral neuroscience perhaps because of a promise of efficient large scale mutagenesis and drug screens that could identify a substantial number of yet undiscovered molecular players involved in complex traits. Learning and memory are complex functions of the brain and the analysis of their mechanisms may benefit from such large scale zebrafish screens. One bottleneck in this research is the paucity of appropriate behavioral screening paradigms, which may be due to the relatively uncharacterized nature of the behavior of this species. Here we show that zebrafish exhibit good learning performance in a task adapted from the mammalian literature, a plus maze in which zebrafish are required to associate a neutral visual stimulus with the presence of conspecifics, the rewarding unconditioned stimulus. Furthermore, we show that MK-801, a non-competitive NMDA-R antagonist, impairs memory performance in this maze when administered right after training or just before recall but not when given before training at a dose that does not impair motor function, perception or motivation. These results suggest that the plus maze associative learning paradigm has face and construct validity and that zebrafish may become an appropriate and translationally relevant study species for the analysis of the mechanisms of vertebrate, including mammalian, learning and memory.

  11. Effects of N-methyl-D-aspartate Receptor Antagonist MK-801 on Expression of Glial Fibrillary Acidic Protein in the Subventricular Zone of Neonatal Rat%NMDA受体拮抗剂MK-801对新生大鼠室管膜下区胶质纤维酸性蛋白表达的影响

    Institute of Scientific and Technical Information of China (English)

    李晓泉; 陈芳芳; 王伟; 来青伟; 耿德勤; 樊红彬

    2013-01-01

    Aim To investigate the effects of the N-methyl-D-aspartate(NMDA)-receptor antagonist MK801 on the expression of glial fibrillary acidic protein(GFAP) in the subventricular zone(SVZ) of neonatal rat.Methods 40 neonatal SD rats were assigned into two groups,a MK-801 group and a control group.Each group was respectively divided into four time points,including P7 d (postnatal 7 days),P14 d,P21 d and P28 d.Rats in the experiment group were intraperitoneally injected selective non-competitive NMDA receptor antagonist MK-801 (10 mg·kg1),while rats in the control group were intraperitoneally injected saline.Immunohistochemical staining was used to assay the number of GFAP-positive cells in the SVZ.Results ① In the control group,the number of GFAP-positive cells increased at P14 d,and the number of GFAP-positive cells reached maximum at P21 d,positive cells decreased significantly at 28 d.② Compared with the control group,the number of GFAP-positive cells reduced significantly at P 14 d (65.40 ± 6.11) and P21 d (239.60 ± 12.92),and the number of GFAP-positive cells increased significantly [P14 d(79.20 ± 5.26),P21 d(265.20 ± 7.40)](P<0.01),while the number of positive cells without obvious changes at P7 d and P28 d in the MK-801 group.Conclusion NMDA-receptor antagonist MK-801 could reduce the expression of GFAP in the SVZ,and inhibit the neural stem cells proliferation and differentiation.%目的 研究N-甲基-D-天冬氨酸(NMDA)受体拮抗剂MK-801对新生7d大鼠室管膜下区(SVZ)胶质纤维酸性蛋白(GFAP)表达的影响.方法 将40只新生SD大鼠分成对照组和MK-801组,各组按出生后口(P)时间点再随机分成4个亚组:P7d、P14d、P21 d、P28d组.新生大鼠均于生后第3天给药,MK-801组腹腔注射MK-801 10 mg·kg-1;对照组腹腔注射同量生理盐水.通过免疫组化学方法观察大鼠SVZ区GFAP阳性细胞数.结果 ①对照组GFAP阳性细胞数于P14 d开始增加,至P21 d达最大值;但P28 d时阳性细胞迅速下降;②MK

  12. The role of purinergic and dopaminergic systems on MK-801-induced antidepressant effects in zebrafish.

    Science.gov (United States)

    da Silva, Raquel Bohrer; Siebel, Anna Maria; Bonan, Carla Denise

    2015-12-01

    Depression is a serious disease characterized by low mood, anhedonia, loss of interest in daily activities, appetite and sleep disturbances, reduced concentration, and psychomotor agitation. There is a growing interest in NMDA antagonists as a promising target for the development of new antidepressants. Considering that purinergic and dopaminergic systems are involved in depression and anxiety states, we characterized the role of these signaling pathways on MK-801-induced antidepressant effects in zebrafish. Animals treated with MK-801 at the doses of 5, 10, 15, or 20μM during 15, 30, or 60min spent longer time in the top area of aquariums in comparison to control group, indicating an anxiolytic/antidepressant effect induced by this drug. Animals treated with MK-801 spent longer time period at top area until 2 (5μM MK-801) and 4 (20μM MK-801) hours after treatment, returning to basal levels from 24h to 7days after exposure. Repeated MK-801 treatment did not induce cumulative effects, since animals treated daily during 7days had the same behavioral response pattern observed since the first until the 7th day. In order to investigate the effects of adenosine A1 and A2A receptor antagonist and agonist and the influence of modulation of adenosine levels on MK-801 effects, we treated zebrafish with caffeine, DPCPX, CPA, ZM 241385, CGS 21680, AMPCP, EHNA, dipyridamole, and NBTI during 30min before MK-801 exposure. The non-specific adenosine receptor antagonist caffeine (50mg/kg) and the selective A1 receptor antagonist DPCPX (15mg/kg) prevented the behavioral changes induced by MK-801. The non-specific nucleoside transporter (NT) inhibitor dipyridamole (10mg/kg) exacerbated the behavioral changes induced by MK-801. Dopamine receptor antagonists (sulpiride and SCH 23390) did not change the behavioral alterations induced by MK-801. Our findings demonstrated that antidepressant-like effects of MK-801 in zebrafish are mediated through adenosine A1 receptor activation.

  13. Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents

    DEFF Research Database (Denmark)

    Bubser, Michael; Bridges, Thomas M; Dencker, Ditte;

    2014-01-01

    an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) in the central...... PAMs, enabling a more extensive characterization of M4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801...

  14. Traumatic brain injury and the effects of diazepam, diltiazem, and MK-801 on GABA-A receptor subunit expression in rat hippocampus

    Directory of Open Access Journals (Sweden)

    Meyer Rebecca C

    2010-05-01

    Full Text Available Abstract Background Excitatory amino acid release and subsequent biochemical cascades following traumatic brain injury (TBI have been well documented, especially glutamate-related excitotoxicity. The effects of TBI on the essential functions of inhibitory GABA-A receptors, however, are poorly understood. Methods We used Western blot procedures to test whether in vivo TBI in rat altered the protein expression of hippocampal GABA-A receptor subunits α1, α2, α3, α5, β3, and γ2 at 3 h, 6 h, 24 h, and 7 days post-injuy. We then used pre-injury injections of MK-801 to block calcium influx through the NMDA receptor, diltiazem to block L-type voltage-gated calcium influx, or diazepam to enhance chloride conductance, and re-examined the protein expressions of α1, α2, α3, and γ2, all of which were altered by TBI in the first study and all of which are important constituents in benzodiazepine-sensitive GABA-A receptors. Results Western blot analysis revealed no injury-induced alterations in protein expression for GABA-A receptor α2 or α5 subunits at any time point post-injury. Significant time-dependent changes in α1, α3, β3, and γ2 protein expression. The pattern of alterations to GABA-A subunits was nearly identical after diltiazem and diazepam treatment, and MK-801 normalized expression of all subunits 24 hours post-TBI. Conclusions These studies are the first to demonstrate that GABA-A receptor subunit expression is altered by TBI in vivo, and these alterations may be driven by calcium-mediated cascades in hippocampal neurons. Changes in GABA-A receptors in the hippocampus after TBI may have far-reaching consequences considering their essential importance in maintaining inhibitory balance and their extensive impact on neuronal function.

  15. Intra-accumbens injection of a dopamine aptamer abates MK-801-induced cognitive dysfunction in a model of schizophrenia.

    Directory of Open Access Journals (Sweden)

    Matthew R Holahan

    Full Text Available Systemic administration of the noncompetitive NMDA-receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. The present work investigated the ability of a dopamine-binding DNA aptamer to regulate these MK-801-induced cognitive deficits when injected into the nucleus accumbens. Rats were trained to bar press for chocolate pellet rewards then randomly assigned to receive an intra-accumbens injection of a DNA aptamer (200 nM; n = 7, tris buffer (n = 6 or a randomized DNA oligonucleotide (n = 7. Animals were then treated systemically with MK-801 (0.1 mg/kg and tested for their ability to extinguish their bar pressing response. Two control groups were also included that did not receive MK-801. Data revealed that injection of Tris buffer or the random oligonucleotide sequence into the nucleus accumbens prior to treatment with MK-801 did not reduce the MK-801-induced extinction deficit. Animals continued to press at a high rate over the entire course of the extinction session. Injection of the dopamine aptamer reversed this MK-801-induced elevation in lever pressing to levels as seen in rats not treated with MK-801. Tests for activity showed that the aptamer did not impair locomotor activity. Results demonstrate the in vivo utility of DNA aptamers as tools to investigate neurobiological processes in preclinical animal models of mental health disease.

  16. Intra-accumbens injection of a dopamine aptamer abates MK-801-induced cognitive dysfunction in a model of schizophrenia.

    Science.gov (United States)

    Holahan, Matthew R; Madularu, Dan; McConnell, Erin M; Walsh, Ryan; DeRosa, Maria C

    2011-01-01

    Systemic administration of the noncompetitive NMDA-receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. The present work investigated the ability of a dopamine-binding DNA aptamer to regulate these MK-801-induced cognitive deficits when injected into the nucleus accumbens. Rats were trained to bar press for chocolate pellet rewards then randomly assigned to receive an intra-accumbens injection of a DNA aptamer (200 nM; n = 7), tris buffer (n = 6) or a randomized DNA oligonucleotide (n = 7). Animals were then treated systemically with MK-801 (0.1 mg/kg) and tested for their ability to extinguish their bar pressing response. Two control groups were also included that did not receive MK-801. Data revealed that injection of Tris buffer or the random oligonucleotide sequence into the nucleus accumbens prior to treatment with MK-801 did not reduce the MK-801-induced extinction deficit. Animals continued to press at a high rate over the entire course of the extinction session. Injection of the dopamine aptamer reversed this MK-801-induced elevation in lever pressing to levels as seen in rats not treated with MK-801. Tests for activity showed that the aptamer did not impair locomotor activity. Results demonstrate the in vivo utility of DNA aptamers as tools to investigate neurobiological processes in preclinical animal models of mental health disease.

  17. Studies on the spinal interaction of morphine and the NMDA antagonist MK-801 on the hyperesthesia observed in a rat model of sciatic mononeuropathy.

    Science.gov (United States)

    Yamamoto, T; Yaksh, T L

    1992-01-20

    This study evaluated the effects of intrathecally coadministered morphine and the N-methyl-D-aspartate (NMDA) antagonist (+)5-methyl-10,11-dihydro-5H- dibenzocyclohepten-5,10-imine maleate (MK-801) on the thermally evoked hindpaw withdrawal latency (PWL) in rats with one paw (ipsilteral) rendered hyperesthetic by the unilateral application of loose ligatures to the sciatic nerve (delta PWL (+/- S.D.) = PWLhyperesthetic paw - PWLnormal paw = -3.1 +/- 1.2 s). Intrathecal morphine produced a dose-dependent (0.1-10 micrograms; P less than 0.0001) elevation in the thermal response latency of both the contralateral (normal) and ipsilateral (hyperesthetic) paw. delta PWL did not vary with morphine, indicating that the dose-response curves were parallel but shifted to the right for the hyperesthetic paw. For the normal paw, MK-801 (10 micrograms) was without effect upon the response latency; whereas, the response latency of the hyperesthetic paw was elevated to the same as the normal paw, i.e. the hyperesthesia was selectively abolished (delta PWL (+/- S.D.) = -0.067 +/- 2.73). Co-administration of MK-801 with morphine did not alter the effects of morphine in the normal paw, but reduced the delta PWL for each dose of morphine. These results suggest that NMDA antagonism (1) does not alter the thermal sensitivity in the normal paw, (2) selectively abolishes the hypersensitivity of the hypersthetic paw and (3) has a simple additive interaction with the antinociceptive effects of morphine in the hyperesthetic paw.

  18. Effect of cannabidiol in a MK-801-rodent model of aspects of schizophrenia.

    Science.gov (United States)

    Gururajan, Anand; Taylor, David Alan; Malone, Daniel Thomas

    2011-09-23

    Cannabidiol is a non-psychoactive phytocannabinoid which, based on several previous preclinical and clinical reports, is purported to have antipsychotic potential. The purpose of this investigation was to further investigate if these effects would be seen using an MK-801-induced rat model of aspects of schizophrenia. MK-801 is an NMDA receptor-antagonist known to produce hyperactivity, deficits in prepulse inhibition and social withdrawal, behaviours which correlate well with some of the positive, cognitive and negative symptoms of schizophrenia. Following a 4-day acclimatisation to the holding room, rats were acclimatised to startle chambers on day 5 and their prepulse inhibition (PPI) determined on day 6 following treatment with cannabidiol or vehicle and MK-801 or vehicle. On day 9, rats were acclimatised to the social interaction testing arena and on day 10, were tested for social interaction and locomotor activity following the same treatments. Cannabidiol treatment alone disrupted PPI and produced hyperactivity but had no effect on social behaviour. Cannabidiol had no effect on MK-801-induced disruption of PPI or hyperactivity but showed potential towards inhibiting MK-801-induced social withdrawal. As a comparator, we also tested the effect of the atypical antipsychotic clozapine which only partially reversed MK-801-induced disruption of PPI but was able to reverse MK-801-induced hyperactivity and social withdrawal. In conclusion, cannabidiol showed both propsychotic activity and partial antipsychotic activity in an MK-801-induced model of aspects of schizophrenia. Further behavioural studies would be required using a range of species, strains, animal models and testing paradigms to conclusively establish the antipsychotic potential of cannabidiol.

  19. Effect of MK-801 and clozapine on the proteome of cultured human oligodendrocytes

    Directory of Open Access Journals (Sweden)

    Juliana Silva Cassoli

    2016-03-01

    Full Text Available Separate lines of evidence have demonstrated the involvement of NMDA receptor and oligodendrocyte dysfunctions in schizophrenia. Here we have carried out shotgun mass spectrometry proteome analysis of oligodendrocytes treated with the NMDA receptor antagonist MK-801 to gain potential insights into these effects at the molecular level. The MK-801 treatment led to alterations in the levels of 68 proteins, which are associated with seven distinct biological processes. Most of these proteins are involved in energy metabolism and many have been found to be dysregulated in previous proteomic studies of post-mortem brain tissues from schizophrenia patients. Finally, addition of the antipsychotic clozapine to MK-801-treated oligodendrocyte cultures resulted in changes in the levels of 45 proteins and treatment with clozapine alone altered 122 proteins and many of these showed opposite changes to the MK-801effects. Therefore, these proteins and the associated energy metabolism pathways should be explored as potential biomarkers of antipsychotic efficacy. In conclusion, MK-801 treatment of oligodendrocytes may provide a useful model for testing the efficacy of novel treatment approaches.

  20. Neurochemical and neuroendocrine effects of ibogaine in rats: comparison to MK-801.

    Science.gov (United States)

    Baumann, M H; Rothman, R B; Ali, S F

    1998-05-30

    Ibogaine (IBO) is a naturally-occurring indole compound that is being evaluated as a potential medication for substance use disorders. Although the precise mechanism of IBO action is unclear, recent in vitro data show this drug displays properties similar to the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801. The purpose of the present work was to compare in vivo neurobiological effects of IBO and MK-801 in rats. Groups of male rats (n = 6-8/group) were decapitated 30 and 60 min after receiving intraperitoneal (i.p.) IBO (10 & 100 mg/kg), MK-801 (0.1 & 1.0 mg/kg) or vehicle. Trunk blood was collected for the analysis of plasma prolactin and corticosterone; brains were harvested and dissected for determination of dopamine (DA), serotonin (5-HT) and their metabolites. Both IBO and MK-801 increased corticosterone secretion, but only IBO elevated plasma prolactin. IBO produced dramatic reductions in tissue DA levels with concurrent increases in the metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This profile of IBO-induced changes in DA transmission was observed in the striatum, olfactory tubercle, and hypothalamus. The effects of MK-801 on DA metabolism did not mimic IBO, as MK-801 tended to increase DA and its metabolites. Neither drug appreciably affected 5-HT systems. Our results suggest that the effects of IBO on neuroendocrine function and DA transmission are not due to MK-801-like properties of IBO. Thus, the in vivo mechanism of IBO action cannot be explained simply on the basis of antagonism at NMDA receptors.

  1. Clinical Physiology and Mechanism of Dizocilpine (MK-801: Electron Transfer, Radicals, Redox Metabolites and Bioactivity

    Directory of Open Access Journals (Sweden)

    Peter Kovacic

    2010-01-01

    Full Text Available Dizocilpine (MK-801, an extensively investigated drug possessing secondary amine and benzenoid functions, displays a wide array of biological properties, including anticonvulsant and anesthetic. There is scant discussion of biomechanism. A relevant, important finding is formation of oxidative metabolites in the hydroxylamine and phenolic categories. Analogy to cocaine metabolites suggests participation of redox entities, such as, hydroxylamine, nitroxide and nitrosonium, which can lead to electron transfer and radical formation. There is also similarity to metabolism by 3,3′-iminodipropionitrile and phencyclidine. Alternatively, the phenolic metabolites are well-known precursors of ET quinones. The review documents various physiological effects, mainly involving the central nervous system. Also of interest are the pro- and anti-oxidant properties. Considerable attention has been paid to MK-801 as an antagonist of the N-methyl-D-aspartate receptor in the glutamate category. This aspect is often associated with effects on the central nervous system. The review also provides recent literature dealing with MK-801/NMDA receptor in various areas of bioactivity. Studies were made of MK-801 involvement in working memory processing. Deficits in behavior were noted after administration of the drug. Treatment of mice with dizocilpine induced learning impairment. The influence of MK-801 on fear has been investigated. The substance is known to exert an analgesic effect in pain control. A number of reports deal with anesthetic properties.

  2. Intrathecal MK-801 inhibits formalin-induced activation of spinal p38-MAPK in rats

    Institute of Scientific and Technical Information of China (English)

    Zhifeng Peng; Xin Zhao; Xing Jin; Xiaochun Yan; Xiaorong Yang; Ce Zhang

    2008-01-01

    BACKGROUND: p38 mitogen-activated protein kinase (MAPK) plays an instrumental role in signal transduction from the cell surface to the nucleus, while subcutaneous injection of formalin can induce increased activation of spinal p38 MAPK. However, the mechanisms underlying the formalin-induced activation of spinal p38 MAPK in rats are unclear. OBJECTIVE: To observe the effects of N-methyl-D-aspartic acid (NMDA) receptor antagonist MK-801 on the formalin-induced activation of spinal p38 MAPK in rats. DESIGN, TIME AND SETTING: This randomized grouping, controlled animal experiment was performed at the Department of Physiology and Neurobiology, Shanxi Medical University between May and November 2007. MATERIALS: Forty eight healthy, adult Wistar rats were randomly divided into two groups: formalin + normal saline (n = 12) and formalin + MK-801 (n = 36). The formalin + MK-801 group was further divided into three subgroups according to the dosage of MK-801 (10, 50, and 100 nmol/L, 12 rats for each subgroup) METHODS: Following anesthesia, polyethylene tubing filled with sterile normal saline was implanted into the subarachnoid cavity. On postoperative days 5-8, rats received a 15 minute perfusion of normal saline or MK-801 (10, 50, and 100 nmol/L) in the formalin + normal saline and formalin + MK-801 groups, respectively, followed by formalin injection for the induction of nociceptive behavior. MAIN OUTCOME MEASURES: Detection of total p38 MAPK and of phosphorylated p38 MAPK by western Blot analysis; observation of nociceptive behaviors in the 1 hour after formalin injection. RESULTS: Western Blot analysis revealed that injection of formalin had no effect on total p38 MAPK expression but resulted in increased phosphorylation of p38 MAPK in the spinal cord. This increase was apparent after 5 minutes, peaked at 20 minutes, and thereafter descended and reached control levels after 45 minutes. Pretreatment with MK-801 (10, 50, 100 nmol/L) resulted in a dose-dependent reduction

  3. A novel physiological property of snake bradykinin-potentiating peptides-reversion of MK-801 inhibition of nicotinic acetylcholine receptors.

    Science.gov (United States)

    Nery, Arthur A; Trujillo, Cleber A; Lameu, Claudiana; Konno, Katsuhiro; Oliveira, Vitor; Camargo, Antonio C M; Ulrich, Henning; Hayashi, Mirian A F

    2008-10-01

    The first naturally occurring angiotensin-converting enzyme (ACE) inhibitors described are pyroglutamyl proline-rich oligopeptides, found in the venom of the viper Bothrops jararaca, and named as bradykinin-potentiating peptides (BPPs). Biochemical and pharmacological properties of these peptides were essential for the development of Captopril, the first active site-directed inhibitor of ACE, currently used for the treatment of human hypertension. However, a number of data have suggested that the pharmacological activity of BPPs could not only be explained by their inhibitory action on enzymatic activity of somatic ACE. In fact, we showed recently that the strong and long-lasting anti-hypertensive effect of BPP-10c [pheochromocytoma cell line, which following induction to neuronal differentiation expresses most of the nicotinic receptor subtypes. BPP-10c did not induce receptor-mediated ion flux, nor potentiated carbamoylcholine-provoked receptor activity as determined by whole-cell recording. This peptide, however, alleviated MK-801-induced inhibition of nicotinic acetylcholine receptor activity. Although more data are needed for understanding the mechanism of the BPP-10c effect on nicotinic receptor activity and its relationship with the anti-hypertensive activity, this work reveals possible therapeutic applications for BPP-10c in establishing normal acetylcholine receptor activity.

  4. Hippocampal serotonin depletion unmasks differences in the hyperlocomotor effects of phencyclidine and MK-801: quantitative versus qualitative analyses

    Directory of Open Access Journals (Sweden)

    Wendy K Adams

    2013-08-01

    Full Text Available Antagonism of N-methyl-D-aspartate (NMDA receptors by phencyclidine is thought to underlie its ability to induce a schizophrenia-like syndrome in humans, yet evidence indicates it has a broader pharmacological profile. Our previous lesion studies highlighted a role for serotonergic projections from the median, but not dorsal, raphe nucleus in mediating the hyperlocomotor effects of phencyclidine, without changing the action of the more selective NMDA receptor antagonist, MK-801. Here we compared locomotor responses to phencyclidine and MK 801 in rats that were administered 5,7 dihydroxytryptamine (5,7-DHT into either the dorsal or ventral hippocampus, which are preferentially innervated by median and dorsal raphe, respectively. Dorsal hippocampus lesions potentiated phencyclidine-induced hyperlocomotion (0.5, 2.5 mg/kg, but not the effect of MK-801 (0.1 mg/kg. Ventral hippocampus lesions did not alter the hyperlocomotion elicited by either compound. Given that phencyclidine and MK-801 may induce different spatiotemporal patterns of locomotor behavior, together with the known role of the dorsal hippocampus in spatial processing, we also assessed whether the 5,7-DHT-lesions caused any qualitative differences in locomotor responses. Treatment with phencyclidine or MK-801 increased the smoothness of the path travelled (reduced spatial d and decreased the predictability of locomotor patterns within the chambers (increased entropy. 5,7-DHT-lesions of the dorsal hippocampus did not alter the effects of phencyclidine on spatial d or entropy—despite potentiating total distance moved—but caused a slight reduction in levels of MK-801-induced entropy. Taken together, serotonergic lesions targeting the dorsal hippocampus unmask a functional differentiation of the hyperlocomotor effects of phencyclidine and MK 801. These findings have implications for studies utilising NMDA receptor antagonists in modeling glutamatergic dysfunction in schizophrenia.

  5. Neuroprotective effects of MK-801 on L-2-chloropropionic acid-induced neurotoxicity.

    Science.gov (United States)

    Williams, R E; Lock, E A; Bachelard, H S

    2001-02-01

    L-2-Chloropropionic acid is selectively toxic to the cerebellum in rats; the granule cell necrosis observed within 48 h can be prevented by prior administration of MK-801. Short-term treatment (2 h) with L-2-chloropropionic acid has also been shown to activate the mitochondrial pyruvate dehydrogenase complex in fasted adult rats. This study aimed to investigate the effect of prior exposure to MK-801 on the biochemical and neurotoxicological effects of L-2-chloropropionic acid. Extracts were prepared from the forebrain and cerebellum of animals that had been treated with L-2-chloropropionic acid, with and without prior treatment with MK-801, and were analysed using magnetic resonance spectroscopy and amino acid analysis. Glucose metabolism was studied by monitoring the metabolism of [1-(13)C]-glucose using GC/MS. L-2-Chloropropionic acid caused increased glucose metabolism in both brain regions 6 h after administration, confirming activation of the pyruvate dehydrogenase complex, which was not prevented by MK-801. After 48 h an increase in lactate and a decrease in N-acetylaspartate was observed only in the cerebellum, whereas phosphocreatine and ATP decreased in both tissues. MK-801 prevented the changes in lactate and N:-acetylaspartate, but not those on the energy state. These studies suggest that L-2-chloropropionic acid-induced neurotoxicity is only partly mediated by the NMDA subtype of glutamate receptor.

  6. Comparison of the MK-801-induced appetitive extinction deficit with pressing for reward and associated pERK1/2 staining in prefrontal cortex and nucleus accumbens.

    Science.gov (United States)

    Holahan, Matthew R; Westby, Erin P; Albert, Katrina

    2012-03-01

    Administration of the noncompetitive N-methyl-d-aspartate (NMDA)-receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) has been shown to produce extinction deficits on appetitive operant tasks. The present study sought to further explore this by comparing extinction pressing to pressing for the primary reward and examining associated neural correlates to determine if the MK-801 extinction profile resembled the behavioral and neural profile associated with pressing for primary reward. Immunohistochemical labeling of phosphorylated extracellular signal-regulated kinase-1 and -2(pERK1/2) in the prelimbic (PrL) and infralimbic (IL) cortices and nucleus accumbens shell (AcbSh) and core (AcbC) was examined after rewarded or extinction lever pressing conditions. A dose-response curve revealed a within-day extinction deficit following administration of 0.05 mg/kg MK-801. All doses of MK-801 were associated with reduced IL pERK1/2 staining but only the 0.05 mg/kg dose was associated with elevated AcbSh pERK1/2 labeling. Extinction pressing under the influence of MK-801 was elevated compared to that seen during rewarded pressing-whether on MK-801 or saline. Rewarded pressing following saline or MK-801 was associated with elevated pERK1/2 in the PrL with no similar patterns in the MK-801/extinction group. There was more pERK1/2 labeling in the AcbSh of the MK-801 extinction group than any other condition. These data suggest that the MK-801-induced extinction deficit may be due to the combination of an underactive cortical behavioral inhibition system and an overactive AcbSh reward system.

  7. Effect of chronic MK-801 and/or phenytoin on the acquisition of complex behaviors in rats.

    Science.gov (United States)

    Wright, L K M; Popke, E J; Allen, R R; Pearson, E C; Hammond, T G; Paule, M G

    2007-01-01

    The purpose of the present experiment was to assess the effects of chronic MK-801 (an N-methyl-D-aspartate receptor antagonist) and/or phenytoin (a sodium channel blocker) treatment on behavioral acquisition and performance in rats. Learning, audio/visual discrimination and motivation were modeled using incremental repeated acquisition (IRA), audio/visual discrimination (AVD) and progressive ratio (PR) tasks, respectively. MK-801 and/or phenytoin were administered daily, 7 days/week by orogastric gavage beginning just after weaning on postnatal day (PND) 23 and continuing until PND 306. Monday through Friday behavioral assessments began on PND 27 and continued until PND 430. Throughout treatment, subjects in the high dose MK-801 (1.0 mg/kg/day) and the high dose drug combination (1.0 mg/kg/day MK-801+150 mg/kg/day phenytoin) groups exhibited decreased body weight gains compared to control subjects. For these two affected groups, response rates were also decreased in all tasks. Task acquisition, as evidenced by an increase in response accuracy, was decreased for both these groups in the AVD task, but only for the high dose MK-801 group in the IRA task. The data suggest that chronic MK-801 treatment adversely affects the acquisition of IRA and AVD task performance and that the inclusion of phenytoin in the MK-801 dosing regimen blocks some of the adverse effects of chronic MK-801 treatment on IRA task acquisition. These findings are in marked contrast with those observed in nonhuman primates and suggest important species differences associated with chronic exposure to compounds that block NMDA receptors and/or sodium channels.

  8. Antinociceptive Interactions between Intrathecal Gabapentin and MK801 or NBQX in Rat Formalin Test

    OpenAIRE

    Yoon, Myung Ha; Bae, Hong Beom; Choi, Jeong Il

    2005-01-01

    Antagonists for spinal N-methyl-D-aspartate (NMDA) and amino-hydroxy-methtyl-isoxazolepropionate (AMPA) receptors are effective in attenuating acute nociception or injury-induced hyperalgesia. The antinociception of spinal gabapentin is developed in injury-induced hyperalgesia without affecting acute nociception. The authors evaluated the effects of intrathecal gabapentin, NMDA antagonist (MK801) and AMPA antagonist (NBQX) in the formalin test which shows injury-induced hyperalgesia as well a...

  9. Kindling-induced potentiation of excitatory and inhibitory inputs to hippocampal dentate granule cells. II. Effects of the NMDA antagonist MK-801.

    LENUS (Irish Health Repository)

    Robinson, G B

    1991-10-18

    The effect of the non-competitive N-methyl-D-aspartate antagonist MK-801 on the early development of kindling-induced potentiation was examined in the rabbit hippocampal dentate gyrus. MK-801 (0.5 mg\\/kg) was administered 2 h before each daily kindling stimulation was applied to the perforant path. This treatment continued for the first 10 days of kindling. MK-801 depressed the growth of the afterdischarge duration and suppressed development of behavioral seizures. MK-801 did not block kindling-induced potentiation of either the perforant path-dentate granule cell population spike or excitatory postsynaptic potential. Random impulse train stimulation and non-linear systems analytic techniques were used to examine kindling-induced potentiation of presumed GABAergic recurrent inhibitory circuits. Both the magnitude and duration of kindling-induced response inhibition, to the second of each pair of impulses within the train, were reduced in rabbits pretreated with MK-801. These results suggest that MK-801 differentially affects kindling-induced potentiation of excitatory and inhibitory circuits within the rabbit hippocampal dentate gyrus.

  10. Attenuation of MK-801-induced behavioral perseveration by typical and atypical antipsychotic pretreatment in rats.

    Science.gov (United States)

    Tuplin, Erin W; Stocco, Marlaina R; Holahan, Matthew R

    2015-08-01

    The noncompetitive NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5-10-imine maleate (MK-801) has been shown to increase the probability of operant responding during extinction and reduce infralimbic prefrontal cortical activation, possibly modeling the cognitive dysfunction symptomology, and underlying cause, in patients with schizophrenia. The present study sought to determine if typical and/or atypical antipsychotics would attenuate the MK-801-induced behavioral perseveration and whether this would be associated with concomitant changes in phosphorylated ERK1/2 (pERK1/2) labeling in the infralimbic cortex (IL). Male, Long Evans rats were pretreated with the typical antipsychotic, Flupenthixol (0, 0.125, 0.25 or 0.5 mg/kg) or the atypical antipsychotic, aripiprazole (0, 0.3, 1.0, 3.0 mg/kg), then given 0.1 mg/kg MK-801 followed by a 60-min appetitive operant extinction session. Flupenthixol produced a dose-dependent decrease in MK-801-induced bar pressing behavior and locomotor activity and a dose-dependent increase in IL pERK1/2 labeling. Aripiprazole produced a U-shaped dose-response curve on MK-801-induced bar pressing behavior, a dose-dependent decrease in locomotor activity but no changes in IL pERK1/2 labeling. The attenuation of the MK-801-induced behavioral (bar pressing, locomotion) profile by Flupenthixol indicates a clear dopaminergic contribution to this behavior. The behavioral effect of aripiprazole may be due to its a) binding to presynaptic dopamine receptors at the midrange dose decreasing dopamine output and b) binding to postsynaptic dopamine receptors at the higher dose increasing dopamine tone. While both classes of antipsychotics can normalize perseverative behavioral symptoms, the underlying prefrontal cortical dysregulation seems to persist.

  11. Dizocilpine (MK-801) arrests status epilepticus and prevents brain damage induced by Soman. (Reannouncement with new availability information)

    Energy Technology Data Exchange (ETDEWEB)

    Sparenborg, S.; Brennecke, L.H.; Jaax, N.K.; Braitman, D.J.

    1992-12-31

    The involvement of the NMDA receptor in the neurotoxicity induced by soman, an organophosphorus compound which irreversibly inhibits cholinesterase, was studied in guinea pigs. The drug MK-801 (0.5, 1 or 5 mg/kg, i.p.) was given as a pretreatment before a convulsant dose of soman or as a post treatment (30, 100 or 300 micron g/kg, i.m.) 5 min after the development of soman-induced status epilepticus. Pyridostigmine, atropine and pralidoxime chloride were also given to each subject to counteract the lethality of soman. All subjects that were challenged with soman and given the vehicle for MK-801 (saline) exhibited severe convulsions and electrographic seizure activity. Neuronal necrosis was found in the hippocampus, amygdala, thalamus and the pyriform and cerebral cortices of those subjects surviving for 48 hr. Pretreatment with 0.5 or 1 mg/kg doses of MK-801 did not prevent nor delay the onset of seizure activity but did diminish its intensity and led to its early arrest. At the largest dose (5 mg/kg), MK-801 completely prevented the development of seizure activity and brain damage. Post treatment with MK-801 prevented, arrested or reduced seizure activity, convulsions and neuronal necrosis in a dose-dependent manner. The NMDA receptor may play a more critical role in the spread and maintenance, rather than the initiation of cholinergically-induced seizure activity....Seizure-related brain damage, Organophosphorus compound, Nerve agent, Cholinesterase inhibition, Excitotoxicity, Guinea pig.

  12. Hypothermia but not the N-methyl-D-aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia.

    Science.gov (United States)

    Buchan, A; Pulsinelli, W A

    1990-01-01

    Several laboratories have reported a significant reduction of ischemia-induced injury to hippocampal neurons in rodents treated with competitive and noncompetitive N-methyl-D-aspartate (NMDA) receptor-channel antagonists. This study examined the effects of the noncompetitive antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) in Mongolian gerbils subjected to 5 min of bilateral carotid artery occlusion. In adult female gerbils, single doses of MK-801 injected 1 hr prior to ischemia significantly (p less than 0.01) reduced damage to CA1 hippocampal neurons. However, the drug rendered the postischemic animals comatose and hypothermic for several hours compared with the saline-treated animals. In subsequent experiments, animals pretreated with MK-801 and maintained normothermic during and after forebrain ischemia demonstrated no amelioration of hippocampal damage. Gerbils not treated with MK-801, but kept hypothermic in the postischemic period to approximately the same degree (34.5 degrees C) and duration (8 hr) as was induced by MK-801 therapy showed significant (p less than 0.01) protection of CA1 neurons against ischemia. The neuroprotective activity of MK-801 against transient global ischemia appears to be largely a consequence of postischemic hypothermia rather than a direct action on NMDA receptor-channels.

  13. MK-801 treatment affects glycolysis in oligodendrocytes more than in astrocytes and neuronal cells: insights for schizophrenia

    Directory of Open Access Journals (Sweden)

    Paul C Guest

    2015-05-01

    Full Text Available As a multifactorial disease, the underlying causes of schizophrenia require analysis by multiplex methods such as proteomics to allow identification of whole protein networks. Previous post-mortem proteomic studies on brain tissues from schizophrenia patients have demonstrated changes in activation of glycolytic and energy metabolism pathways. However, it is not known whether these changes occur in neurons or in glial cells. To address this question, we treated neuronal, astrocyte and oligodendrocyte cell lines with the NMDA receptor antagonist MK-801 and measured the levels of six glycolytic enzymes by Western blot analysis. MK-801 acts on the glutamatergic system and has been proposed as a pharmacological means of modeling schizophrenia. Treatment with MK-801 resulted in significant changes in the levels of glycolytic enzymes in all cell types. Most of the differences were found in oligodendrocytes, which had altered levels of hexokinase 1 (HK1, enolase 2 (ENO2, phosphoglycerate kinase (PGK and phosphoglycerate mutase 1 (PGAM1 after acute MK-801 treatment (8 hours, and HK1, ENO2, PGK and triosphosphate isomerase (TPI following long term treatment (72 hours. Addition of the antipsychotic clozapine to the cultures resulted in counter-regulatory effects to the MK-801 treatment by normalizing the levels of ENO2 and PGK in both the acute and long term cultures. In astrocytes, MK-801 affected only aldolase C (ALDOC under both acute conditions and HK1 and ALDOC following long term treatment, and TPI was the only enzyme affected under long term conditions in the neuronal cells. In conclusion, MK-801 affects glycolysis in oligodendrocytes to a larger extent than neuronal cells and this may be modulated by antipsychotic treatment. Although cell culture studies do not necessarily reflect the in vivo pathophysiology and drug effects within the brain, these results suggest that neurons, astrocytes and oligodendrocytes are affected differently in

  14. Comparison of the MK-801-induced increase in non-rewarded appetitive responding with dopamine agonists and locomotor activity in rats.

    Science.gov (United States)

    Davis-MacNevin, Parnell L; Dekraker, Jordan; LaDouceur, Liane; Holahan, Matthew R

    2013-09-01

    Systemic administration of the noncompetitive N-methyl-D-aspartate (NMDA)- receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. Evidence has shown that MK-801 increases the probability of operant responding during extinction, possibly modeling perseveration, as would be seen in patients with schizophrenia. This MK-801-induced behavioral perseveration is reversed by dopamine receptor antagonism. To further explore the role of dopamine in this behavioral change, the current study sought to determine if the MK-801-induced increase in non-rewarded operant responding could be mimicked by dopamine agonism and determine how it was related to locomotor activity. Male Long Evans rats were treated systemically with MK-801, cocaine, GBR12909 or apomorphine (APO) and given a single trial operant extinction session, followed by a separate assessment of locomotor activity. Both MK-801 (0.05 mg/kg) and cocaine (10 mg/kg) significantly increased responding during the extinction session and both increased horizontal locomotor activity. No dose of GBR-12909 (5, 10 or 20 mg/kg) was found to effect non-rewarded operant responding or locomotor activity. APO (0.05, 0.5, 2 or 5 mg/kg) treatment produced a dose-dependent decrease in both operant responding and locomotor activity. These results suggest the possibility that, rather than a primary influence of increased dopamine concentration on elevating bar-pressing responses during extinction, other neurotransmitter systems may be involved.

  15. Postnatal MK-801 treatment of female rats impairs acquisition of working memory, but not reference memory in an eight-arm radial maze; no beneficial effects of enriched environment.

    Science.gov (United States)

    Nozari, Masoumeh; Mansouri, Farshad Alizadeh; Shabani, Mohammad; Nozari, Hojat; Atapour, Nafiseh

    2015-07-01

    Memory impairment has been documented in MK-801 (NMDA receptor antagonist) model of schizophrenia, but less is known on the rescue and/or differential effects of MK-801 on short- and long-term memories. We determined the effects of MK-801 treatment and/or enriched environment (EE) on acquisition of reference and working memory in developing rats. Female Wistar rats were injected with MK-801 (1 mg/kg) from postnatal days (P) 6-10. Task acquisition, working memory error (WME), and reference memory error (RME) were assessed in an eight-arm radial maze task. Behavioral performance of rats was also tested in an open field test before (P35-P40) and after (P65-P70) radial maze training to assess anxiety and locomotion. EE was applied from birth up to the end of experiments. MK-801 treatment did not influence task acquisition in the radial maze; however, by the end of training, MK-801-treated rats made significantly more WME, but not RME, compared to control rats. Ratio of WME to total error was also significantly higher in MK-801 group. EE prevented MK-801-associated behaviors in the open field but did not exert beneficial effects on working memory deficit in the radial maze task. EE per se affected behavioral performance of rats only in the open field test. Our results suggest that postnatal MK-801 treatment differentially affects working and reference memory in a young brain. Anxiety and hyperactivity associated with MK-801 are observed more severely in adulthood. Dissociation of the positive effects of EE may suggest selective modification of distinct pathways.

  16. MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms via Wnt/β-Catenin Signaling in Parkinsonian Rats.

    Science.gov (United States)

    Singh, Sonu; Mishra, Akanksha; Srivastava, Neha; Shukla, Shubha

    2017-03-15

    Adult hippocampal neurogenesis is directly involved in regulation of stress, anxiety, and depression that are commonly observed nonmotor symptoms in Parkinson's disease (PD). These symptoms do not respond to pharmacological dopamine replacement therapy. Excitotoxic damage to neuronal cells by N-methyl-d-aspartate (NMDA) receptor activation is also a major contributing factor in PD development, but whether it regulates hippocampal neurogenesis and nonmotor symptoms in PD is yet unexplored. Herein, for the first time, we studied the effect of MK-801, an NMDA receptor antagonist, on adult hippocampal neurogenesis and behavioral functions in 6-OHDA (6-hydroxydopamine) induced rat model of PD. MK-801 treatment (0.2 mg/kg, ip) increased neural stem cell (NSC) proliferation, self-renewal capacity, long-term survival, and neuronal differentiation in the hippocampus of rat model of PD. MK-801 potentially enhanced long-term survival, improved dendritic arborization of immature neurons, and reduced 6-OHDA induced neurodegeneration via maintaining the NSC pool in hippocampus, leading to decreased anxiety and depression-like phenotypes in the PD model. MK-801 inhibited glycogen synthase kinase-3β (GSK-3β) through up-regulation of Wnt-3a, which resulted in the activation of Wnt/β-catenin signaling leading to enhanced hippocampal neurogenesis in PD model. Additionally, MK-801 treatment protected the dopaminergic (DAergic) neurons in the nigrostriatal pathway and improved motor functions by increasing the expression of Nurr-1 and Pitx-3 in the PD model. Therefore, MK-801 treatment serves as a valuable tool to enhance hippocampal neurogenesis in PD, but further studies are needed to revisit the role of MK-801 in the neurodegenerative disorder before proposing a potential therapeutic candidate.

  17. Dose-dependent and combined effects of N-methyl- D-aspartate receptor antagonist MK-801 and nitric oxide synthase inhibitor nitro-L-arginine on the survival of retinal ganglion cells in adult hamsters

    Institute of Scientific and Technical Information of China (English)

    Yaoyu Li; An'an Yang; Tingting Zhu; Zhao Liu; Siwei You; Kwok-Fai So

    2012-01-01

    This study investigated the effects of daily intraperitoneal injections of N-methyl-D-aspartate receptor antagonist MK-801 and nitric oxide synthase inhibitor nitro-L-arginine (L-NA) on the survival of retinal ganglion cells (RGCs) at 1 and 2 weeks after unilateral optic nerve transection in adult hamsters. The left optic nerves of all animals were transected intraorbitally 1 mm from the optic disc and RGCs were retrogradely labeled with Fluorogold before they received different daily dosages of single MK-801 or L-NA as well as daily combinational treatments of these two chemicals. All experimental and control animals survived for 1 or 2 weeks after optic nerve transection. Our results revealed that the mean numbers of surviving RGCs increased and then decreased when the dosage of MK-801 (1.0, 3.0 and 4.5 mg/kg) and L-NA (1.5, 3.0, 4.5 and 6.0 mg/kg) increased at both 1 and 2 weeks survival time points. Daily combinational use of 1.0 mg/kg MK-801 and 1.5 mg/kg L-NA lead to a highest RGC number that was even higher than the sum of the RGC numbers in 1.0 mg/kg MK-801 and 1.5 mg/kg L-NA subgroups at 2 weeks. These findings indicated that both MK-801 and L-NA can protect axotomized RGCs in a dose-dependent manner and combinational treatment of these chemicals possesses a potentiative and protective effect.

  18. N-methyl-D-aspartate receptor antagonist MK-801 impairs learning but not memory fixation or expression of classical fear conditioning in goldfish (Carassius auratus).

    Science.gov (United States)

    Xu, X; Davis, R E

    1992-04-01

    The amnestic effects of the noncompetitive antagonist MK-801 on visually mediated, classic fear conditioning in goldfish (Carassius auratus) was examined in 5 experiments. MK-801 was administered 30 min before the training session on Day 1 to look for anterograde amnestic effects, immediately after training to look for retrograde amnestic effects, and before the training or test session, or both, to look for state-dependence effects. The results showed that MK-801 produced anterograde amnesia at doses that did not produce retrograde amnesia or state dependency and did not impair the expression of conditioned or unconditioned branchial suppression responses (BSRs) to the conditioned stimulus. The results indicate that MK-801 disrupts the mechanism of learning of the conditioned stimulus-unconditioned stimulus relation. Evidence is also presented that the learning processes that are disrupted by MK-801 occur during the initial stage of BSR conditioning.

  19. DEVELOPMENTAL LEAD (PB) EXPOSURE REDUCES THE ABILITY OF THE NNDA ANTAGONIST MK801 TO SUPPRESS LONG-TERM POTENTIATION (LTP) IN THE RAT DENTATE GYRUS, IN VIVO

    Science.gov (United States)

    Chronic developmental lead (Pb) exposure increases the threshold and enhances decay of long-term potentiation (LTP) in the dentate gyrus of the hippocampal formation. MK-801 and other antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype impair induction of LT...

  20. Effects of a glycine transporter-1 inhibitor and D-serine on MK-801-induced immobility in the forced swimming test in rats.

    Science.gov (United States)

    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.

  1. Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block.

    Science.gov (United States)

    Dravid, Shashank M; Erreger, Kevin; Yuan, Hongjie; Nicholson, Katherine; Le, Phuong; Lyuboslavsky, Polina; Almonte, Antoine; Murray, Ernest; Mosely, Cara; Barber, Jeremy; French, Adam; Balster, Robert; Murray, Thomas F; Traynelis, Stephen F

    2007-05-15

    We have compared the potencies of structurally distinct channel blockers at recombinant NR1/NR2A, NR1/NR2B, NR1/NR2C and NR1/NR2D receptors. The IC50 values varied with stereochemistry and subunit composition, suggesting that it may be possible to design subunit-selective channel blockers. For dizocilpine (MK-801), the differential potency of MK-801 stereoisomers determined at recombinant NMDA receptors was confirmed at native receptors in vitro and in vivo. Since the proton sensor is tightly linked both structurally and functionally to channel gating, we examined whether blocking molecules that interact in the channel pore with the gating machinery can differentially sense protonation of the receptor. Blockers capable of remaining trapped in the pore during agonist unbinding showed the strongest dependence on extracellular pH, appearing more potent at acidic pH values that promote channel closure. Determination of pK(a) values for channel blockers suggests that the ionization of ketamine but not of other blockers can influence its pH-dependent potency. Kinetic modelling and single channel studies suggest that the pH-dependent block of NR1/NR2A by (-)MK-801 but not (+)MK-801 reflects an increase in the MK-801 association rate even though protons reduce channel open probability and thus MK-801 access to its binding site. Allosteric modulators that alter pH sensitivity alter the potency of MK-801, supporting the interpretation that the pH sensitivity of MK-801 binding reflects the changes at the proton sensor rather than a secondary effect of pH. These data suggest a tight coupling between the proton sensor and the ion channel gate as well as unique subunit-specific mechanisms of channel block.

  2. Systemic dizocilpine (MK-801 facilitates performance in opposition to response bias

    Directory of Open Access Journals (Sweden)

    Lauwereyns Johan

    2007-09-01

    Full Text Available Abstract Previous research has established that dopamine signals are crucial in orienting behavior to reward. Less is known, however, about the psychopharmacology of task performance under small-reward conditions as compared to large-reward conditions. The current study examined the effects of the noncompetitive N-methyl-D-aspartate (NMDA-receptor antagonist dizocilpine (MK-801 on reaction time (RT in a nose-poke task with rats completing an asymmetric reward schedule. In all trials, the rats were required to poke their nose in either the left or the right peripheral hole immediately adjacent to the centre hole when the corresponding light was illuminated. Depending on the stimulus-reward mapping, however, one position was associated with a large reward, while the alternative position was associated with a small reward. Correct performance was required in every trial; if the rat did not make a correct response within 20 s, the trial was aborted, and the same stimulus was presented again on the next trial. In this way, the rat was forced to perform the same visuo-spatial discrimination task under different reward conditions. Reaction times (ms were faster for large-reward trials than for small-reward trials, replicating previous findings. At a dosage of MK-801 (0.04 mg/kg, there was no significant influence of on RT in large-reward trials. In contrast, the same dosage of MK-801 in small-reward trials produced a decrease in RT as compared to the control condition, implying an improvement of performance. Below 0.04 mg/kg of MK-801, a steady decrease of RT in small-trials was seen as a function of dosage. Above 0.04 mg/kg of MK-801, the majority of rats failed to perform the task at all, whereas the rats that did manage to perform the criterion of 80 correct trials in a session showed no difference in RT between large- and small-reward trials. These data indicate that the systemic administration of a relatively small dosage of MK-801 facilitates

  3. Microinfusion of the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of wistar rats does not affect latent inhibition and prepulse inhibition, but increases startle reaction and locomotor activity.

    Science.gov (United States)

    Zhang, W N; Bast, T; Feldon, J

    2000-01-01

    Latent inhibition (the retarded conditioning to a stimulus following its repeated non-reinforced pre-exposure) and prepulse inhibition (the reduction in the startle response to an intense acoustic stimulus when this stimulus is immediately preceded by a prepulse) reflect cognitive and sensorimotor gating processes, respectively, and are deficient in schizophrenic patients. The disruption of latent inhibition and prepulse inhibition in the rat is used as an animal model for the attentional deficits associated with schizophrenia. The present study tested the extent to which latent inhibition and prepulse inhibition, startle reaction and locomotor activity in the open field were affected by infusing the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of Wistar rats. We used the same dose of MK-801 (6.25microg/0.5microl per side) previously found to be effective in the disruption of prepulse inhibition when infused into the dorsal hippocampus of Sprague-Dawley rats [Bakshi V. P. and Geyer M. A. (1998) J. Neurosci. 18, 8394-8401; Bakshi V. P. and Geyer M. A. (1999) Neuroscience 92, 113-121]. Bilateral infusion of MK-801 into the dorsal hippocampus did not disrupt latent inhibition. Furthermore, in contrast to previous studies, we failed to find a significant disruption of prepulse inhibition after MK-801 infusion into the dorsal hippocampus, although MK-801 infusion was effective in increasing the startle amplitude as well as locomotor activity in an open field. From our results, we suggest that N-methyl-D-aspartate receptor-mediated processes within the dorsal hippocampus are not necessary for the normal maintenance of the attentional processes reflected by latent inhibition and prepulse inhibition.

  4. Histamine ameliorates spatial memory deficits induced by MK-801 infusion into ventral hippocampus as evaluated by radial maze task in rats

    Institute of Scientific and Technical Information of China (English)

    Li-sha XU; Li-xia YANG; Wei-wei HU; Xiao YU; Li MA; Lu-ying LIU; Er-qing WEI; Zhong CHEN

    2005-01-01

    Aim: To investigate the role of histamine in memory deficits induced by MK-801 infusion into the ventral hippocampus in rats. Methods: An 8-arm radial maze (4arms baited) was used to assess spatial memory. Results: Bilateral ventral intrahippocampal (ih) infusion of MK-801 (0.3 μg/site), an N-methyl-D-aspartate (NMDA) antagonist, impaired the retrieval process in both working memory and reference memory. Intrahippocampal injection of histamine (25 or 50 ng/site) or intraperitoneal (ip) injection of histidine (25, 50 or 100 mg/kg) markedly ameliorated the spatial memory deficits induced by MK-801. Both the histamine H1 antagonist pyrilamine (0.5 or 1.0 μg/site, ih) and the H2 antagonist cimetidine (2.5 μg/site,ih) abolished the ameliorating effect of histidine (100 mg/kg, ip) on reference memory deficits, but not that on working memory deficits induced by MK-801. Conclusion:The results indicate that histamine in the ventral hippocampus can ameliorate MK-801-induced spatial memory deficits, and that histamine's effect on reference memory is mediated by postsynaptic histamine H1 and H2 receptors.

  5. Pre- and post-treatment with MK-801 but not pretreatment alone reduces neocortical damage after focal cerebral ischemia in the rat.

    Science.gov (United States)

    Dirnagl, U; Tanabe, J; Pulsinelli, W

    1990-09-10

    The effect of treatment with the potent, non-competitive NMDA receptor-channel antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5,10-imine maleate (MK-801) on ischemia-induced brain damage was studied in a well-characterized model of focal neocortical infarction in spontaneously hypertensive rats. Anesthesia exposure was minimized to the surgical procedure and the infarcts were allowed to mature over a 24-h period. Pretreatment with 5 mg/kg i.p. MK-801 (n = 11 control, n = 12 treated animals) 30 min before induction of focal cerebral ischemia had no statistically significant influence on infarct volumes. However, pre- and post-treatment with MK-801 5 mg/kg i.p. 30 min before induction of ischemia and 2.5 mg/kg each at 8 and 16 h after onset of ischemia, reduced infarct volumes in two separate studies by 29% (investigator J.T., n = 5 control and n = 7 treated animals) and 20% (investigator U.D., n = 8 control and n = 8 treated animals), respectively. The combined reduction in infarct volume in MK-801-treated animals for both investigators was 23% (P = 0.016, ANOVA). The findings indicate a smaller neuroprotective effect of MK-801 in spontaneously hypertensive rats subjected to focal ischemia than in previous reports using normotensive animals.

  6. Latent inhibition in rats neonatally treated chronically with MK-801: differential effects on conditioned taste aversion and conditioned emotional response.

    Science.gov (United States)

    Niikura, Ryo; Nozawa, Takashi; Yamada, Kazuo; Kato, Katsunori; Ichitani, Yukio

    2015-04-15

    Chronic neonatal blockade of N-methyl-d-aspartate (NMDA) receptors produces various abnormal behaviors in adulthood animals. This study investigated the effects of neonatal treatment chronically with MK-801 in rats on the preexposure-induced retardation of CS-US association, i.e. latent inhibition (LI), of two aversive classical conditioning tasks in adulthood. In conditioned taste aversion (CTA) using sucrose taste and LiCl, neonatal chronic MK-801 (0.4 mg/kg twice/day) treatment attenuated the inhibitory effect of sucrose preexposure on the aversive conditioning, although the treatment did not affect CTA conditioning itself. On the other hand, in conditioned emotional response (CER) using tone and electrical foot shock, rats neonatally treated with MK-801 showed the same degree of inhibitory effect of tone preexposure on the aversive conditioning compared with neonatally vehicle-treated rats, and also showed the same level of CER conditioning itself. Thus, the effect of chronic neonatal blockade of NMDA receptors on the LI of classical conditioning in adulthood was differentiated by the task employed. Results suggest that LI of CTA paradigm compared with that of CER is more sensitive to abnormal development after chronic neonatal blockade of NMDA receptors as an index of cognitive/attentional deficits caused by the treatment.

  7. Effects of acute and chronic administration of MK-801 on c-Fos protein expression in mice brain regions implicated in schizophrenia and antagonistic action of clozapine

    Institute of Scientific and Technical Information of China (English)

    ZUO Dai-ying; CAO Yue; ZHANG Lan; WANG Hai-feng; WU Ying-liang

    2008-01-01

    Objective To investigate the effects of acute and chronic administration of the non-competitive NMDA receptor antagonists MK-801 on c-Fos protein expression in different brain regions of mice and antagonistic action of clozapine. Methods Immunohistochemistry was used to detect the expression of c-Fos protein. Results MK-801 (0.6 mg·kg-1) acute administration produced a significant increase in the expression of c-Fos protein in the layers Ⅲ-Ⅳ of posterior cingulate and retrosplenial (PC/RS) cortex, which was consistent with the previous reports. Moreover, we presented a new finding that MK-801 (0.6 mg·kg-1) chronic administration for 8 days produced a significant increase of c-Fos protein expression in the PC/RS cortex, prefrontal cortex (PFC) and hypothalamus of mice. Among that, c-Fos protein expression in the PC/ RS cortex of mice was most significant. Compared acute administration with chronic administration, we found that MK-801 chronic administration significantly increased the expression of c-Fos protein in the PC/ RS cortex, PFC and hypothalamus. Furthermore, pretreatment of mice with clozapine significantly decreased the expression of c-Fos protein induced by MK-801 acute and chronic administration. Conclusions Marked expression of c-Fos protein induced by MK-801 is associated with neurotransmitters' change noted in our previous studies, and c-Fos protein, the marker of neuronal activation, might play an important role in the chronic pathophysiological process of schizophrenic model induced by NMDA receptor antagonist.

  8. 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.

  9. Neuroprotection by Combined Administration with Maslinic Acid, a Natural Product from Olea europaea, and MK-801 in the Cerebral Ischemia Model

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    Yisong Qian

    2016-08-01

    Full Text Available Glutamate-mediated excitotoxicity is a major cause of ischemic brain damage. MK-801 confers neuroprotection by attenuating the activation of the N-methyl-d-aspartate (NMDA receptor, but it failed in clinical use due to the short therapeutic window. Here we aim to investigate the effects of maslinic acid, a natural product from Olea europaea, on the therapeutic time window and dose range for the neuroprotection of MK-801. Rats were administered with maslinic acid intracerebroventricularly and cerebral ischemia was induced by middle cerebral artery occlusion (MCAO followed by reperfusion. MK-801 was administered at 1 h, 2 h, 3 h and 4 h after ischemia, respectively. The cerebral infarct volume was determined by 2,3,5-Triphenyltetrazolium chloride (TTC staining, neuronal damage was assessed by Haematoxylin Eosin (H&E staining, and the expression of glial glutamate transporters and glial fibrillary acidic protein (GFAP was evaluated by immunohistochemistry and Western blot post-ischemia. Results showed that the presence of maslinic acid extended the therapeutic time window for MK-801 from 1 h to 3 h. Co-treatment of maslinic acid and MK-801 at a subthreshold dosage obviously induced neuroprotection after ischemia. The combination of these two compounds improved the outcome in ischemic rats. Moreover, maslinic acid treatment promoted the expression of GLT-1 and GFAP post-ischemia. These data suggest that the synergistic effect of maslinic acid on neurological protection might be associated with the improvement of glial function, especially with the increased expression of GLT-1. The combination therapy of maslinic acid and MK-801 may prove to be a potential strategy for treating acute ischemic stroke.

  10. The N-methyl-D-aspartate antagonist, MK-801, fails to protect against neuronal damage caused by transient, severe forebrain ischemia in adult rats.

    Science.gov (United States)

    Buchan, A; Li, H; Pulsinelli, W A

    1991-04-01

    The neuroprotective effects of dizocilipine maleate (MK-801), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor/channel, were tested in the 4-vessel occlusion rat model of forebrain ischemia. Adult Wistar rats, treated intraperitoneally with MK-801 or saline using several different treatment paradigms were subjected to 5 (n = 208) or 15 (n = 62) min of severe, transient forebrain ischemia. In saline-treated animals, 15 min of ischemia (n = 13) produced extensive and consistent loss of pyramidal neurons in the CA1 zone of hippocampus. The degree and distribution of cell loss were not reduced by single dose preischemic administration of MK-801 at 1 (n = 7), 2.5 (n = 4), or 5 mg/kg (n = 8). In other animals subjected to 15 min of forebrain ischemia, multiple doses of MK-801 (5, 2.5, and 2.5 mg/kg) given immediately and at approximately 8 and 20 hr after cerebral reperfusion (n = 5) did not alter CA1 injury compared to saline-treated controls (n = 5). Five minutes of forebrain ischemia in saline-treated animals, (n = 82) resulted in significantly fewer (p less than 0.001) dead CA1 pyramidal cells and a greater variance compared to animals subjected to 15 min of ischemia. Power analysis of the preliminary saline-treated animals subjected to 5 min of ischemia (n = 22) indicated that 60 animals per group were necessary to detect a 15% difference between MK-801 and vehicle-treated groups. Multidose treatment with MK-801 (1 mg/kg) given 1 hr prior to 5 min of ischemia (n = 60) and again at approximately 8 and 16 hr after recirculation failed to attenuate hippocampal injury.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Manganese inhibits NMDA receptor channel function: implications to psychiatric and cognitive effects.

    Science.gov (United States)

    Guilarte, Tomás R; Chen, Ming-Kai

    2007-11-01

    Humans exposed to excess levels of manganese (Mn(2+)) express psychiatric problems and deficits in attention and learning and memory. However, there is a paucity of knowledge on molecular mechanisms by which Mn(2+) produces such effects. We now report that Mn(2+) is a potent inhibitor of [(3)H]-MK-801 binding to the NMDA receptor channel in rat neuronal membrane preparations. The inhibition of [(3)H]-MK-801 to the NMDA receptor channel by Mn(2+) was activity-dependent since Mn(2+) was a more potent inhibitor in the presence of the NMDA receptor co-agonists glutamate and glycine (K(i)=35.9+/-3.1 microM) than in their absence (K(i)=157.1+/-6.5 microM). We also show that Mn(2+) is a NMDA receptor channel blocker since its inhibition of [(3)H]-MK-801 binding to the NMDA receptor channel is competitive in nature. That is, Mn(2+) significantly increased the affinity constant (K(d)) with no significant effect on the maximal number of [(3)H]-MK-801 binding sites (B(max)). Under stimulating conditions, Mn(2+) was equipotent in inhibiting [(3)H]-MK-801 binding to NMDA receptors expressed in neuronal membrane preparations from different brain regions. However, under basal, non-stimulated conditions, Mn(2+) was more potent in inhibiting NMDA receptors in the cerebellum than other brain regions. We have previously shown that chronic Mn(2+) exposure in non-human primates increases Cu(2+), but not zinc or iron concentrations in the basal ganglia [Guilarte TR, Chen M-K, McGlothan JL, Verina T, Wong DF, Zhou Y, Alexander M, Rohde CA, Syversen T, Decamp E, Koser AJ, Fritz S, Gonczi H, Anderson DW, Schneider JS. Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates. Exp Neurol 2006a;202:381-90]. Therefore, we also tested the inhibitory effects of Cu(2+) on [(3)H]-MK-801 binding to the NMDA receptor channel. The data shows that Cu(2+) in the presence of glutamate and glycine is a more potent inhibitor of the NMDA receptor than Mn(2

  12. Combined Diazepam and MK-801 Therapy Provides Synergistic Protection from Tetramethylenedisulfotetramine-induced Tonic-Clonic Seizures and Lethality in Mice

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    Shakarjian, Michael P.; Ali, Mahil S.; Velíšková, Jana; Stanton, Patric K.; Heck, Diane E.; Velíšek, Libor

    2015-01-01

    The synthetic rodenticide, tetramethylenedisulfotetramine (TMDT), is a persistent and highly lethal GABA-gated Cl− channel blocker. TMDT is clandestinely produced, remains popular in mainland China, and causes numerous unintentional and deliberate poisonings worldwide. TMDT is odorless, tasteless, and easy to manufacture, features that make it a potential weapon of terrorism. There is no effective treatment. We previously characterized the effects of TMDT in C57BL/6 mice and surveyed efficacies of GABAergic and glutamatergic anticonvulsant treatments. At 0.4 mg/kg i.p., TMDT produced neurotoxic symptomatology consisting of twitches, clonic and tonic-clonic seizures, often progressing to status epilepticus and death. If administered immediately after the occurrence of the first clonic seizure, the benzodiazepine diazepam (DZP) effectively prevented all subsequent seizure symptoms, whereas the NMDA receptor antagonist dizocilpine (MK-801) primarily prevented tonic-clonic seizures. The latter agent, however, appeared to be more effective at preventing delayed death. The present study further explored these phenomena, and characterized the therapeutic actions of DZP and MK-801 as combinations. Joint treatment with both DZP and MK-801 displayed synergistic protection against tonic-clonic seizures and 24 hour lethality as determined by isobolographic analysis. Clonic seizures, however, remained poorly controlled. A modification of the treatment regimen, where DZP was followed 10 min later by MK-801, yielded a reduction in both types of seizures and improved overall outcome. Simultaneous monitoring of subjects via EEG and videography confirmed effectiveness of this sequential regimen. We conclude that TMDT blockage at GABAA receptors involves early activation of NMDA receptors, which contribute to persistent ictogenic activity. Our data predict that a sequential combination treatment with DZP followed by MK-801 will be superior to either individual therapy with, or

  13. The delayed effects of DTG and MK-801 on latent inhibition in a conditioned taste-aversion paradigm.

    Science.gov (United States)

    Turgeon, S M; Auerbach, E A; Duncan-Smith, M K; George, J R; Graves, W W

    2000-07-01

    The delayed effects of phencyclidine (PCP) have been shown to disrupt latent inhibition (LI) in a conditioned taste-aversion paradigm. In an attempt to understand the mechanism of this disruption, the delayed effects of the selective sigma receptor agonist 1,3-Di(2-tolyl)guanidine (DTG) and the selective NMDA receptor antagonist MK-801 on latent inhibition were assessed in the same paradigm. Water-deprived male rats were allowed access to either water (nonpreexposed; NPE) or 5% sucrose (preexposed; PE) for 30 min on 2 consecutive days. On the third day, animals were allowed access to sucrose and subsequently injected with lithium chloride. On the forth day, animals were allowed access to both sucrose and water. LI was assessed by comparing the percent sucrose consumed in PE and NPE groups on the fourth day. DTG (1.0, 5.0, or 10.0 mg/kg), MK-801 (0.5, 1.0, or 2.0 mg/kg), or vehicle was administered IP 20 h before preexposure (days 1 and 2) and conditioning (day 3). In vehicle-treated groups, PE animals consumed a significantly higher percent sucrose on the test day than NPE animals, indicating the presence of LI. DTG (10.0 mg/kg) and MK-801 (2.0 mg/kg) decreased the percent sucrose consumed by animals in the PE group to the level observed in the NPE group, indicating disrupted LI. However, this dose of MK-801 was found to produce a decrease in percent sucrose consumed in PE animals not treated with lithium chloride, indicating that the decrease observed in the LI paradigm could be due to MK-801-induced decrease in taste preference for sucrose rather than a disruption of LI. Lower doses of MK-801 that did not produce a decrease in taste preference for sucrose did not significantly disrupt LI. None of the doses of DTG tested altered taste preference for sucrose. These data suggest a role for sigma receptors in the previously observed PCP-induced disruption of LI. Published by Elsevier Science Inc., 2000

  14. Acute Administration of MK-801 in an Animal Model of Psychosis in Rats Interferes with Cognitively Demanding Forms of Behavioral Flexibility on a Rotating Arena

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    Jan eSvoboda

    2015-04-01

    Full Text Available Patients with schizophrenia often manifest deficits in behavioral flexibility. Non-competitive NMDA receptor antagonists such as MK-801 induce schizophrenia-like symptoms in rodents, including cognitive functions. Despite work exploring flexibility has been done employing behavioral paradigms with simple stimuli, much less is known about what kinds of flexibility are affected in an MK-801 model of schizophrenia-like behavior in the spatial domain. We used a rotating arena-based apparatus (Carousel requiring rats to avoid an unmarked sector defined in either the reference frame of the rotating arena (arena frame task, AF or the stationary room (room frame task, RF. We investigated behavioral flexibility in four conditions involving different cognitive loads. Each condition encompassed an initial (five sessions and a test phase (five sessions in which some aspects of the task were changed to test flexibility in which rats were given saline, 0.05 mg/kg or 0.1 mg/kg MK-801 thirty minutes prior to a session. In the first condition, rats acquired avoidance in RF with clockwise rotation of the arena while in the test phase the arena rotated counterclockwise. In the second condition, rats initially acquired avoidance in RF with the sector on the north and then it was reversed to south (spatial reversal. In the third and fourth conditions, rats initially performed an AF (RF, respectively task, followed by an RF (AF, respectively task, testing the ability of cognitive set-shifting. We found no effect of MK-801 either on simple motor adjustment after reversal of arena rotation or on spatial reversal within the RF. In contrast, administration of MK-801 at a dose of 0.1 mg/kg interfered with set-shifting in both conditions. Furthermore, we observed MK-801 0.1 mg/kg elevated locomotion in all cases. These data suggest that blockade of NMDA receptors by acute system administration of MK-801 preferentially affects set-shifting in the cognitive domain rather

  15. Neuroprotective effects of nimodipine and MK-801 on acute infectious brain edema induced by injection of pertussis bacilli to neocortex of rats

    Institute of Scientific and Technical Information of China (English)

    陈立华; 刘丽旭; 杨于嘉; 刘运生; 曹美鸿

    2003-01-01

    Objective: To explore the mechanism and type of acute infectious brain edema induced by injection of pertussis bacilli (PB) in rat neocortex, to study the neuroprotective effect of non-competitive antagonist of N-methl-D-aspartate ( NMDA ) receptor ( MK-801 ) and antagonist of Ca2+ channels ( nimodipine )on brain edema, and to investigate the relationship between percentage of water content and cytosolic free calcium concentration ([Ca2+]i) in synaptosomes or content of Evans Blue (EB).Methods: 95 SD rats were randomly divided into five groups, ie, normal control group, sham-operated control group, PB group, nimodipine treatment group and MK-801 pretreatment group. The acute infectious brain edema was induced by injection of PB into the rats. Quantitative measurements of water content and the concentration of EB were performed. [Ca2+]i was determined in calcium fluorescent indication Fura-2/AM loaded neuronal synaptosome with a spectrofluorophotometer. To observe the effect of MK-801 and nimodipine, we administered MK-801 48 hours and 24 hours before the injection of PB in MK-801 pretreatment group, and nimodipine after the injection of PB in nimodipine treatment group. The specific binding of NMDA receptor was measured with [3H]-MK-801 in the neuronal membrane of cerebral cortex. Results: The levels of water content and EB content of brain tissues, and [Ca2+]i in the neuronal synaptosomes increased more significantly in the PB-injected cerebral hemisphere in the PB group than those of normal control group and sham-operated control group (P0.05). Conclusions: The changes in the permeability of blood-brain barrier (BBB) and Ca2+-overload may participate in the pathogenesis of infectious brain edema. Treatment with nimodipine can dramatically reduce the damage of brain edema and demonstrate neuroprotective effect on brain edema by inhibiting the excess of Ca2+ influx and reducing the permeability of BBB. MK-801 pretreatment may inhibit the delayed Ca2+ influx into

  16. Secretory phospholipase A2-mediated neuronal cell death involves glutamate ionotropic receptors

    DEFF Research Database (Denmark)

    de Turco, Elena B; Diemer, Nils Henrik; Bazan, Nicolas G

    2002-01-01

    To define the significance of glutamate ionotropic receptors in sPLA -mediated neuronal cell death we used the NMDA receptor antagonist MK-801 and the AMPA receptor antagonist PNQX. In primary neuronal cell cultures both MK-801 and PNQX inhibited sPLA - and glutamate-induced neuronal death. [ H]A...

  17. Effects of histamine on MK-801-induced memory deficits in radial maze performance in rats.

    Science.gov (United States)

    Chen, Z; Zhao, Q; Sugimoto, Y; Fujii, Y; Kamei, C

    1999-08-21

    The effects of histamine on the spatial memory deficits induced by MK-801 were investigated using the eight-arm radial maze paradigm in rats. Intracerebroventricular (i.c.v.) injection of histamine or thioperamide, and intraperitoneal (i.p.) injection of histidine improved the spatial memory deficits induced by MK-801. Similar results were obtained with 2-thiazolylethylamine. In contrast, 4-methylhistamine showed no significant effect. Based on these observations, it seems likely that the protective effect of histamine on MK-801-induced spatial memory deficit is mediated by H(1)-receptors.

  18. mGluR3 knockout mice show a working memory defect and an enhanced response to MK-801 in the T- and Y-maze cognitive tests.

    Science.gov (United States)

    Lainiola, Mira; Procaccini, Chiara; Linden, Anni-Maija

    2014-06-01

    Polymorphisms in the metabotropic glutamate receptor 3 (mGluR3) encoding gene GRM3 have been linked to schizophrenia and cognitive performance in humans. Our aim was to analyze the role of mGluR3 in basal working memory and attentional processes, and also when these functions were distracted by the psychotomimetic N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine (MK-801). mGluR3 knockout (KO) mice were used. Spontaneous alternation in a T-maze test was significantly reduced in mGluR3-KO mice compared to wildtype (WT) mice, particularly after a low dose of MK-801 (0.03 mg/kg, i.p., 30 min). In a Y-maze novelty discrimination test, the locomotor stimulatory effect of MK-801 (0.1mg/kg) was enhanced in mGluR3-KO mice. Interestingly, mGluR3-KO mice showed the significantly reduced alternation in the spontaneous alternation T-maze test and the significantly enhanced sensitivity to MK-801 in the Y-maze test only when forced to enter the right arm first, not when the forced arm was on the left. A side-biased response was also found in a rewarded alternation T-maze test, where mGluR3-KO mice made significantly more incorrect visits to the left arm than the right arm after a 25-s delay. No genotype difference was found in the novelty discrimination in the Y-maze test, rewarded alternation with a 5-s delay, preference for left or right when free to enter either arm or in MK-801-induced circling. Our findings indicate cognitive disturbance and left-right asymmetry in certain behavioral responses of mGluR3-KO mice. This novel observation warrants further elucidation, and should also be considered in other studies of mGluR3 in brain functions.

  19. Postnatal BDNF Expression Profiles in Prefrontal Cortex and Hippocampus of a Rat Schizophrenia Model Induced by MK-801 Administration

    Directory of Open Access Journals (Sweden)

    Chunmei Guo

    2010-01-01

    Full Text Available Neonatal blockade of N-methyl-D-aspartic acid (NMDA receptors represents one of experimental animal models for schizophrenia. This study is to investigate the long-term brain-derived neurotrophic factor (BDNF expression profiles in different regions and correlation with “schizophrenia-like” behaviors in the adolescence and adult of this rat model. The NMDA receptor antagonist MK801 was administered to female Sprague-Dawley rats on postnatal days (PND 5 through 14. Open-field test was performed on PND 42, and PND 77 to examine the validity of the current model. BDNF protein levels in hippocampus and prefrontal cortex (PFC were analyzed on PND 15, PND 42, and PND 77. Results showed that neonatal challenge with MK-801 persistently elevated locomotor activity as well as BDNF expression; the alterations in BDNF expression varied at different developing stages and among brain regions. However, these findings provide neurochemical evidence that the blockade of NMDA receptors during brain development results in long-lasting alterations in BDNF expression and might contribute to neurobehavioral pathology of the present animal model for schizophrenia. Further study in the mechanisms and roles of the BDNF may lead to better understanding of the pathophysiology of schizophrenia.

  20. The investigation of neonatal MK-801 administration and physical environmental enrichment on emotional and cognitive functions in adult Balb/c mice.

    Science.gov (United States)

    Akillioglu, Kubra; Babar Melik, Emine; Melik, Enver; Kocahan, Sayad

    2012-09-01

    N-methyl-D-aspartate (NMDA) receptors play an important role in brain maturation and developmental processes. It is known that growing up in an enriched environment has effects on emotional and cognitive performance. In our study, we evaluated the effects of physically enriched environment on the emotional and cognitive functions of the adult brain in the setting of previous NMDA receptor hypoactivity during the critical developmental period of the nervous system. In this study, NMDA receptor blockade was induced 5-10 days postnatally (PD5-10) using MK-801 in mice Balb/c (twice a day 0.25 mg/kg, for 5 days, intraperitoneal). MK-801 was given to developing mice living in a standard (SE) and an enrichment environment (EE) and once the animals reached adulthood, emotional behaviors were evaluated using an open field test (OF) and an elevated plus maze (EPM) test whereas cognitive processes were evaluated using the Morris water-maze (MWM). The EE group showed decreased locomotor activity (pfear of heights/anxiety-like behaviour (pfear of height (pfear of heights/anxiety-like behaviour with NMDA receptor blockade was not reversed by EE. NMDA receptor blockade during the critical period of development led to deterioration in the emotional and cognitive processes during adulthood. An enriched environmental did not reverse the deleterious effects of the NMDA receptor blockade on emotional and cognitive functions. Copyright © 2012. Published by Elsevier Inc.

  1. NMDA and non-NMDA receptor gene expression following global brain ischemia in rats: effect of NMDA and non-NMDA receptor antagonists.

    Science.gov (United States)

    Pellegrini-Giampietro, D E; Pulsinelli, W A; Zukin, R S

    1994-03-01

    Transient forebrain or global ischemia in rats induces selective and delayed damage of hippocampal CA1 neurons. In a previous study, we have shown that expression of GluR2, the kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit that governs Ca2+ permeability, is preferentially reduced in CA1 at a time point preceding neuronal degeneration. Postischemic administration of the selective AMPA receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), protects CA1 neurons against delayed death. In this study we examined the effects of NBQX (at a neuroprotective dose) and of MK-801 (a selective NMDA receptor antagonist, not protective in this model) on kainate/AMPA receptor gene expression changes after global ischemia. We also examined the effects of transient forebrain ischemia on expression of the NMDA receptor subunit NMDAR1. In ischemic rats treated with saline, GluR2 and GluR3 mRNAs were markedly reduced in CA1 but were unchanged in CA3 or dentate gyrus. GluR1 and NMDAR1 mRNAs were not significantly changed in any region examined. Administration of NBQX or MK-801 did not alter the ischemia-induced changes in kainate/AMPA receptor gene expression. These findings suggest that NBQX affords neuroprotection by a direct blockade of kainate/AMPA receptors, rather than by a modification of GluR2 expression changes.

  2. MK801 attenuates secondary injury in a mouse experimental compression model of spinal cord trauma

    Directory of Open Access Journals (Sweden)

    Meli Rosaria

    2011-04-01

    Full Text Available Abstract Background Glutamergic excitotoxicity has been shown to play a deleterious role in the pathophysiology of spinal cord injury (SCI. The aim of this study was to investigate the neuroprotective effect of dizocilpine maleate, MK801 (2 mg/Kg, 30 min and 6 hours after injury in a mice model of SCI. The spinal cord trauma was induced by the application of vascular clips to the dura via a four-level T5-T8 laminectomy. Results Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration and apoptosis. In this study we clearly demonstrated that administration of MK801 attenuated all inflammatory parameters. In fact 24 hours after injury, the degree of spinal cord inflammation and tissue injury (evaluated as histological score, infiltration of neutrophils, NF-κB activation, iNOS, cytokines levels (TNF-α and IL-1β, neurotrophin expression were markedly reduced by MK801 treatment. Moreover, in a separate set of experiments, we have demonstrated that MK801 treatment significantly improved the recovery of locomotory function. Conclusions Blockade of NMDA by MK801 lends support to the potential importance of NMDA antagonists as therapeutic agents in the treatment of acute spinal cord injury.

  3. N-Methyl-D-Aspartate Receptor Antagonist MK-801 and Radical Scavengers Protect Cholinergic Nucleus Basalis Neurons against β-Amyloid Neurotoxicity

    NARCIS (Netherlands)

    Harkany, T.; Mulder, J.; Sasvári, M.; Ábrahám, I.; Kónya, C.; Zarándi, M.; Penke, B.; Luiten, P.G.M.; Nyakas, C.

    1999-01-01

    Previous experimental data indicate the involvement of Ca2+-related excitotoxic processes, possibly mediated by N-Methyl-D-Aspartate (NMDA) receptors, in β-amyloid (βA) neurotoxicity. On the other hand, other lines of evidence support the view that free radical generation is a critical step in the β

  4. N-methyl-D-aspartate receptor antagonist MK-801 and radical scavengers protect cholinergic nucleus basalis neurons against beta-amyloid neurotoxicity

    NARCIS (Netherlands)

    Harkany, T; Mulder, J; Sasvari, M; Abraham, [No Value; Konya, C; Zarandi, M; Penke, B; Luiten, PGM; Nyakas, C

    1999-01-01

    Previous experimental data indicate the involvement of Ca2+-related excitotoxic processes, possibly mediated by N-Methyl-D-Aspartate (NMDA) receptors, in beta-amyloid (beta A) neurotoxicity. On the other hand, other lines of evidence support the view that free radical generation is a critical step i

  5. Effects of intracerebroventricular NMDA and non-NMDA receptor agonists or antagonists on general anesthesia of propofol in mice

    Institute of Scientific and Technical Information of China (English)

    XU Aijun; DUAN Shiming; TIAN Yuke

    2007-01-01

    The efiects of intracerebroventricular(icv)agonists and antagonists of N-methyl-D-aspartate(NMDA)and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors on the general anesthesia of propofol were studied.A tohal of 144 Kunming mice,male and female with body mass of(22±3)g,were used.Part One of the Experiment:a total of 104 Kunming mice,male and female,were randomly divided into 13 groups.Intracerebroventricular artificial cerebral fluid (aCSF)or different doses of NMDA,AMPA,MK-801 or NBOX was iniected immediately after intravenously administered propofol 25 mg/kg and the recovery time following the loss of righting reflex (LORR)was recorded.Part Two of the Experiment:a total of 40 Kunming female mice were divided randomly into 5 groups and iniected with icv aCSF or NMDA.AMPA.MK-801 or NBQX after intraperitoneally administered propofol 50 mg/kg.The pain threshold of the mice was then investigated by hot-plate test(HPPT).NMDA(0.05 or 0.075μg,icv)or AMPA(0.05 μg,icv)exhibited no effects on the LORR,but NMDA(0.1 μg,icv)or AMPA(0.075 or 0.1 μg,icv)prolonged the LORR significantly compared with the aCSF group(P<0.05,P<0.01).The LORR of the 2 μg MK-801 group had no changes,while those of the 4 or 8 μg MK-801 groups were prolonged significantly.The LORR of the 0.5,2 or 4 μg NBQX groups were all prolonged significantly.NMDA 0.05 μg or AMPA 0.05 μg decreased the pain threshold slightly but did not differ in effect compared with the aCSF group;2 μg MK-801 or 0.5 μg NBQX both increased the pain threshold significantly.Our results indicate that propofol produces general anesthesia partly through an interaction with brain NMDA and AMPA receptors in mice.

  6. The comparison of effects of processed Aconiti tuber, U50488H and MK-801 on the antinociceptive tolerance to morphine.

    Science.gov (United States)

    Shu, Haihua; Hayashida, Masakazu; Huang, Wenqi; An, Ke; Chiba, Shunsuke; Hanaoka, Kazuo; Arita, Hideko

    2008-04-17

    In the previous studies, we demonstrated that an oriental herbal medicine, processed Aconiti tuber (PAT), at subanalgesic doses could inhibit or reverse the antinociceptive tolerance to morphine. In the present study, we compared the effect of PAT, trans-(+/-)-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidin)cyclohexyl)-benzeneacetamide methane sulfonate hydrate (U50488H), a selective kappa opioid receptor (KOR) agonist, and (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine-maleate (MK-801), a N-methyl-D-aspartate (NMDA) receptor antagonist, on the antinociceptive tolerance to morphine in the same experimental condition. Mice received subcutaneous morphine (10 mg/kg), and oral PAT at a subanalgesic dose (0.3 g/kg for mechanical or 1.0 g/kg for thermal test), or intraperitoneal U50488H at a subanalgesic dose (3 mg/kg), or MK-801 at a subanalgesic dose (0.1 mg/kg) once daily for 14 days. The mechanical nociceptive threshold was measured before, and at 60 min by tail pressure testing, and thermal nociceptive latency was measured before, and at 30 min by hot plate testing, after daily morphine injections. PAT and U50488H could not only inhibit the development of morphine tolerance but also reverse the already-developed morphine tolerance, while MK-801 could only inhibit the development of morphine tolerance but not reverse the already-developed morphine tolerance, in both mechanical and thermal nociceptive tests. These data suggested that PAT, an indirect-acting KOR agonist, share the common pharmacological property of KOR agonists on morphine tolerance, and that PAT may be superior to some NMDA receptor antagonists which do not reverse already-developed morphine tolerance.

  7. NMDA receptor antagonism differentially reduces acquisition and expression of sucrose- and fructose-conditioned flavor preferences in BALB/c and SWR mice.

    Science.gov (United States)

    Kraft, Tamar T; Huang, Donald; Lolier, Melanie; Warshaw, Deena; LaMagna, Sam; Natanova, Elona; Sclafani, Anthony; Bodnar, Richard J

    2016-09-01

    Conditioned flavor preferences (CFP) are elicited by sucrose and fructose relative to saccharin in rats and inbred mice. Whereas dopamine, but not opioid receptor antagonists interfere with the acquisition (learning) and expression (maintenance) of sugar-CFP in rats, these antagonists differentially affect acquisition and expression of sucrose- and fructose-CFP in BALB/c and SWR inbred mice. Given that NMDA receptor antagonism with MK-801 blocks acquisition, but not expression of fructose-CFP in rats, the present study examined whether MK-801 altered the expression and acquisition of sucrose- and fructose-CFP in BALB/c and SWR mice. In expression experiments, food-restricted mice alternately consumed a flavored (CS+, e.g., cherry, 5 sessions) 16% sucrose or 8% fructose+0.2% saccharin solution and a differently-flavored (CS-, e.g., grape, 5 sessions) 0.2% saccharin solution. 2-Bottle CS choice tests occurred following vehicle or MK-801 at doses of 100 or 200μg/kg. MK-801 mildly reduced the magnitude of the expression of sucrose- and fructose-CFP in BALB/c mice, and blocked the expression of fructose-, but not sucrose-CFP at the high dose in SWR mice. In acquisition experiments, groups of BALB/c (0, 100μg/kg) and SWR (0, 100, 200μg/kg) mice were treated prior to acquisition training sessions that was followed by 2-bottle CS choice tests without injections. MK-801 (100μg/kg) eliminated acquisition of sucrose- and fructose-CFP in BALB/c, but not SWR mice. The 200μg/kg MK-801 dose eliminated acquisition of sucrose- and fructose-CFP in SWR mice. Thus, NMDA receptor signaling is essential for the learning of both forms of sugar-CFP in both strains with BALB/c mice more sensitive to MK-801 dose effects.

  8. NMDA receptors of dorsal hippocampus are involved in the acquisition, but not in the expression of morphine-induced place preference.

    Science.gov (United States)

    Zarrindast, Mohammad-Reza; Lashgari, Reza; Rezayof, Ameneh; Motamedi, Fereshteh; Nazari-Serenjeh, Farzaneh

    2007-07-30

    In the present study, involvement of the N-methyl-d-aspartate (NMDA) receptors of the CA1 region of dorsal hippocampus (intra-CA1) in the acquisition or expression of morphine-induced conditioned place preference in rats was studied. Male Wistar rats were used in these experiments. NMDA-receptor agonist (NMDA) and antagonist (MK-801) were injected into the CA1 region of the dorsal hippocampus (intra-CA1) and morphine was injected subcutaneously. An unbiased conditioned place preference paradigm was used to study the effect of these agents. In the first set of experiments, the drugs were used during the development of conditioned place preference by morphine or they were used alone in order to see if they induce conditioned place preference or conditioned place aversion. Our data showed that subcutaneous (s.c.) injection of morphine sulphate (2.5-10 mg/kg) induced conditioned place preference in rat. NMDA (0.1-1 microg/rat) or MK-801 (1-4 microg/rat) did not induce conditioned place preference or conditioned place aversion. Intra-CA1 administration of different doses of NMDA (0.1-1 microg/rat) increased, while MK-801 (1-4 microg/rat) decreased morphine-induced place preference. MK-801 reversed the effect of NMDA on morphine response. In the second set of experiments, when the drugs were used before testing on Day 5, in order to test their effects on the expression of morphine (7.5 mg/kg)-induced place preference, intra-CA1 administration of NMDA or MK-801 did not alter the morphine response. None of the drugs influenced locomotion. It is concluded that NMDA receptor of the CA1 region of hippocampus are involved in the acquisition but not expression of morphine-induced place preference.

  9. A Possible Non-genomic Epileptogenic Properties of Estradiol Attenuated by MK801 and DNQX in Amygdala Kindled Rats

    Science.gov (United States)

    Saberi, Mehdi; Saberi, Fatemeh; Vesali Mahmoud, Roshanak

    2014-01-01

    Although the epileptogenic properties of estrogens have been widely demonstrated in several models and species, the mechanism(s) by which estrogens can acutely change seizure parameters including after discharge and seizure durationremains to be determined. In the present study, we examined the role of NMDA (N-methyl-D-aspartate), non-NMDA andestrogen receptors in estradiol benzoate(EB) effects on kindled seizure parameters. Different groups of fully kindled male rats received either EB (30 μg /Kg); EB plus MK801 (2 mg/Kg, as NMDA antagonist); DNQX (7.5 mg/Kg);tamoxifen (TAM, 0.1 mg/Kg, as non- NMDA antagonist) or intra-amygdala injection of anisomycine (30 mmol/mL, a protein synthesis inhibitor). Kindled seizure parameters including after discharge duration (ADD) and stage 5 duration(S5D) were determined at 0.25 and 3 h post sesame oil (EB solvent) or EB treatment. While pretreatment with either MK801 or DNQX could block the ADD prolongation induced by EB at 0.25 h, they had no effect on S5D prolongation at 3 h. Moreover, application of anisomycine or TAM had no effect on estradiol induced ADD and S5D prolongation. These results indicate that both NMDA and non-NMDA receptors could be involved in EB induced ADD prolongation. The observed short termnon-estrogenic receptor or protein synthesis dependent effects of EB may provide a non-genomic mechanism for the stimulatory effects of the steroid on seizure activity. PMID:25276200

  10. Effects of NMDA receptor antagonists on probability discounting depend on the order of probability presentation.

    Science.gov (United States)

    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.

  11. Differential effect of NMDA and AMPA receptor blockade on protein synthesis in the rat infarct borderzone

    DEFF Research Database (Denmark)

    Christensen, Thomas; Bruhn, T; Frank, L

    1996-01-01

    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 trea...... compounds reduce infarct size, it is questionable that acute inhibition of protein synthesis in focal ischemia is of significant importance to the final outcome of a stroke lesion....

  12. NMDA receptor antagonists extend the sensitive period for imprinting.

    Science.gov (United States)

    Parsons, C H; Rogers, L J

    2000-03-01

    Filial imprinting in the domestic chick occurs during a sensitive period of development. The exact timing of this period can vary according to the methods used to measure imprinting. Using our imprinting paradigm, we have shown that normal, dark-reared chicks lose the ability to imprint after the second day post-hatching. Further, we reported that chicks treated 10 h after hatching with a mixture of the noncompetitive NMDA receptor antagonist ketamine (55 mg/kg) and the alpha(2)-adrenergic receptor agonist xylazine (6 mg/kg) were able to imprint on day 8 after hatching, whereas controls treated with saline did not imprint. We now show that the effect of the ketamine-xylazine mixture can be mimicked by treating chicks with ketamine alone or with another noncompetitive NMDA receptor antagonist, MK-801 (5 mg/kg). Treating chicks with a single dose of ketamine (55 mg/kg) or with a single dose of xylazine (6 mg/kg) failed to produce the effect on the sensitive period. However, prolonging the action of ketamine by treating chicks with two doses of ketamine (at 10 and 12 h after hatching) did allow imprinting on day 8. In contrast, prolonging the action of xylazine had no effect on the sensitive period for imprinting. Chicks treated with MK-801 were also able to imprint on day 8. Thus, we have evidence that the NMDA receptor system is involved in the mechanisms that control the sensitive period for imprinting.

  13. Brain-derived neurotrophic factor activation of extracellular signal-regulated kinase is autonomous from the dominant extrasynaptic NMDA receptor extracellular signal-regulated kinase shutoff pathway.

    Science.gov (United States)

    Mulholland, P J; Luong, N T; Woodward, J J; Chandler, L J

    2008-01-24

    NMDA receptors bidirectionally modulate extracellular signal-regulated kinase (ERK) through the coupling of synaptic NMDA receptors to an ERK activation pathway that is opposed by a dominant ERK shutoff pathway thought to be coupled to extrasynaptic NMDA receptors. In the present study, synaptic NMDA receptor activation of ERK in rat cortical cultures was partially inhibited by the highly selective NR2B antagonist Ro25-6981 (Ro) and the less selective NR2A antagonist NVP-AAM077 (NVP). When Ro and NVP were added together, inhibition appeared additive and equal to that observed with the NMDA open-channel blocker MK-801. Consistent with a selective coupling of extrasynaptic NMDA receptors to the dominant ERK shutoff pathway, pre-block of synaptic NMDA receptors with MK-801 did not alter the inhibitory effect of bath-applied NMDA on ERK activity. Lastly, in contrast to a complete block of synaptic NMDA receptor activation of ERK by extrasynaptic NMDA receptors, activation of extrasynaptic NMDA receptors had no effect upon ERK activation by brain-derived neurotrophic factor. These results suggest that the synaptic NMDA receptor ERK activation pathway is coupled to both NR2A and NR2B containing receptors, and that the extrasynaptic NMDA receptor ERK inhibitory pathway is not a non-selective global ERK shutoff.

  14. The myelinated fiber loss in the corpus callosum of mouse model of schizophrenia induced by MK-801.

    Science.gov (United States)

    Xiu, Yun; Kong, Xiang-ru; Zhang, Lei; Qiu, Xuan; Gao, Yuan; Huang, Chun-xia; Chao, Feng-lei; Wang, San-rong; Tang, Yong

    2015-04-01

    Previous magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) investigations have shown that the white matter volume and fractional anisotropy (FA) were decreased in schizophrenia (SZ), which indicated impaired white matter integrity in SZ. However, the mechanism underlying these abnormalities has been less studied. The current study was designed to investigate the possible reasons for white matter abnormalities in the mouse model of SZ induced by NMDA receptor antagonist using the unbiased stereological methods and transmission electron microscope technique. We found that the mice treated with MK-801 demonstrated a series of schizophrenia-like behaviors including hyperlocomotor activity and more anxiety. The myelinated fibers in the corpus callosum (CC) of the mice treated with MK-801 were impaired with splitting lamellae of myelin sheaths and segmental demyelination. The CC volume and the total length of the myelinated fibers in the CC of the mice treated with MK-801 were significantly decreased by 9.4% and 16.8% when compared to those of the mice treated with saline. We further found that the loss of the myelinated fibers length was mainly due to the marked loss of the myelinated nerve fibers with the diameter of 0.4-0.5 μm. These results indicated that the splitting myelin sheaths, demyelination and the loss of myelinated fibers with small diameter might provide one of the structural bases for impaired white matter integrity of CC in the mouse model of SZ. These results might also provide a baseline for further studies searching for the treatment of SZ through targeting white matter.

  15. Predictive validity of a MK-801-induced cognitive impairment model in mice: implications on the potential limitations and challenges of modeling cognitive impairment associated with schizophrenia preclinically.

    Science.gov (United States)

    Brown, Jordan W; Rueter, Lynne E; Zhang, Min

    2014-03-03

    Cognitive impairment associated with schizophrenia (CIAS) is a major and disabling symptom domain of the disease that is generally unresponsive to current pharmacotherapies. Critically important to the discovery of novel therapeutics for CIAS is the utilization of preclinical models with robust predictive validity. We investigated the predictive validity of MK-801-induced memory impairments in mouse inhibitory avoidance (MK-IA) as a preclinical model for CIAS by investigating compounds that have been tested in humans, including antipsychotics, sodium channel blocker mood stabilizers, and putative cognitive enhancers. The atypical antipsychotic clozapine, as well as risperidone and olanzapine (see Brown et al., 2013), had no effect on MK-801-induced memory impairments. For sodium channel blockers, carbamazepine significantly attenuated memory impairments induced by MK-801, whereas lamotrigine had no effect. Nicotine, donepezil, modafinil, and xanomeline all significantly attenuated MK-801-induced memory impairments, but the magnitude of effects and the dose-responses observed varied across compounds. Clinically, only acute administration of nicotine has demonstrated consistent positive effects on CIAS, while inconsistent results have been reported for lamotrigine, donepezil, and modafinil; atypical antipsychotics produce only moderate improvements at best. A positive clinical signal has been observed with xanomeline, but only in a small pilot trial. The results presented here suggest that the MK-IA model lacks robust predictive validity for CIAS as the model is likely permissive and may indicate false positive signals for compounds and mechanisms that lack clear clinical efficacy for CIAS. Our findings also highlight the potential limitations and challenges of using NMDA receptor antagonists in rodents to model CIAS.

  16. Disruption of long-term alcohol-related memory reconsolidation: Role of β-adrenoceptors and NMDA receptors

    Directory of Open Access Journals (Sweden)

    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.

  17. Effects of the NMDA receptor antagonists on deltamethrin-induced striatal dopamine release in conscious unrestrained rats.

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    Morikawa, Takuya; Furuhama, Kazuhisa

    2009-08-01

    To better understand the neurotoxicity caused by the pyrethroid pesticide, we examined the effects of the N-methyl-D-aspartate (NMDA) receptor antagonists MK-801, a non-competitive cation channel blocker, and 2-amino-5-phosphonovaleric acid (APV), a competitive Na(+) channel blocker, on extracellular dopamine levels in male Sprague-Dawley rats receiving the type II pyrethroid deltamethrin using an in vivo microdialysis system. Deltamethrin (60 mg/kg, i.p.) evidently increased striatal dopamine levels with a peak time of 120 min, and the local infusion (i.c.) of either MK-801(650 muM) or APV (500 muM) completely blocked these actions. The fluctuation in the dopamine metabolite 3-MT also resembled that in dopamine. Our results suggest that dopamine-releasing neurons would be modulated via the NMDA receptor by the excitatory glutamatergic neurons after deltamethrin treatment.

  18. Role of the NMDA receptor and iron on free radical production and brain damage following transient middle cerebral artery occlusion.

    Science.gov (United States)

    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.

  19. Effect of MK-801 on methamphetamine-induced dopaminergic neurotoxicity: long-term attenuation of methamphetamine-induced dopamine release

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    Kim, Sang Eun; Kim, Yu Ri; Hwang, Se Hwan [Sungkyunkwan Univ., School of Medicine, Seoul (Korea, Republic of)

    2001-08-01

    Repeated administration of methamphetamine (METH) produces high extracellular levels of dopamine (DA) and subsequent striatal DA terminal damage. The effect of MK-801, a noncompetitive N-methyl-D-aspartate receptor antagonist, on METH-induced changes in DA transporter (DAT) and DA release evoked by an acute METH challenge was evaluated in rodent striatum using [{sup 3}H] WIN 38,428 ex vivo auto-radiography and in vivo microdialysis. Four injections of METH (10 mg/kg, i.p.), each given 2 h apart, produced 71% decrease in DAT levels in mouse striatum 3 d after administration. Pretreatment with MK-801 (2.5 g/kg, i.p.) 15 min before each of the four METH injections protected completely against striatal DAT depletions. Four injections of MK-801 alone did not significantly change striatal DAT levels. Striatal DA release evoked by an acute METH challenge (4mg/kg, i.p.) at 3 d after repeated administration of METH in rats was decreased but significant compared with controls, which was attenuated by repeated pretreatment with MK-801. Also, repeated injections of MK-801 alone attenuated acute METH-induced striatal DA release 3 d after administration. These results suggest that repeated administration of MK-801 may exert a preventive effect against METH-induced DA terminal injury through long-term attenuation of DA release induced by METH and other stimuli.

  20. NMDA receptor antagonism potentiates the L-DOPA-induced extracellular dopamine release in the subthalamic nucleus of hemi-parkinson rats.

    Science.gov (United States)

    El Arfani, Anissa; Bentea, Eduard; Aourz, Najat; Ampe, Ben; De Deurwaerdère, Philippe; Van Eeckhaut, Ann; Massie, Ann; Sarre, Sophie; Smolders, Ilse; Michotte, Yvette

    2014-10-01

    Long term treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) is associated with several motor complications. Clinical improvement of this treatment is therefore needed. Lesions or high frequency stimulation of the hyperactive subthalamic nucleus (STN) in Parkinson's disease (PD), alleviate the motor symptoms and reduce dyskinesia, either directly and/or by allowing the reduction of the L-DOPA dose. N-methyl-D-aspartate (NMDA) receptor antagonists might have similar actions. However it remains elusive how the neurochemistry changes in the STN after a separate or combined administration of L-DOPA and a NMDA receptor antagonist. By means of in vivo microdialysis, the effect of L-DOPA and/or MK 801, on the extracellular dopamine (DA) and glutamate (GLU) levels was investigated for the first time in the STN of sham and 6-hydroxydopamine-lesioned rats. The L-DOPA-induced DA increase in the STN was significantly higher in DA-depleted rats compared to shams. MK 801 did not influence the L-DOPA-induced DA release in shams. However, MK 801 enhanced the L-DOPA-induced DA release in hemi-parkinson rats. Interestingly, the extracellular STN GLU levels remained unchanged after nigral degeneration. Furthermore, administration of MK 801 alone or combined with L-DOPA did not alter the STN GLU levels in both sham and DA-depleted rats. The present study does not support the hypothesis that DA-ergic degeneration influences the STN GLU levels neither that MK 801 alters the GLU levels in lesioned and non-lesioned rats. However, NMDA receptor antagonists could be used as a beneficial adjuvant treatment for PD by enhancing the therapeutic efficacy of l-DOPA at least in part in the STN.

  1. EFECTO DE LA ADMINISTRACIÓN INTRACEREBRAL DE MK-801 Y (- NICOTINA EN LAS CONCENTRACIONES EXTRACELULARES DE GLU Y GABA EN EL NÚCLEO PEDUNCULOPONTINO DE RATAS Effect of the Mk801 and (- Nicotine Intracerebral Administration on Glu and Gaba Extracellular Concentration in the Pedunculopontine Nucleus from Rats

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    LISETTE BLANCO LEZCANO

    Full Text Available Aunque la manipulación farmacológica de los sistemas glutamatérgico y colinérgico se ha tratado en modelos experimentales de enfermedad de Parkinson (EP, pocos autores han realizado estudios de esta temática a nivel del núcleo pedunculopontino (NPP. El presente trabajo aborda los cambios en las concentraciones extracelulares (CE de glutamato (Glu y ácido δ-amino butírico (GABA en el NPP de ratas hemiparkinsonizadas por inyección de 6-hidroxidopamina (6-OHDA y sometidas a infusión local de MK-801 (10 µmol/L o (- nicotina (10 mM. La infusión se realizó mediante microdiálisis cerebral y la determinación de CE de neurotransmisores se realizó a través de cromatografía líquida de alta resolución acoplada a detección de fluorescencia. La infusión de MK-801 en el NPP produjo disminución significativa de CE de Glu (pAlthough the pharmacological manipulation of the glutamatergic and cholinergic systems have been studied in animal models of Parkinson´s disease (PD, only some authors have done work on this topic at the pedunculopontine nucleus (PPN. The present work studied the changes in glutamate (Glu and δ-aminobutyric acid (GABA extracellular concentrations (EC in the PPN from hemiparkinsonian rats by 6hydroxydopamine injection. The rats were locally perfused by MK-801 (10 µmol/L or (- nicotine (10 mM solutions by cerebral microdyalisis. The biochemical studies were carried out through high performance liquid chromatography coupled to fluorescence detection. MK-801 infusion induced a significant decrease of Glu (p< 0.01 and GABA (p< 0.01 EC in PPN. On the other hand (- nicotine infusion induced a significant increase of Glu (p< 0.001 and GABA (p< 0.001 EC in PPN from hemiparkinsonian rats. The local blockade of NMDA receptors by MK-801 infusion facilitates the interaction between Glu and their metabotropic receptors that take part in presynaptic inhibition mechanisms and interfere with neurotransmitters release. Meanwhile, the

  2. Critical role of NMDA but not opioid receptors in the acquisition of fat-conditioned flavor preferences in rats.

    Science.gov (United States)

    Dela Cruz, J A D; Bae, V S; Icaza-Cukali, D; Sampson, C; Bamshad, D; Samra, A; Singh, S; Khalifa, N; Touzani, K; Sclafani, A; Bodnar, R J

    2012-11-01

    Animals learn to prefer flavors associated with the intake of dietary fats such as corn oil (CO) solutions. We previously reported that fat-conditioned flavor preferences in rats were relatively unaffected by systemic treatment with dopamine D1 and D2 antagonsits. The present study examined whether systemic opioid (naltrexone, NTX) or NMDA (MK-801) receptor antagonists altered the acquisition and/or expression of CO-CFP. The CFP was produced by training rats to drink one novel flavor (CS+, e.g., cherry) mixed in a 3.5% CO solution and another flavor (CS-, e.g., grape) in a 0.9% CO solution. In expression studies, food-restricted rats drank these solutions in one-bottle sessions (2 h) over 10 d. Subsequent two-bottle tests with the CS+ and CS- flavors mixed in 0.9% CO solutions occurred 0.5h after systemic administration of vehicle (VEH), NTX (0.1-5 mg/kg) or MK-801 (50-200 μg/kg). Rats displayed a robust CS+ preference following VEH treatment (85-88%) which was significantly though moderately attenuated by NTX (69-70%). The lower doses of MK-801 slightly reduced the CS+ preference; the high dose blocked the CS+ preference (49%) but also markedly reduced overall CS intake. In separate acquisition studies, rats received VEH or NTX (0.1, 0.5, 1mg/kg) or MK-801 (100 μg/kg) 0.5h prior to 1-bottle training trials with CS+/3.5% CO and CS-/0.9% CO training solutions. Additional Limited VEH groups were trained with intakes limited to that of the NTX and MK-801 groups. Subsequent two-bottle CS+ vs. CS- tests were conducted without injections. Significant and persistent CS+ preferences were observed in VEH (77-84%) and Limited VEH (88%) groups. NTX treatment during training failed to block the acquisition of CO-CFP although the magnitude of the CS+ preference was reduced by 0.5 (70%) and 1.0 (72%) mg/kg doses relative to the Limited VEH treatment (88%). In contrast, MK-801 (100 μg/kg) treatment during training blocked the acquisition of the CO-CFP. These data suggest a

  3. Effects of nicotine on quinpirole- and dizocilpine (MK-801)-induced sensorimotor gating impairments in rats.

    Science.gov (United States)

    Nespor, Amy A; Tizabi, Yousef

    2008-10-01

    Prepulse inhibition (PPI) of the acoustic startle response (ASR) is used as an index of sensorimotor gating to assess preattentive processes. Impairments in PPI have been observed in many neuropsychiatric disorders, especially schizophrenia. Administration of the glutamate N-methyl-D-aspartate receptor antagonist dizocilpine (MK-801) or dopamine receptor (D2/D3) agonist quinpirole (QNP) results in impairment (reduction) of PPI in rats. Nicotine, on the other hand, may have beneficial effects on attentional/cognitive functions. The purpose of the current set of experiments was to investigate the effects of acute and chronic nicotine on MK-801- and QNP-induced PPI impairments. Adult female Sprague-Dawley rats were treated acutely or chronically by various doses of nicotine alone or followed by an acute dose of MK-801 (0.15 mg/kg) or QNP (0.5 mg/kg). All drugs were administered intraperitoneally. Controls received saline in lieu of any drug, and ASR and PPI in each animal was evaluated 10 min after the last injection. Both MK-801 and QNP consistently impaired PPI. Administration of nicotine acutely (0.05-0.4 mg/kg) or chronically (0.2 or 0.4 mg/kg daily for 1 week) did not have any effect of its own on ASR or PPI or on MK-801-induced PPI impairment. Acute administration of 0.2 mg/kg nicotine did not have any effect on QNP-induced reduction in PPI, whereas the higher dose of 0.4 mg/kg significantly attenuated this impairment. Chronic daily administration of either 0.2 or 0.4 mg/kg nicotine for 1 week nearly normalized the QNP-induced impairments in PPI. The effect of nicotine on sensorimotor gating is dependent on the procedure as well as the dose of nicotine and appears to be efficacious against dopaminergic rather than glutamatergic disruption of PPI in rats.

  4. AC-3933, a benzodiazepine partial inverse agonist, improves memory performance in MK-801-induced amnesia mouse model.

    Science.gov (United States)

    Hashimoto, Takashi; Iwamura, Yoshihiro

    2016-05-01

    AC-3933, a novel benzodiazepine receptor partial inverse agonist, is a drug candidate for cognitive disorders including Alzheimer's disease. We have previously reported that AC-3933 enhances acetylcholine release in the rat hippocampus and ameliorates scopolamine-induced memory impairment and age-related cognitive decline in both rats and mice. In this study, we further evaluated the procognitive effect of AC-3933 on memory impairment induced by MK-801, an N-methyl-d-aspartate receptor antagonist, in mice. Unlike the acetylcholinesterase inhibitor donepezil and the benzodiazepine receptor inverse agonist FG-7142, oral administration of AC-3933 significantly ameliorated MK-801-induced memory impairment in the Y-maze test and in the object location test. Interestingly, the procognitive effects of AC-3933 on MK-801-induced memory impairment were not affected by the benzodiazepine receptor antagonist flumazenil, although this was not the case for the beneficial effects of AC-3933 on scopolamine-induced memory deficit. Moreover, the onset of AC-3933 ameliorating effect on scopolamine- or MK-801-induced memory impairment was different in the Y-maze test. Taken together, these results indicate that AC-3933 improves memory deficits caused by both cholinergic and glutamatergic hypofunction and suggest that the ameliorating effect of AC-3933 on MK-801-induced memory impairment is mediated by a mechanism other than inverse activation of the benzodiazepine receptor.

  5. Blocking NMDA receptors delays death in rats with acute liver failure by dual protective mechanisms in kidney and brain.

    Science.gov (United States)

    Cauli, Omar; González-Usano, Alba; Cabrera-Pastor, Andrea; Gimenez-Garzó, Carla; López-Larrubia, Pilar; Ruiz-Sauri, Amparo; Hernández-Rabaza, Vicente; Duszczyk, Malgorzata; Malek, Michal; Lazarewicz, Jerzy W; Carratalá, Arturo; Urios, Amparo; Miguel, Alfonso; Torregrosa, Isidro; Carda, Carmen; Montoliu, Carmina; Felipo, Vicente

    2014-06-01

    Treatment of patients with acute liver failure (ALF) is unsatisfactory and mortality remains unacceptably high. Blocking NMDA receptors delays or prevents death of rats with ALF. The underlying mechanisms remain unclear. Clarifying these mechanisms will help to design more efficient treatments to increase patient's survival. The aim of this work was to shed light on the mechanisms by which blocking NMDA receptors delays rat's death in ALF. ALF was induced by galactosamine injection. NMDA receptors were blocked by continuous MK-801 administration. Edema and cerebral blood flow were assessed by magnetic resonance. The time course of ammonia levels in brain, muscle, blood, and urine; of glutamine, lactate, and water content in brain; of glomerular filtration rate and kidney damage; and of hepatic encephalopathy (HE) and intracranial pressure was assessed. ALF reduces kidney glomerular filtration rate (GFR) as reflected by reduced inulin clearance. GFR reduction is due to both reduced renal perfusion and kidney tubular damage as reflected by increased Kim-1 in urine and histological analysis. Blocking NMDA receptors delays kidney damage, allowing transient increased GFR and ammonia elimination which delays hyperammonemia and associated changes in brain. Blocking NMDA receptors does not prevent cerebral edema or blood-brain barrier permeability but reduces or prevents changes in cerebral blood flow and brain lactate. The data show that dual protective effects of MK-801 in kidney and brain delay cerebral alterations, HE, intracranial pressure increase and death. NMDA receptors antagonists may increase survival of patients with ALF by providing additional time for liver transplantation or regeneration.

  6. Opioid/NMDA receptors blockade reverses the depressant-like behavior of foot shock stress in the mouse forced swimming test.

    Science.gov (United States)

    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.

  7. Chronic NMDA receptor blockade in early postnatal period, but not in adulthood, impairs methamphetamine-induced conditioned place preference in rats.

    Science.gov (United States)

    Furuie, Hiroki; Yamada, Kazuo; Ichitani, Yukio

    2016-03-15

    Early postnatal glutamatergic N-methyl-d-aspartate (NMDA) receptor blockade in animals is known to produce various behavioral deficits in adulthood. In the present study rats postnatally (day 7-20) treated chronically with MK-801, an NMDA receptor antagonist, were tested later in adulthood in methamphetamine (MAP)-induced conditioned place preference (CPP) using a unbiased procedure in a three-compartment apparatus. Rats with the same chronic treatment in adulthood were also tested. CPP test consisted of a baseline test before conditioning, place conditioning, and a preference test after conditioning. Rats postnatally treated with MK-801 did not show any evidence of preference for MAP-paired compartment compared with that for unpaired one in the preference test that was shown in rats postnatally treated with saline. On the other hand, rats treated with MK-801 in adulthood were not affected by the treatment and showed significant CPP as was shown in saline-treated control animals. Results suggest the possibility that chronic early postnatal, but not adulthood, NMDA receptor blockade induces persistent deficit of subsequent appetitive classical conditioning.

  8. 谷氨酸和MK-801对正常和帕金森模型大鼠纹状体内多巴胺代谢的影响%Effects of glutamate and MK-801 on the metabolism of dopamine in the striatum of normal and parkinsonian rats

    Institute of Scientific and Technical Information of China (English)

    段春礼; 孙晓红; 姬曼; 杨慧

    2005-01-01

    The direct effects of glutamate and dizocilpine maleate (MK-801, non-competitive N-Methyl-D-aspartate glutamate receptor antagonist) on the metabolism of dopamine were investigated in the striatum of normal and parkinsonian rats. L-dopa, L-glutamic acid and MK-801 were administered in the striatum locally by microdialysis. 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were simultaneously sampled by microdialysis. The concentrations of DOPAC and HVA were assayed by high performance liquid chromatography with electrochemical detection (HPLC-ECD). L-dopa increased the concentrations of DOPAC and HVA in the striatum of normal and parkinsonian rats. L-glutamic acid decreased the concentrations of DOPAC and HVA in striatum of normal rats but not parkinsonian rats. MK-801 increased the concentrations of DOPAC and HVA in the striatum of normal rats but not parkinsonian rats. MK-801 prevented the L-glutamic acid-induced decrease of DOPAC and HVA in the striatum of normal rats. Our results indicate that glutamate modulates the metabolism of dopamine (DA) through NMDA receptors and that the improvement of PD by MK-801 is not through improving the metabolism of DA.%采用微透析和高效液相色谱-电化学(HPLC-ECD)技术研究了谷氨酸和MK-801对正常和帕金森模型大鼠纹状体内多巴胺代谢的影响.用微透析技术在大鼠纹状体内分别定位给以左旋多巴、L-谷氨酸和/或MK-801,同时收集透析液,用HPLC-ECD方法测定透析液中多巴胺代谢产物的浓度.微透析和HPLC-ECD分析结果表明:纹状体内定位给以左旋多巴,正常大鼠和帕金森模型大鼠纹状体内多巴胺代谢产物的浓度均升高;纹状体内定位给以L-谷氨酸,可使正常大鼠纹状体内多巴胺代谢产物的浓度降低,但对帕金森大鼠模型纹状体内多巴胺代谢产物浓度的降低不显著;纹状体内定位给以MK-801,正常大鼠纹状体内多巴胺代谢产物的浓度升高;但对帕金森

  9. Dopaminergic responses in the core part of the nucleus accumbens to subcutaneous MK801 administration are increased following postnatal transient blockade of the prefrontal cortex.

    Science.gov (United States)

    Tagliabue, Emmanuelle; Pouvreau, Tiphaine; Eybrard, Séverine; Meyer, Francisca; Louilot, Alain

    2017-09-29

    Schizophrenia is a complex and devastating neuropsychiatric disease thought to result from impaired connectivity between several integrative regions, stemming from developmental failures. In particular, the left prefrontal cortex of schizophrenia patients seems to be targeted by such early developmental disturbances. Data obtained over the last three decades support the hypothesis of a dopaminergic dysfunction in schizophrenia. Striatal dopaminergic dysregulation in schizophrenia may result from a dysconnection between the prefrontal cortex and the striatum (dorsal and ventral) involving glutamatergic N-methyl-d-aspartate (NMDA) receptors. In the context of animal modeling of the pathophysiology of schizophrenia, the present study was designed to investigate the effects of MK 801 (dizocilpine) on locomotor activity and dopaminergic responses in the left core part of the nucleus accumbens (ventral striatum) in adult rats following neonatal tetrodotoxin inactivation of the left prefrontal cortex (infralimbic/prelimbic region) at postnatal day 8. Dopaminergic variations were recorded in the nucleus accumbens by means of in vivo voltammetry in freely moving adult animals. Following MK 801 administration, and in comparison to control (PBS) animals, animals microinjected with tetrodotoxin display locomotor hyperactivity and increased extracellular dopamine levels in the core part of the nucleus accumbens. These findings suggest neonatal functional inactivation of the prefrontal cortex may lead to a dysregulation of dopamine release in the core part of the nucleus accumbens involving NMDA receptors. The results obtained may provide new insight into the involvement of NMDA receptors in the pathophysiology of schizophrenia and suggest that future studies should look carefully at the core of the nucleus accumbens. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Unilateral block of NMDA receptors in the amygdala prevents predator stress-induced lasting increases in anxiety-like behavior and unconditioned startle--effective hemisphere depends on the behavior.

    Science.gov (United States)

    Adamec, R E; Burton, P; Shallow, T; Budgell, J

    Lasting increases in anxiety-like behavior (ALB) in the elevated plus-maze are produced by a single 5-min exposure of a rat to a cat. Rats become more anxious in the plus-maze for up to 3 weeks after the exposure. The first study in this series demonstrated that blockade of NMDA receptors in rats with MK-801, AP7, or CPP, given systemically 30 min prior to exposure to a cat prevents the increase in ALB assessed 1 week later in the elevated plus-maze. To localize the site of action of systemic MK-801, MK-801 was injected in the amygdala 30 min prior to predator stress. Injections were given either unilaterally in either hemisphere, or bilaterally in both hemispheres. The target of the injection was the basolateral amygdala. The effects of injection depended on both the type of behavior and the hemisphere of injection. Injections of MK-801 in a variety of sites in the basolateral amygdala had no effect on the suppression of open-arm exploration produced by predator stress. Other amygdala nuclei or other limbic sites likely mediate the effects of systemically administered MK-801 on this behavior. In contrast, NMDA receptors in the left lateral amygdala mediate lasting suppression of risk assessment. MK-801, in a variety of sites in the left but not right lateral amygdala, blocked the effects of predator stress on risk assessment. This is clear evidence of separability of neural mechanisms controlling open-arm exploration and risk assessment. Different NMDA-dependent amygdala circuitry mediated effects of predator stress on unconditioned acoustic startle 1 week after cat exposure. The data indicate that integrity of the left lateral amygdala is necessary for potentiation of startle amplitude by predator stress, though NMDA receptors are not involved in this function. Nevertheless, NMDA receptors in the right, but not the left lateral amygdala, mediate initiation of changes in startle. The data also suggest that the right amygdala action is "downstream" from the left

  11. Region-selective effects of neuroinflammation and antioxidant treatment on peripheral benzodiazepine receptors and NMDA receptors in the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    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.

  12. A quantitative method to assess extrasynaptic NMDA receptor function in the protective effect of synaptic activity against neurotoxicity

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    Bading Hilmar

    2008-01-01

    Full Text Available Abstract Background Extrasynaptic NMDA receptors couple to a CREB shut-off pathway and cause cell death, whereas synaptic NMDA receptors and nuclear calcium signaling promote CREB-mediated transcription and neuronal survival. The distribution of NMDA receptors (synaptic versus extrasynaptic may be an important parameter that determines the susceptibility of neurons to toxic insults. Changes in receptor surface expression towards more extrasynaptic NMDA receptors may lead to neurodegeneration, whereas a reduction of extrasynaptic NMDA receptors may render neurons more resistant to death. A quantitative assessment of extrasynaptic NMDA receptors in individual neurons is needed in order to investigate the role of NMDA receptor distribution in neuronal survival and death. Results Here we refined and verified a protocol previously used to isolate the effects of extrasynaptic NMDA receptors using the NMDA receptor open channel blocker, MK-801. Using this method we investigated the possibility that the known neuroprotective shield built up in hippocampal neurons after a period of action potential bursting and stimulation of synaptic NMDA receptors is due to signal-induced trafficking of extrasynaptic NMDA receptors or a reduction in extrasynaptic NMDA receptor function. We found that extrasynaptic NMDA receptor-mediated calcium responses and whole cell currents recorded under voltage clamp were surprisingly invariable and did not change even after prolonged (16 to 24 hours periods of bursting and synaptic NMDA receptor activation. Averaging a large number of calcium imaging traces yielded a small (6% reduction of extrasynaptic NMDA receptor-mediated responses in hippocampal neurons that were pretreated with prolonged bursting. Conclusion The slight reduction in extrasynaptic NMDA receptor function following action potential bursting and synaptic NMDA receptor stimulation could contribute to but is unlikely to fully account for activity

  13. Expressions of Neuregulin 1β and ErbB4 in Prefrontal Cortex and Hippocampus of a Rat Schizophrenia Model Induced by Chronic MK-801 Administration

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    Yu Feng

    2010-01-01

    Full Text Available Recent human genetic studies and postmortem brain examinations of schizophrenia patients strongly indicate that dysregulation of NRG1 and ErbB4 may be important pathogenic factors of schizophrenia. However, this hypothesis has not been validated and fully investigated in animal models of schizophrenia. In this study we quantitatively examined NRG1 and ErbB4 protein expressions by immunohistochemistry and Western blot in the brain of a rat schizophrenia model induced by chronic administration of MK-801 (a noncompetitive NMDA receptor antagonist. Our data showed that NRG1β and ErbB4 expressions were significantly increased in the rat prefrontal cortex and hippocampus but in different subregions. These findings suggest that altered expressions of NRG1 and ErbB4 might be attributed to the schizophrenia. Further study in the role and mechanism of NRG1 and ErbB4 may lead to better understanding of the pathophysiology for this disorder.

  14. Low dose MK-801 reduces social investigation in mice.

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    Zou, Hong; Zhang, Chenghao; Xie, Qinglian; Zhang, Manfang; Shi, Junwei; Jin, Meilei; Yu, Lei

    2008-10-01

    To characterize MK-801's effect on social behavior in mice, we examined adult male ICR mice for interaction with companion mice (juvenile male). Test mice were injected with either saline or MK-801 (0.1 mg/kg), and were tested 30 min later for their social behavior during a 5-min session. A second encounter took place 30 min later, with either a familiar companion mouse (the same as in the initial encounter) or a novel mouse. In saline controls, second encounter with a familiar companion mouse showed reduced social investigative behaviors (anogenital sniffing and staying together), indicating habituation toward a familiar mouse. Second encounter with a novel companion mouse did not show habituation in social investigative behaviors. Pretreatment with MK-801 reduced anogenital sniffing during the first encounter. At the second encounter, these mice displayed non-discriminative habituation of social investigative behaviors, with reduced anogenital sniffing and staying together, regardless of whether the companion mouse was a familiar or a novel one. These results indicate that MK-801 affected exploratory activities of mice, resulting in both reduced social investigative behaviors during first encounter with a companion mouse, and diminished discriminative capacities for a familiar vs. a novel companion mouse during subsequent encounter.

  15. Therapeutic effect of ifenprodil,a NMDA receptor antagonist,on drug dependence

    Institute of Scientific and Technical Information of China (English)

    SuzukT; NaritM

    2002-01-01

    Although drug dependence has been treated by the adonist-therapy,the specific drug therapy for drug dependence has not been established.Ifenprodil is consibdred to specifically block the NMDA receptor consisted of NR1/NR2B subunits without undesirable adverse reactions,such as psychotomimetic action and psychological dependence,while ketamine and MK-801 can block both NMDA receptors consisted of NR1/NR2A and NR1/NR2B subunits with the undesirable adverse reactions.In the present study,we designed to examine the effect of ifenprodil on drug dependence in rodents.Pretreatment with ifenprodil suppressed the expression of withdrawal signs in morphine-, diazepam-and alcohol-dependent rats and mics.Rewarding effects of morphine,methamphetamine and cocaine as well as physical dependence,were suppressed by pretreatment with ifenprodil in rats and mice.These results suggest that ifenprodil be useful in treating drug dependence.

  16. A bolus/infusion paradigm for the novel NMDA receptor SPET tracer [{sup 123}i]CNS 1261

    Energy Technology Data Exchange (ETDEWEB)

    Bressan, Rodrigo A; Erlandsson, Kjell E-mail: k.erlandsson@nucmed.ucl.ac.uk; Mulligan, Rachel S; Gunn, Roger N.; Cunningham, Vincent J.; Owens, Jonathan; Cullum, Ian D.; Ell, Peter J.; Pilowsky, Lyn S

    2004-02-01

    We have previously performed quantitative kinetic modeling of [{sup 123}I]CNS 1261, a new SPET ligand for the MK801 intrachannel site of the NMDA receptor. We now report a bolus-infusion protocol, which eliminates the need for arterial blood sampling. Dynamic SPET scanning and venous blood sampling were performed in 7 healthy volunteers. Good agreement was obtained between kinetic and equilibrium analysis. SPET scanning with a bolus-infusion protocol is a valid method to estimate the total volume of distribution for [{sup 123}I]CNS 1261 in clinical populations.

  17. Increased NMDA receptor inhibition at an increased Sevoflurane MAC

    Directory of Open Access Journals (Sweden)

    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.

  18. EFECTO DE LA ADMINISTRACIÓN INTRACEREBRAL DE MK-801 Y (- NICOTINA EN LAS CONCENTRACIONES EXTRACELULARES DE GLU Y GABA EN EL NÚCLEO PEDUNCULOPONTINO DE RATAS.

    Directory of Open Access Journals (Sweden)

    Blanco Lezcano Vivian

    2011-04-01

    Full Text Available Aunque la manipulación farmacológica de los sistemas glutamatérgico y colinérgico se ha tratado en modelos experimentales de enfermedad de Parkinson (EP, pocos autores han realizado estudios de esta temática a nivel del núcleo pedunculopontino (NPP. El presente trabajo aborda los cambios en las concentraciones extracelulares (CE de glutamato (Glu y ácido δ-amino butírico (GABA en el NPP de ratas hemiparkinsonizadas por inyección de 6-hidroxidopamina (6-OHDA y sometidas a la infusión local de MK-801 (10 mol/L o (- nicotina (10mM. La infusión se realizó mediante microdiálisis cerebral y la determinación de las CE de los neurotransmisores se realizó a través de cromatografía líquida de alta resolución acoplada a detección de fluorescencia. La infusión de MK-801 en el NPP produjo una disminución significativa de las CE de Glu (p<0.01 y de GABA (p<0.01 en las ratas hemiparkinsonizadas y controles. La infusión de (- nicotina mostró un incremento significativo de las CE de Glu (p<0.001 y GABA (p<0.001 en el NPP de las ratas hemiparkinsonizadas y controles. El bloqueo local de los receptores NMDA por MK-801 facilita la interacción del Glu con sus receptores metabotrópicos que participan en mecanismos de inhibición presináptica y bloquean la liberación de neurotransmisores. Mientras que la infusión de nicotina en el NPP suma los efectos de activación de los receptores nicotínicos a los cambios conocidos en la neurotransmisión glutamatérgica y gabaérgica en el NPP en el parkinsonismo. La infusión de fármacos glutamatérgicos y colinérgicos en el NPP impone un reajuste a la neurotransmisión a este nivel que se añade a los cambios neuroquímicos asociados a la denervación dopaminérgica.

  19. EFECTO DE LA ADMINISTRACIÓN INTRACEREBRAL DE MK-801 Y (- NICOTINA EN LAS CONCENTRACIONES EXTRACELULARES DE GLU Y GABA EN EL NÚCLEO PEDUNCULOPONTINO DE RATAS

    Directory of Open Access Journals (Sweden)

    LISETTE BLANCO LEZCANO

    2011-01-01

    Full Text Available Aunque la manipulación farmacológica de los sistemas glutamatérgico y colinérgico se ha tratado en modelos experimentales de enfermedad de Parkinson (EP, pocos autores han realizado estudios de esta temática a nivel del núcleo pedunculopontino (NPP. El presente trabajo aborda los cambios en las concentraciones extracelulares (CE de glutamato (Glu y ácido δ -amino butírico (GABA en el NPP de ratas hemiparkinsonizadas por inyección de 6-hidroxidopamina (6-OHDA y sometidas a infusión local de MK-801 (10 μmol/L o (- nicotina (10 mM. La infusión se realizó mediante microdiálisis cerebral y la determinación de CE de neurotransmisores se realizó a través de cromatografía líquida de alta resolución acoplada a detección de fluorescencia. La infusión de MK-801 en el NPP produjo disminución significativa de CE de Glu (p<0,01 y de GABA (p<0,01 en ratas hemiparkinsonizadas y controles. La infusión de (- ni- cotina mostró un incremento significativo de CE de Glu (p<0,001 y GABA (p<0,001 en el NPP de ratas hemiparkinsonizadas y controles. El bloqueo local de receptores NMDA por MK-801 facilita la interacción de Glu con sus receptores metabotrópicos que participan en mecanismos de inhibición presináptica y bloquean la liberación de neurotransmisores. Mientras que la infusión de nicotina en el NPP suma los efectos de activación de los receptores nicotínicos a los cambios conocidos en la neurotransmisión glutamatérgica y gabaérgica en el NPP en parkinsonismo. La infusión de fármacos glutamatérgicos y colinérgicos en el NPP, impone un reajuste a la neurotransmisión a este nivel que se añade a los cambios neuroquímicos asociados a denervación dopaminérgica.

  20. Polygalasaponin F induces long-term potentiation in adult rat hippocampus via NMDA receptor activation

    Institute of Scientific and Technical Information of China (English)

    Feng SUN; Jian-dong SUN; Ning HAN; Chuang-jun LI; Yu-he YUAN; Dong-ming ZHANG; Nai-hong CHEN

    2012-01-01

    Aim:To investigate the effect and underlying mechanisms of polygalasaponin F (PGSF),a triterpenoid saponin isolated from Polygala japonica,on long-term potentiation (LTP)in hippocampus dentate gyrus (DG)of anesthetized rats.Methods:Population spike (PS)of hippocampal DG was recorded in anesthetized male Wistar rats.PGSF,the NMDAR inhibitor MK801 and the CaMKll inhibitor KN93 were intracerebroventricularly administered.Western blotting analysis was used to examine the phosphorylation expressions of NMDA receptor subunit 2B (NR2B),Ca2+/calmodulin-dependent kinase Ⅱ (CaMKII),extracellular signalregulated kinase (ERK),and cAMP response element-binding protein (CREB).Results:Intracerebroventricular administration of PGSF (1 and 10 μmol/L)produced long-lasting increase of PS amplitude in hippocampal DG in a dose-dependent manner.Pre-injection of MK801 (100 μmol/L)or KN93 (100 μmol/L)completely blocked PGSFinduced LTP.Furthermore,the phosphorylation of NR2B,CaMKII,ERK,and CREB in hippocampus was significantly increased 5-60min after LTP induction.The up-regulation of p-CaMKII expression could be completely abolished by pre-injection of MK801.The upregulation of p-ERK and p-CREB expressions could be partially blocked by pre-injection of KN93.Conclusion:PGSF could induce LTP in hippocampal DG in anesthetized rats via NMDAR activation mediated by CaMKII,ERK and CREB signaling pathway.

  1. Combined action of MK-801 and ceftriaxone impairs the acquisition and reinstatement of morphine-induced conditioned place preference,and delays morphine extinction in rats

    Institute of Scientific and Technical Information of China (English)

    Yaodong Fan; Haichen Niu; Joshua D.Rizak; Ling Li; Guimei Wang; Liqi Xu; He Ren; Hao Lei; Hualin Yu

    2012-01-01

    Objective It is well established that glutamate and its receptors,particularly the N-methyl-D-aspartate receptor (NMDAR),play a significant role in addiction and that the inhibition of glutamatergic hyperfunction reduces addictive behaviors in experimental animals.Specifically,NMDAR antagonists such as MK-801,and an inducer of the expression of glutamate transporter subtype-1 (GLT-1) (cefiriaxone) are known to inhibit addictive behavior.The purpose of this study was to determine whether the combined action of a low dose of MK-801 and a low dose of ceftriaxone provides better inhibition of the acquisition,extinction,and reinstatement of morphine-induced conditioned place preference (CPP) than either compound alone.Methods A morphine-paired CPP experiment was used to study the effects of low doses of MK-801,ceftriaxone and a combination of both on reward-related memory (acquisition,extinction,and reinstatement of morphine preference) in rats.Results A low dose of neither MK-801 (0.05 mg/kg,i.p.) nor ceftriaxone (25 mg/kg,i.p.) alone effectively impaired CPP behaviors.However,when applied in combination,they reduced the acquisition of morphine-induced CPP and completely prevented morphine reinstatement.Their combination also notably impaired the extinction of morphine-induced CPP.Conclusion The combined action of a low dose of an NMDAR antagonist (MK-801)and GLT-1 activation by ceftriaxone effectively changed different phases of CPP behavior.

  2. Risperidone reverses the spatial object recognition impairment and hippocampal BDNF-TrkB signalling system alterations induced by acute MK-801 treatment.

    Science.gov (United States)

    Chen, Guangdong; Lin, Xiaodong; Li, Gongying; Jiang, Diego; Lib, Zhiruo; Jiang, Ronghuan; Zhuo, Chuanjun

    2017-03-01

    The aim of the present study was to investigate the effects of a commonly-used atypical antipsychotic, risperidone, on alterations in spatial learning and in the hippocampal brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signalling system caused by acute dizocilpine maleate (MK-801) treatment. In experiment 1, adult male Sprague-Dawley rats subjected to acute treatment of either low-dose MK801 (0.1 mg/kg) or normal saline (vehicle) were tested for spatial object recognition and hippocampal expression levels of BDNF, TrkB and the phophorylation of TrkB (p-TrkB). We found that compared to the vehicle, MK-801 treatment impaired spatial object recognition of animals and downregulated the expression levels of p-TrkB. In experiment 2, MK-801- or vehicle-treated animals were further injected with risperidone (0.1 mg/kg) or vehicle before behavioural testing and sacrifice. Of note, we found that risperidone successfully reversed the deleterious effects of MK-801 on spatial object recognition and upregulated the hippocampal BDNF-TrkB signalling system. Collectively, the findings suggest that cognitive deficits from acute N-methyl-D-aspartate receptor blockade may be associated with the hypofunction of hippocampal BDNF-TrkB signalling system and that risperidone was able to reverse these alterations.

  3. [Blockade of NMDA receptor enhances corticosterone-induced downregulation of brain-derived neurotrophic factor gene expression in the rat hippocampus through cAMP response element binding protein pathway].

    Science.gov (United States)

    Feng, Hao; Lu, Li-Min; Huang, Ying; Zhu, Yi-Chun; Yao, Tai

    2005-10-25

    High concentration of corticosterone leads to morphological and functional impairments in hippocampus, ranging from a reversible atrophy of pyramidal CA3 apical dendrites to the impairment of long-term potentiation (LTP) and hippocampus-dependent learning and memory. Glutamate and N-methyl-D-aspartate (NMDA) receptor play an important role in this effect. Because of the importance of brain-derived neurotrophic factor (BDNF) in the functions of the hippocampal neurons, alteration of the expression of BDNF is thought to be involved in the corticosterone effect on the hippocampus. To determine whether change in BDNF in the hippocampus is involved in the corticosterone effect, we injected corticosterone (2 mg/kg, s.c.) to Sprague-Dawley rats and measured the mRNA, proBDNF and mature BDNF protein levels in the hippocampus. We also measured the phosphorylation level of the transcription factor cAMP response element binding protein (CREB). Furthermore, we intraperitoneally injected NMDA receptor antagonist MK801 (0.1 mg/kg) 30 min before corticosterone administration to investigate whether and how MK801 affected the regulation of BDNF gene expression by corticosterone. Our results showed that 3 h after single s.c. injection of corticsterone, the expression of BDNF mRNA, proBDNF and mature BDNF protein decreased significantly (PBDNF gene expression in the rat hippocampus by corticosterone. We also found that either applying corticosterone or co-applying corticosterone with MK801 downregulated the phosphoration level of CREB, the latter (corticosterone plus MK801) being more effective (PBDNF gene expression in the rat hippocampus through CREB pathway and that blockade of NMDA receptor enhances this effect of corticosterone in reducing BDNF expression.

  4. Neonatal NMDA receptor blockade disrupts spike timing and glutamatergic synapses in fast spiking interneurons in a NMDA receptor hypofunction model of schizophrenia.

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    Kevin S Jones

    Full Text Available The dysfunction of parvalbumin-positive, fast-spiking interneurons (FSI is considered a primary contributor to the pathophysiology of schizophrenia (SZ, but deficits in FSI physiology have not been explicitly characterized. We show for the first time, that a widely-employed model of schizophrenia minimizes first spike latency and increases GluN2B-mediated current in neocortical FSIs. The reduction in FSI first-spike latency coincides with reduced expression of the Kv1.1 potassium channel subunit which provides a biophysical explanation for the abnormal spiking behavior. Similarly, the increase in NMDA current coincides with enhanced expression of the GluN2B NMDA receptor subunit, specifically in FSIs. In this study mice were treated with the NMDA receptor antagonist, MK-801, during the first week of life. During adolescence, we detected reduced spike latency and increased GluN2B-mediated NMDA current in FSIs, which suggests transient disruption of NMDA signaling during neonatal development exerts lasting changes in the cellular and synaptic physiology of neocortical FSIs. Overall, we propose these physiological disturbances represent a general impairment to the physiological maturation of FSIs which may contribute to schizophrenia-like behaviors produced by this model.

  5. Increased NMDA receptor inhibition at an increased Sevoflurane MAC.

    Science.gov (United States)

    Brosnan, Robert J; Thiesen, Roberto

    2012-06-06

    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. 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. 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 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.

  6. Identification and characterization of the NMDA receptor and its role in regulating reproduction in the cockroach Diploptera punctata.

    Science.gov (United States)

    Huang, Juan; Hult, Ekaterina F; Marchal, Elisabeth; Tobe, Stephen S

    2015-04-01

    The NMDA receptor (NMDAR) plays important roles in excitatory neurotransmission and in the regulation of reproduction in mammals. NMDAR in insects comprises two subunits, NR1 and NR2. In this study, we identified two NR1 paralogs and eleven NR2 alternatively spliced variants in the cockroach Diploptera punctata. This is the first report of NR1 paralogs in insects. The tissue distributions and expression profiles of DpNR1A, DpNR1B and DpNR2 in different tissues were also investigated. Previous studies have demonstrated NMDA-stimulated biosynthesis of juvenile hormone (JH) in the corpora allata through the influx of extracellular Ca(2+) in Diploptera punctata. However, our data show that the transcript levels of DpNR1A, DpNR1B and DpNR2 were low in the corpora allata. MK-801, a high-affinity antagonist of NMDAR, did not show any effect on JH biosynthesis in vitro. In addition, neither partial knockdown of DpNR2 nor in vivo treatment with a physiologically relevant dose of MK-801 resulted in any significant change in JH biosynthesis or basal oocyte growth. Injection of animals with a high dose of MK-801 (30 µg per animal per injection), which paralyzed the animals for 4-5 h, resulted in a significant decrease in JH biosynthesis on days 4 and 5. However, the reproductive events during the first gonadotrophic cycle in female D. punctata were unaffected. Thus, NMDAR does not appear to play important roles in the regulation of JH biosynthesis or mediate reproduction of female D. punctata.

  7. NMDA-dependent mechanisms only affect the BOLD response in the rat dentate gyrus by modifying local signal processing

    Science.gov (United States)

    Tiede, Regina; Krautwald, Karla; Fincke, Anja; Angenstein, Frank

    2012-01-01

    The role of N-methyl--aspartate (NMDA) receptor-mediated mechanisms in the formation of a blood oxygen level-dependent (BOLD) response was studied using electrical stimulation of the right perforant pathway. Stimulation of this fiber bundle triggered BOLD responses in the right hippocampal formation and in the left entorhinal cortex. The perforant pathway projects to and activates the dentate gyrus monosynaptically, activation in the contralateral entorhinal cortex is multisynaptic and requires forwarding and processing of signals. Application of the NMDA receptor antagonist MK801 during stimulation had no effect on BOLD responses in the right dentate gyrus, but reduced the BOLD responses in the left entorhinal cortex. In contrast, application of MK801 before the first stimulation train reduced the BOLD response in both regions. Electrophysiological recordings revealed that the initial stimulation trains changed the local processing of the incoming signals in the dentate gyrus. This altered electrophysiological response was not further changed by a subsequent application of MK801, which is in agreement with an unchanged BOLD response. When MK801 was present during the first stimulation train, a dissimilar electrophysiological response pattern was observed and corresponds to an altered BOLD response, indicating that NMDA-dependent mechanisms indirectly affect the BOLD response, mainly via modifying local signal processing and subsequent propagation. PMID:22167232

  8. Involvement of NMDA receptors in the antidepressant-like effect of tramadol in the mouse forced swimming test.

    Science.gov (United States)

    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.

  9. Pharmacological blockade of serotonin 5-HT₇ receptor reverses working memory deficits in rats by normalizing cortical glutamate neurotransmission.

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    Pascal Bonaventure

    Full Text Available The role of 5-HT₇ receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT₇ antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg significantly reversed the deficits induced by MK-801 (0.1 mg/kg but augmented the deficit induced by scopolamine (0.06 mg/kg. The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT₇ receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission.

  10. N-methyl-D-aspartate receptor blockade inhibits estrogenic support of dendritic growth in a sexually dimorphic rat spinal nucleus.

    Science.gov (United States)

    Hebbeler, Sara Louise; Verhovshek, Tom; Sengelaub, Dale Robert

    2002-09-16

    The lumbar spinal cord of rats contains the sexually dimorphic, steroid-sensitive spinal nucleus of the bulbocavernosus (SNB). Dendritic development of SNB motoneurons requires the action of both androgens and estrogens. Estrogenic effects are limited to the initial growth of SNB dendrites through 4 weeks of age. During this postnatal period, dendritic growth in other spinal motoneurons is regulated by N-methyl-D-aspartate (NMDA) receptor activation. In this study, we tested whether NMDA receptor activation was involved in SNB dendritic growth and whether the estrogenic support of SNB dendritic growth was dependent on the activation of NMDA receptors. Motoneuron morphology was assessed in normal males, intact males treated daily with the NMDA receptor antagonist MK-801, castrated males treated with estradiol benzoate (EB), and castrated males treated with both EB and MK-801. SNB motoneurons were retrogradely labeled with cholera toxin-horseradish peroxidase at 4 weeks of age (when dendritic length is normally maximal) and reconstructed in three dimensions. Somal area and dendritic length of SNB motoneurons in MK-801-treated, intact males were below those of normal males. Dendritic growth was partially supported in EB-treated castrates, but this growth was blocked by MK-801 treatment. These results suggest that, as in other motoneurons, dendritic development in the SNB involves NMDA receptors and, furthermore, that the estrogen-sensitive component of SNB dendritic development requires their activation. Copyright 2002 Wiley-Liss, Inc.

  11. Protection by imidazol(ine) drugs and agmatine of glutamate-induced neurotoxicity in cultured cerebellar granule cells through blockade of NMDA receptor

    Science.gov (United States)

    Olmos, Gabriel; DeGregorio-Rocasolano, Nuria; Regalado, M Paz; Gasull, Teresa; Boronat, M Assumpció; Trullas, Ramón; Villarroel, Alvaro; Lerma, Juan; García-Sevilla, Jesús A

    1999-01-01

    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 μM) caused a concentration-dependent neurotoxicity, as determined 24 h later by a decrease in the ability of the cells to metabolize 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) into a reduced formazan product. L-glutamate-induced neurotoxicity (EC50=5 μM) was blocked by the specific NMDA receptor antagonist MK-801 (dizocilpine).Imidazol(ine) drugs and agmatine fully prevented neurotoxicity induced by 20 μM (EC100) L-glutamate with the rank order (EC50 in μM): 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)>RX821002 (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 μM at 0 mV.It is concluded that imidazol(ine) drugs and agmatine are

  12. MK-801诱导的精神分裂症小鼠行为学和胼胝体髓鞘的改变%Behavioral alterations and demyelization of the corpus callosum in the mouse model of MK-801 induced schizophrenia

    Institute of Scientific and Technical Information of China (English)

    修芸; 张蕾; 仇玄; 陈林; 卢伟; 彭超; 程国华; 晁凤蕾; 唐勇

    2013-01-01

    Objective To explore the role of white matter injuries in the schizophrenia induced by the NMDA re-ceptor antagonist. Methods Adult male C57BL/6J mice (8 week old) were equally divided into four groups. One group was sub-chronically treated with saline solution, and the other three groups were intraperitoneally treated with MK-801 at dose of 0.025 mg/mL (M1), 0.050 mg/mL (M2) and 0.100 mg/mL (M3) in a volume 10 ml per kilogram body weight. All ani-mals were tested using Morris water maze at the 9th-15th day and using the Hole Board exploration as well as Rota Rod performance tests on the 16th day. The myelin basic protein (MBP) and the ultrastructure of the myelin sheaths in the cor-pus callosum were then examined using immunohistochemical methods, transmission electron microscope technique and stereological methods. Results The repeated sub-chronic MK-801 treatment did not induce impairment of spatial learning and memory in Morris water maze. The MK-801 treatment at 0.25 mg/kg and 1.00 mg/kg but not at 0.50 mg/kg resulted in less exploration to a new environment. The myelin staining with anti-MBP antibody was less intense in all three schizo-phrenic groups when compared to saline control group (P0.05),M1和M3组小鼠较对照组表现出对新环境探索减少的SZ阴性症状;大脑胼胝体区MBP染色M1组(179±10)%、M2组(235±7)%、M3组(152±9)%小鼠较对照组(288±18)%均降低(均P<0.01),其内有髓神经纤维髓鞘出现板层分离、节段性脱髓鞘等病变,M3组小鼠胼胝体内损伤有髓神经纤维比例高于对照组[(22.42±4.24)%vs.(3.84±1.35)%],差异有统计学意义(P<0.01)。结论胼胝体脱髓鞘改变可能是MK-801慢性给药诱导SZ的病因之一。

  13. Involvement of pre- and postsynaptic NMDA receptors at local circuit interneuron connections in rat neocortex.

    Science.gov (United States)

    De-May, C L; Ali, A B

    2013-01-03

    To investigate the involvement of N-Methyl-D-aspartate (NMDA) receptors in local neocortical synaptic transmission, dual whole-cell recordings - combined with biocytin labelling - were obtained from bitufted adapting, multipolar adapting or multipolar non-adapting interneurons and pyramidal cells in layers II-V of rat (postnatal days 17-22) sensorimotor cortex. The voltage dependency of the amplitude of Excitatory postsynaptic potentials (EPSPs) received by the three types of interneuron appeared to coincide with the interneuron subclass; upon depolarisation, EPSPs received by multipolar non-adapting interneurons either decreased in amplitude or appeared insensitive, multipolar adapting interneuron EPSP amplitudes increased or appeared insensitive, whereas bitufted interneuron EPSP amplitudes increased or decreased. Connections were challenged with the NMDA receptor antagonist d-(-)-2-amino-5-phosphonopentanoic acid (d-AP5) (50μM) revealing NMDA receptors to contribute to EPSPs received by all cell types, this also abolished the non-conventional voltage dependency. Reciprocal connections were frequent between pyramidal cells and multipolar interneurons, and inhibitory postsynaptic potentials (IPSPs) elicited in pyramidal cells by both multipolar adapting and multipolar non-adapting interneurons were sensitive to a significant reduction in amplitude by d-AP5. The involvement of presynaptic NMDA receptors was indicated by coefficient of variation analysis and an increase in the failures of transmission. Furthermore, by loading MK-801 into the pre- or postsynaptic neurons, we observed that a reduction in inhibition requires presynaptic and not postsynaptic NMDA receptors. These results suggest that NMDA receptors possess pre- and postsynaptic roles at selective neocortical synapses that are probably important in governing spike-timing and information flow.

  14. Involvement of glutamatergic and GABAergic transmission in MK-801-increased gamma band oscillation power in rat cortical electroencephalograms.

    Science.gov (United States)

    Hiyoshi, T; Kambe, D; Karasawa, J; Chaki, S

    2014-11-07

    Hypofunction of the N-methyl-D-aspartic acid receptor (NMDAr) has been considered to play a crucial role in the pathophysiology of schizophrenia. In rodent electroencephalogram (EEG) studies, non-competitive NMDAr antagonists have been reported to produce aberrant basal gamma band oscillation (GBO), as observed in schizophrenia. Aberrations in GBO power have attracted attention as a translational biomarker for the development of novel antipsychotic drugs. However, the neuronal mechanisms as well as the pharmacological significance of NMDAr antagonist-induced aberrant GBO power have not been fully investigated. In the present study, to address the above questions, we examined the pharmacological properties of MK-801 (0.1 mg/kg)-increased basal GBO power in rat cortical EEG. Riluzole (3-10 mg/kg), a glutamate release inhibitor, reduced the MK-801-increased basal GBO power. In contrast, L-838,417 (1-3 mg/kg), an α2/3/5 subunit-selective GABAA receptor-positive allosteric modulator, enhanced the GBO increase. Antipsychotics such as haloperidol (0.05-0.3 mg/kg) and clozapine (1-10 mg/kg) dose-dependently attenuated the MK-801-increased GBO power. Likewise, LY379268 (0.3-3 mg/kg), an metabotropic glutamate 2/3 receptor (mGlu2/3 receptor) agonist, reduced the GBO increase in a dose-dependent manner, which was antagonized by an mGlu2/3 receptor antagonist LY341495. These results suggest that an increase in cortical GBO power induced by NMDAr hypofunction can be attributed to the aberrant activities of both excitatory pyramidal neurons and inhibitory interneurons in local circuits. The aberrant cortical GBO power reflecting cortical network dysfunction observed in schizophrenia might be a useful biomarker for the discovery of novel antipsychotic drugs.

  15. Differential antagonism of tetramethylenedisulfotetramine-induced seizures by agents acting at NMDA and GABA{sub A} receptors

    Energy Technology Data Exchange (ETDEWEB)

    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, E-mail: jana_veliskova@nymc.edu [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, E-mail: libor_velisek@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); 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

  16. 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.

  17. Convulsions induced by centrally administered NMDA in mice: effects of NMDA antagonists, benzodiazepines, minor tranquilizers and anticonvulsants.

    Science.gov (United States)

    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

  18. An excessive increase in glutamate contributes to glucose-toxicity in β-cells via activation of pancreatic NMDA receptors in rodent diabetes

    Science.gov (United States)

    Huang, Xiao-Ting; Li, Chen; Peng, Xiang-Ping; Guo, Jia; Yue, Shao-Jie; Liu, Wei; Zhao, Fei-Yan; Han, Jian-Zhong; Huang, Yan-Hong; Yang-Li, Y -L; Cheng, Qing-Mei; Zhou, Zhi-Guang; Chen, Chen; Feng, Dan-Dan; Luo, Zi-Qiang

    2017-01-01

    In the nervous system, excessive activation of NMDA receptors causes neuronal injury. Although activation of NMDARs has been proposed to contribute to the progress of diabetes, little is known about the effect of excessive long-term activation of NMDARs on β-cells, especially under the challenge of hyperglycemia. Here we thoroughly investigated whether endogenous glutamate aggravated β-cell dysfunction under chronic exposure to high-glucose via activation of NMDARs. The glutamate level was increased in plasma of diabetic mice or patients and in the supernatant of β-cell lines after treatment with high-glucose for 72 h. Decomposing the released glutamate improved GSIS of β-cells under chronic high-glucose exposure. Long-term treatment of β-cells with NMDA inhibited cell viability and decreased GSIS. These effects were eliminated by GluN1 knockout. The NMDAR antagonist MK-801 or GluN1 knockout prevented high-glucose-induced dysfunction in β-cells. MK-801 also decreased the expression of pro-inflammatory cytokines, and inhibited I-κB degradation, ROS generation and NLRP3 inflammasome expression in β-cells exposed to high-glucose. Furthermore, another NMDAR antagonist, Memantine, improved β-cells function in diabetic mice. Taken together, these findings indicate that an increase of glutamate may contribute to the development of diabetes through excessive activation of NMDARs in β-cells, accelerating β-cells dysfunction and apoptosis induced by hyperglycemia. PMID:28303894

  19. Roles of NMDA and dopamine D1 and D2 receptors in the acquisition and expression of flavor preferences conditioned by oral glucose in rats.

    Science.gov (United States)

    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

  20. 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.

  1. Fluoxetine reverses the behavioral despair induced by neurogenic stress in mice: role of N-methyl-d-aspartate and opioid receptors.

    Science.gov (United States)

    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.

  2. Holographic Quantitative Structure-Activity Relationships of Tryptamine Derivatives at NMDA, 5HT1A and 5HT2A Receptors

    Directory of Open Access Journals (Sweden)

    Peter Wolschann

    2013-07-01

    Full Text Available Tryptamine derivatives (Ts were found to inhibit the binding of [3H]MK-801, [3H]ketanserin and [3H]8-OH-DPAT to rat brain membranes. [3H]MK-801 labels the NMDA (N-methyl-D-aspartate receptor, a ionotropic glutamate receptor which controls synaptic plasticity and memory function in the brain, whereas [3H]ketanserin and [3H]8-OH-DPAT label 5HT2A and 5HT1A receptors, respectively. The inhibitory potencies of 64 Ts (as given by IC50 values were correlated with their structural properties by using the Holographic QSAR procedure (HQSAR. This method uses structural fragments and connectivities as descriptors which were encoded in a hologram thus avoiding the usual problems with conformation and alignment of the structures. Four correlation equations with high predictive ability and appropriate statistical test values could be established. The results are visualized by generation of maps reflecting the contribution of individual structural parts to the biological activities.

  3. Involvement of NMDA receptors and L-arginine/nitric oxide/cyclic guanosine monophosphate pathway in the antidepressant-like effects of topiramate in mice forced swimming test.

    Science.gov (United States)

    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.

  4. Role of NMDA, opioid and dopamine D1 and D2 receptor signaling in the acquisition of a quinine-conditioned flavor avoidance in rats.

    Science.gov (United States)

    Rotella, Francis M; Badalia, Arzman; Duenas, Sean M; Hossain, Maruf; Saeed, Shermeen; Touzani, Khalid; Sclafani, Anthony; Bodnar, Richard J

    2014-04-10

    A conditioned flavor preference (CFP) can be produced by pairing a flavor (conditioned stimulus, CS+) with the sweet taste of fructose. Systemic dopamine (DA) D1, D2 and NMDA, but not opioid, receptor antagonists significantly reduce the acquisition of the fructose-CFP. A conditioned flavor avoidance (CFA) can be produced by pairing a CS+flavor with the bitter taste of quinine. To evaluate whether fructose-CFP and quinine-CFA share common neurochemical substrates, the present study determined the systemic effects of DA D1 (SCH23390: SCH), DA D2 (raclopride: RAC), NMDA (MK-801) or opioid (naltrexone: NTX) receptor antagonists on the acquisition of quinine-CFA. In Experiment 1, food-restricted male rats were trained over 8 alternating one-bottle sessions to drink an 8% fructose+0.2% saccharin solution (FS) mixed with one flavor (CS-, e.g., grape) and a different flavor (CS+, e.g., cherry) mixed in a solution (FSQ) containing fructose+saccharin and quinine at 0.001-0.030% concentrations. In six subsequent two-bottle choice tests (1-3: two sessions each) with the CS- and CS+ flavors presented in FS solutions, only rats trained with 0.03% quinine displayed a CS+ avoidance in Test 1. In Experiment 2, rats received vehicle (Veh), SCH (200 nmol/kg), RAC (200 nmol/kg), MK-801 (100 μg/kg) or NTX (1 mg/kg) 30 min prior to the 8 one-bottle training sessions with CS-/FS and CS+/FSQ (0.03% quinine) solutions. An additional vehicle group (Veh 0.06%) was trained with a CS+/FSQ containing 0.06% quinine. In the two-bottle choice tests, the Veh and RAC groups avoided the CS+ flavor in Test 1 only, whereas the SCH, MK801, and NTX groups significantly avoided the CS+ in Tests 1-3. The Veh.06% group trained avoided the CS+ in Tests 1 and 2, but not Test 3. In Experiment 3, Veh and SCH groups were trained as in Experiment 2, but were tested with CS flavors presented in 0.2% saccharin solutions. The SCH group avoided the CS+ flavor in Tests 1-3 while the Veh group avoided the CS+ in Test

  5. Paradoxical proepileptic response to NMDA receptor blockade linked to cortical interneuron defect in stargazer mice

    Directory of Open Access Journals (Sweden)

    Atul eMaheshwari

    2013-09-01

    Full Text Available Paradoxical seizure exacerbation by antiepileptic medication is a well-known clinical phenomenon in epilepsy, but the cellular mechanisms remain unclear. One possibility is enhanced network disinhibition by unintended suppression of inhibitory interneurons. We investigated this hypothesis in the stargazer mouse model of absence epilepsy, which bears a mutation in stargazin, an AMPA receptor trafficking protein. If AMPA signaling onto inhibitory GABAergic neurons is impaired, their activation by glutamate depends critically upon NMDA receptors. Indeed, we find that stargazer seizures are exacerbated by NMDA receptor blockade with CPP and MK-801, whereas other genetic absence epilepsy models are sensitive to these antagonists. To determine how an AMPA receptor trafficking defect could lead to paradoxical network activation, we analyzed stargazin and AMPA receptor localization and found that stargazin is detected exclusively in parvalbumin-positive (PV+ fast-spiking interneurons in somatosensory cortex, where it is co-expressed with the AMPA receptor subunit GluA4. PV+ cortical interneurons in stargazer show a near two-fold decrease in the dendrite:soma GluA4 expression ratio compared to wild type littermates. We explored the functional consequence of this trafficking defect on network excitability in neocortical slices. Both NMDA receptor antagonists suppressed 0 Mg2+ induced network discharges in wild type but augmented bursting in stargazer cortex. Interneurons mediate this paradoxical response, since the difference between genotypes was masked by GABA receptor blockade. Our findings provide a cellular locus for AMPA receptor-dependent signaling defects in stargazer cortex and define an interneuron-dependent mechanism for paradoxical seizure exacerbation in absence epilepsy.

  6. The NMDA receptor ion channel: a site for binding of Huperzine A.

    Science.gov (United States)

    Gordon, R K; Nigam, S V; Weitz, J A; Dave, J R; Doctor, B P; Ved, H S

    2001-12-01

    Huperzine A (HUP-A), first isolated from the Chinese club moss Huperzia serrata, is a potent, reversible and selective inhibitor of acetylcholinesterase (AChE) over butyrylcholinesterase (BChE) (Life Sci. 54: 991-997). Because HUP-A has been shown to penetrate the blood-brain barrier, is more stable than the carbamates used as pretreatments for organophosphate poisoning (OP) and the HUP-A:AChE complex has a longer half-life than other prophylactic sequestering agents, HUP-A has been proposed as a pretreatment drug for nerve agent toxicity by protecting AChE from irreversible OP-induced phosphonylation. More recently (NeuroReport 8: 963-968), pretreatment of embryonic neuronal cultures with HUP-A reduced glutamate-induced cell death and also decreased glutamate-induced calcium mobilization. These results suggest that HUP-A might interfere with and be beneficial for excitatory amino acid overstimulation, such as seen in ischemia, where persistent elevation of internal calcium levels by activation of the N-methyl-D-aspartate (NMDA) glutamate subtype receptor is found. We have now investigated the interaction of HUP-A with glutamate receptors. Freshly frozen cortex or synaptic plasma membranes were used, providing 60-90% specific radioligand binding. Huperzine A (< or =100 microM) had no effect on the binding of [3H]glutamate (low- and high-affinity glutamate sites), [3H]MDL 105,519 (NMDA glycine regulatory site), [3H]ifenprodil (NMDA polyamine site) or [3H]CGS 19755 (NMDA antagonist). In contrast with these results, HUP-A non-competitively (Hill slope < 1) inhibited [3H]MK-801 and [3H]TCP binding (co-located NMDA ion channel PCP site) with pseudo K(i) approximately 6 microM. Furthermore, when neuronal cultures were pretreated with HUP-A for 45 min prior to NMDA exposure, HUP-A dose-dependently inhibited the NMDA-induced toxicity. Although HUP-A has been implicated to interact with cholinergic receptors, it was without effect at 100 microM on muscarinic (measured by

  7. NMDA受体通道参与大鼠脊髓背角C纤维诱发电位LTP的表达%NMDA Receptor Channels Are Involved in The Expression of Long-term Potentiation of C-fiber Evoked Field Potentials in Rat Spinal Dorsal Horn

    Institute of Scientific and Technical Information of China (English)

    张红梅; 周利君; 胡能伟; 张彤; 刘先国

    2006-01-01

    以往研究表明,激动NMDA受体是引起海马长时程增强(LTP)的必备条件,而LTP的表达主要与AMPA受体的磷酸化及其受体组装到突触后膜有关.但是,近年来有研究表明NMDA受体通道也参与了LTP的表达.为探讨NMDA受体通道是否参与了脊髓背角C纤维诱发电位LTP的表达,诱导LTP后,分别静脉或脊髓局部给予NMDA受体拮抗剂MK 801或APV,观察其作用.发现静脉注射非竞争性NMDA受体MK 801(0.1 mg/kg)对脊髓LTP无影响,注射0.5 mg/kg显著抑制LTP,但是当剂量增高到1.0mg/kg时,抑制作用并未进一步增大.脊髓局部给予MK 801也能抑制脊髓背角LTP.为验证上述结果,使用了竞争性NMDA受体拮抗剂APV.结果显示,脊髓局部给予50μmol/L APV对LTP无影响,100 μmol/L对LTP有显著的抑制作用,当浓度升至200 μmol/L时,抑制作用并未见进一步增强.因此认为,NMDA受体通道部分地参与了脊髓背角C纤维诱发电位LTP的表达.%In hippocampus, numerous studies have shown that N-methyl-D-aspartate (NMDA) receptors are essential for the initiation of long-term potentiation (LTP), whereas the expression of LTP is primarily mediated by the phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and the increased insertion of postsynaptic AMPA receptors. However, in recent years there is also evidence that NMDA receptor channels contribute to the expression of LTP under physiological conditions. It was examined whether NMDA receptor channels contributed to the expression of LTP of C-fiber evoked field potentials in rat spinal dorsal horn by intravenous or spinal application of NMDA receptor antagonists after the establishment of LTP. It was found that MK 801 (a non-competitive NMDA receptor antagonist) at dose of 0.1 mg/kg (iv) had no effect on the spinal LTP and at the dose of 0.5 mg/kg depressed the LTP significantly. However, the inhibitory effect of MK 801 at higher dose (1.0 mg/kg)was not

  8. NMDA and PACAP receptor signaling interact to mediate retinal-induced scn cellular rhythmicity in the absence of light.

    Directory of Open Access Journals (Sweden)

    Ian C Webb

    Full Text Available The "core" region of the suprachiasmatic nucleus (SCN, a central clock responsible for coordinating circadian rhythms, shows a daily rhythm in phosphorylation of extracellular regulated kinase (pERK. This cellular rhythm persists under constant darkness and, despite the absence of light, is dependent upon inputs from the eye. The neural signals driving this rhythmicity remain unknown and here the roles of glutamate and PACAP are examined. First, rhythmic phosphorylation of the NR1 NMDA receptor subunit (pNR1, a marker for receptor activation was shown to coincide with SCN core pERK, with a peak at circadian time (CT 16. Enucleation and intraocular TTX administration attenuated the peak in the pERK and pNR1 rhythms, demonstrating that activation of the NMDA receptor and ERK in the SCN core at CT16 are dependent on retinal inputs. In contrast, ERK and NR1 phosphorylation in the SCN shell region were unaffected by these treatments. Intraventricular administration of the NMDA receptor antagonist MK-801 also attenuated the peak in SCN core pERK, indicating that ERK phosphorylation in this region requires NMDA receptor activation. As PACAP is implicated in photic entrainment and is known to modulate glutamate signaling, the effects of a PAC1 receptor antagonist (PACAP 6-38 on SCN core pERK and pNR1 also were examined. PACAP 6-38 administration attenuated SCN core pERK and pNR1, suggesting that PACAP induces pERK directly, and indirectly via a modulation of NMDA receptor signaling. Together, these data indicate that, in the absence of light, retinal-mediated NMDA and PAC1 receptor activation interact to induce cellular rhythms in the SCN core. These results highlight a novel function for glutamate and PACAP release in the hamster SCN apart from their well-known roles in the induction of photic circadian clock resetting.

  9. Sex differences in the effect of MK-801 on normal and spinal cord injured rats.

    Science.gov (United States)

    Nieto-Sampedro, M; Bailón, C; Rivas, F; Moreno, M T

    1991-01-01

    The induction of functional paraplegia in female rats by contusive spinal cord injury was not prevented by compound MK-801. However, the treatment reduced cavitation around the lesion epicenter to 14 mm3 compared to 17 mm3 in untreated controls t-test, P vaginal frotis. Also, beginning 24 h after MK-801 injection, the proportion of PMN increased 400% in female blood, whereas males maintained control values. Arthritis-like joint inflammation was prominent in the toes of female rats, but males were unaffected. After continued treatment with the drug for 15 days, PMN count in female rats decreased and the animals resumed cycling. However, during this period female rats lost 20% of their weight, whereas males gained 26%. One hour after MK-801 injection large increases in blood pressure occurred in both sexes, returning to normal values 2 h later. Hypothermia does not appear to be a factor in the neuroprotective effect of MK-801, but the drug has a number of potentially dangerous side effects, particularly in female rats. Because polymorphonuclear cells are known sources of oxygen free radicals, neuroprotection by MK-801 treatment ought to be much more efficient in males than in females and the drug should be used in combination with a free-radical scavenger.

  10. The metabotropic glutamate receptor agonist 1S,3R-ACPD stimulates and modulates NMDA receptor mediated excitotoxicity in organotypic hippocampal slice cultures

    DEFF Research Database (Denmark)

    Blaabjerg, M; Kristensen, Bjarne Winther; Bonde, C;

    2001-01-01

    The potential toxic effects of the metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) and its interactions with the N-methyl-D-aspartate (NMDA) receptor were studied in hippocampal brain slice cultures, using densitometric measurements of the cellular....... The neurodegeneration induced by 2 mM ACPD was completely abolished by addition of 10 microM of the NMDA receptor antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), while 20 microM of the 2-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainic acid receptor antagonist...... of metabotropic glutamate receptors with ACPD at concentrations of 2 mM or higher induces a distinct subfield-related and time and concentration dependent pattern of hippocampal degeneration, and that ACPD at subtoxic concentrations modulates NMDA-induced excitotoxicity through the mGluR5 receptor in a time...

  11. 新型tacrine双联体对培养大鼠海马神经元NMDA受体作用位点的研究%Effect of Bis(7)-tacrine to NMDA Receptor Modulatory Site in Cultured Rat Hippocampal Neurons

    Institute of Scientific and Technical Information of China (English)

    刘宇炜; 李超英

    2011-01-01

    目的:研究新型tacrine双联体bis(7)-tacrine对NMDA受体的作用位点.方法:大鼠海马神经元原代培养,全细胞膜片钳记录培养大鼠海马神经元上NMDA激活电流变化.结果:细胞外液pH值从8.1改变到6.7,在细胞外液中加入二硫苏糖醇(2 mmol/L)、精胺(10 mol/L)、镁离子(50~500 mol/L)或锌离子(5~20 mol/L)均不引起bis(7)-tacrine对NMDA电流抑制率的改变.电极内液中加入5 mol/L bis(7)-tacrine也未观察到外加的0.5 mol/L bis(7)-tacrine对30 mol/L NMDA激活电流抑制率的改变.0.5 mol/L bis(7)-tacrine及1 mol/L dizocilpine(MK-801)分别对30 mol/L NMDA激活电流抑制了36%和22%,而在两种药物都存在的条件下,30 mol/L NMDA电流仅被抑制了37%.结论:bis(7)-tacrine虽然不大可能作用于MK-801位点,但MK-801和bis(7)-tacrine之间可能存在着相互的负性调节作用.%Objective:To study the modulatory site of bis(7)-tacrine on NMDA receptors.Methods:The effect of bis(7)-tacrine on NMDA-activated currents was investigated using whole-cell patch-clamp recording in cultured rat hippocampal neurons in the absence and presence of different NMDA receptor modulaters.Results:The inhibitory rates NMDA-activated currents by bis(7)-tacrine were neither altered by changing extracellular pH(pH 8.1~6.7),nor by adding dithiothreitol(2 mmol/L),spermine(10 mol/L),Mg2+(50~500 mol/L),or Zn2+(5~20 mol/L) to the external solution.5 mol/L bis-tacrine in the recording pipette solution did not alter the inhibition rate of 30 mol/L NMDA-activated current by 0.5 mol/L bis(7)-tacrine applied externally.0.5 mol/L bis(7)-tacrine and 1 mol/L dizocilpine(MK-801) inhibited NMDA-activated currents by 36 % and 22 %,respectively;co-application of these two drugs only inhibited NMDA-activated current by 37 %.Conclusion:Although bis(7)-tacrine is very unlikely acting at the MK-801

  12. Latent inhibition of cued fear conditioning: an NMDA receptor-dependent process that can be established in the presence of anisomycin.

    Science.gov (United States)

    Lewis, Michael C; Gould, Thomas J

    2004-08-01

    Much of the research examining the biological basis for long-term memories has focused on mechanisms that support the formation of conditioned associations. Less information is available on biological mechanisms which underlie processes that modify the strength of conditioned associations. Latent inhibition is a phenomenon by which pre-exposure to a to-be-conditioned stimulus (CS) weakens subsequent conditioning of that CS to an unconditioned stimulus (US). Here we report that latent inhibition of cued fear conditioning is dependent on NMDA receptor activation. MK-801 (1 mg/kg), an NMDA receptor antagonist, abolished latent inhibition of cued fear conditioning. This dose of MK-801 administered before training did not disrupt cued fear conditioning. Conversely, anisomycin (150 mg/kg), a protein synthesis inhibitor, had no effect on latent inhibition of cued fear conditioning when administered 20 min before, immediately after, or 2, 4, 6, or 8 h after CS pre-exposure. Furthermore, continuous anisomycin administration (50 mg/kg, administered every 2 h for 6 h starting 20 min prior to pre-exposure) did not disrupt latent inhibition of cued fear conditioning. In addition, anisomycin had no effect on a long-lasting version of latent inhibition of cued fear conditioning that was maintained over a 7-day interval. Anisomycin administered before training, however, disrupted learning of the CS-US association. These findings suggest that latent inhibition of cued fear conditioning is a long-lasting NMDA receptor-dependent process that can develop during the inhibition of protein synthesis.

  13. The participation of NMDA receptors, PKC, and MAPK in the formation of memory following operant conditioning in Lymnaea

    Directory of Open Access Journals (Sweden)

    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.

  14. Brain purine metabolism and xanthine dehydrogenase/oxidase conversion in hyperammonemia are under control of NMDA receptors and nitric oxide.

    Science.gov (United States)

    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.

  15. Unlearning: NMDA receptor-mediated metaplasticity in the anterior piriform cortex following early odor preference training in rats.

    Science.gov (United States)

    Mukherjee, Bandhan; Morrison, Gillian L; Fontaine, Christine J; Hou, Qinlong; Harley, Carolyn W; Yuan, Qi

    2014-04-09

    Here we demonstrate metaplastic effect of a change in NMDA receptor (NMDAR) number in the anterior piriform cortex (aPC) in rat induced by a 10 min pairing of peppermint odor + stroking, which significantly modifies later learning and memory. Using isolated synaptoneurosomes, we found NR1 receptor downregulation 3 h after training and upregulation at 24 h. Consistent with the NR1 pattern, the NMDAR-mediated EPSP was smaller at 3 h and larger at 24 h. Subunit composition was unchanged. Whereas LTP was reduced at both times by training, LTD was facilitated only at 3 h. Behaviorally, pups, given a pairing of peppermint + stroking 3 h after an initial peppermint + stroking training, lost the normally acquired peppermint preference 24 h later. To probe the pathway specificity of this unlearning effect, pups were trained first with peppermint and then, at 3 h, given a second training with peppermint or vanillin. Pups given peppermint training at both times lost the learned peppermint preference. Pups given vanillin retraining at 3 h had normal peppermint preference. Downregulating NR1 with siRNA prevented odor preference learning. Finally, the NMDAR antagonist MK-801 blocked the LTD facilitation seen 3 h after training, and giving MK-801 before the second peppermint training trial eliminated the loss of peppermint odor preference. A training-associated reduction in NMDARs facilitates LTD 3 h later; training at the time of LTD facilitation reverses an LTP-dependent odor preference. Experience-dependent, pathway-specific metaplastic effects in a cortical structure have broad implications for the optimal spacing of learning experiences.

  16. Combination of behaviorally sub-effective doses of glutamate NMDA and dopamine D1 receptor antagonists impairs executive function.

    Science.gov (United States)

    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 D1 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 D1 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 D1 receptor antagonists individually or in combination prior to task performance. Separate injections of the NMDA receptor antagonist, MK-801, and the dopamine D1 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 D1 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.

  17. Propofol attenuates pancreatic cancer malignant potential via inhibition of NMDA receptor.

    Science.gov (United States)

    Chen, Xiangyuan; Wu, Qichao; You, Li; Chen, Sisi; Zhu, Minmin; Miao, Changhong

    2017-01-15

    Propofol is a commonly used intravenous anesthetic, and could attenuate cancer cells malignant potential via inhibiting hypoxia-inducible factor-1α (HIF-1α) expression. However, the mechanism is still inclusive. In the present study, we mainly focus on the mechanism by which propofol down-regulated HIF-1α expression and malignant potential in pancreatic cancer cells. Human pancreatic cancer cells (Miapaca-2 and Panc-1) in vitro and murine pancreatic cancer cell (Panc02) in vivo were used to assess the effect of propofol on vascular endothelial growth factor (VEGF) expression and migration of pancreatic cancer cells. Propofol inhibited cells migration, expression of VEGF and HIF-1α, phosphorylation of extracellular regulated protein kinases (ERK), AKT, Ca(2+)/calmodulin dependent protein kinases II (CaMK II), and Ca(2+) concentration in a concentration-dependent manner (5, 25, 50, 100μM). Furthermore, MK801, an inhibitor of NMDA receptor, and KN93, an inhibitor of CaMK II, could inhibit the expression of VEGF, HIF-1a, p-AKT, p-ERK, p-CaMK II in vitro, growth of tumor and VEGF expression in vivo, which were similar to the effect of propofol. In addition, the anti-tumor effect of propofol could be counteracted by rapastinel, an activator of NMDA receptor. Our study indicated that propofol suppressed VEGF expression and migration ability of pancreatic cancer cells in vitro and in vivo, probably via inhibiting NMDA receptor. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. DNA microarray unravels rapid changes in transcriptome of MK-801 treated rat brain

    Institute of Scientific and Technical Information of China (English)

    Yuka; Kobayashi; Sofya; P; Kulikova; Junko; Shibato; Randeep; Rakwal; Hiroyuki; Satoh; Didier; Pinault; Yoshinori; Masuo

    2015-01-01

    AIM:To investigate the impact of MK-801 on gene expression patterns genome wide in rat brain regions. METHODS:Rats were treated with an intraperitoneal injection of MK-801 [0.08(low-dose) and 0.16(highdose) mg/kg] or NaC l(vehicle control). In a first series of experiment,the frontoparietal electrocorticogram was recorded 15 min before and 60 min after injection. In a second series of experiments,the whole brain of each animal was rapidly removed at 40 min post-injection,and different regions were separated:amygdala,cerebral cortex,hippocampus,hypothalamus,midbrain and ventral striatum on ice followed by DNA microarray(4 × 44 K whole rat genome chip) analysis.RESULTS:Spectral analysis revealed that a single systemic injection of MK-801 significantly and selectively augmented the power of baseline gamma frequency(30-80 Hz) oscillations in the frontoparietal electroencephalogram. DNA microarray analysis showed the largest number(up- and down- regulations) of gene expressions in the cerebral cortex(378),midbrain(376),hippocampus(375),ventral striatum(353),amygdala(301),and hypothalamus(201) under low-dose(0.08 mg/kg) of MK-801. Under high-dose(0.16 mg/kg),ventral striatum(811) showed the largest number of gene expression changes. Gene expression changes were functionally categorized to reveal expression of genes and function varies with each brain region.CONCLUSION:Acute MK-801 treatment increases synchrony of baseline gamma oscillations,and causes very early changes in gene expressions in six individual rat brain regions,a first report.

  19. Metabolomic analysis reveals metabolic disturbance in the cortex and hippocampus of subchronic MK-801 treated rats.

    Directory of Open Access Journals (Sweden)

    Liya Sun

    Full Text Available BACKGROUND: Although a number of proteins and genes relevant to schizophrenia have been identified in recent years, few are known about the exact metabolic pathway involved in this disease. Our previous proteomic study has revealed the energy metabolism abnormality in subchronic MK-801 treated rat, a well-established animal model for schizophrenia. This prompted us to further investigate metabolite levels in the same rat model to better delineate the metabolism dysfunctions and provide insights into the pathology of schizophrenia. METHODS: Metabolomics, a high-throughput investigatory strategy developed in recent years, can offer comprehensive metabolite-level insights that complement protein and genetic findings. In this study, we employed a nondestructive metabolomic approach (1H-MAS-NMR to investigate the metabolic traits in cortex and hippocampus of MK-801 treated rats. Multivariate statistics and ingenuity pathways analyses (IPA were applied in data processing. The result was further integrated with our previous proteomic findings by IPA analysis to obtain a systematic view on our observations. RESULTS: Clear distinctions between the MK-801 treated group and the control group in both cortex and hippocampus were found by OPLS-DA models (with R(2X = 0.441, Q(2Y = 0.413 and R(2X = 0.698, Q(2Y = 0.677, respectively. The change of a series of metabolites accounted for the separation, such as glutamate, glutamine, citrate and succinate. Most of these metabolites fell in a pathway characterized by down-regulated glutamate synthesis and disturbed Krebs cycle. IPA analysis further confirmed the involvement of energy metabolism abnormality induced by MK-801 treatment. CONCLUSIONS: Our metabolomics findings reveal systematic changes in pathways of glutamate metabolism and Krebs cycle in the MK-801 treated rats' cortex and hippocampus, which confirmed and improved our previous proteomic observation and served as a valuable reference to

  20. β-arrestin1 mediates the effect of MK-801 on levodopa-induced dyskinesia in Parkinson ', s disease%β-arrestin1参与MK-801治疗帕金森病异动症的研究

    Institute of Scientific and Technical Information of China (English)

    吴娜; 宋璐; 杨新新; 刘振国

    2011-01-01

    . 95 ± 0. 44) × 104) in LID rats were decreased compared to the contralateral side ( ( 3.78 ± 0. 37 ) × 104, t = 5. 415, P < 0. 05 ).Western blot showed that the levels of β-arrestinl in PD group ( presented as lesioned side/contralateral side) were ( 81.02% ± 2. 23% ). The levels of β-arrestin1 (64. 88% ± 3. 10% ) were deceased in LID rats compared to PD rats ( t = 9.47, P < 0. 01 ). However, the levels of β-arrestin1 ( 89. 26% ± 1.90% )were increased in MK-801-treated rats (t = 14. 82, P <0. 01). Conclusions MK-801 reduces LID in PD rats. The beneficial effect of MK-801 may be mediated through the increased expression of β-arrestinl which in turninhibits the overactivation of glutamate receptors.

  1. Effects of ionotropic glutamate receptor antagonists on rat dural artery diameter in an intravital microscopy model

    DEFF Research Database (Denmark)

    Chan, K Y; Gupta, S; de Vries, R;

    2010-01-01

    studies have shown that glutamate receptor antagonists affect the pathophysiology of migraine. This study investigated whether antagonists of NMDA (ketamine and MK801), AMPA (GYKI52466) and kainate (LY466195) glutamate receptors affected dural vasodilatation induced by alpha-CGRP, capsaicin......During migraine, trigeminal nerves may release calcitonin gene-related peptide (CGRP), inducing cranial vasodilatation and central nociception; hence, trigeminal inhibition or blockade of craniovascular CGRP receptors may prevent this vasodilatation and abort migraine headache. Several preclinical...

  2. The involvement of NMDA receptor/NO/cGMP pathway in the antidepressant like effects of baclofen in mouse force swimming test.

    Science.gov (United States)

    Khan, Muhammad Imran; Ostadhadi, Sattar; Zolfaghari, Samira; Ejtemaei Mehr, Shahram; Hassanzadeh, Gholamreza; Dehpour, Ahmad-Reza

    2016-01-26

    In the current study, the involvement of N-methyl-d-aspartate receptor (NMDAR) and nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) system in the antidepressant-like effects of baclofen was evaluated by using animal model in forced swimming test. Followed by an open field test for the evaluation of locomotor activity, the immobility time for mice in force swimming test was recorded. Only the last four min was analyzed. Administration of Baclofen (0.5 and 1mg/kg, i.p.) reduced the immobility interval in the FST. Prior administration of l-arginine (750mg/kg, i.p.,) a nitric oxide synthase substrate or sildenafil (5mg/kg, i.p.) a phosphodiesterase 5 into mice suppressed the antidepressant-like activity of baclofen (1mg/kg, i.p.).Co-treatment of 7-nitroindazole (50mg/kg, i.p.,) an inhibitor of neuronal nitric oxide synthase, L-NAME (10mg/kg, i.p.,) a non-specific inhibitor of nitric oxide synthase or MK-801 (0.05mg/kg, i.p.) an NMDA receptor antagonist with subeffective dose of baclofen (0.1mg/kg, i.p.), reduced the immobility time in the FST as compared to the drugs when used alone. Co-administrated of lower doses of MK-801 (0.01mg/kg) or l-NAME (1mg/kg) failed to effect immobility time however, simultaneous administration of these two agents in same dose with subeffective dose of baclofen (0.1mg/kg, i.p.), minimized the immobility time in the FST. Thus, our results support the role of NMDA receptors and l-arginine-NO-GMP pathway in the antidepressant-like action of baclofen.

  3. Relationships between hippocampal NMDA receptor and NOS positive neurons in myenteric nerve plexus in stomach of CUMS rats%海马NDMA受体与胃肌间神经丛NOS阳性神经元在慢性应激性胃运动变化中的关系

    Institute of Scientific and Technical Information of China (English)

    乔卉; 何娟; 饶志萍; 徐畅; 安书成

    2012-01-01

    目的 探讨慢性应激对大鼠胃功能和胃肠神经系统的影响,并分析其海马谷氨酸(Glu)离子型受体机制.方法 通过建造慢性应激性抑郁模型大鼠,结合脑立体定位及微量注射Glu和N-甲基-D-天冬氨酸(NMDA)受体阻断剂MK-801,对实验鼠进行糖水偏爱等行为学检测、胃内压记录及胃内在神经丛的一氧化氮合酶(NOS)阳性神经元表达的组织化学检测.结果 慢性不可预见性温和应激(CUMS)动物表现出抑郁样行为,且胃运动减弱;海马注射NMDA受体阻断剂MK-801,可以反转CUMS的效应;海马注射Glu,能增加游泳不动时间,但对胃运动无影响.CUMS使胃肌间神经丛NOS阳性神经元数量减少[(73.74±16.38 )/LPF,P<0.05],神经节数量减少[(4.25±1.34)/LPF,P<0.05],但每个神经节内神经元数量明显增加(6.55±2.37,P<0.05);海马注射MK-801能改善CUMS引起的神经节数量减少的现象.结论 慢性应激诱发的抑郁样行为与海马Glu及其NMDA受体有关,而胃活动的减弱可能与海马NMDA受体变化影响胃肌间神经丛NOS神经元分布格局有关.%Objective To investigate the involvement of hippocampal glutamate and NMDA receptor in the effect of CUMS on gastric function and enteric nervous system ( ENS) . Methods Chronic unpredictability mild stress (CUMS)-induced depression model was established in SD rats, intra-hippocampal microinjections of Glu and non-competitive antagonist of N-methyl-D-aspartic acid (NMDA) receptor (MK-801) were respectively adopted by rat brain stereotaxic coordinates. The behavioral observations were conducted by sucrose preference test and forced swimming test. The intra-gastric pressure was recorded and the expression of Nitric oxide synthase (NOS) positiveneurons in myenteric nerve plexus in stomach was detected as well. Results CUMS rats showed depression-like behavioral changes and weaker gastric motility as compared to control. Preheated with MK-801 could reverse these

  4. In vivo evaluation of [{sup 11}C]N-(2-chloro-5-thiomethylphenyl)-N'- (3-methoxy-phenyl)-N'-methylguanidine ([{sup 11}C]GMOM) as a potential PET radiotracer for the PCP/NMDA receptor

    Energy Technology Data Exchange (ETDEWEB)

    Waterhouse, Rikki N. E-mail: rnw7@columbia.edu; Slifstein, Mark; Dumont, Filip; Zhao Jun; Chang, Raymond C.; Sudo, Yasuhiko; Sultana, Abida; Balter, Andrew; Laruelle, Marc

    2004-10-01

    The development of imaging methods to measure changes in NMDA ion channel activation would provide a powerful means to probe the mechanisms of drugs and device based treatments (e.g., ECT) thought to alter glutamate neurotransmission. To provide a potential NMDA/PCP receptor PET tracer, we synthesized the radioligand [{sup 11}C]GMOM (K{sub i} = 5.2 {+-}0.3 nM; log P = 2.34) and evaluated this ligand in vivo in awake male rats and isoflurane anesthetized baboons. In rats, the regional brain uptake of [{sup 11}C]GMOM ranged from 0.75{+-}0.13% ID/g in the medulla and pons to 1.15{+-}0.17% ID/g in the occipital cortex. MK801 (1 mg/kg i.v.) significantly reduced (24-28%) [{sup 11}C]GMOM uptake in all regions. D-serine (10 mg/kg i.v.) increased [{sup 11}C]GMOM %ID/g values in all regions (10-24%) reaching significance in the frontal cortex and cerebellum only. The NR2B ligand RO 25-6981 (10 mg/kg i.v.) reduced [{sup 11}C]GMOM uptake significantly (24-38%) in all regions except for the cerebellum and striatum. Blood activity was 0.11{+-}0.03 %ID/g in the controls group and did not vary significantly across groups. PET imaging in isoflurane-anesthetized baboons with high specific activity [{sup 11}C]GMOM provided fairly uniform regional brain distribution volume (V{sub T}) values (12.8-17.1 ml g{sup -1}). MK801 (0.5 mg/kg, i.v., n = 1, and 1.0 mg/kg, i.v., n = 1) did not significantly alter regional V{sub T} values, indicating a lack of saturable binding. However, the potential confounding effects associated with ketamine induction of anesthesia along with isoflurane maintenance must be considered because both agents are known to reduce NMDA ion channel activation. Future and carefully designed studies, presumably utilizing an optimized NMDA/PCP site tracer, will be carried out to further explore these hypotheses. We conclude that, even though [{sup 11}C]GMOM is not an optimized PCP site radiotracer, its binding is altered in vivo in awake rats as expected by modulation of

  5. Potentiation of NMDA receptor-dependent cell responses by extracellular high mobility group box 1 protein.

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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.

  6. Synergistic antidepressant-like effect of the joint administration of caffeine and NMDA receptor ligands in the forced swim test in mice.

    Science.gov (United States)

    Serefko, Anna; Szopa, Aleksandra; Wlaź, Aleksandra; Wośko, Sylwia; Wlaź, Piotr; Poleszak, Ewa

    2016-04-01

    The optimal treatment of depressed patients remains one of the most important challenges concerning depression. The identification of the best treatment strategies and development of new, safer, and more effective agents are crucial. The glutamatergic system seems to be a promising drug target, and consequently the use of the NMDA receptor ligands, particularly in co-administration with other substances exerting the antidepressant activity, has emerged among the new ideas. The objective of this study was to examine the effect of caffeine on the performance of mice treated with various NMDA modulators in the forced swim test. We demonstrated a significant interaction between caffeine (5 mg/kg) and the following NMDA receptor ligands: MK-801 (an antagonist binding in the ion channel, 0.05 mg/kg), CGP 37849 (an antagonist of the glutamate site, 0.312 mg/kg), L-701,324 (an antagonist of the glycine site, 1 mg/kg), and D-cycloserine (a high-efficacy partial agonist of the glycine site, 2.5 mg/kg), while the interaction between caffeine and the inorganic modulators, i.e., Zn(2+) (2.5 mg/kg) and Mg(2+) (10 mg/kg), was not considered as significant. Based on the obtained results, the simultaneous blockage of the adenosine and NMDA receptors may be a promising target in the development of new antidepressants.

  7. [Anti-NMDA-receptor encephalitis].

    Science.gov (United States)

    Engen, Kristine; Agartz, Ingrid

    2016-06-01

    BACKGROUND In 2007 a clinical disease caused by autoantibodies directed against the N-methyl-D-aspartate (NMDA) receptor was described for the first time. Anti-NMDA-receptor encephalitis is a subacute, autoimmune neurological disorder with psychiatric manifestations. The disease is a form of limbic encephalitis and is often paraneoplastic. The condition is also treatable. In this review article we examine the development of the disease, clinical practice, diagnostics and treatment.MATERIAL AND METHOD The article is based on references retrieved from searches in PubMed, and a discretionary selection of articles from the authors' own literature archive.RESULTS The disease most frequently affects young women. It may initially be perceived as a psychiatric condition, as it usually presents in the form of delusions, hallucinations or mania. The diagnosis should be suspected in patients who later develop neurological symptoms such as various movement disorders, epileptic seizures and autonomic instability. Examination of serum or cerebrospinal fluid for NMDA receptor antibodies should be included in the assessment of patients with suspected encephalitis. MRI, EEG and assessment for tumours are important tools in diagnosing the condition and any underlying malignancy.INTERPRETATION If treatment is initiated early, the prognosis is good. Altogether 75 % of patients will fully recover or experience significant improvement. Apart from surgical resection of a possible tumour, the treatment consists of immunotherapy. Because of good possibilities for treatment, it is important that clinicians, particularly those in acute psychiatry, are aware of and alert to this condition.

  8. Mitochondria and NMDA receptor-dependent toxicity of berberine sensitizes neurons to glutamate and rotenone injury.

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    Kai Kysenius

    Full Text Available The global incidence of metabolic and age-related diseases, including type 2 diabetes and Alzheimer's disease, is on the rise. In addition to traditional pharmacotherapy, drug candidates from complementary and alternative medicine are actively being pursued for further drug development. Berberine, a nutraceutical traditionally used as an antibiotic, has recently been proposed to act as a multi-target protective agent against type 2 diabetes, dyslipidemias, ischemic brain injury and neurodegenerative diseases, such as Parkinson's and Alzheimer's disease. However, the safety profile of berberine remains controversial, as isolated reports suggest risks with acute toxicity, bradycardia and exacerbation of neurodegeneration. We report that low micromolar berberine causes rapid mitochondria-dependent toxicity in primary neurons characterized by mitochondrial swelling, increased oxidative stress, decreased mitochondrial membrane potential and depletion of ATP content. Berberine does not induce caspase-3 activation and the resulting neurotoxicity remains unaffected by pan-caspase inhibitor treatment. Interestingly, inhibition of NMDA receptors by memantine and MK-801 completely blocked berberine-induced neurotoxicity. Additionally, subtoxic nanomolar concentrations of berberine were sufficient to sensitize neurons to glutamate excitotoxicity and rotenone injury. Our study highlights the need for further safety assessment of berberine, especially due to its tendency to accumulate in the CNS and the risk of potential neurotoxicity as a consequence of increasing bioavailability of berberine.

  9. Antidepressant-like effects of ketamine, norketamine and dehydronorketamine in forced swim test: Role of activity at NMDA receptor.

    Science.gov (United States)

    Sałat, Kinga; Siwek, Agata; Starowicz, Gabriela; Librowski, Tadeusz; Nowak, Gabriel; Drabik, Urszula; Gajdosz, Ryszard; Popik, Piotr

    2015-12-01

    Ketamine produces rapid and long-lasting antidepressant effects in patients. The involvement of ketamine metabolites in these actions has been proposed. The effects of ketamine and its metabolites norketamine and dehydronorketamine on ligand binding to 80 receptors, ion channels and transporters was investigated at a single concentration of 10 μM. The affinities of all three compounds were then assessed at NMDA receptors using [3H]MK-801 binding. The dose-response relationships of all 3 compounds in the forced swim test were also investigated in mice 30 min after IP administration. The effects of ketamine and norketamine (both 50 mg/kg) were then examined at 30 min, 3 days and 7 days post administration. Among the 80 potential targets examined, only NMDA receptors were affected with a magnitude of >50% by ketamine and norketamine at the concentration of 10 μM. The Ki values of ketamine, norketamine and dehydronorketamine at NMDA receptors were 0.119±0.01, 0.97±0.1 and 3.21±0.3 μM, respectively. Ketamine and norketamine reduced immobility with minimum effective doses (MEDs) of 10 and 50 mg/kg, respectively; dehydronorketamine did not affect immobility at doses of up to 50 mg/kg. Neither ketamine nor norketamine reduced immobility in the forced swim test 3 and 7 days following administration. Further, oral administration of ketamine (5-50 mg/kg) did not affect immobility. We demonstrate that ketamine and norketamine but not dehydronorketamine given acutely at subanesthetic doses reduced immobility in the forced swim test. These antidepressant-like effects appear attributable to NMDA receptor inhibition.

  10. Permeation of Polymethoxyflavones into the Mouse Brain and Their Effect on MK-801-Induced Locomotive Hyperactivity.

    Science.gov (United States)

    Okuyama, Satoshi; Miyazaki, Kohei; Yamada, Rie; Amakura, Yoshiaki; Yoshimura, Morio; Sawamoto, Atsushi; Nakajima, Mitsunari; Furukawa, Yoshiko

    2017-02-24

    Accumulating data have indicated that citrus polymethoxyflavones (PMFs) have the ability to affect brain function. In the present study, we showed that 3,5,6,7,8,3',4'-heptamethoxy- flavone (HMF) given intraperitoneally to mice was immediately detected in the brain and that the permeability of the brain tissues to it was significantly higher than that of other citrus PMFs (nobiletin, tangeretin, and natsudaidain). The permeation of these PMFs into the brain well correlated with their abilities to suppress MK-801-induced locomotive hyperactivity, suggesting that HMF had the ability to act directly in the brain. We also obtained data suggesting that the suppressive effect of HMF on MK-801-induced locomotive hyperactivity was mediated by phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) in the hippocampus.

  11. Destruction of the noradrenergic system with DSP4 potentiates the behavioral effects of MK-801 in rats.

    Science.gov (United States)

    Hatip-Al-Khatib, I; Bolukbasi, F

    1999-02-01

    In this study we investigated the effect of lesioning the noradrenergic systems on the behavioral effects of (5R, 10S)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine hydrogen maleate--MK-801, in rats. The noradrenergic system was lesioned with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride--DSP4 (60 mg/kg IP). MK-801 increased the locomotor activity and rearing. DSP4 significantly further increased the hyperlocomotor activity, circling (especially to the left side), sniffing, rolling, and falling that were induced by MK-801. These results showed that destruction of the noradrenergic system increased MK-801-hyperlocomotor activity, ataxia and stereotypy.

  12. NMDA receptors and memory encoding.

    Science.gov (United States)

    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

  13. Nicotinic α7 receptor activation selectively potentiates the function of NMDA receptors in glutamatergic terminals of the nucleus accumbens

    Directory of Open Access Journals (Sweden)

    Stefania eZappettini

    2014-10-01

    Full Text Available We here provide functional and immunocytochemical evidence supporting the co-localization and functional interaction between nicotinic acetylcholine receptors (nAChRs and N-methyl-D-aspartic acid receptors (NMDARs in glutamatergic terminals of the nucleus accumbens (NAc. Immunocytochemical studies showed that a significant percentage of NAc terminals were glutamatergic and possessed GluN1 and α7-containing nAChR. A short-term pre-exposure of synaptosomes to nicotine (30 µM or choline (1 mM caused a significant potentiation of the 100 µM NMDA-evoked [3H]D-aspartate ([3H]D-Asp outflow, which was prevented by α-bungarotoxin (100 nM. The pre-exposure to nicotine (100 µM or choline (1 mM also enhanced the NMDA-induced cytosolic free calcium levels, as measured by FURA-2 fluorescence imaging in individual NAc terminals, an effect also prevented by α-bungarotoxin. Pre-exposure to the α4-nAChR agonists 5IA85380 (10 nM or RJR2429 (1 µM did not modify NMDA-evoked ([3H]D-Asp outflow and calcium transients. The NMDA-evoked ([3H]D-Asp overflow was partially antagonized by the NMDAR antagonists MK801, D-AP5, 5,7-DCKA and R(-CPP and unaffected by the GluN2B-NMDAR antagonists Ro256981 and ifenprodil. Notably, pre-treatment with choline increased GluN2A biotin-tagged proteins. In conclusion, our results show that the GluN2A-NMDA receptor function can be positively regulated in NAc terminals in response to a brief incubation with α7 but not α4 nAChRs agonists. This might be a general feature in different brain areas since a similar nAChR-mediated bolstering of NMDA-induced ([3H]D-Aspoverflow was also observed in hippocampal synaptosomes.

  14. A serotonin-1A receptor agonist and an N-methyl-D-aspartate receptor antagonist oppose each others effects in a genetic rat epilepsy model.

    Science.gov (United States)

    Filakovszky, J; Gerber, K; Bagdy, G

    1999-02-12

    The WAG/RIJ rats exhibit spontaneously occurring spike-wave discharges (SWD) accompanied by behavioural phenomena, with characteristics similar to the human absence type epilepsy. To study the mechanisms involved in this type of epileptiform activity we investigated the effects of the serotonin-1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the N-methyl-D-aspartate (NMDA) receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK-801). Intracerebroventricular (i.c.v.) injection of 8-OH-DPAT caused marked, dose dependent increase, MK-801 a decrease in the cumulative duration and number of spike-wave discharges. Pretreatment with MK-801 (10 microg/rat i.c.v.) abolished the increase caused by 8-OH-DPAT (20 microg/rat i.c.v.), but the decrease in SWD to MK-801 was counterbalanced by 8-OH-DPAT. These data provide evidence for an interaction of glutamatergic and serotonergic mechanisms in the triggering and maintenance of epileptic activity in this genetic model of absence epilepsy.

  15. NOC/oFQ and NMDA contribute to piglet hypoxic ischemic hypotensive cerebrovasodilation impairment.

    Science.gov (United States)

    Armstead, William M

    2002-05-01

    Previous studies have observed that hypotensive pial artery dilation was blunted after hypoxia-ischemia. In unrelated studies, the opioid nociceptin/orphanin FQ (NOC/oFQ) was observed to contribute to hypoxic ischemic impairment of N-methyl-D-aspartate (NMDA)-induced pial dilation. This study determined the contribution of NOC/oFQ and NMDA to hypoxic ischemic hypotensive cerebrovasodilation impairment in newborn pigs equipped with a closed cranial window. Global cerebral ischemia was produced via elevated intracranial pressure. Hypoxia decreased PO(2) to 33 +/- 3 mm Hg. Topical NOC/oFQ (10(-10) M), the cerebrospinal fluid concentration after hypoxia-ischemia, had no effect on pial artery diameter by itself but attenuated hypotension (mean arterial blood pressure decrease of 44 +/- 2%) -induced pial artery dilation (35 +/- 2% versus 22 +/- 3%). Hypotensive pial artery dilation was blunted by hypoxia-ischemia, but such dilation was partially protected by pretreatment with the putative NOC/oFQ receptor antagonist, [F/G] NOC/oFQ (1-13) NH(2) (10(-6) M; 29 +/- 2%, sham control; 7 +/- 2%, hypoxia-ischemia; and 13 +/- 2%, hypoxia-ischemia and [F/G] NOC/oFQ (1-13) NH(2)). Coadministration of the NMDA antagonist MK801 (10(-5) M) with NOC/oFQ(10(-10) M) partially prevented hypotensive pial dilation impairment. Similarly, pretreatment with MK801 partially protected hypoxic ischemia impairment of hypotensive pial dilation (35 +/- 2%, sham control; 7 +/- 1%, hypoxia-ischemia; 22 +/- 2%, hypoxia-ischemia + MK801). These data show that NOC/oFQ and NMDA contribute to hypoxic ischemic hypotensive cerebrovasodilation impairment. These data suggest that NOC/oFQ modulation of NMDA vascular activity also contributes to such hypotensive impairment.

  16. Autoimmune NMDA receptor encephalitis.

    Science.gov (United States)

    Lazar-Molnar, Eszter; Tebo, Anne E

    2015-01-01

    Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is a treatable autoimmune disease of the central nervous system (CNS) with prominent neurologic and psychiatric features at disease onset. The disease is associated with the production of autoantibodies to NMDAR, a protein involved in memory function and synaptic plasticity. Affected patients develop a multistage progressive illness with symptoms ranging from memory deficits, seizures and psychosis, to potentially lethal catatonia, and autonomic and breathing instability. The outcome can be much improved with accurate diagnosis and early treatment using adequate immunosuppressive therapy. However, since the neurological and psychiatric symptoms as well as the clinical examination results can be non-specific, the disease is probably under-recognized. Reliable and accurate clinical testing for the identification of NMDAR autoantibodies is crucial for diagnosis, timely treatment selection, and monitoring. Recently, a cell-based indirect immunofluorescent antibody test for the detection of IgG antibodies to NMDAR has become available for diagnostic use. This review highlights the progress and challenges of laboratory testing in the evaluation and management anti-NMDAR encephalitis, and perspectives for the future.

  17. MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors.

    Science.gov (United States)

    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.

  18. Pathologically activated neuroprotection via uncompetitive blockade of N-methyl-D-aspartate receptors with fast off-rate by novel multifunctional dimer bis(propyl)-cognitin.

    Science.gov (United States)

    Luo, Jialie; Li, Wenming; Zhao, Yuming; Fu, Hongjun; Ma, Dik-Lung; Tang, Jing; Li, Chaoying; Peoples, Robert W; Li, Fushun; Wang, Qinwen; Huang, Pingbo; Xia, Jun; Pang, Yuanping; Han, Yifan

    2010-06-25

    Uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and gamma-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate hydrophobic interaction between bis(propyl)-cognitin and the MK-801 binding region in the ion channel pore of the NMDA receptor. Bis(propyl)-cognitin was further found to compete with [(3)H]MK-801 with a K(i) value of 0.27 mum, and the mutation of NR1(N616R) significantly reduced its inhibitory potency. Under glutamate-mediated pathological conditions, bis(propyl)-cognitin, in contrast to bis(heptyl)-cognitin, prevented excitotoxicity with increasing effectiveness against escalating levels of glutamate and much more effectively protected against middle cerebral artery occlusion-induced brain damage than did memantine. More interestingly, under NMDA receptor-mediated physiological conditions, bis(propyl)-cognitin enhanced long-term potentiation in hippocampal slices, whereas MK-801 reduced and memantine did not alter this process. These results suggest that bis(propyl)-cognitin is a UFO antagonist of NMDA receptors with moderate affinity, which may provide a pathologically activated therapy for various neurodegenerative disorders associated with NMDA receptor dysregulation.

  19. Molecular pharmacology of human NMDA receptors

    DEFF Research Database (Denmark)

    Hedegaard, Maiken; Hansen, Kasper Bø; Andersen, Karen Toftegaard

    2012-01-01

    current knowledge of the relationship between NMDA receptor structure and function. We summarize studies on the biophysical properties of human NMDA receptors and compare these properties to those of rat orthologs. Finally, we provide a comprehensive pharmacological characterization that allows side......-by-side comparison of agonists, un-competitive antagonists, GluN2B-selective non-competitive antagonists, and GluN2C/D-selective modulators at recombinant human and rat NMDA receptors. The evaluation of biophysical properties and pharmacological probes acting at different sites on the receptor suggest...... that the binding sites and conformational changes leading to channel gating in response to agonist binding are highly conserved between human and rat NMDA receptors. In summary, the results of this study suggest that no major detectable differences exist in the pharmacological and functional properties of human...

  20. Human Neuroepithelial Cells Express NMDA Receptors

    Directory of Open Access Journals (Sweden)

    Cappell B

    2003-11-01

    Full Text Available Abstract L-glutamate, an excitatory neurotransmitter, binds to both ionotropic and metabotropic glutamate receptors. In certain parts of the brain the BBB contains two normally impermeable barriers: 1 cerebral endothelial barrier and 2 cerebral epithelial barrier. Human cerebral endothelial cells express NMDA receptors; however, to date, human cerebral epithelial cells (neuroepithelial cells have not been shown to express NMDA receptor message or protein. In this study, human hypothalamic sections were examined for NMDA receptors (NMDAR expression via immunohistochemistry and murine neuroepithelial cell line (V1 were examined for NMDAR via RT-PCR and Western analysis. We found that human cerebral epithelium express protein and cultured mouse neuroepithelial cells express both mRNA and protein for the NMDA receptor. These findings may have important consequences for neuroepithelial responses during excitotoxicity and in disease.

  1. NMDA and D1 receptors are involved in one-trial tolerance to the anxiolytic-like effects of diazepam in the elevated plus maze test in rats.

    Science.gov (United States)

    Zhou, Heng; Yu, Cheng-Long; Wang, Li-Ping; Yang, Yue-Xiong; Mao, Rong-Rong; Zhou, Qi-Xin; Xu, Lin

    2015-08-01

    The elevated plus maze (EPM) test is used to examine anxiety-like behaviors in rodents. One interesting phenomenon in the EPM test is one-trial tolerance (OTT), which refers to the reduction in the anxiolytic-like effects of benzodiazepines when rodents are re-exposed to the EPM. However, the underlying mechanism of OTT is still unclear. In this study, we reported that OTT occurred when re-exposure to the EPM (trial 2) only depended on the prior experience of the EPM (trial 1) rather than diazepam treatment. This process was memory-dependent, as it was prevented by the N-methyl-D-aspartate (NMDA) receptors antagonist MK-801 1.5h before trial 2. In addition, OTT was maintained for at least one week but was partially abolished after an interval of 28 days. Furthermore, the administration of the D1-like receptors agonist SKF38393 to the bilateral dorsal hippocampus largely prevented OTT, as demonstrated by the ability of the diazepam treatment to produce significant anxiolytic-like effects in trial 2 after a one-day interval. These findings suggest that OTT to the EPM test may occur via the activation of NMDA receptors and the inactivation of D1-like receptors in certain brain regions, including the hippocampus.

  2. NMDA-Receptors Are Involved in Cu2+/Paraquat-Induced Death of Cultured Cerebellar Granule Neurons.

    Science.gov (United States)

    Stelmashook, E V; Genrikhs, E E; Aleksandrova, O P; Amelkina, G A; Zelenova, E A; Isaev, N K

    2016-08-01

    Rat cultured cerebellar granule neurons (CGNs) were not sensitive to CuCl2 (1-10 µM, 24 h), whereas paraquat (150 µM) decreased neuronal survival to 79 ± 3% of control level. Simultaneous treatment of CGNs with paraquat and CuCl2 (2, 5, or 10 µM Cu2+/paraquat) caused significant copper dose-dependent death, lowering their survival to 56 ± 4, 37 ± 3, or 16 ± 2%, respectively, and stimulating elevated production of free radicals in CGNs. Introduction of vitamin E, a non-competitive antagonist of NMDA subtype of glutamate receptors (MK-801), and also removal of glutamine from the incubation medium decreased toxicity of Cu2+/paraquat mixture. However, addition of Cu2+ into the incubation medium did not affect CGNs death caused by glutamate. These data emphasize that excessive copper in the brain may trigger oxidative stress, which in turn results in release of glutamate, overstimulation of glutamate receptors, and neuronal death.

  3. Prolonged nicotine exposure down-regulates presynaptic NMDA receptors in dopaminergic terminals of the rat nucleus accumbens.

    Science.gov (United States)

    Salamone, Alessia; Zappettini, Stefania; Grilli, Massimo; Olivero, Guendalina; Agostinho, Paula; Tomé, Angelo R; Chen, Jiayang; Pittaluga, Anna; Cunha, Rodrigo A; Marchi, Mario

    2014-04-01

    The presynaptic control of dopamine release in the nucleus accumbens (NAc) by glutamate and acetylcholine has a profound impact on reward signaling. Here we provide immunocytochemical and neurochemical evidence supporting the co-localization and functional interaction between nicotinic acetylcholine receptors (nAChRs) and N-methyl-D-aspartic acid (NMDA) receptors in dopaminergic terminals of the NAc. Most NAc dopaminergic terminals possessed the nAChR α4 subunit and the pre-exposure of synaptosomes to nicotine (30 μM) or to the α4β2-containing nAChR agonist 5IA85380 (10 nM) selectively inhibited the NMDA (100 μM)-evoked, but not the 4-aminopyridine (10 μM)-evoked, [(3)H] dopamine outflow; this inhibition was blunted by mecamylamine (10 μM). Nicotine and 5IA85380 pretreatment also inhibited the NMDA (100 μM)-evoked increase of calcium levels in single nerve terminals, an effect prevented by dihydro-β-erythroidine (1 μM). This supports a functional interaction between α4β2-containing nAChR and NMDA receptors within the same terminal, as supported by the immunocytochemical co-localization of α4 and GluN1 subunits in individual NAc dopaminergic terminals. The NMDA-evoked [(3)H]dopamine outflow was blocked by MK801 (1 μM) and inhibited by the selective GluN2B-selective antagonists ifenprodil (1 μM) and RO 25-6981 (1 μM), but not by the GluN2A-preferring antagonists CPP-19755 (1 μM) and ZnCl2 (1 nM). Notably, nicotine pretreatment significantly decreased the density of biotin-tagged GluN2B proteins in NAc synaptosomes. These results show that nAChRs dynamically and negatively regulate NMDA receptors in NAc dopaminergic terminals through the internalization of GluN2B receptors.

  4. Transient focal ischemia results in persistent and widespread neuroinflammation and loss of glutamate NMDA receptors

    Energy Technology Data Exchange (ETDEWEB)

    Dhawan, J.; Biegon, A.; Dhawan, J.; Benveniste, H.; Nawrocky, M.; Smith, S.D.; Biegon, A.

    2010-03-04

    Stroke is accompanied by neuroinflammation in humans and animal models. To examine the temporal and anatomical profile of neuroinflammation and NMDA receptors (NMDAR) in a stroke model, rats (N = 17) were subjected to a 90 min occlusion of the middle cerebral artery (MCAO) and compared to sham (N = 5) and intact (N = 4) controls. Striatal and parietal cortical infarction was confirmed by MRI 24 h after reperfusion. Animals were killed 14 or 30-40 days later and consecutive coronal cryostat sections were processed for quantitative autoradiography with the neuroinflammation marker [{sup 3}H]PK11195 and the NMDAR antagonist [{sup 3}H]MK801. Significantly increased specific binding of [{sup 3}H]PK11195 relative to non-ischemic controls was observed in the ipsilateral striatum (> 3 fold, p < 0.0001), substantia innominata (> 2 fold) with smaller (20%-80%) but statistically significant (p = 0.002-0.04) ipsilateral increases in other regions partially involved in the infarct such as the parietal and piriform cortex, and in the lateral septum, which was not involved in the infarct. Trends for increases in PBR density were also observed in the contralateral hemisphere. In the same animals, NMDAR specific binding was significantly decreased bilaterally in the septum, substantia innominata and ventral pallidum. Significant decreases were also seen in the ipsilateral striatum, accumbens, frontal and parietal cortex. The different anatomical distribution of the two phenomena suggests that neuroinflammation does not cause the observed reduction in NMDAR, though loss of NMDAR may be locally augmented in ipsilateral regions with intense neuroinflammation. Persistent, bilateral loss of NMDAR, probably reflecting receptor down regulation and internalization, may be responsible for some of the effects of stroke on cognitive function which cannot be explained by infarction alone.

  5. Transient focal ischemia results in persistent and widespread neuroinflammation and loss of glutamate NMDA receptors

    Science.gov (United States)

    Dhawan, Jasbeer; Benveniste, Helene; Nawrocky, Marta; Smith, S. David; Biegon, Anat

    2010-01-01

    Stroke is accompanied by neuroinflammation in humans and animal models. To examine the temporal and anatomical profile of neuroinflammation and NMDA receptors (NMDAR) in a stroke model, rats (N=17) were subjected to 90 minutes occlusion of the middle cerebral artery (MCAO) and compared to sham (N=5) and intact (N=4) controls. Striatal and partial cortical Infarction was confirmed by MRI 24 hr after reperfusion. Animals were killed 14 or 30–40 days later and consecutive coronal cryostat sections processed for quantitative autoradiography with the neuroinflammation marker [3H]PK11195 and the NMDAR antagonist [3H]MK801. Significantly Increased specific binding of [3H]PK11195 relative to non-ischemic controls was observed in the ipsilateral striatum (>3 fold, p2 fold) with smaller (20%–80%) but statistically significant (p=0.002–0.04) ipsilateral increases in other regions partially involved in the infarct such as the parietal and piriform cortex, and in the lateral septum, which was not involved in the infarct. Trends for increases in PBR density were also observed in the contralateral hemisphere. . In the same animals, NMDAR specific binding was significantly decreased bilaterally in the septum, substantia innominata and ventral pallidum. Significant decreases were also seen in the ipsilateral striatum, accumbens, frontal and parietal cortex. The different anatomical distribution of the two phenomena suggests that neuroinflammation does not cause the observed reduction in NMDAR, though loss of NMDAR may be locally augmented in ipsilateral regions with intense neuroinflammation. . Persistent, bilateral loss of NMDAR, probably reflecting receptor down regulation and internalization, may be responsible for some of the effects of stroke on cognitive function which can not be explained by infarction alone. PMID:20206701

  6. NMDA receptor and schizophrenia: a brief history.

    Science.gov (United States)

    Coyle, Joseph T

    2012-09-01

    Although glutamate was first hypothesized to be involved in the pathophysiology of schizophrenia in the 1980s, it was the demonstration that N-methyl-D-aspartate (NMDA) receptor antagonists, the dissociative anesthetics, could replicate the full range of psychotic, negative, cognitive, and physiologic features of schizophrenia in normal subjects that placed the "NMDA receptor hypofunction hypothesis" on firm footing. Additional support came from the demonstration that a variety of agents that enhanced NMDA receptor function at the glycine modulatory site significantly reduced negative symptoms and variably improved cognition in patients with schizophrenia receiving antipsychotic drugs. Finally, persistent blockade of NMDA receptors recreates in experimental animals the critical pathologic features of schizophrenia including downregulation of parvalbumin-positive cortical GABAergic neurons, pyramidal neuron dendritic dysgenesis, and reduced spine density.

  7. Aspects of dopamine and acetylcholine release induced by glutamate receptors; Aspectos das liberacoes de dopamina e acetilcolina mediadas por receptores de glutamato

    Energy Technology Data Exchange (ETDEWEB)

    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)

  8. A Metabotropic-Like Flux-Independent NMDA Receptor Regulates Ca2+ Exit from Endoplasmic Reticulum and Mitochondrial Membrane Potential in Cultured Astrocytes

    Science.gov (United States)

    Montes de Oca Balderas, Pavel; Aguilera, Penélope

    2015-01-01

    Astrocytes were long thought to be only structural cells in the CNS; however, their functional properties support their role in information processing and cognition. The ionotropic glutamate N-methyl D-aspartate (NMDA) receptor (NMDAR) is critical for CNS functions, but its expression and function in astrocytes is still a matter of research and debate. Here, we report immunofluorescence (IF) labeling in rat cultured cortical astrocytes (rCCA) of all NMDAR subunits, with phenotypes suggesting their intracellular transport, and their mRNA were detected by qRT-PCR. IF and Western Blot revealed GluN1 full-length synthesis, subunit critical for NMDAR assembly and transport, and its plasma membrane localization. Functionally, we found an iCa2+ rise after NMDA treatment in Fluo-4-AM labeled rCCA, an effect blocked by the NMDAR competitive inhibitors D(-)-2-amino-5-phosphonopentanoic acid (APV) and Kynurenic acid (KYNA) and dependent upon GluN1 expression as evidenced by siRNA knock down. Surprisingly, the iCa2+ rise was not blocked by MK-801, an NMDAR channel blocker, or by extracellular Ca2+ depletion, indicating flux-independent NMDAR function. In contrast, the IP3 receptor (IP3R) inhibitor XestosponginC did block this response, whereas a Ryanodine Receptor inhibitor did so only partially. Furthermore, tyrosine kinase inhibition with genistein enhanced the NMDA elicited iCa2+ rise to levels comparable to those reached by the gliotransmitter ATP, but with different population dynamics. Finally, NMDA depleted the rCCA mitochondrial membrane potential (mΔψ) measured with JC-1. Our results demonstrate that rCCA express NMDAR subunits which assemble into functional receptors that mediate a metabotropic-like, non-canonical, flux-independent iCa2+ increase. PMID:25954808

  9. Multiple signaling pathways involved in stimulation of osteoblast differentiation by N-methyl-D-aspartate receptors activation in vitro

    Institute of Scientific and Technical Information of China (English)

    Jie-li LI; Lin ZHAO; Bin CUI; Lian-fu DENG; Guang NING; Jian-min LIU

    2011-01-01

    Aim: Glutamate receptors are expressed in osteoblastic cells. The present study was undertaken to investigate the mechanisms underlying the stimulation of osteoblast differentiation by N-methyl-D-aspartate (NMDA) receptor activation in vitro.Methods: Primary culture of osteoblasts was prepared from SD rats. Microarray was used to detect the changes of gene expression.The effect of NMDA receptor agonist or antagonist on individual gene was examined using RT-PCR. The activity of alkaloid phosphotase (ALP) was assessed using a commercial ALP staining kit.Results: Microarray analyses revealed that 10 genes were up-regulated by NMDA (0.5 mmol/L) and down-regulated by MK801 (100μmol/L), while 13 genes down-regulated by NMDA (0.5 mmol/L) and up-regulated by MK801 (100 μmol/L). Pretreatment of osteoblasts with the specific PKC inhibitor Calphostin C (0.05 μmol/L), the PKA inhibitor H-89 (20 nmol/L), or the PI3K inhibitor wortmannin (100 nmol/L) blocked the ALP activity increase caused by NMDA (0.5 mmol/L). Furthermore, NMDA (0.5 mmol/L) rapidly increased PI3K phosphorylation, which could be blocked by pretreatment of wortmannin (100 nmol/L).Conclusion: The results suggest that activation of NMDA receptors stimulates osteoblasts differentiation through PKA, PKC, and PI3K signaling pathways, which is a new role for glutamate in regulating bone remodeling.

  10. Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation through activating the NR2B subunits of NMDA receptors

    Energy Technology Data Exchange (ETDEWEB)

    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.

  11. NMDA receptor activity in neuropsychiatric disorders

    Directory of Open Access Journals (Sweden)

    Shaheen E Lakhan

    2013-06-01

    Full Text Available N-Methyl-D-aspartate (NMDA receptors play a variety of physiologic roles and their proper signaling is essential for cellular homeostasis. Any disruption in this pathway, leading to either enhanced or decreased activity, may result in the manifestation of neuropsychiatric pathologies such as schizophrenia, mood disorders, substance induced psychosis, Huntington's disease, Alzheimer's disease, and neuropsychiatric systemic lupus erythematosus. Here, we explore the notion that the overlap in activity of at least one biochemical pathway, the NMDA receptor pathway, may be the link to understanding the overlap in psychotic symptoms between diseases. This review intends to present a broad overview of those neuropsychiatric disorders for which alternations in NMDA receptor activity is prominent thus suggesting that continued direction of pharmaceutical intervention to this pathway may present a viable option for managing symptoms.

  12. Anti-NMDA Receptor Encephalitis in a Pregnant Woman

    OpenAIRE

    Kim, JiYoung; Park, Seung Ha; Jung, Yu Ri; Park, Soon Won; Jung, Dae Soo

    2015-01-01

    Anti N-methyl-D-aspartate (NMDA) receptor encephalitis is one of the most common types of autoimmune synaptic encephalitis. Anti-NMDA receptor encephalitis commonly occurs in young women with ovarian teratoma. It has variable clinical manifestations and treatment responses. Sometimes it is misdiagnosed as a psychiatric disorder or viral encephalitis. To the best of our knowledge, anti-NMDA receptor encephalitis is a rare condition in pregnant women. We report a case of anti-NMDA receptor ence...

  13. 海马NMDA受体经SP-NK1受体通路参与慢性应激诱发的抑郁样行为%Hippocampal NMDA Receptor is involved in Chronic Stress Induced Depressive-Like Behaviors via SP-NK1 Receptor Pathway

    Institute of Scientific and Technical Information of China (English)

    董素平; 徐畅; 原婷婷; 安书成

    2011-01-01

    theoretic mechanisms for depression, such as monoamine neurotransmitter imbalance theory, neural plasticity theory, but none of them can fully elucidate the formation of depression. Due to weakness of the antidepressant-like effect of monoamines, glutamate (Glu)and its receptors, especially N-methyl-D-aspartic acid (NMDA) receptor, and neuropeptides such as neuropeptide Y (NPY), substance P (SP), are drawing closer attention in recent years. Here, we are attempted to explore the interaction between Glu/NMDA receptor and SP/neurokinin 1 (NK1) receptor in chronic unpredictable mild stress (CUMS)-induced depression.CUMS-induced depression model was established in 250~300g weighted 90-day old Sprague-Dawley rats. Intrahippocampal microinjection of NK1 receptor antagonist CP-96345, NMDA receptor agonist NMDA or NMDA receptor antagonist MK-801 was performed under stereotaxic guide cannula. The body weight of rats was weighed on the 1st, 7th, 14th, and 21st days during the experiment. The behavioral conducts were observed by means of sucrose consumption test, open field test and tail suspension test. The substance P (SP) and glutamate (Glu) content in hippocampus were separately determined by High performance liquid chromatography (HPLC). One-way ANOVA, LSD and repeated measures in SPSS were used in datum analysis.Our data suggest that CUMS significantly induced the depressive-like behaviors in animals and the content of SP and Glu in hippocampus had increased significantly. Microinjection of NMDA into hippocampus resulted in similar animal depressive-like behaviors and an increased SP content compared to the CON/SAL group. Intrahippocampal injections of CP-96345 or MK-801 had effectively improved the depression-like behaviors induced by CUMS, and the elevation of SP level in hippocampus was attenuated in MK-801 injection, whereas Glu level remained unchanged in CP-96345 injection.Our results imply that hippocampal NMDA receptor may contribute to chronic stress induced depressive

  14. Anti-NMDA Receptor Encephalitis and Vaccination

    Science.gov (United States)

    Wang, Hsiuying

    2017-01-01

    Anti-N-methyl-d-aspartate (Anti-NMDA) receptor encephalitis is an acute autoimmune neurological disorder. The cause of this disease is often unknown, and previous studies revealed that it might be caused by a virus, vaccine or tumor. It occurs more often in females than in males. Several cases were reported to be related to vaccination such as the H1N1 vaccine and tetanus/diphtheria/pertussis and polio vaccines. In this study, we reported an anti-NMDA receptor encephalitis case that may be caused by Japanese encephalitis vaccination. To investigate the association between anti-NMDA receptor encephalitis and vaccination, we analyzed the phylogenetic relationship of the microRNAs, which significantly regulate these vaccine viruses or bacteria, and the phylogenetic relationship of these viruses and bacteria. This reveals that anti-NMDA receptor encephalitis may be caused by Japanese encephalitis vaccination, as well as H1N1 vaccination or tetanus/diphtheria/pertussis and polio vaccinations, from the phylogenetic viewpoint. PMID:28106787

  15. Seizures and Anti-NMDA-Receptor Encephalitis

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2008-12-01

    Full Text Available The clinical and immunological features of 100 patients with encephalitis associated with antibodies against NR1-NR2 heteromers of the NMDA receptor were analyzed in a study at the Children’s Hospital of Philadelphia, and University of Pennsylvania.

  16. Anti-NMDA Receptor Encephalitis and Vaccination

    Directory of Open Access Journals (Sweden)

    Hsiuying Wang

    2017-01-01

    Full Text Available Anti-N-methyl-d-aspartate (Anti-NMDA receptor encephalitis is an acute autoimmune neurological disorder. The cause of this disease is often unknown, and previous studies revealed that it might be caused by a virus, vaccine or tumor. It occurs more often in females than in males. Several cases were reported to be related to vaccination such as the H1N1 vaccine and tetanus/diphtheria/pertussis and polio vaccines. In this study, we reported an anti-NMDA receptor encephalitis case that may be caused by Japanese encephalitis vaccination. To investigate the association between anti-NMDA receptor encephalitis and vaccination, we analyzed the phylogenetic relationship of the microRNAs, which significantly regulate these vaccine viruses or bacteria, and the phylogenetic relationship of these viruses and bacteria. This reveals that anti-NMDA receptor encephalitis may be caused by Japanese encephalitis vaccination, as well as H1N1 vaccination or tetanus/diphtheria/pertussis and polio vaccinations, from the phylogenetic viewpoint.

  17. Anti-NMDA Receptor Encephalitis and Vaccination.

    Science.gov (United States)

    Wang, Hsiuying

    2017-01-18

    Anti-N-methyl-d-aspartate (Anti-NMDA) receptor encephalitis is an acute autoimmune neurological disorder. The cause of this disease is often unknown, and previous studies revealed that it might be caused by a virus, vaccine or tumor. It occurs more often in females than in males. Several cases were reported to be related to vaccination such as the H1N1 vaccine and tetanus/diphtheria/pertussis and polio vaccines. In this study, we reported an anti-NMDA receptor encephalitis case that may be caused by Japanese encephalitis vaccination. To investigate the association between anti-NMDA receptor encephalitis and vaccination, we analyzed the phylogenetic relationship of the microRNAs, which significantly regulate these vaccine viruses or bacteria, and the phylogenetic relationship of these viruses and bacteria. This reveals that anti-NMDA receptor encephalitis may be caused by Japanese encephalitis vaccination, as well as H1N1 vaccination or tetanus/diphtheria/pertussis and polio vaccinations, from the phylogenetic viewpoint.

  18. fMRI study of the role of glutamate NMDA receptor in the olfactory adaptation in rats: Insights into cellular and molecular mechanisms of olfactory adaptation.

    Science.gov (United States)

    Zhao, Fuqiang; Wang, Xiaohai; Zariwala, Hatim A; Uslaner, Jason M; Houghton, Andrea K; Evelhoch, Jeffrey L; Hostetler, Eric; Winkelmann, Christopher T; Hines, Catherine D G

    2017-02-03

    Olfactory adaptation, characterized by attenuation of response to repeated odor stimulations or continuous odor exposure, is an intrinsic feature of olfactory processing. Adaptation can be induced by either "synaptic depression" due to depletion of neurotransmitters, or "enhanced inhibition" onto principle neurons by local inhibitory interneurons in olfactory structures. It is not clear which mechanism plays a major role in olfactory adaptation. More importantly, molecular sources of enhanced inhibition have not been identified. In this study, olfactory responses to either repeated 40-s stimulations with interstimulus intervals (ISI) of 140-s or 30-min, or a single prolonged 200-s stimulus were measured by fMRI in different naïve rats. Olfactory adaptations in the olfactory bulb (OB), anterior olfactory nucleus (AON), and piriform cortex (PC) were observed only with repeated 40-s odor stimulations, and no olfactory adaptations were detected during the prolonged 200-s stimulation. Interestingly, in responses to repeated 40-s odor stimulations in the PC, the first odor stimulation induced positive activations, and odor stimulations under adapted condition induced negative activations. The negative activations suggest that "sparse coding" and "global inhibition" are the characteristics of olfactory processing in PC, and the global inhibition manifests only under an adapted condition, not a naïve condition. Further, we found that these adaptations were NMDA receptor dependent; an NMDA receptor antagonist (MK801) blocked the adaptations. Based on the mechanism that glutamate NMDA receptor plays a role in the inhibition onto principle neurons by interneurons, our data suggest that the olfactory adaptations are caused by enhanced inhibition from interneurons. Combined with the necessity of the interruption of odor stimulation to observe the adaptations, the molecular source for the enhanced inhibition is most likely an increased glutamate release from presynaptic

  19. The Neuroprotective Effect of Cannabinoid Receptor Agonist (WIN55,212-2 in Paraoxon Induced Neurotoxicity in PC12 Cells and N-methyl-D-aspartate Receptor Interaction

    Directory of Open Access Journals (Sweden)

    Hedayat Sahraei

    2010-01-01

    Full Text Available Objective: Considering that cannabinoids protect neurons against neurodegeneration, inthis study, the neuroprotective effect of WIN55,212-2 in paraoxon induced neurotoxicity inPC12 cells and the role of the N-methyl-D-aspartate (NMDA receptor were evaluated.Materials and Methods: In this study PC12 cells were maintained in Dulbecco's modifiedeagle’s medium (DMEM+F12 culture medium supplemented with 10% fetal bovineserum. The cells were treated with paraoxon (200 μM in the presence or absence ofWIN55,212-2 (0.1 μM, NMDA receptor agonist NMDA (100 μM, cannabinoid receptorantagonist AM251 and NMDA receptor antagonist MK801 (1 μM at 15 minutes intervals.After 48 hours of exposure, cellular viability and protein expression of the CB1 receptorwere evaluated in PC12 cells.Results: Following the exposure of PC12 cells to paraoxon (200 μM, a reduction in cellsurvival and protein level of the CB1 receptor was observed (p<0.01. Treatment of thecells with WIN55,212-2 (0.1 μM and NMDA (100 μM prior to paraoxon exposure significantlyelevated cell survival and protein level of the CB1 receptor (p<0.01. Also, AM251(1μM did not inhibit the cell survival and protein level of the CB1 receptor increase inducedby WIN55,212-2 (p<0.001. However, MK801 (1 μM did inhibit cell survival andprotein expression of the CB1 receptor increase induced by NMDA (p<0.001.Conclusion: The results indicate that WIN55,212-2 and NMDA protect PC12 cellsagainst paraoxon induced toxicity. In addition, the neuroprotective effect of WIN55,212-2and NMDA was cannabinoid receptor-independent and NMDA receptor dependent, respectively.

  20. Environmental Enrichment Ameliorates Behavioral Impairments Modeling Schizophrenia in Mice Lacking Metabotropic Glutamate Receptor 5.

    Science.gov (United States)

    Burrows, Emma L; McOmish, Caitlin E; Buret, Laetitia S; Van den Buuse, Maarten; Hannan, Anthony J

    2015-07-01

    Schizophrenia arises from a complex interplay between genetic and environmental factors. Abnormalities in glutamatergic signaling have been proposed to underlie the emergence of symptoms, in light of various lines of evidence, including the psychotomimetic effects of NMDA receptor antagonists. Metabotropic glutamate receptor 5 (mGlu5) has also been implicated in the disorder, and has been shown to physically interact with NMDA receptors. To clarify the role of mGlu5-dependent behavioral expression by environmental factors, we assessed mGlu5 knockout (KO) mice after exposure to environmental enrichment (EE) or reared under standard conditions. The mGlu5 KO mice showed reduced prepulse inhibition (PPI), long-term memory deficits, and spontaneous locomotor hyperactivity, which were all attenuated by EE. Examining the cellular impact of genetic and environmental manipulation, we show that EE significantly increased pyramidal cell dendritic branching and BDNF protein levels in the hippocampus of wild-type mice; however, mGlu5 KO mice were resistant to these alterations, suggesting that mGlu5 is critical to these responses. A selective effect of EE on the behavioral response to the NMDA receptor antagonist MK-801 in mGlu5 KO mice was seen. MK-801-induced hyperlocomotion was further potentiated in enriched mGlu5 KO mice and treatment with MK-801 reinstated PPI disruption in EE mGlu5 KO mice only, a response that is absent under standard housing conditions. Together, these results demonstrate an important role for mGlu5 in environmental modulation of schizophrenia-related behavioral impairments. Furthermore, this role of the mGlu5 receptor is mediated by interaction with NMDA receptor function, which may inform development of novel therapeutics.

  1. Antidepressant effect of pramipexole in mice forced swimming test: A cross talk between dopamine receptor and NMDA/nitric oxide/cGMP pathway.

    Science.gov (United States)

    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.

  2. Effects of the non-competitive NMDA receptor antagonist memantine on the volitional consumption of ethanol by alcohol-preferring rats.

    Science.gov (United States)

    Malpass, Gloria E; Williams, Helen L; McMillen, Brian A

    2010-05-01

    Potent N-methyl-d-aspartate (NMDA) receptor antagonists decrease volitional consumption of ethanol by rats. This study examined the effects of memantine, a low-affinity, open channel NMDA antagonist, on volitional consumption of ethanol by alcohol-preferring rats and potential locomotor, sedative and hypothermic effects. Volitional consumption of ethanol in a 24-hr two-choice paradigm was determined for male Myers' high-ethanol-preferring (mHEP) rats. Effects of memantine (0.3, 1.0, 3.0 and 10.0 mg/kg, i.p., b.i.d. [twice daily] for 3 days) or vehicle on volitional consumption of ethanol, proportion of ethanol to total fluids consumed, total fluid intake and consumption of food were observed. Potential sedating and locomotor effects of memantine (10.0 mg/kg, i.p., b.i.d.) were determined using an elevated plus maze and an Auto-Track Opto-Varimex activity monitoring system. Rectal temperature was measured to determine if memantine (10.0 mg/kg, i.p.) produces a hypothermic effect. The results indicate that memantine dose-dependently decreased the amount of ethanol and proportion of ethanol to total fluids consumed daily, reaching 48% and 24%, respectively, at the highest dose. These effects did not appear to be anti-caloric. Memantine (10.0 mg/kg) partially reversed both the sedation and the reductions in locomotor activity induced by ethanol. This dose did, however, produce a small, partially reversible hypothermic effect. In conclusion, memantine may decrease ethanol consumption with fewer side effects than other NMDA receptor antagonists, such as phencyclidine (PCP), MK 801 and ketamine.

  3. Blockade of NMDA receptors 2A subunit in the dorsal striatum impairs the learning of a complex motor skill.

    Science.gov (United States)

    Lemay-Clermont, Julie; Robitaille, Christine; Auberson, Yves P; Bureau, Geneviève; Cyr, Michel

    2011-10-01

    Accumulating evidence proposes that the striatum, known to control voluntary movement, may also play a role in learning and memory. Striatum learning is thought to require long-lasting reorganization of striatal circuits and changes in the strength of synaptic connections during the memorization of a complex motor task. Whether the ionotropic glutamate receptor N-methyl-D-aspartate (NMDAR) contributes to the molecular mechanisms of these memory processes is still unclear. The aim of the present study was to investigate the role of striatal NMDAR and its subunit composition during the learning of the accelerating rotarod task in mice. To this end, we injected directly into the dorsal striatum of mice, via chronically implanted cannula, the NMDAR channel blocker MK-801 as well as the NR2A and NR2B subunit-selective antagonists NVP-AAM077 and Ro 25-6981, respectively, before rotarod training. There was no effect in the motor performances of mice treated with 1.0 μg/side of MK-801, 0.1 μg/side of NVP-AAM077, or 5 and 10 μg/side of Ro 25-6981. In contrast, injections of 2.5 and 5 μg/side of MK-801 or 0.5 and 1 μg/side of NVP-AAM077 impaired motor learning at Day 3 and 8. Interestingly, treatments with MK-801 and NVP-AAM077 did not alter the general motor capacities of mice as revealed by the stepping, wire suspension, and pole tests. Our study demonstrates that the NMDAR of the dorsal striatum contributes to motor learning, especially during the slow acquisition phase, and that NR2A subunits play a critical role in this process.

  4. MK-801诱导的精神分裂症发育模型大鼠脑组织DA,DOPAC,Glu和GABA浓度的变化%Concentration change of DA, DOPAC, Glu and GABA in brain tissues in schizophrenia developmental model rats induced by MK-801

    Institute of Scientific and Technical Information of China (English)

    刘勇; 唐亚梅; 蒲唯丹; 张向晖; 赵靖平

    2011-01-01

    产期N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)受体阻断致SZ的神经生化机制.方法:60只新生雄性SD大鼠于出生后6天按批次随机分为SZ发育模型组(MK-801F)、SZ慢性给药模型组(MK-801M)和正常对照组(Control);SZ发育模型大鼠于出生后7 ~10d皮下注射MK-801(0.1 mg/kg,Bid),SZ慢性给药模型大鼠于出生后47 ~60 d腹腔注射MK-801(0.2 mg/kg,Qd),对照组大鼠于相应时段注射0.9%的生理盐水.出生后第60天分批进行行为学测试,出生后第63天取各组大鼠大脑内侧前额叶皮质(medial prefrontal cortex,mPFC)和海马组织并匀浆,以高效液相色谱-库仑阵列电化学法检测组织匀浆中的DA,DOPAC,Glu和GABA水平,并计算分析DA和Glu的利用率.结果:SZ发育模型大鼠mPFC和海马DA及DOPAC的浓度较正常对照组明显降低(P <0.05);mPFC区GABA浓度和Glu利用率较正常对照组明显降低(P<0.05);mPFC区DA浓度较SZ慢性给药模型组明显降低(P<0.05);海马DOPAC浓度及DA利用率较SZ慢性给药模型组明显降低(分别P<0.01,P<0.05).结论:SZ发育模型成年大鼠mPFC区DA,Glu和GABA系统功能减退,海马DA系统功能减退.

  5. Characterisation of the Redox Sensitive NMDA Receptor

    KAUST Repository

    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

  6. Mice lacking NMDA receptors in parvalbumin neurons display normal depression-related behavior and response to antidepressant action of NMDAR antagonists.

    Directory of Open Access Journals (Sweden)

    Laura Pozzi

    Full Text Available The underlying circuit imbalance in major depression remains unknown and current therapies remain inadequate for a large group of patients. Discovery of the rapid antidepressant effects of ketamine--an NMDA receptor (NMDAR antagonist--has linked the glutamatergic system to depression. Interestingly, dysfunction in the inhibitory GABAergic system has also been proposed to underlie depression and deficits linked to GABAergic neurons have been found with human imaging and in post-mortem material from depressed patients. Parvalbumin-expressing (PV GABAergic interneurons regulate local circuit function through perisomatic inhibition and their activity is NMDAR-dependent, providing a possible link between NMDAR and the inhibitory system in the antidepressant effect of ketamine. We have therefore investigated the role of the NMDAR-dependent activity of PV interneurons for the development of depression-like behavior as well as for the response to rapid antidepressant effects of NMDAR antagonists. We used mutant mice lacking NMDA neurotransmission specifically in PV neurons (PV-Cre+/NR1f/f and analyzed depression-like behavior and anhedonia. To study the acute and sustained effects of a single NMDAR antagonist administration, we established a behavioral paradigm of repeated exposure to forced swimming test (FST. We did not observe altered behavioral responses in the repeated FST or in a sucrose preference test in mutant mice. In addition, the behavioral response to administration of NMDAR antagonists was not significantly altered in mutant PV-Cre+/NR1f/f mice. Our results show that NMDA-dependent neurotransmission in PV neurons is not necessary to regulate depression-like behaviors, and in addition that NMDARs on PV neurons are not a direct target for the NMDAR-induced antidepressant effects of ketamine and MK801.

  7. Role of N-methyl-D-aspartate receptor one in visceral hypersensitivity forming of transient intestinal infection induced rat%N-甲基-D-天冬氨酸受体1在一过性肠道感染大鼠内脏高敏感形成中的意义

    Institute of Scientific and Technical Information of China (English)

    杨小军; 沈蕾; 钱伟; 官阳; 侯晓华

    2012-01-01

    目的 研究N-甲基-D-天冬氨酸受体1(NMDA-R1)在SD大鼠—过性肠道感染旋毛虫后形成的内脏高敏感中的作用.方法 40只SD大鼠均分为健康对照组、内脏高敏感组、0.9%氯化钠溶液组、MK-801组,其中内脏高敏感组、0.9%氯化钠溶液组和MK 801组分别予旋毛虫感染造模.8周后,0.9%氯化钠溶液组和MK-801组分别予0.9%氯化钠溶液和NMDA-R1拮抗剂MK-801.观察各组在20、40、60和80 mm Hg(1 mm Hg=0.133 kPa)结直肠扩张压力下腹壁肌电活动反应.测定腹壁肌电活动后,取大鼠结肠标本,采用Western印迹检测NMDA-R1蛋白水平的表达.统计学处理采用Bivariate相关分析和LSD检验.结果 健康对照组、内脏高敏感组、0.9%氯化钠溶液组和MK-801组腹壁肌电图曲线下面积(AUC)与扩张压力之间均有相关性(r=0.823、0.618、0.913、0.889,均P<0.01).在20、40、60和80 mm Hg扩张压力下,MK-801组与内脏高敏感组AUC间差异均有统计学意义(LSD检验,P值均<0.05),MK-801组AUC均小于健康对照组,但只在80 mm Hg扩张压力下差异有统计学意义(LSD检验,P=0.029).MK-801NMDA-R1蛋白积分吸光度相对值为1.238±0.210,较内脏高敏感组(2.231±0.450)和0.9%氯化钠溶液组(2.104±0.220)均显著降低(LSD检验,P=0.025和0.046),内脏高敏感组NMDA-R1蛋白积分吸光度相对值和0.9%氯化钠溶液组较健康对照组显著升高(1SD检验,P=0.007和0.014).结论 内脏高敏感的形成与突触后NMDA-R1的高表达密切相关,抑制肠道神经系统中NMDA-R1的表达可调节内脏高敏感性.%Objective To investigate the role of N-methyl-D-aspartate receptor one(NMDA-R1 )in visceral hypersensitivity forming of Sprague-Dawley rat model induced by transient Trichinella spiralis intestinal infection.Methods Forty male Sprague-Dawley rats were divided into healthy control group,visceral hypersensitivity group,0.9% NaCl group and MK-801 group.The rats in visceral

  8. NMDA receptors in the basolateral amygdala and gustatory neophobia.

    Science.gov (United States)

    Figueroa-Guzmán, Yazmín; Reilly, Steve

    2008-05-19

    The attenuation of gustatory neophobia occurs during repeated exposures to an initially novel taste solution that is increasingly perceived as safe and familiar. The present study examined whether NMDA receptors in the basolateral region of the amygdala (BLA) are involved in this important behavioral phenomenon. The results, which show that the attenuation, but not initial occurrence, of gustatory neophobia is dependent upon NMDA receptors in the BLA, are discussed with reference to a similar finding involving NMDA receptors in the insular cortex.

  9. TRPA1, NMDA receptors and nitric oxide mediate mechanical hyperalgesia induced by local injection of magnesium sulfate into the rat hind paw.

    Science.gov (United States)

    Srebro, Dragana P; Vučković, Sonja M; Savić Vujović, Katarina R; Prostran, Milica Š

    2015-02-01

    Previous studies have shown that while magnesium, an antagonist of the glutamate subtype of N-methyl-D-aspartate receptors, possesses analgesic properties, it can induce writhing in rodents. The aim of this study was to determine the effect and mechanism of action of local (intraplantar) administration of magnesium sulfate (MS) on the paw withdrawal threshold (PWT) to mechanical stimuli. The PWT was evaluated by the electronic von Frey test in male Wistar rats. Tested drugs were either co-administered intraplantarly (i.pl.) with MS or given into the contralateral paw to exclude systemic effects. MS at doses of 0.5, 1.5, 3 and 6.2 mg/paw (i.pl.) induced a statistically significant (as compared to 0.9% NaCl) and dose-dependent mechanical hyperalgesia. Only isotonic MS (250 mmol/l or 6.2% or 6.2 mg/paw) induced mechanical hyperalgesia that lasted at least six hours. Isotonic MS-induced mechanical hyperalgesia was reduced in a dose-dependent manner by co-injection of camphor, a non-selective TRPA1 antagonist (0.3, 1 and 2.5 μg/paw), MK-801, a NMDA receptor antagonist (0.001, 0.025 and 0.1 μg/paw), L-NAME, a non-selective nitric oxide (NO) synthase inhibitor (20, 50 and 100 μg/paw), ARL 17477, a selective neuronal NOS inhibitor (5.7 and 17 μg/paw), SMT, a selective inducible NOS inhibitor (1 and 2.78 μg/paw), and methylene blue, a guanylate cyclase inhibitor (5, 20 and 125 μg/paw). Drugs injected into the contralateral hind paw did not produce significant effects. These results suggest that an i.pl. injection of MS produces local peripheral mechanical hyperalgesia via activation of peripheral TRPA1 and NMDA receptors and peripheral production of NO.

  10. Comparison of excitotoxic profiles of ATPA, AMPA, KA and NMDA in organotypic hippocampal slice cultures

    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...

  11. Comparison of excitotoxic profiles of ATPA, AMPA, KA and NMDA in organotypic hippocampal slice cultures

    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...

  12. Anti-NMDA Receptor Encephalitis in a Pregnant Woman.

    Science.gov (United States)

    Kim, Jiyoung; Park, Seung Ha; Jung, Yu Ri; Park, Soon Won; Jung, Dae Soo

    2015-06-01

    Anti N-methyl-D-aspartate (NMDA) receptor encephalitis is one of the most common types of autoimmune synaptic encephalitis. Anti-NMDA receptor encephalitis commonly occurs in young women with ovarian teratoma. It has variable clinical manifestations and treatment responses. Sometimes it is misdiagnosed as a psychiatric disorder or viral encephalitis. To the best of our knowledge, anti-NMDA receptor encephalitis is a rare condition in pregnant women. We report a case of anti-NMDA receptor encephalitis in a pregnant woman who presented with abnormal behavior, epileptic seizure, and hypoventilation.

  13. Maturation of anoxia-induced gasping in the rat: potential role for N-methyl-D-aspartate glutamate receptors.

    Science.gov (United States)

    Gozal, D; Torres, J E

    1997-12-01

    After anoxia-induced apnea, gasping remains the last operative mechanism for survival. In developing rats, the gasping response to anoxia exhibits triphasic characteristics. Because anoxia is associated with enhanced release of glutamate, we hypothesized that N-methyl-D-aspartate (NMDA) glutamate receptors may underlie components of the gasping response. Rat pups aged 2 d (n = 50), 5 d (n = 43), 10 d (n = 42), and 15 d (n = 45) underwent anoxic challenges with 100% N2 in a whole body plethysmograph, 30 min after intraperitoneal administration of MK801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate; dizocilpine] (3 mg/kg), a noncompetitive NMDA glutamate receptor channel antagonist, or normal saline. In control pups, after primary apnea onset, a triphasic gasping pattern was apparent at all postnatal ages and included two distinct types of gasps (I and II). In 2- and 5-d MK801-treated animals, phase 1 and type I gasps were absent, leading to marked prolongations of the gasp latency and phase 2, the latter displaying type II gasps only. In addition, phase 3 duration was also prolonged with increased type II gasp frequencies. In contrast, in some 10-d-old (40%) and in all 15-d-old MK801-treated pups, although overall gasping duration was prolonged, the triphasic gasping pattern seen in matched controls was also present. We conclude that NMDA glutamate receptors mediate particular phasic components of the gasping response during early postnatal life but not at later stages of development. We speculate that developmental changes occur in both function and expression of NMDA and other neurotransmitters within brainstem regions underlying the neural substrate for gasp generation.

  14. Preference for high-fat diet is developed by young Swiss CD1 mice after short-term feeding and is prevented by NMDA receptor antagonists.

    Science.gov (United States)

    Buttigieg, Angie; Flores, Osvaldo; Hernández, Alejandro; Sáez-Briones, Patricio; Burgos, Héctor; Morgan, Carlos

    2014-01-01

    Obesity is a worldwide epidemic that is increasing at an alarming rate. One of its causes is the increased availability and consumption of diets rich in fat. In the present study, we investigated the effects of short-term consumption of a high fat diet (HFD) on dietary preferences in Swiss CD1 mice and its relation in time to specific metabolic effects. Mice that were weaned 21days postpartum and fed a chow diet for one week were afterward subjected to a diet preference test for 5days, exposed to both a regular diet (RD) and HFD. We found that mice did not show any preferences. In a second experiment, two groups of mice that were weaned 21days postpartum and subjected to a chow diet for one week were fed either RD or HFD for 18days, and a diet preference test was performed for 5days. After this short-term consumption of HFD, mice preferred HFD, while mice subjected to RD did not show any preference. Importantly, no differences in blood glucose levels were found between the groups prior to and after the experiments. The results support our hypothesis that the preference for HFD is not a spontaneous behavior in CD1 mice, but it can be observed after short-term consumption; additionally, this preference develops before metabolic effects appear. Finally, this preference for HFD could not be observed when the mice were i.p. injected daily with low doses of the NMDA receptor antagonists, ketamine, ifenprodil or MK-801 during the HFD feeding period. These data suggest that acquisition of dietary preference for HFD is a NMDA receptor-dependent learning process. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. GABAA overactivation potentiates the effects of NMDA blockade during the brain growth spurt in eliciting locomotor hyperactivity in juvenile mice.

    Science.gov (United States)

    Oliveira-Pinto, Juliana; Paes-Branco, Danielle; Cristina-Rodrigues, Fabiana; Krahe, Thomas E; Manhães, Alex C; Abreu-Villaça, Yael; Filgueiras, Cláudio C

    2015-01-01

    Both NMDA receptor blockade and GABAA receptor overactivation during the brain growth spurt may contribute to the hyperactivity phenotype reminiscent of attention-deficit/hyperactivity disorder. Here, we evaluated the effects of exposure to MK801 (a NMDA antagonist) and/or to muscimol (a GABAA agonist) during the brain growth spurt on locomotor activity of juvenile Swiss mice. This study was carried out in two separate experiments. In the first experiment, pups received a single i.p. injection of either saline solution (SAL), MK801 (MK, 0.1, 0.3 or 0.5 mg/kg) or muscimol (MU, 0.02, 0.1 or 0.5 mg/kg) at the second postnatal day (PND2), and PNDs 4, 6 and 8. In the second experiment, we investigated the effects of a combined injection of MK (0.1 mg/kg) and MU (doses: 0.02, 0.1 or 0.5 mg/kg) following the same injection schedule of the first experiment. In both experiments, locomotor activity was assessed for 15 min at PND25. While MK promoted a dose-dependent increase in locomotor activity, exposure to MU failed to elicit significant effects. The combined exposure to the highest dose of MU and the lowest dose of MK induced marked hyperactivity. Moreover, the combination of the low dose of MK and the high dose of MU resulted in a reduced activity in the center of the open field, suggesting an increased anxiety-like behavior. These findings suggest that, during the brain growth spurt, the blockade of NMDA receptors induces juvenile locomotor hyperactivity whereas hyperactivation of GABAA receptors does not. However, GABAA overactivation during this period potentiates the effects of NMDA blockade in inducing locomotor hyperactivity. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Hippocampal NMDA receptors and the previous experience effect on memory.

    Science.gov (United States)

    Cercato, Magalí C; Colettis, Natalia; Snitcofsky, Marina; Aguirre, Alejandra I; Kornisiuk, Edgar E; Baez, María V; Jerusalinsky, Diana A

    2014-01-01

    N-methyl-D-aspartate receptors (NMDAR) are thought to be responsible for switching synaptic activity specific patterns into long-term changes in synaptic function and structure, which would support learning and memory. Hippocampal NMDAR blockade impairs memory consolidation in rodents, while NMDAR stimulation improves it. Adult rats that explored twice an open field (OF) before a weak though overthreshold training in inhibitory avoidance (IA), expressed IA long-term memory in spite of the hippocampal administration of MK-801, which currently leads to amnesia. Those processes would involve different NMDARs. The selective blockade of hippocampal GluN2B-containing NMDAR with ifenprodil after training promoted memory in an IA task when the training was weak, suggesting that this receptor negatively modulates consolidation. In vivo, after 1h of an OF exposure-with habituation to the environment-, there was an increase in GluN1 and GluN2A subunits in the rat hippocampus, without significant changes in GluN2B. Coincidentally, in vitro, in both rat hippocampal slices and neuron cultures there was an increase in GluN2A-NMDARs surface expression at 30min; an increase in GluN1 and GluN2A levels at about 1h after LTP induction was also shown. We hypothesize that those changes in NMDAR composition could be involved in the "anti-amnesic effect" of the previous OF. Along certain time interval, an increase in GluN1 and GluN2A would lead to an increase in synaptic NMDARs, facilitating synaptic plasticity and memory; while then, an increase in GluN2A/GluN2B ratio could protect the synapse and the already established plasticity, perhaps saving the specific trace.

  17. LOCALIZATION OF NMDA AND AMPA RECEPTORS IN RAT BARREL FIELD

    NARCIS (Netherlands)

    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

  18. Anti-NMDA-receptor antibody encephalitis in infants

    Directory of Open Access Journals (Sweden)

    Amr A. Matoq

    2015-01-01

    Conclusion: Infants with anti-NMDA-receptor antibody encephalitis can present with frank seizures or seizure mimics. Regardless, prompt recognition and aggressive treatment of anti-NMDA-receptor antibody encephalitis, while challenging, can quickly arrest deterioration and hasten recovery, thereby, limiting neurological morbidity.

  19. Agmatine enhances the antidepressant-like effect of lithium in mouse forced swimming test through NMDA pathway.

    Science.gov (United States)

    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.

  20. Alterations in ethanol-induced behaviors and consumption in knock-in mice expressing ethanol-resistant NMDA receptors.

    Directory of Open Access Journals (Sweden)

    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.

  1. NMDA Receptor Modulators in the Treatment of Drug Addiction.

    Science.gov (United States)

    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.

  2. NMDA Receptor Modulators in the Treatment of Drug Addiction

    Directory of Open Access Journals (Sweden)

    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.

  3. Exogenous t-PA administration increases hippocampal mature BDNF levels. plasmin- or NMDA-dependent mechanism?

    Science.gov (United States)

    Rodier, Marion; Prigent-Tessier, Anne; Béjot, Yannick; Jacquin, Agnès; Mossiat, Claude; Marie, Christine; Garnier, Philippe

    2014-01-01

    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 (r)t-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.

  4. Exogenous t-PA administration increases hippocampal mature BDNF levels. plasmin- or NMDA-dependent mechanism?

    Directory of Open Access Journals (Sweden)

    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.

  5. Cellular prion protein and NMDA receptor modulation: protecting against excitotoxicity

    Directory of Open Access Journals (Sweden)

    Stefanie A.G. Black

    2014-08-01

    Full Text Available Although it is well established that misfolding of the cellular prion protein (PrPC into the beta-sheet-rich, aggregated scrapie conformation (PrPSc causes a variety of transmissible spongiform encephalopathies (TSEs, the physiological roles of PrPC are still incompletely understood. There is accumulating evidence describing the roles of PrPC in neurodegeneration and neuroinflammation. Recently, we identified a functional regulation of NMDA receptors by PrPC that involves formation of a physical protein complex between these proteins. Excessive NMDA receptor activity during conditions such as ischemia mediates enhanced Ca2+ entry into cells and contributes to excitotoxic neuronal death. In addition, NMDA receptors and/or PrPC play critical roles in neuroinflammation and glial cell toxicity. Inhibition of NMDA receptor activity protects against PrPSc-induced neuronal death. Moreover, in mice lacking PrPC, infarct size is increased after focal cerebral ischemia, and absence of PrPC increases susceptibility of neurons to NMDA receptor-dependent death. Recently, PrPC was found to be a receptor for oligomeric beta-amyloid (Abeta peptides, suggesting a role for PrPC in Alzheimer’s disease. Our recent findings suggest that Abeta peptides enhance NMDA receptor current by perturbing the normal copper- and PrPC-dependent regulation of these receptors. Here, we review evidence highlighting a role for PrPC in preventing NMDA receptor-mediated excitotoxicity and inflammation. There is a need for more detailed molecular characterization of PrPC-mediated regulation of NMDA receptors, such as determining which NMDA receptor subunits mediate pathogenic effects upon loss of PrPC-mediated regulation and identifying PrPC binding site(s on the receptor. This knowledge will allow development of novel therapeutic interventions for not only TSEs, but also for Alzheimer’s disease and other neurodegenerative disorders involving dysfunction of PrPC.

  6. Role of glutamate receptors and nitric oxide on the effects of glufosinate ammonium, an organophosphate pesticide, on in vivo dopamine release in rat striatum.

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    Faro, Lilian R F; Ferreira Nunes, Brenda V; Alfonso, Miguel; Ferreira, Vania M; Durán, Rafael

    2013-09-15

    The purpose of the present work was to assess the possible role of glutamatergic receptors and nitric oxide (NO) production on effects of glufosinate ammonium (GLA), an organophosphate pesticide structurally related to glutamate, on in vivo striatal dopamine release in awake and freely moving rats. For this, we used antagonists of NMDA (MK-801 and AP5) or AMPA/kainate (CNQX) receptors, or nitric oxide synthase (NOS) inhibitors (l-NAME and 7-NI), to study the effects of GLA on release of dopamine from rat striatum. So, intrastriatal infusion of 10mM GLA significantly increased dopamine levels (1035±140%, compared with basal levels) and administration of GLA to MK-801 (250μM) or AP5 (650μM) pretreated animals, produced increases in dopamine overflow that were ∼40% and ∼90% smaller than those observed in animals not pretreated with MK-801 or AP5. Administration of GLA to CNQX (500μM) pretreated animals produced an effect that was not significantly different from the one produced in animals not pretreated with CNQX. On the other hand, administration of GLA to l-NAME (100μM) or 7-NI (100μM) pretreated animals, produced increases in dopamine overflow that were ∼80% and ∼75% smaller than those observed in animals not pretreated with these inhibitors. In summary, GLA appears to act, at least in part, through an overstimulation of NMDA (and not AMPA/kainate) receptors with possible NO production to induce in vivo dopamine release. Administration of NMDA receptor antagonists and NOS inhibitors partially blocks the release of dopamine from rat striatum.

  7. GABAB receptors modulate NMDA receptor calcium signals in dendritic spines.

    Science.gov (United States)

    Chalifoux, Jason R; Carter, Adam G

    2010-04-15

    Metabotropic GABA(B) receptors play a fundamental role in modulating the excitability of neurons and circuits throughout the brain. These receptors influence synaptic transmission by inhibiting presynaptic release or activating postsynaptic potassium channels. However, their ability to directly influence different types of postsynaptic glutamate receptors remains unresolved. Here we examine GABA(B) receptor modulation in layer 2/3 pyramidal neurons from the mouse prefrontal cortex. We use two-photon laser-scanning microscopy to study synaptic modulation at individual dendritic spines. Using two-photon optical quantal analysis, we first demonstrate robust presynaptic modulation of multivesicular release at single synapses. Using two-photon glutamate uncaging, we then reveal that GABA(B) receptors strongly inhibit NMDA receptor calcium signals. This postsynaptic modulation occurs via the PKA pathway and does not affect synaptic currents mediated by AMPA or NMDA receptors. This form of GABA(B) receptor modulation has widespread implications for the control of calcium-dependent neuronal function.

  8. Study on the behavior of rat model of schizophrenia induced by MK-801 in early postnatal period%MK-801诱导出生早期大鼠精神分裂症模型的行为学研究

    Institute of Scientific and Technical Information of China (English)

    蔡菡; 李泽爱; 刘寰忠; 任振华

    2013-01-01

    Objective To study the learning and memory eharaoteristie of rat models of schizophrenia induced by chronic MK-801 treatment in the early postnatal period. Methods 22 SD rats 6 d after birth were divided into MK-801 group and normal saline group of 11 each, and the rats in the two groups accepted intraperitoneal administration of MK-801 ( 0.3 mg/kg ) or saline ( 0. 3 ml/kg ) twice a day for 2 weeks, respectively. Body weights of rats in two groups were measured before and every three days after injection, and continued up to the end of the experiment. After 1 week of injection endpoint, open field and water maze were detected in the rats of two groups. Results Compared with the normal group, body weights of rats in MK-801 group were gradually decreased during the injection process ( P <0. 01 ) and at least continued for 4 weeks after the end of injection. The results of behavior showed that, compared with the normal saline group, the spontaneous activity in rats of MK-801 group significantly reduced ( P < 0. 01 ), and the ability of learn and memory significantly were declined in rats of MK-801 group ( P < 0. 05 ). Conclusion The decrease in the spontaneous activity of rat model of schizophrenia induced by MK-801 in the early postnatal period could partially imitate the negative symptoms of schizophrenia, and the dysfunction in learning and memory is similar to the cognitive impairment of schizophrenia.%目的 建立地卓西平马来酸盐(MK-801)慢性处理的出生早期大鼠精神分裂症(SZ)模型,探讨其神经行为学变化.方法 11只出生后6 d的SD仔鼠,腹腔注射0.3 mg/kg的MK-801(MK-801组),一天2次,连续注射2周;11只同龄的SD仔鼠腹腔注射等体积的生理盐水(NS组).给药前称重1次,给药完毕后每隔2 d称重1次,直至实验结束.给药后1周,检测旷场和水迷宫等行为学的变化.结果 与NS组比较,MK-801组大鼠体重显著降低(P<0.01),并至少持续至注射结束后4周.行为学检测结果 显示,与NS组比较,MK

  9. Sexually dimorphic effects of NMDA receptor antagonism on brain-pituitary-gonad axis development in the platyfish

    Science.gov (United States)

    Flynn, Katherine M.; Miller, Shelly A.; Sower, Stacia A.; Schreibman, Martin P.

    2002-01-01

    The N-methyl-D-aspartate glutamate receptor (NMDAR) is found in hypothalamic nuclei involved in the regulation of reproduction in several species of mammals and fishes. NMDAR is believed to affect reproductive development and function by regulating gonadotropin releasing hormone (GnRH)-producing cells. These pathways are likely to be sexually dimorphic, as are several other neurotransmitter systems involved in reproductive function. In this report, male and female platyfish received intraperitoneal injections of 0, 5, 10, 20, 40 or 60 microg/g body wt. of the non-competitive NMDAR antagonist MK-801. Injections began at 6 weeks of age and continued thrice weekly until control animals reached puberty, as evidenced by anal fin maturation. The percent of pubescent animals was significantly affected by sex and treatment, with fewer MK-801-injected females in puberty than control females at each dose (PHistological analyses revealed typical immature gonads and pituitary glands in treated females, and typical mature morphology in control females and all males. Immunocytochemical distribution of the R1 subunit of the NMDAR within the brain-pituitary-gonad (BPG) axis was limited to GnRH-containing brain cells in all animals; however, NMDAR1 distribution was in an immature pattern in treated females and a mature pattern in all others. Neural concentrations of GnRH were unaffected by MK-801 treatment in both sexes. These data suggest that in the platyfish, NMDAR influence on reproductive development is sexually dimorphic and occurs at, or above, the level of GnRH-containing cells of the BPG axis.

  10. The role of striatal NMDA receptors in drug addiction.

    Science.gov (United States)

    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.

  11. NMDA Receptors Regulate the Structural Plasticity of Spines and Axonal Boutons in Hippocampal Interneurons

    Directory of Open Access Journals (Sweden)

    Marta Perez-Rando

    2017-06-01

    Full Text Available N-methyl-D-aspartate receptors (NMDARs are present in both pyramidal neurons and interneurons of the hippocampus. These receptors play an important role in the adult structural plasticity of excitatory neurons, but their impact on the remodeling of interneurons is unknown. Among hippocampal interneurons, somatostatin-expressing cells located in the stratum oriens are of special interest because of their functional importance and structural characteristics: they display dendritic spines, which change density in response to different stimuli. In order to understand the role of NMDARs on the structural plasticity of these interneurons, we have injected acutely MK-801, an NMDAR antagonist, to adult mice which constitutively express enhanced green fluorescent protein (EGFP in these cells. We have behaviorally tested the animals, confirming effects of the drug on locomotion and anxiety-related behaviors. NMDARs were expressed in the somata and dendritic spines of somatostatin-expressing interneurons. Twenty-four hours after the injection, the density of spines did not vary, but we found a significant increase in the density of their en passant boutons (EPB. We have also used entorhino-hippocampal organotypic cultures to study these interneurons in real-time. There was a rapid decrease in the apparition rate of spines after MK-801 administration, which persisted for 24 h and returned to basal levels afterwards. A similar reversible decrease was detected in spine density. Our results show that both spines and axons of interneurons can undergo remodeling and highlight NMDARs as regulators of this plasticity. These results are specially relevant given the importance of all these players on hippocampal physiology and the etiopathology of certain psychiatric disorders.

  12. [Transient brain ischemia: NMDA receptor modulation and delayed neuronal death].

    Science.gov (United States)

    Benquet, Pascal; Gee, Christine E; Gerber, Urs

    2008-02-01

    Transient global ischemia induces delayed neuronal death in certain cell types and brain regions while sparing cells in other areas. A key process through which oxygen-glucose deprivation triggers cell death is the excessive accumulation of the neurotransmitter glutamate leading to over excitation of neurons. In certain neurons this increase in glutamate will potentiate the NMDA type of glutamate receptor, which can then initiate cell death. This review provides an update of the neurophysiological, cellular and molecular mechanisms inducing post-ischemic plasticity of NMDA receptors, focusing on the sensitive CA1 pyramidal neurons in the hippocampus as compared to the relatively resistant neighboring CA3 neurons. Both a change in the equilibrium between protein tyrosine kinases/phosphatases and an increased density of surface NMDA receptors in response to ischemia may explain the selective vulnerability of specific cell types. Implications for the treatment of stroke and reasons for the failures of human clinical trials utilizing NMDA receptor antagonists are also discussed.

  13. Effects of ziprasidone, SCH23390 and SB277011 on spatial memory in the Morris water maze test in naive and MK-801 treated mice.

    Science.gov (United States)

    Tanyeri, Pelin; Buyukokuroglu, Mehmet Emin; Mutlu, Oguz; Ulak, Güner; Akar, Füruzan Yildiz; Celikyurt, Ipek Komsuoglu; Erden, Bekir Faruk

    2015-11-01

    Introduction: Patients with schizophrenia have cognitive dysfunctions; positive psychotic symptoms are the primary purposes for schizophrenia treatment. Improvements in cognitive function should be a characteristic of all newly developed drugs for the treatment of schizophreniawith dementia. Thus,we investigated the effects of the second-generation antipsychotic ziprasidone, dopamine D1 antagonist SCH-23390 and dopamine D3 antagonist SB-277011 on spatial learning and memory. Materials and methods: Male inbred mice were used. The effects of ziprasidone, SCH-23390 and SB-277011 were investigated using the Morris water maze test. Results: Ziprasidone (0.5 and 1mg/kg), SCH-23390 (0.05 and 0.1 mg/kg) and SB-277011 (10 and 20 mg/kg) had no effect on the time spent in the target quadrant in naive mice.MK-801 (0.1mg/kg) significantly decreased the time spent in the target quadrant. The time spent in the target quadrant was significantly prolonged by Ziprasidone (0.5 and 1 mg/kg) and SCH-23390 (0.1 mg/kg), but not with SB-277011 (20 mg/kg) in MK-801-treated mice. Ziprasidone (0.5 and 1mg/kg), SCH-23390 (0.05 and 0.1 mg/kg) and SB-277011 (10 and 20 mg/kg) had no effect on themean distance to the platformin naivemice.MK-801 significantly increased themean distance to the platform. Ziprasidone (1 mg/kg) and SCH-23390 (0.1 mg/kg) significantly decreased the mean distance to the platform in MK-801-treated mice, but SB-277011 (20 mg/kg) didn't. MK-801 significantly increased the total distance moved. Ziprasidone (0.5 and 1 mg/kg), SCH-23390 (0.05 and 0.1 mg/kg) and SB-277011 (10 and 20 mg/kg) had no effect on the total distance moved in naive mice. Ziprasidone (1 mg/kg) and SCH-23390 (0.1 mg/kg) significantly decreased the total distance moved in MK-801-treated mice, but SB-277011 (20 mg/kg) didn't. Conclusions: The second-generation antipsychotic drug ziprasidone and D1 antagonist SCH23390, but not the D3 antagonist SB277011, might be clinically useful for the treatment of

  14. Effects of 5-HT1A receptor agonists and NMDA receptor antagonists in the social interaction test and the elevated plus maze.

    Science.gov (United States)

    Dunn, R W; Corbett, R; Fielding, S

    1989-10-01

    The effects of several 5-HT1A agonists and excitatory amino acid antagonists were compared to the standard benzodiazepines, diazepam and chlordiazepoxide (CDP) in two assays predictive of anxiolytic activity, the social interaction and elevated plus maze procedures. Indicative of anxiolytic effects the 5-HT1A agonists, buspirone, gepirone and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) all significantly increased social interaction time and open arm exploration time in the social interaction and elevated plus maze procedures, respectively. Likewise, anxiolytic activity in these assays were also produced by the competitive N-methyl-D-aspartate (NMDA) antagonists, 2-amino-5-phosphonovaleric acid (AP-5), 2-amino-7-phosphonoheptanoic acid (AP-7), 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and the non-competitive NMDA antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) while NMDA produced anxiogenic effects. Furthermore, the anxiolytic effects of these agents were of equal magnitude to the benzodiazepines. These two classes of compounds were differentiated in the yohimbine-induced seizure assay, with the NMDA antagonists dose dependently antagonizing seizures similar to the benzodiazepines while the 5-HT1A agonists were inactive. These results suggest that the 5-HT1A agonists and the NMDA antagonists may be potential non-classical anxiolytic agents with different mechanisms of action.

  15. Cortical hypometabolism demonstrated by PET in relapsing NMDA receptor encephalitis.

    Science.gov (United States)

    Pillai, Sekhar C; Gill, Deepak; Webster, Richard; Howman-Giles, Robert; Dale, Russell C

    2010-09-01

    N-methyl-d-aspartate (NMDA) receptor encephalitis is a newly defined type of autoimmune encephalitis. Two girls (age 3 years, case 1, and 7 years, case 2) with relapsing NMDA receptor encephalitis each had the classic clinical features of encephalopathy, movement disorders, psychiatric symptoms, seizures, insomnia, and mild autonomic dysfunction. Both patients had persistent neuropsychiatric disability, despite immune therapies. Positron emission tomography (PET) scans were performed during clinical relapse at 6 weeks (case 1) and 5 months (case 2). In both cases, the scans demonstrated reduced fluorodeoxyglucose metabolism in the cerebral cortex, with the temporal regions being most affected. PET imaging was more sensitive than magnetic resonance imaging in these patients. In contrast, the one previous report of acute NMDA receptor encephalitis indicated cortical hypermetabolism. Thus, NMDA receptor encephalitis may be associated with variable PET findings, possibly dependent upon the timing of the study, or other factors. Future studies should investigate whether cortical hypometabolism is associated with a relapsing course, and whether it is predictive of a poorer outcome in NMDA receptor encephalitis.

  16. 脊髓和海马锌含量在吗啡耐受和MK-801抗吗啡耐受中的作用%Roles of Zinc Concentration of Spinal Cord and Hippocampus in Morphine Tolerance and Inhibition of Morphine Tolerance by MK-801

    Institute of Scientific and Technical Information of China (English)

    郭瑞鲜; 张梅; 崔宇; 刘微; 杨春涛; 陈培熹; 冯鉴强

    2009-01-01

    [目的]探讨吗啡耐受大鼠脊髓和海马锌(Zn~(2+))含量的变化及其在MK-801抗吗啡耐受中的作用.[方法]采用SD成年雄性大鼠,建立慢性吗啡耐受大鼠模型,用热水甩尾法测定甩尾潜伏期观察痛反应变化.将实验动物随机地分为如下4组:生理盐水-生理盐水(NS-NS)组,生理盐水-吗啡(NS-Mor)组,MK-801-生理盐水(MK-NS)组,MK-801-吗啡(MK-Mor)组.用原子吸收光谱法测定脊髓和海马Zn~(2+)含量在吗啡耐受中的变化.[结果]吗啡耐受大鼠的脊髓和海马Zn~(2+)含量明显降低(P<0.05);MK-801(0.1 mg/kg)本身对基础痛阈及Zn~(2+)含量无明显影响,但与吗啡合用则具有显著的抗吗啡耐受作用,并阻断慢性吗啡引起的脊髓和海马Zn~(2+)含量的降低(P<0.001).[结论]吗啡耐受过程中,大鼠脊髓和海马组织中的Zn~(2+)含量明显减少,翻转吗啡耐受时脊髓与海马Zn~(2+)含量的减少,可能是MK-801抗吗啡耐受的机制之一.

  17. EVALUATING THE NMDA-GLUTAMATE RECEPTOR AS A SITE OF ACTION FOR TOLUENE, IN VIVO

    Science.gov (United States)

    In vitro, toluene disrupts the function of NMDA-glutamate receptors, indicating that effects on NMDA receptor function may contribute to toluene neurotoxicity. NMDA-glutamate receptors are widely present in the visual system and contribute to pattern-elicited visual evoked potent...

  18. Effects of ifenprodil on the antidepressant-like activity of NMDA ligands in the forced swim test in mice.

    Science.gov (United States)

    Poleszak, Ewa; Wośko, Sylwia; Serefko, Anna; Szopa, Aleksandra; Wlaź, Aleksandra; Szewczyk, Bernadeta; Nowak, Gabriel; Wlaź, Piotr

    2013-10-01

    Multiple pre-clinical and clinical studies clearly displayed implication of the NMDA receptors in development of depressive disorders since a variety of NMDA receptor antagonists exhibit an antidepressant-like effect. The main aim of our study was to assess the influence of ifenprodil - an allosteric modulator selectively binding at the NR2B subunit on the performance in the forced swim test in mice of various NMDA receptor ligands interacting with distinct components of the NMDA receptor complex. Ifenprodil at a dose of 10mg/kg enhanced the antidepressant-like effect of CGP 37849 (a competitive NMDA receptor antagonist, 0.312mg/kg), L-701,324 (an antagonist at glycine site, 1mg/kg), MK-801 (a non-competitive antagonist, 0.05mg/kg) and d-cycloserine (a partial agonist of a glycine site, 2.5mg/kg) but it did not shorten the immobility time of animals which concurrently received an inorganic modulator of the NMDA receptor complex, such as Zn(2+) (2.5mg/kg) or Mg(2+) (10mg/kg). On the other hand, the antidepressant-like effect of ifenprodil (20mg/kg) was reversed by N-methyl-d-aspartic acid (an agonist at the glutamate site, 75mg/kg) or d-serine (an agonist at the glycine site, 100nmol/mouse). In conclusion, the antidepressant-like potential of ifenprodil given concomitantly with NMDA ligands was either reinforced (in the case of both partial agonist and antagonists, except for magnesium and zinc) or diminished (in the case of conventional full agonists).

  19. Enhanced dopamine-dependent hippocampal plasticity after single MK-801 application.

    NARCIS (Netherlands)

    Bartsch, J.C.; Fidzinski, P.; Huck, J.H.; Hortnagl, H.; Kovacs, R.; Liotta, A.; Priller, J.; Wozny, C.; Behr, J.

    2015-01-01

    Dopaminergic hyperfunction and N-methyl-D-aspartate receptor (NMDAR) hypofunction have both been implicated in psychosis. Dopamine-releasing drugs and NMDAR antagonists replicate symptoms associated with psychosis in healthy humans and exacerbate symptoms in patients with schizophrenia. Though hippo

  20. Adult forebrain NMDA receptors gate social motivation and social memory.

    Science.gov (United States)

    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.

  1. Tandospirone, a 5-HT1A partial agonist, ameliorates aberrant lactate production in the prefrontal cortex of rats exposed to blockade of N-methy-D-aspartate receptors; Towards the therapeutics of cognitive impairment of schizophrenia

    Directory of Open Access Journals (Sweden)

    Takashi eUehara

    2014-09-01

    Full Text Available Rationale Augmentation therapy with serotonin-1A (5-HT1A receptor partial agonists has been suggested to improve cognitive deficits in patients with schizophrenia. Decreased activity of prefrontal cortex may provide a basis for cognitive deficits of the disease. Lactate plays a significant role in the supply of energy to the brain, and glutamatergic neurotransmission contributes to lactate production.Objectives and methods The purposes of this study were to examine the effect of repeated administration (once a daily for 4 days of tandospirone (0.05 and 5 mg/kg on brain energy metabolism, as represented by extracellular lactate concentration (eLAC in the medial prefrontal cortex (mPFC of young adult rats..Results Four-day treatment with MK-801, an NMDA-R antagonist, prolonged eLAC elevation induced by foot shock stress (FS. Co-administration with the high-dose tandospirone suppressed prolonged FS-induced eLAC elevation in rats receiving MK-801, whereas tandospirone by itself did not affected eLAC increment.Conclusions These results suggest that stimulation of 5-HT1A receptors ameliorates abnormalities of energy metabolism in the mPFC due to blockade of NMDA receptors. These findings provide a possible mechanism based on brain energy metabolism by which 5-HT1A agonism improve cognitive impairment in schizophrenia and related disorders.

  2. [Two cases of anti-NMDA receptor encephalitis].

    Science.gov (United States)

    Nakamura, Kazue; Takahashi, Tsutomu; Matsuoka, Tadasu; Kido, Mikio; Uehara, Takashi; Suzuki, Michio

    2011-01-01

    Anti-NMDA receptor encephalitis, reported by Dalmau et al., is a paraneoplastic encephalitis frequently associated with ovarian teratoma. After the manifestation of schizophrenia-like psychotic symptoms in the initial stage, serious neurological symptoms such as convulsions and central hypoventilation develop. We report two cases of 17-year-old girls with anti-NMDA receptor encephalitis who exhibited different clinical courses. Case 1 showed a typical course of anti-NMDA receptor encephalitis associated with sustained consciousness disturbance requiring long-term artificial respiration. Case 2 underwent surgery for an ovarian teratoma in the early stages of the disorder, did not show convulsions or central hypoventilation, and recovered without any sequelae. Early resection of the ovarian teratoma and the immune suppression therapy may have contributed to the rapid recovery and favorable outcome in case 2. Psychiatrists are the first to see a majority of patients with anti-NMDA receptor encephalitis because of psychiatric symptoms and behavioral changes observed in the initial stage. For successful treatment, psychiatrists need to cooperate with neurologists and gynecologists early in the course of this disorder. Psychiatrists' knowledge of the symptoms and clinical course of this form of encephalitis is essential for early detection and adequate treatment, which may be life-saving and contribute to good functional outcomes.

  3. [Anti-NMDA-receptor encephalitis. An interdisciplinary clinical picture].

    Science.gov (United States)

    Prüss, H; Dalmau, J; Arolt, V; Wandinger, K-P

    2010-04-01

    Anti-NMDA-receptor encephalitis is a severe and considerably underdiagnosed form of encephalitis with characteristic clinical features including psychiatric symptoms, decreased levels of consciousness, hypoventilation, epileptic seizures, autonomic dysfunction and dyskinesias. Most patients are primarily seen by psychiatrists, often on the assumption of a drug-induced psychosis. Anti-NMDA-receptor encephalitis had initially been described in young women with ovarian teratoma, but is also common in women without tumour, in men and in children. The diagnosis is based on the characteristic clinical picture, supporting findings of brain MRI, electroencephalogram and cerebrospinal fluid (CSF), and the presence of highly specific autoantibodies directed against the NR1 subunit of NMDA-type glutamate receptors in the serum or CSF. In particular, anti-NMDA-receptor encephalitis must be excluded in patients with 'encephalitis of unknown cause'. In principle, the prognosis is favourable and recovery from symptoms can be expected even after prolonged intensive care treatment and mechanical ventilation. However, improvement correlates with prompt identification of the disorder, early immunotherapy and - in the case of a malignancy - with complete tumour removal. Patient care requires an interdisciplinary approach including neurologists, psychiatrists, paediatricians, oncologists and gynaecologists.

  4. Novel Fluorine-Containing NMDA Antagonists for Brain Imaging: In Vitro Evaluation

    Energy Technology Data Exchange (ETDEWEB)

    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.

  5. Open-channel blockers of the NMDA receptor complex.

    Science.gov (United States)

    Albensi, Benedict C; Ilkanich, Erin

    2004-11-01

    A variety of compounds have been shown to limit or prevent excitotoxicity by blocking N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission. However, many first-generation NMDA antagonists did not live up to clinical expectations in trials of acute brain injury because of the manifestation of multiple side effects. In spite of this, development of NMDA antagonists continues, where some of the newer agents block excitotoxicity through alternative mechanisms. For example, blockers selective to the NR2B subunit or agents that block metabotropic glutamate receptors or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors are currently under investigation. Several years ago, the arylalkylamine spider toxins were demonstrated to function as open-channel blockers similar to memantine, which was very recently approved by the U.S. FDA for use in patients with Alzheimer's dementia. With this said, programs focusing on NMDA antagonism via alternative mechanisms may still hold promise for treating acute injury and even chronic forms of dementia.

  6. NMDA receptors and the differential ischemic vulnerability of hippocampal neurons.

    Science.gov (United States)

    Gee, Christine E; Benquet, Pascal; Raineteau, Olivier; Rietschin, Lotty; Kirbach, Sebastian W; Gerber, Urs

    2006-05-01

    Transient cerebral ischemia causes an inhomogeneous pattern of cell death in the brain. We investigated mechanisms, which may underlie the greater susceptibility of hippocampal CA1 vs. CA3 pyramidal cells to ischemic insult. Using an in vitro oxygen-glucose deprivation (OGD) model of ischemia, we found that N-methyl-D-aspartate (NMDA) responses were enhanced in the more susceptible CA1 pyramidal cells and transiently depressed in the resistant CA3 pyramidal cells. The long-lasting potentiation of NMDA responses in CA1 cells was associated with delayed cell death and was prevented by blocking tyrosine kinase-dependent up-regulation of NMDA receptor function. In CA3 cells, the energy deprivation-induced transient depression of NMDA responses was converted to potentiation by blocking protein phosphatase signalling. These results suggest that energy deprivation differentially shifts the intracellular equilibrium between the tyrosine kinase and phosphatase activities that modulate NMDA responses in CA1 and CA3 pyramidal cells. Therapeutic modulation of tyrosine phosphorylation may thus prove beneficial in mitigating ischemia-induced neuronal death in vulnerable brain areas.

  7. Intracerebroventricular application of competitive and non-competitive NMDA antagonists induce similar effects upon rat hippocampal electroencephalogram and local cerebral glucose utilization

    NARCIS (Netherlands)

    Boddeke, H.W.G.M.; Wiederhold, K.H.; Palacios, J.M.

    1992-01-01

    In this study we have used electrophysiological and metabolic markers to investigate the effects of competitive and non-competitive NMDA antagonists in rats after central or peripheral administration. The non-competitive antagonist, MK-801, induced dose-dependent suppression of rat hippocampal EEG e

  8. INTRACEREBROVENTRICULAR APPLICATION OF COMPETITIVE AND NONCOMPETITIVE NMDA ANTAGONISTS INDUCE SIMILAR EFFECTS UPON RAT HIPPOCAMPAL ELECTROENCEPHALOGRAM AND LOCAL CEREBRAL GLUCOSE-UTILIZATION

    NARCIS (Netherlands)

    BODDEKE, HWGM; WIEDERHOLD, KH; PALACIOS, JM

    1992-01-01

    In this study we have used electrophysiological and metabolic markers to investigate the effects of competitive and non-competitive NMDA antagonists in rats after central or peripheral administration. The non-competitive antagonist, MK-801, induced dose-dependent suppression of rat hippocampal EEG e

  9. Synthesis and NMDA receptor affinity of fluorinated dioxadrol analogues.

    Science.gov (United States)

    Banerjee, Ashutosh; Schepmann, Dirk; Wünsch, Bernhard

    2010-06-01

    A series of dioxadrol analogues with fluorine substituents in position 4 of the piperidine ring has been synthesized and pharmacologically evaluated. The key step in the synthesis was the fluorination of diastereomeric piperidones 6a and 6c as well as diastereomeric alcohols 9a and 9c with DAST. The reaction of the alcohols 9a and 9c took place with inversion of configuration. After removal of the Cbz-protective group, the NMDA receptor affinities of the resulting secondary amines 8a, 8c, 12b, and 12d were investigated in receptor binding studies. It was shown that the like-configuration of the ring junction was crucial for high NMDA receptor affinity. An axially oriented fluorine atom in position 4 led to 2-(2,2-diphenyl-1,3-dioxolan-4-yl)-4-fluoropiperidine (12d, WMS-2517) with a K(i)-value of 27nM. The NMDA receptor affinity of 8c (WMS-2513) with an additional fluorine atom in equatorial 4-position was slightly reduced (K(i)=81 nM). Both fluorinated dioxadrol derivatives 8c and 12d showed high selectivity against sigma(1) and sigma(2) receptors as well as the polyamine binding site of NR2B receptors.

  10. Metabotropic glutamate receptor 5 upregulates surface NMDA receptor expression in striatal neurons via CaMKII

    OpenAIRE

    Jin, Dao-Zhong; Xue, Bing; Mao, Li-Min; Wang, John Q

    2015-01-01

    Metabotropic and ionotropic glutamate receptors are closely clustered in postsynaptic membranes and are believed to interact actively with each other to control excitatory synaptic transmission. Metabotropic glutamate receptor 5 (mGluR5), for example, has been well documented to potentiate ionotropic NMDA receptor activity, although underlying mechanisms are poorly understood. In this study, we investigated the role of mGluR5 in regulating trafficking and subcellular distribution of NMDA rece...

  11. The effect of NMDA-R antagonism on simultaneously acquired local field potentials and tissue oxygen levels in the brains of freely-moving rats.

    Science.gov (United States)

    Kealy, John; Commins, Sean; Lowry, John P

    2017-01-11

    Non-competitive NMDA receptor antagonists are known to induce psychosis-like symptoms in rodents. Administration of such compounds cause behavioural effects such as memory impairment and hyperlocomotion. Additionally, drugs such as phencyclidine (PCP), ketamine and MK-801 all cause distinctive increases in striatal local field potential (LFP) in the high frequency oscillation (HFO) band in the power spectrum (140-180 Hz). Amperometric sensors provide a means to measure tissue oxygen (tO2; a BOLD-like signal) in the brains of freely-moving rats while simultaneously acquiring LFP using the same electrode. Carbon paste electrodes were implanted into the striatum and hippocampus of male Wistar rats. Rats were administered with saline, ketamine (10 mg/kg), MK-801 (0.1 mg/kg) and PCP (2.5 mg/kg) and recordings were made at 1 kHz using three different potentials (-650 mV to measure tO2; 0 mV and +700 mV as control conditions). NMDA receptor antagonism caused significant increases in tO2 in both the striatum and the hippocampus. Power spectrum analysis showed significant increases in HFO power in the striatum but not in the hippocampus. Conversely, there were significant decreases in delta and alpha power along with increases in theta and gamma power in the hippocampus that were absent in the striatum. This supports findings that LFP can be obtained from an amperometric sensor signal; allowing simultaneous acquisition of two translational biomarkers of neuronal activity (LFP and tO2).

  12. Relationship between G protein-coupled receptor kinase 6 and N-methyl-D-aspartate receptor in the mechanism study underlying motor complications in Parkinson's disease%帕金森病运动并发症发生机制中G蛋白偶联受体激酶6与N-甲基-D-天冬氨酸受体关系的研究

    Institute of Scientific and Technical Information of China (English)

    吴娜; 杨新新; 宋璐; 刘振国

    2011-01-01

    目的 研究G蛋白偶联受体激酶6(GRK6)在帕金森病(PD)运动并发症发生机制中与N-甲基-D-天冬氨酸(NMDA)受体的关系.方法 建立PD运动并发症大鼠模型,25只大鼠分为3组.异动症(LID)组10只,腹腔注射左旋多巴甲酯23 d;MK-801处理组10只,第23天左旋多巴甲酯注射前腹腔注射MK-801;PD组5只,腹腔注射0.2%维生素C液.另设假手术组5只为对照组.观察MK-801处理左旋多巴诱导的运动并发症模型大鼠的行为变化,并用免疫组织化学方法和Western印迹方法检测大鼠纹状体区GRK6蛋白的表达情况.结果 PD组大鼠长期使用左旋多巴后出现明显的异常不自主运动,与人类LID具有相似特征.免疫组化结果显示.PD组损伤侧纹状体区GRK6阳性细胞指数减少至(4.81±1.31)×103(P<0.05),LID组损伤侧GRK6阳性细胞指数进一步减少至(3.23±0.41)×103(P<0.01).MK-801组LID大鼠异常不自主运动评分减少,药效期延长,同时损伤侧纹状体区GRK6阳性细胞指数增多至(4.64±1.39)×103(P<0.05).Western印迹法检测结果同免疫组化基本相符,PD组损毁侧/未损毁侧纹状体区GRK6含量比值为(83.7±2.1)%,LID组GRK6值降低为(76.8±2.2)%,而MK-801组GRK6值升高至(91.1±2.7)%(P<0.01).结论 NMDA受体拮抗剂能逆转大鼠运动并发症的发生,其机制可能与GRK6增多,抑制了谷氨酸受体的过度活化有关.%Objective To investigate the relationship between G protein-coupled receptor kinase 6 (GRK6) and N-methyl-D-aspartate (NMDA) receptor in the mechanism study underlying motor complications in Parkinson's disease (PD).Methods The rat models (n= 25) of Parkinsonism related motor complications were established and were randomly divided into levodopa-induced dyskinesia (LID) group (n= 10,intraperitoneal injection of levodopa for 23 d),MK-801 treatment group (n= 10,intraperitoneal injection of MK-801 at day23 after intraperitoneal injection with levodopa for 22 days) and PD group (n

  13. Endogenous ion channel complexes: the NMDA receptor.

    Science.gov (United States)

    Frank, René A W

    2011-06-01

    Ionotropic receptors, including the NMDAR (N-methyl-D-aspartate receptor) mediate fast neurotransmission, neurodevelopment, neuronal excitability and learning. In the present article, the structure and function of the NMDAR is reviewed with the aim to condense our current understanding and highlight frontiers where important questions regarding the biology of this receptor remain unanswered. In the second part of the present review, new biochemical and genetic approaches for the investigation of ion channel receptor complexes will be discussed.

  14. Efficacies of treatments for anti-NMDA receptor encephalitis.

    Science.gov (United States)

    Wang, Hsiuying

    2016-01-01

    Treatments for anti-N-methyl-D-aspartate (NMDA) receptor encephalitis include immunotherapy with steroids, intravenous immunoglobulin, plasma exchange, or plasmapheresis as first-line treatments, immunotherapy with rituximab or cyclophosphamide as second-line treatments, and tumor removal. In this systematic review, we evaluated previous studies and examined the association between certain microRNAs and anti-NMDA receptor encephalitis to investigate the performance of different treatment combinations. The efficacies of different combinations of treatments classified into the following four categories were compared: (I) intravenous immunoglobulin administration, (II) plasmapheresis or plasma exchange, (III) treatment with rituximab or cyclophosphamide and (IV) tumor removal. Statistical analyses showed that treatment combinations including at least two of these categories resulted in higher efficacy rates than treatment with a single form of therapy. These findings suggest that if a patient is not recovering, converting to other therapies is more likely to result in early recovery than continuing on the original therapy.

  15. NMDA and dopamine D1 receptors within NAc-shell regulate IEG proteins expression in reward circuit during cocaine memory reconsolidation.

    Science.gov (United States)

    Li, Y; Ge, S; Li, N; Chen, L; Zhang, S; Wang, J; Wu, H; Wang, X; Wang, X

    2016-02-19

    Reactivation of consolidated memory initiates a memory reconsolidation process, during which the reactivated memory is susceptible to strengthening, weakening or updating. Therefore, effective interference with the memory reconsolidation process is expected to be an important treatment for drug addiction. The nucleus accumbens (NAc) has been well recognized as a pathway component that can prevent drug relapse, although the mechanism underlying this function is poorly understood. We aimed to clarify the regulatory role of the NAc in the cocaine memory reconsolidation process, by examining the effect of applying different pharmacological interventions to the NAc on Zif 268 and Fos B expression in the entire reward circuit after cocaine memory reactivation. Through the cocaine-induced conditioned place preference (CPP) model, immunohistochemical and immunofluorescence staining for Zif 268 and Fos B were used to explore the functional activated brain nuclei after cocaine memory reactivation. Our results showed that the expression of Zif 268 and Fos B was commonly increased in the medial prefrontal cortex (mPFC), the infralimbic cortex (IL), the NAc-core, the NAc-shell, the hippocampus (CA1, CA2, and CA3 subregions), the amygdala, the ventral tegmental area (VTA), and the supramammillary nucleus (SuM) following memory reconsolidation, and Zif 268/Fos B co-expression was commonly observed (for Zif 268: 51-68%; for Fos B: 52-66%). Further, bilateral NAc-shell infusion of MK 801 and SCH 23390, but not raclopride or propranolol, prior to addictive memory reconsolidation, decreased Zif 268 and Fos B expression in the entire reward circuit, except for the amygdala, and effectively disturbed subsequent CPP-related behavior. In summary, N-methyl-d-aspartate (NMDA) and dopamine D1 receptors, but not dopamine D2 or β adrenergic receptors, within the NAc-shell, may regulate Zif 268 and Fos B expression in most brain nuclei of the reward circuit after cocaine memory reactivation

  16. Transient brain ischemia: NMDA receptor modulation and delayed neuronal death

    OpenAIRE

    Benquet, Pascal; Gee, Christine E.; Gerber, Urs

    2008-01-01

    Transient global ischemia induces delayed neuronal death in certain cell types and brain regions while sparing cells in other areas. A key process through which oxygen-glucose deprivation triggers cell death is the excessive accumulation of the neurotransmitter glutamate leading to over excitation of neurons. In certain neurons this increase in glutamate will potentiate the NMDA type of glutamate receptor, which can then initiate cell death. This review provides an update of the neurophysiolo...

  17. Catatonic Syndrome in Anti-NMDA Receptor Encephalitis

    Science.gov (United States)

    Mythri, Starlin Vijay; Mathew, Vivek

    2016-01-01

    Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a newly recognised autoimmune condition. With its typical clinical pattern, consistent association with the presence of auto antibodies and rapid improvement with immunotherapy, this condition is giving insights into the boundaries between psychiatry and other neurosciences, and is opening avenues for future research. In a young lady who presented with catatonia, we considered anti-NMDA receptor encephalitis, after ruling out other aetiologies. After a positive antibody test we treated her with immunotherapy. She showed gradual improvement in her psychotic and catatonic symptoms. Knowledge regarding the nature and function of NMDA receptors and pathophysiology of this particular encephalitis is important for psychiatric practice. The great opportunity for research in this area due to its association with psychotic disorders is evident but an appeal to temper the enthusiasm by considering the historical lessons learnt from Karl Jaspers’ critique of General Paresis of Insane, is in place. Catatonic syndrome has to be conceptualised broadly and should be recognised with a separate nosological position. PMID:27114630

  18. Catatonic syndrome in anti-NMDA receptor encephalitis

    Directory of Open Access Journals (Sweden)

    Starlin Vijay Mythri

    2016-01-01

    Full Text Available Anti-N-methyl-D-aspartate (NMDA receptor encephalitis is a newly recognised autoimmune condition. With its typical clinical pattern, consistent association with the presence of auto antibodies and rapid improvement with immunotherapy, this condition is giving insights into the boundaries between psychiatry and other neurosciences, and is opening avenues for future research. In a young lady who presented with catatonia, we considered anti-NMDA receptor encephalitis, after ruling out other aetiologies. After a positive antibody test we treated her with immunotherapy. She showed gradual improvement in her psychotic and catatonic symptoms. Knowledge regarding the nature and function of NMDA receptors and pathophysiology of this particular encephalitis is important for psychiatric practice. The great opportunity for research in this area due to its association with psychotic disorders is evident but an appeal to temper the enthusiasm by considering the historical lessons learnt from Karl Jaspers′ critique of General Paresis of Insane, is in place. Catatonic syndrome has to be conceptualised broadly and should be recognised with a separate nosological position.

  19. Alcohol and NMDA Receptor: Current research and future direction

    Directory of Open Access Journals (Sweden)

    Raman eChandrasekar

    2013-05-01

    Full Text Available The brain is one of the major targets of alcohol actions. Most of the excitatory synaptic transmission in the central nervous system is mediated by NMDA receptors. However, one of the most devastating effects of alcohol leads to brain shrinkage, loss of nerve cells at specific regions through a mechanism involving excitotoxicity, oxidative stress. Earlier studies have indicated that chronic exposure to ethanol both in vivo and in vitro, increases NR1 and NR2B gene expression and their polypeptide levels. The effect of alcohol and molecular changes on the regulatory process, which modulates NMDAR functions including factors altering transcription, translation, post-translational modifications and protein expression, as well as those influencing their interactions with different regulatory proteins (downstream effectors are incessantly increasing at the cellular level. Further, I discuss the various genetically altered mice approaches that have been used to study NMDA receptor subunits and their functional implication. In a recent countable review, epigenetic dimension (i.e., histone modification-induced chromatin remodeling and DNA methylation, in the process of alcohol related neuroadapation is one of the key molecular mechanisms in alcohol mediated NMDAR alteration. Here, I provide a recount on what has already been achieved, current trends and how the future research/studies of the NMDA receptor might lead to even greater engagement with many possible new insights into the neurobiology and treatment of alcoholism.

  20. Alcohol and NMDA receptor: current research and future direction.

    Science.gov (United States)

    Chandrasekar, Raman

    2013-01-01

    The brain is one of the major targets of alcohol actions. Most of the excitatory synaptic transmission in the central nervous system is mediated by N-methyl-D-aspartate (NMDA) receptors. However, one of the most devastating effects of alcohol leads to brain shrinkage, loss of nerve cells at specific regions through a mechanism involving excitotoxicity, oxidative stress. Earlier studies have indicated that chronic exposure to ethanol both in vivo and in vitro, increases NR1 and NR2B gene expression and their polypeptide levels. The effect of alcohol and molecular changes on the regulatory process, which modulates NMDAR functions including factors altering transcription, translation, post-translational modifications, and protein expression, as well as those influencing their interactions with different regulatory proteins (downstream effectors) are incessantly increasing at the cellular level. Further, I discuss the various genetically altered mice approaches that have been used to study NMDA receptor subunits and their functional implication. In a recent countable review, epigenetic dimension (i.e., histone modification-induced chromatin remodeling and DNA methylation, in the process of alcohol related neuroadaptation) is one of the key molecular mechanisms in alcohol mediated NMDAR alteration. Here, I provide a recount on what has already been achieved, current trends and how the future research/studies of the NMDA receptor might lead to even greater engagement with many possible new insights into the neurobiology and treatment of alcoholism.

  1. Catatonic Syndrome in Anti-NMDA Receptor Encephalitis.

    Science.gov (United States)

    Mythri, Starlin Vijay; Mathew, Vivek

    2016-01-01

    Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a newly recognised autoimmune condition. With its typical clinical pattern, consistent association with the presence of auto antibodies and rapid improvement with immunotherapy, this condition is giving insights into the boundaries between psychiatry and other neurosciences, and is opening avenues for future research. In a young lady who presented with catatonia, we considered anti-NMDA receptor encephalitis, after ruling out other aetiologies. After a positive antibody test we treated her with immunotherapy. She showed gradual improvement in her psychotic and catatonic symptoms. Knowledge regarding the nature and function of NMDA receptors and pathophysiology of this particular encephalitis is important for psychiatric practice. The great opportunity for research in this area due to its association with psychotic disorders is evident but an appeal to temper the enthusiasm by considering the historical lessons learnt from Karl Jaspers' critique of General Paresis of Insane, is in place. Catatonic syndrome has to be conceptualised broadly and should be recognised with a separate nosological position.

  2. Role of hydrogen bonding in ligand interaction with the N-methyl-D-aspartate receptor ion channel

    Energy Technology Data Exchange (ETDEWEB)

    Leeson, P.D.; Carling, R.W.; James, K.; Smith, J.D.; Moore, K.W.; Wong, E.H.; Baker, R. (Merck Sharp Laboratory, Harlow, Essex (England))

    1990-05-01

    Displacement of (3H)MK-801 (dizocilpine, 1) binding to rat brain membranes has been used to evaluate the affinities of novel dibenzocycloalkenimines related to 1 for the ion channel binding site (also known as the phencyclidine or PCP receptor) on the N-methyl-D-aspartate (NMDA) subtype of excitory amino acid receptor. In common with many other agents having actions in the central nervous system, these compounds contain a hydrophobic aromatic moiety and a basic nitrogen atom. The conformational rigidity of these ligands provides a unique opportunity to evaluate the importance of specific geometrical properties that influence active-site recognition, in particular the role of the nitrogen atom in hydrogen-bonding interactions. The relative affinities (IC50s) of hydrocarbon-substituted analogues of 1 and ring homologated cyclooctenimines illustrate the importance of size-limited hydrophobic binding of both aryl rings and of the quaternary C-5 methyl group. Analysis of the binding of a series of the 10 available structurally rigid dibenzoazabicyclo(x.y.z)alkanes, by using molecular modeling techniques, uncovered a highly significant correlation between affinity and a proposed ligand-active site hydrogen bonding vector (r = 0.950, p less than 0.001). These results are used to generate a pharmacophore of the MK-801 recognition site/PCP receptor, which accounts for the binding of all of the known ligands.

  3. Electrophysiological study, biodistribution in mice, and preliminary PET evaluation in a rhesus monkey of 1-amino-3-[{sup 18}F]fluoromethyl-5-methyl-adamantane ({sup 18}F-MEM): a potential radioligand for mapping the NMDA-receptor complex

    Energy Technology Data Exchange (ETDEWEB)

    Samnick, Samuel; Ametamey, Simon; Leenders, Klaus L.; Vontobel, Peter; Quack, Guenter; Parsons, Chris G.; Neu, Henrik; Schubiger, Pius A

    1998-05-01

    The effect of the fluorinated memantine derivative and NMDA receptor antagonist, 1-amino-3-fluoromethyl-5-methyl-adamantane ({sup 19}F-MEM), at the NMDA receptor ion channel was studied by patch clamp recording. The results showed that {sup 19}F-MEM is a moderate NMDA receptor channel blocker. A procedure for the routine preparation of the {sup 18}F-labelled analog {sup 18}F-MEM has been developed using a two-step reaction sequence. This involves the no-carrier-added nucleophilic radiofluorination of 1-[N-(tert-butyloxy)carbamoyl]-3-(toluenesulfonyloxy)methyl-5- methyl-adamantane and the subsequent cleavage of the BOC-protecting group using aqueous HCl. The {sup 18}F-MEM was obtained in 22{+-}7% radiochemical yield (decay-corrected to EOB) in a total synthesis time including HPLC purification of 90 min. A biodistribution study after IV injection of {sup 18}F-MEM in mice showed a fast clearance of radioactivity from blood and relatively high initial uptake in the kidney and in the lung, which gradually decreased with time. The brain uptake was high (up to 3.6% ID/g, 60 min postinjection) with increasing brain-blood ratios: 2.40, 5.10, 6.33, and 9.27 at 5, 30, 60, and 120 min, respectively. The regional accumulation of the radioactivity in the mouse brain was consistent with the known distribution of the PCP recognition site. Preliminary PET evaluation of the radiotracer in a rhesus monkey demonstrated good uptake and prolonged retention in the brain, with a plateau from 35 min onwards p.i. in the NMDA receptor-rich regions (frontal cortex, striata, and temporal cortex). Delineation of the hippocampus, a region known to contain a high density of NMDA receptors, was not possible owing to the resolution of the PET tomograph. The regional brain uptake of {sup 18}F-MEM was changed by memantine and by a pharmacological dose of (+)-MK-801, indicating competition for the same binding sites. In a preliminary experiment, haloperidol, a dopamine D2 and sigma receptor

  4. NMDA-receptor trafficking and targeting: implications for synaptic transmission and plasticity.

    Science.gov (United States)

    Carroll, Reed C; Zukin, R Suzanne

    2002-11-01

    Dynamic regulation of synaptic efficacy is thought to play a crucial role in formation of neuronal connections and in experience-dependent modification of neural circuitry. The molecular and cellular mechanisms by which synaptic changes are triggered and expressed are the focus of intense interest. This articles reviews recent evidence that NMDA receptors undergo dynamically regulated targeting and trafficking, and that the physical transport of NMDA receptors in and out of the synaptic membrane contributes to several forms of long-lasting synaptic plasticity. The identification of targeting and internalization sequences in NMDA-receptor subunits has begun the unraveling of some mechanisms that underlie activity-dependent redistribution of NMDA receptors. Given that NMDA receptors are widely expressed throughout the CNS, regulation of NMDA-receptor trafficking provides a potentially important way to modulate efficacy of synaptic transmission.

  5. The role of NMDA receptors in human eating behavior: evidence from a case of anti-NMDA receptor encephalitis

    OpenAIRE

    Perogamvros, Lampros; Schnider, Armin; Leemann, Béatrice Anne Valérie

    2012-01-01

    Research in animal models has implicated N-methyl-D-aspartate (NMDA) receptors (NMDARs) in the control of food intake. Until now, these findings have been not replicated in humans. Here we describe a 22-year-old woman with anti-NMDAR encephalitis and no prior neurological or psychiatric history. Her clinical course was marked by successive eating disorders: anorexia followed by hyperphagia. We propose that, much as they do in other animals, NMDARs in humans interact with the neuroendocrine, h...

  6. Anti-NMDA Receptor antibody encephalitis with concomitant detection of Varicella zoster virus.

    Science.gov (United States)

    Solís, Natalia; Salazar, Lucrecia; Hasbun, Rodrigo

    2016-10-01

    The typical presentation of anti-NMDA (N-Methyl-d-Aspartate) receptor encephalitis involves young women with psychiatric, neurologic and autonomic symptoms; it is often associated with mature ovarian teratomas. NMDA receptor encephalitis has been described following Herpes simplex virus (HSV) encephalitis. This case describes a classic presentation of anti-NMDA receptor encephalitis with the concomitant presence of Varicella zoster virus in the cerebrospinal fluid.

  7. NMDA receptors and fear extinction: implications for cognitive behavioral therapy.

    Science.gov (United States)

    Davis, Michael

    2011-01-01

    Based primarily on studies that employ Pavlovian fear conditioning, extinction of conditioned fear has been found to be mediated by N-methyi-D-aspartate (NMDA) receptors in the amygdala and medial prefrontal cortex. This led to the discovery that an NMDA partial agonist, D-cycloserine, could facilitate fear extinction when given systemically or locally into the amygdala. Because many forms of cognitive behavioral therapy depend on fear extinction, this led to the successful use of D-cycloserine as an adjunct to psychotherapy in patients with so-called simple phobias (fear of heights), social phobia, obsessive-compulsive behavior, and panic disorder. Data in support of these conclusions are reviewed, along with some of the possible limitations of D-cycloserine as an adjunct to psychotherapy.

  8. Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis.

    Science.gov (United States)

    Wandinger, Klaus-Peter; Saschenbrecker, Sandra; Stoecker, Winfried; Dalmau, Josep

    2011-02-01

    Anti-NMDA-receptor encephalitis is a severe, treatable and potentially reversible disorder presenting with memory deficits, psychiatric symptoms and seizures. Initially described in young patients with ovarian teratoma, the disease is meanwhile increasingly recognized also in women without tumours, in men and in children. The presence of anti-glutamate receptor (type NMDA) autoantibodies in serum or cerebrospinal fluid is specific for this novel and widely underdiagnosed disorder. Early recognition is crucial since prognosis largely depends on adequate immunotherapy and, in paraneoplastic cases, complete tumour removal. Indirect immunofluorescence using NMDA-type glutamate receptors recombinantly expressed in human cells is a highly competent method for diagnosing anti-NMDA-receptor encephalitis.

  9. Bilobalide, a constituent of Ginkgo biloba, inhibits NMDA-induced phospholipase A2 activation and phospholipid breakdown in rat hippocampus.

    Science.gov (United States)

    Weichel, O; Hilgert, M; Chatterjee, S S; Lehr, M; Klein, J

    1999-12-01

    In rat hippocampal slices superfused with magnesium-free buffer, glutamate (1 mM) caused the release of large amounts of choline due to phospholipid breakdown. This phenomenon was mimicked by N-methyl-D-aspartate (NMDA) in a calcium-sensitive manner and was blocked by NMDA receptor antagonists such as MK-801 and 7-chlorokynurenate. The NMDA-induced release of choline was not caused by activation of phospholipase D but was mediated by phospholipase A2 (PLA2) activation as the release of choline was accompanied by the formation of lyso-phosphatidylcholine (lyso-PC) and glycerophospho-choline (GPCh) and was blocked by 5-[2-(2-carboxyethyl)-4-dodecanoyl-3,5-dimethylpyrrol-1-yl]pentano ic acid, a PLA2 inhibitor. Bilobalide, a constituent of Ginkgo biloba, inhibited the NMDA-induced efflux of choline with an IC50 value of 2.3 microM and also prevented the formation of lyso-PC and GPCh. NMDA also caused a release of choline in vivo when infused into the hippocampus of freely moving rats by retrograde dialysis. Again, the effect was completely inhibited by bilobalide which was administered systemically (20 mg/kg i.p.). Interestingly, convulsions which were observed in the NMDA-treated rats were almost totally suppressed by bilobalide. We conclude that release of choline is a sensitive marker for NMDA-induced phospholipase A2 activation and phospholipid breakdown. Bilobalide inhibited the glutamatergic excitotoxic membrane breakdown both in vitro and in vivo, an effect which may be beneficial in the treatment of brain hypoxia and/or neuronal hyperactivity.

  10. The role of NMDA and non-NMDA receptors in the NTS in mediating three distinct sympathoinhibitory reflexes.

    Science.gov (United States)

    Sartor, Daniela M; Verberne, Anthony J M

    2007-12-01

    Cholecystokinin (CCK) elicits a sympathetic vasomotor reflex that is implicated in gastrointestinal circulatory control. We sought to determine (1) the site in the solitary tract nucleus (NTS) responsible for mediating this reflex and (2) the possible involvement of excitatory amino acid (EAA) receptors. In addition, we sought to determine whether the NTS site responsible for mediating the baroreflex (phenylephrine, PE, 10 microg/kg i.v.) and the von Bezold-Jarisch reflex (phenylbiguanide, PBG, 10 microg/kg i.v) overlap with that involved in the CCK-induced reflex (CCK, 4 microg/kg, i.v.), and to compare the relative importance of NMDA and non-NDMA receptors in these reflexes. In separate experiments, the effects of PE, PBG, and CCK on mean arterial blood pressure, heart rate, and splanchnic sympathetic nerve discharge were tested before and after bilateral microinjection into the NTS of the gamma-aminobutyric acid(A) (GABA(A)) agonist muscimol, the EAA antagonist kynurenate, the NMDA receptor antagonist D: (-)-2-amino-5-phosphopentanoic acid (AP-5), the non-NMDA receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), AP-5 + NBQX, or vehicle. While all treatments (except vehicle) significantly attenuated/abolished/reversed the splanchnic sympathoinhibitory responses to PE, PBG, and CCK, the extent of blockade varied between the different treatment groups. Both NMDA and non-NMDA receptors were essential to the baroreflex and the von Bezold-Jarisch reflex, whereas the CCK reflex was more dependent on non-NMDA receptors. Muscimol, kynurenate, and AP-5 + NBQX significantly attenuated the bradycardic responses to PE and PBG (P NTS responsible for eliciting all three reflexes, NMDA and non-NMDA receptors are recruited differentially for the full expression of these reflexes. The CCK-induced sympathoinhibitory reflex is unique in that it relies predominantly on non-NMDA receptors in the NTS and elicits bradycardic effects that

  11. Role of glutamatergic receptors located in the nucleus raphe magnus on antinociceptive effect of morphine microinjected into the nucleus cuneiformis of rat.

    Science.gov (United States)

    Haghparast, Abbas; Soltani-Hekmat, Ava; Khani, Abbas; Komaki, Alireza

    2007-10-29

    Neurons in the nucleus cuneiformis (CnF), located just ventrolateral to the periaqueductal gray, project to medullary nucleus raphe magnus (NRM), which is a key medullary relay for descending pain modulation and is critically involved in opioid-induced analgesia. Previous studies have shown that antinociceptive response of CnF-microinjected morphine can be modulated by the specific subtypes of glutamatergic receptors within the CnF. In this study, we evaluated the role of NMDA and kainate/AMPA receptors that are widely distributed within the NRM on morphine-induced antinociception elicited from the CnF. Hundred and five male Wistar rats weighing 250-300 g were used. Morphine (10, 20 and 40 microg) and NMDA receptor antagonist, MK-801 (10 microg) or kainate/AMPA receptor antagonist, DNQX (0.5 microg) in 0.5 microl saline were stereotaxically microinjected into the CnF and NRM, respectively. The latency of tail-flick response was measured at set intervals (2, 7, 12, 17, 22, 27 min after microinjection) by using an automated tail-flick analgesiometer. The results showed that morphine microinjection into the CnF dose-dependently causes increase in tail-flick latency (TFL). MK-801 microinjected into the NRM, just 1 min before morphine injection into the CnF, significantly attenuated antinociceptive effects of morphine. On the other hand, DNQX microinjected into the NRM, significantly increased TFL after local application of morphine into the CnF. We suggest that morphine related antinociceptive effect elicited from the CnF is mediated, in part, by NMDA receptor at the level of the NRM whereas kainite/AMPA receptor has a net inhibitory influence at the same pathway.

  12. Cholesterol modulates open probability and desensitization of NMDA receptors

    Science.gov (United States)

    Korinek, Miloslav; Vyklicky, Vojtech; Borovska, Jirina; Lichnerova, Katarina; Kaniakova, Martina; Krausova, Barbora; Krusek, Jan; Balik, Ales; Smejkalova, Tereza; Horak, Martin; Vyklicky, Ladislav

    2015-01-01

    NMDA receptors (NMDARs) are glutamate-gated ion channels that mediate excitatory neurotransmission in the CNS. Although these receptors are in direct contact with plasma membrane, lipid–NMDAR interactions are little understood. In the present study, we aimed at characterizing the effect of cholesterol on the ionotropic glutamate receptors. Whole-cell current responses induced by fast application of NMDA in cultured rat cerebellar granule cells (CGCs) were almost abolished (reduced to 3%) and the relative degree of receptor desensitization was increased (by seven-fold) after acute cholesterol depletion by methyl-β-cyclodextrin. Both of these effects were fully reversible by cholesterol repletion. By contrast, the responses mediated by AMPA/kainate receptors were not affected by cholesterol depletion. Similar results were obtained in CGCs after chronic inhibition of cholesterol biosynthesis by simvastatin and acute enzymatic cholesterol degradation to 4-cholesten-3-one by cholesterol oxidase. Fluorescence anisotropy measurements showed that membrane fluidity increased after methyl-β-cyclodextrin pretreatment. However, no change in fluidity was observed after cholesterol enzymatic degradation, suggesting that the effect of cholesterol on NMDARs is not mediated by changes in membrane fluidity. Our data show that diminution of NMDAR responses by cholesterol depletion is the result of a reduction of the open probability, whereas the increase in receptor desensitization is the result of an increase in the rate constant of entry into the desensitized state. Surface NMDAR population, agonist affinity, single-channel conductance and open time were not altered in cholesterol-depleted CGCs. The results of our experiments show that cholesterol is a strong endogenous modulator of NMDARs. Key points NMDA receptors (NMDARs) are tetrameric cation channels permeable to calcium; they mediate excitatory synaptic transmission in the CNS and their excessive activation can lead to

  13. Non-ionotropic signaling by the NMDA receptor: controversy and opportunity.

    Science.gov (United States)

    Gray, John A; Zito, Karen; Hell, Johannes W

    2016-01-01

    Provocative emerging evidence suggests that the N-methyl-d-aspartate (NMDA) receptor can signal in the absence of ion flux through the receptor. This non-ionotropic signaling is thought to be due to agonist-induced conformational changes in the receptor, independently of channel opening. Non-ionotropic NMDA receptor signaling has been proposed to be sufficient to induce synaptic long-term depression (LTD), directly challenging the decades-old model that prolonged low-level calcium influx is required to induce LTD. Here, we briefly review these recent findings, focusing primarily on the potential role of non-ionotropic signaling in NMDA receptor-mediated LTD. Further reports concerning additional roles of non-ionotropic NMDA receptor signaling are also discussed. If validated, this new view of NMDA receptor-mediated signaling will usher in an exciting new era of exploring synapse function and dysfunction.

  14. Non-ionotropic signaling by the NMDA receptor: controversy and opportunity [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    John A. Gray

    2016-05-01

    Full Text Available Provocative emerging evidence suggests that the N-methyl-D-aspartate (NMDA receptor can signal in the absence of ion flux through the receptor. This non-ionotropic signaling is thought to be due to agonist-induced conformational changes in the receptor, independently of channel opening. Non-ionotropic NMDA receptor signaling has been proposed to be sufficient to induce synaptic long-term depression (LTD, directly challenging the decades-old model that prolonged low-level calcium influx is required to induce LTD. Here, we briefly review these recent findings, focusing primarily on the potential role of non-ionotropic signaling in NMDA receptor-mediated LTD. Further reports concerning additional roles of non-ionotropic NMDA receptor signaling are also discussed. If validated, this new view of NMDA receptor-mediated signaling will usher in an exciting new era of exploring synapse function and dysfunction.

  15. 脊髓NMDA受体对心包内注射缓激肽诱发大鼠心脏-躯体运动反射的调节作用%Modulation of NMDA receptor to rat cardiacsomatic motor reflex induced by intrapericardial bradykinin in spinal cord

    Institute of Scientific and Technical Information of China (English)

    韩曼; 孙娜; 刘晓华; 杜剑青

    2012-01-01

    目的:观察鞘内注射N-甲基-D-天门冬氨酸(NMDA)受体激动剂NMDA及拮抗剂5-甲基-二氢-丙环庚烯-亚胺马来酸(MK801)对心包内注射缓激肽(BK)诱发大鼠心脏-躯体运动反射(CMR)的影响,探讨脊髓水平的谷氨酸受体亚型-NMDA对心脏伤害性感受的调节作用.方法:26只雄性SD大鼠随机分为BK组(n=8)、BK+NMDA组(n=6)、BK+MK801组(n=6)及BK+ MK801+ NMDA组(n=6),观察大鼠心包内注射BK诱发的CMR及鞘内注射药物后CMR的变化,CMR以背斜方肌肌电(EMG)反应为观测指标.结果:心包内间隔40 min重复4次注射BK诱发的CMR无明显改变(P>0.05);鞘内注射NMDA后EMG由基础对照的100%增加到(149.86±8.54)%,注射前后EMG比较差异有统计学意义(P<0.05);鞘内注射MK801后EMG由基础对照的100%减少到(96.22±2.31)%,但注射前后EMG比较差异无统计学意义(P>0.05);鞘内联合注射MK801NMDA,EMG由基础对照的100%增加到(103.09±4.13)%,但注射前后EMG比较差异无统计学意义(P>0.05).结论:心包内注射BK诱发的CMR具有可靠的重复性,脊髓水平的NMDA受体参与了CMR的调节.

  16. Glutamate Transporters Regulate Extrasynaptic NMDA Receptor Modulation of Kv2.1 Potassium Channels

    OpenAIRE

    Mulholland, Patrick J.; Carpenter-Hyland, Ezekiel P.; Hearing, Matthew C.; Becker, Howard C.; Woodward, John J.; Chandler, L. Judson

    2008-01-01

    Delayed-rectifier Kv2.1 potassium channels regulate somatodendritic excitability during periods of repetitive, high-frequency activity. Recent evidence suggests Kv2.1 channel modulation is linked to glutamatergic neurotransmission. Since NMDA-type glutamate receptors are critical regulators of synaptic plasticity, we investigated NMDA receptor modulation of Kv2.1 channels in rodent hippocampus and cortex. Bath application of NMDA potently unclustered and dephosphorylated Kv2.1 and produced a ...

  17. Latent N-methyl-D-aspartate receptors in the recurrent excitatory pathway between hippocampal CA1 pyramidal neurons: Ca(2+)-dependent activation by blocking A1 adenosine receptors.

    Science.gov (United States)

    Klishin, A; Tsintsadze, T; Lozovaya, N; Krishtal, O

    1995-01-01

    When performed at increased external [Ca2+]/[Mg2+] ratio (2.5 mM/0.5 mM), temporary block of A1 adenosine receptors in hippocampus [by 8-cyclopentyltheophylline (CPT)] leads to a dramatic and irreversible change in the excitatory postsynaptic current (EPSC) evoked by Schaffer collateral/commissural (SCC) stimulation and recorded by in situ patch clamp in CA1 pyramidal neurons. The duration of the EPSC becomes stimulus dependent, increasing with increase in stimulus strength. The later occurring component of the EPSC is carried through N-methyl-D-aspartate (NMDA) receptor-operated channels but disappears under either the NMDA antagonist 2-amino-5-phosphonovaleric acid (APV) or the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). These findings indicate that the late component of the SCC-evoked EPSC is polysynaptic: predominantly non-NMDA receptor-mediated SCC inputs excite CA1 neurons that recurrently excite each other by predominantly NDMA receptor-mediated synapses. These recurrent connections are normally silent but become active after CPT treatment, leading to enhancement of the late component of the EPSC. The activity of these connections is maintained for at least 2 hr after CPT removal. When all functional NMDA receptors are blocked by dizocilpine maleate (MK-801), subsequent application of CPT leads to a partial reappearance of NMDA receptor-mediated EPSCs evoked by SCC stimulation, indicating that latent NMDA receptors are recruited. Altogether, these findings indicate the existence of a powerful system of NMDA receptor-mediated synaptic contacts in SCC input to hippocampal CA1 pyramidal neurons and probably also in reciprocal connections between these neurons, which in the usual preparation are kept latent by activity of A1 receptors. PMID:8618915

  18. Source memory in rats is impaired by an NMDA receptor antagonist but not by PSD95-nNOS protein-protein interaction inhibitors

    Science.gov (United States)

    Smith, Alexandra E.; Xu, Zhili; Lai, Yvonne Y.; Kulkarni, Pushkar M.; Thakur, Ganesh A.; Hohmann, Andrea G.; Crystal, Jonathon D.

    2016-01-01

    Limitations of preclinical models of human memory contribute to the pervasive view that rodent models do not adequately predict therapeutic efficacy in producing cognitive impairments or improvements in humans. We used a source-memory model (i.e. a representation of the origin of information) we developed for use in rats to evaluate possible drug-induced impairments of both spatial memory and higher order memory functions in the same task. Memory impairment represents a major barrier to use of NMDAR antagonists as pharmacotherapies. The scaffolding protein postsynaptic density 95kDa (PSD95) links NMDARs to the neuronal enzyme nitric oxide synthase (nNOS), which catalyzes production of the signaling molecule nitric oxide (NO). Therefore, interrupting PSD95-nNOS protein-protein interactions downstream of NMDARs represents a novel therapeutic strategy to interrupt NMDAR-dependent NO signaling while bypassing unwanted side effects of NMDAR antagonists. We hypothesized that the NMDAR antagonist MK-801 would impair source memory. We also hypothesized that PSD95-nNOS inhibitors (IC87201 and ZL006) would lack the profile of cognitive impairment associated with global NMDAR antagonists. IC87201 and ZL006 suppressed NMDA-stimulated formation of cGMP, a marker of NO production, in cultured hippocampal neurons. MK-801, at doses that did not impair motor function, impaired source memory under conditions in which spatial memory was spared. Thus, source memory was more vulnerable than spatial memory to impairment. By contrast, PSD95-nNOS inhibitors, IC87201 and ZL006, administered at doses that are behaviorally effective in rats, spared source memory, spatial memory, and motor function. Thus, PSD95-nNOS inhibitors are likely to exhibit favorable therapeutic ratios compared to NMDAR antagonists. PMID:26909849

  19. AMPA receptor pHluorin-GluA2 reports NMDA receptor-induced intracellular acidification in hippocampal neurons

    DEFF Research Database (Denmark)

    Rathje, Mette; Fang, Huaqiang; Bachman, Julia L;

    2013-01-01

    NMDA receptor activation promotes endocytosis of AMPA receptors, which is an important mechanism underlying long-term synaptic depression. The pH-sensitive GFP variant pHluorin fused to the N terminus of GluA2 (pH-GluA2) has been used to assay NMDA-mediated AMPA receptor endocytosis and recycling...

  20. Opposing action of conantokin-G on synaptically and extrasynaptically-activated NMDA receptors.

    Science.gov (United States)

    Balsara, Rashna; Li, Neill; Weber-Adrian, Danielle; Huang, Louxiu; Castellino, Francis J

    2012-06-01

    Synaptic and extrasynaptic activation of the N-methyl-D-aspartate receptor (NMDAR) has distinct consequences on cell signaling and neuronal survival. Since conantokin (con)-G antagonism is NR2B-selective, which is the key subunit involved in extrasynaptic activation of the receptor, its ability to specifically elicit distinct signaling outcomes in neurons with synaptically or extrasynaptically-activated NMDARs was evaluated. Inhibition of Ca(2+) influx through extrasynaptic NMDAR ion channels was neuroprotective, as it effectively enhanced levels of activated extracellular signal-regulated kinase 1/2 (ERK1/2), activated cAMP response element binding protein (CREB), enhanced mitochondrial viability, and attenuated the actin disorganization observed by extrasynaptic activation of NMDARs. Conversely, the pro-signaling pathways stimulated by synaptically-induced Ca(2+) influx were abolished by con-G. Furthermore, subunit non-selective con-T was unable to successfully redress the impairments in neurons caused by extrasynaptically-activated NMDARs, thus indicating that NR2B-specific antagonists are beneficial for neuron survival. Neurons ablated for the NR2B subunit showed weak synaptic Ca(2+) influx, reduced sensitivity to MK-801 blockage, and diminished extrasynaptic current compared to WT and NR2A(-/-) neurons. This indicates that the NR2B subunit is an integral component of both synaptic and extrasynaptic NMDAR channels. Altogether, these data suggest that con-G specifically targets the NR2B subunit in the synaptic and extrasynaptic locations, resulting in the opposing action of con-G on differentially activated pools of NMDARs.

  1. NMDA receptors are not required for pattern completion during associative memory recall.

    Directory of Open Access Journals (Sweden)

    Bing Mei

    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.

  2. N-Methyl-D-aspartate Receptor Excessive Activation Inhibited Fetal Rat Lung Development In Vivo and In Vitro

    Directory of Open Access Journals (Sweden)

    Zhengchang Liao

    2016-01-01

    Full Text Available Background. Intrauterine hypoxia is a common cause of fetal growth and lung development restriction. Although N-methyl-D-aspartate receptors (NMDARs are distributed in the postnatal lung and play a role in lung injury, little is known about NMDAR’s expression and role in fetal lung development. Methods. Real-time PCR and western blotting analysis were performed to detect NMDARs between embryonic days (E 15.5 and E21.5 in fetal rat lungs. NMDAR antagonist MK-801’s influence on intrauterine hypoxia-induced retardation of fetal lung development was tested in vivo, and NMDA’s direct effect on fetal lung development was observed using fetal lung organ culture in vitro. Results. All seven NMDARs are expressed in fetal rat lungs. Intrauterine hypoxia upregulated NMDARs expression in fetal lungs and decreased fetal body weight, lung weight, lung-weight-to-body-weight ratio, and radial alveolar count, whereas MK-801 alleviated this damage in vivo. In vitro experiments showed that NMDA decreased saccular circumference and area per unit and downregulated thyroid transcription factor-1 and surfactant protein-C mRNA expression. Conclusions. The excessive activation of NMDARs contributed to hypoxia-induced fetal lung development retardation and appropriate blockade of NMDAR might be a novel therapeutic strategy for minimizing the negative outcomes of prenatal hypoxia on lung development.

  3. Protection from inorganic mercury effects on the in vivo dopamine release by ionotropic glutamate receptor antagonists and nitric oxide synthase inhibitors.

    Science.gov (United States)

    Vidal, Lucía; Durán, Rafael; Faro, Lilian F; Campos, Francisco; Cervantes, Rosa C; Alfonso, Miguel

    2007-09-05

    The possible role of ionotropics glutamate receptors on the HgCl(2)-induced dopamine (DA) release from rat striatum was investigated by using in vivo brain microdialysis technique after administration of selective NMDA and AMPA/Kainate receptors antagonists dizocilpine (MK-801), D (-)-2-amino-5-phoshonopentanoic acid (AP5), and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Moreover, we have also studied the effects of nitric oxide synthase (NOS) inhibitors L-nitro-arginine methyl ester (L-NAME) and 7-nitro-indazol (7-NI) on HgCl(2)-induced DA release. Intraestriatal infusion of 1mM HgCl(2) increased striatal DA to 1717.2+/-375.4% respect to basal levels. Infusion of 1mM HgCl(2) in 400 microM MK-801 pre-treated animals produced an increase on striatal DA levels 61% smaller than that induced in non-pre-treated animals. In the case of AP5, this treatment reduced 92% the increase produced by HgCl(2) as compared to non-pre-treated rats. Nevertheless, the administration of CNQX did not produce any effect on HgCl(2)-induced dopamine release. Intrastriatal infusion of 1mM HgCl(2) in 100 microM L-NAME pre-treated animals produced an increase on extracellular DA levels 82% smaller than produced by HgCl(2) alone. In addition, the pre-treatment with 7-NI reduced 90% the increase produced by infusion of HgCl(2) alone in rats. Thus, HgCl(2)-induced DA release could be produced at last in part, by overstimulation of NMDA receptors with NO production, since administration of NMDA receptor antagonists and NOS inhibitors protected against HgCl(2) effects on DA release.

  4. The role of NMDA receptors in human eating behavior: evidence from a case of anti-NMDA receptor encephalitis.

    Science.gov (United States)

    Perogamvros, Lampros; Schnider, Armin; Leemann, Beatrice

    2012-06-01

    Research in animal models has implicated N-methyl-D-aspartate (NMDA) receptors (NMDARs) in the control of food intake. Until now, these findings have been not replicated in humans. Here we describe a 22-year-old woman with anti-NMDAR encephalitis and no prior neurological or psychiatric history. Her clinical course was marked by successive eating disorders: anorexia followed by hyperphagia. We propose that, much as they do in other animals, NMDARs in humans interact with the neuroendocrine, homeostatic, and reward systems controlling food intake in the central and peripheral nervous system structures related to feeding and satiety.

  5. BDNF Reduces Toxic Extrasynaptic NMDA Receptor Signaling via Synaptic NMDA Receptors and Nuclear-Calcium-Induced Transcription of inhba/Activin A

    Directory of Open Access Journals (Sweden)

    David Lau

    2015-08-01

    Full Text Available The health of neurons is critically dependent on the relative signaling intensities of survival-promoting synaptic and death-inducing extrasynaptic NMDA receptors. Here, we show that BDNF is a regulator of this balance and promotes neuroprotection by reducing toxic NMDA receptor signaling. BDNF acts by initiating synaptic NMDA-receptor/nuclear-calcium-driven adaptogenomics, leading to increased expression of inhibin β-A (inhba. Inhibin β-A (its homodimer is known as activin A in turn reduces neurotoxic extrasynaptic NMDA-receptor-mediated calcium influx, thereby shielding neurons against mitochondrial dysfunction, a major cause of excitotoxicity. Thus, BDNF induces acquired neuroprotection by enhancing synaptic activity and lowering extrasynaptic NMDA receptor death signaling through a nuclear calcium-inhibin β-A pathway. This process, which confers protection against ischemic brain damage in a mouse stroke model, may be compromised in Huntington’s disease, Alzheimer’s disease, or aging-related neurodegenerative conditions that are associated with reduced BDNF levels and/or enhanced extrasynaptic NMDA receptor signaling.

  6. Intrathecal injection of glutamate receptor antagonists/agonist selectively attenuated rat pain-related behaviors induced by the venom of scorpion Buthus martensi Karsch.

    Science.gov (United States)

    Liu, Tong; Pang, Xue-Yan; Bai, Zhan-Tao; Chai, Zhi-Fang; Jiang, Feng; Ji, Yong-Hua

    2007-12-15

    The present study investigated the involvement of spinal glutamate receptors in the induction and maintenance of the pain-related behaviors induced by the venom of scorpion Buthus martensi Karsch (BmK). (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-10-imine hydrogen maleate (MK-801; 40nmol; a non-competitive NMDA receptor antagonist), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 40nmol; a non-NMDA receptor antagonist), dl-amino-3-phosphonopropionic acid (dl-AP3; 100nmol; a group I metabotropic glutamate receptor antagonist) and 4-aminopyrrolidine-2,4-dicarboxylate (APDC; 100nmol; a group II metabotropic glutamate receptor agonist) were employed. On intrathecal injection of glutamate receptor antagonists/agonist before BmK venom administration by 10min, BmK venom-induced spontaneous nociceptive responses could be suppressed by all tested agents. Primary thermal hyperalgesia could be inhibited by MK-801 and dl-AP3, while bilateral mechanical hyperalgesia could be inhibited by CNQX and dl-AP3 and contralateral mechanical hyperalgesia could be inhibited by APDC. On intrathecal injection of glutamate receptor antagonists/agonist after BmK venom injection by 4.5h, primary thermal hyperalgesia could be partially reversed by all tested agents, while bilateral mechanical hyperalgesia could only be inhibited by APDC. The results suggest that the role of spinal glutamate receptors may be different on the various manifestations of BmK venom-induced pain-related behaviors.

  7. Role of NMDA receptor in spinal cord in diabetic neuropathic pain in rats%脊髓NMDA受体在大鼠糖尿病神经病理性痛中的作用

    Institute of Scientific and Technical Information of China (English)

    柯昌斌; 黄晓霞; 李元涛; 秦成名; 王贤裕; 许先成; 罗向红; 刘菊英; 周青山

    2009-01-01

    Objective To evaluate the role played by NMDA receptor (NR1) in spinal cord in diabetic neuropathic pain (DNP) in rats.Methods One hundred and twenty-eight female Wistar rats 3 months old weighing 180-220 g were randomly divided into 4 groups : group Ⅰ control ( group C) ;group Ⅱ DNP;group Ⅲ SB203580 (selective p38MAPK inhibitor) + DNP and group Ⅳ MK-801 + DNP.Diabetes mellitus was induced by intraperitoneal streptozocin 65 mg/kg.Blood glucose level was measured every week for 4 weeks.Diabetes mellitus was confirmed by blood glucose level ≥ 16.0 mmol/L in the 4th week.Mechanical paw withdrawal threshold (MWT) to yon Frey filament stimulation was measured at the end of the 4th week.Diabetic rats with significant decrease in MWT were used in group Ⅱ ,Ⅲ and Ⅳ.Starting from the 1st week after DNP model had successed,SB203580 1 mg/kg and MK-801 1 mg/kg were injected IP once a day in group Ⅲ and Ⅳ respectively.Eight animals were taken from each group for MWT measurement at the end of the 1st,3rd,5th and 7th week after the model was successfully made respectively.The rats were anesthetized and nerve conduction velocity (NCV) of the left sciatic nerve was measured.The rats were then killed and fight sciatic nerve,the lumbar segment of the spinal cord and dorsal root ganglion (DRG) were removed for microscopic examination and determination of the level of DOI: 10.3760/cma.j.issn.0254-1416.2009.05.010phosphorylated p38 MARK (p-p38MAPK) and the expression of NR1 in the neurons of DRG and spinal cord.Results The MWT and NCV were significantly lower and the p-p38MAPK level and NR1 expression in the spinal cord and DRG were significantly higher in group Ⅱ ,Ⅲ and Ⅳ than in group C at all time points.SB203580 and MK-801 significantly attenuated the diabetes-induced changes in group Ⅲ and Ⅳ respectively.Conclusion Activation of NMDA receptor in spinal cord is involved in the diabetic neuropathic pain.%目的 评价脊髓NMDA受体在大鼠糖尿病神

  8. ROLE OF NMDA, NICOTINIC, AND GABA RECEPTORS IN THE STEADY STATE VISUAL EVOKED POTENTIAL IN RATS.

    Science.gov (United States)

    This manuscript characterizes the receptor pathways involved in pattern-evoked potential generation in rats" NMDA and nicotinic acetylcholine receptors appear to be involved in the generation of the steady-state pattern evoked response in vivo." The pattern evok...

  9. BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals.

    Science.gov (United States)

    Chen, Wenling; Walwyn, Wendy; Ennes, Helena S; Kim, Hyeyoung; McRoberts, James A; Marvizón, Juan Carlos G

    2014-05-01

    NMDA receptors in primary afferent terminals can contribute to hyperalgesia by increasing neurotransmitter release. In rats and mice, we found that the ability of intrathecal NMDA to induce neurokinin 1 receptor (NK1R) internalization (a measure of substance P release) required a previous injection of BDNF. Selective knock-down of NMDA receptors in primary afferents decreased NMDA-induced NK1R internalization, confirming the presynaptic location of these receptors. The effect of BDNF was mediated by tropomyosin-related kinase B (trkB) receptors and not p75 neurotrophin receptors (p75(NTR) ), because it was not produced by proBDNF and was inhibited by the trkB antagonist ANA-12 but not by the p75(NTR) inhibitor TAT-Pep5. These effects are probably mediated through the truncated form of the trkB receptor as there is little expression of full-length trkB in dorsal root ganglion (DRG) neurons. Src family kinase inhibitors blocked the effect of BDNF, suggesting that trkB receptors promote the activation of these NMDA receptors by Src family kinase phosphorylation. Western blots of cultured DRG neurons revealed that BDNF increased Tyr(1472) phosphorylation of the NR2B subunit of the NMDA receptor, known to have a potentiating effect. Patch-clamp recordings showed that BDNF, but not proBDNF, increased NMDA receptor currents in cultured DRG neurons. NMDA-induced NK1R internalization was also enabled in a neuropathic pain model or by activating dorsal horn microglia with lipopolysaccharide. These effects were decreased by a BDNF scavenger, a trkB receptor antagonist and a Src family kinase inhibitor, indicating that BDNF released by microglia potentiates NMDA receptors in primary afferents during neuropathic pain. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

  10. Comparison of excitotoxic profiles of ATPA, AMPA, KA and NMDA in organotypic hippocampal slice cultures.

    Science.gov (United States)

    Kristensen, B W; Noraberg, J; Zimmer, J

    2001-10-26

    The excitotoxic profiles of (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propionic acid (ATPA), (RS)-2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainic acid (KA) and N-methyl-D-aspartate (NMDA) were evaluated using cellular uptake of propidium iodide (PI) as a measure for induced, concentration-dependent neuronal damage in hippocampal slice cultures. ATPA is in low concentrations a new selective agonist of the glutamate receptor subunit GluR5 confined to KA receptors and also in high concentrations an AMPA receptor agonist. The following rank order of estimated EC(50) 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 was mediated primarily via AMPA receptors. Similar results were found for a high concentration of ATPA (30 microM). In low GluR5 selective concentrations (0.3-3 microM), ATPA did not induce an increase in PI uptake or a reduction in glutamic acid decarboxylase (GAD) activity of hippocampal interneurons. For KA, the excitotoxicity appeared to be mediated via both KA and AMPA receptors. NMDA receptors were not involved in AMPA-, ATPA- and KA-induced excitotoxicity, nor did NMDA-induced excitotoxicity require activation of AMPA and KA receptors. We conclude that hippocampal slice cultures constitute a feasible test system for evaluation of excitotoxic effects and mechanisms of new (ATPA) and classic (AMPA, KA and NMDA) glutamate receptor agonists. Comparison of concentration

  11. 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.

  12. Selective involvement of kappa opioid and phencyclidine receptors in the analgesic and motor effects of dynorphin-A-(1-13)-Tyr-Leu-Phe-Asn-Gly-Pro.

    Science.gov (United States)

    Shukla, V K; Bansinath, M; Dumont, M; Lemaire, S

    1992-09-18

    Dynorphin A-(1-13)-Tyr-Leu-Phe-Asn-Gly-Pro (Dyn Ia; 1-8 nmol) injected intracerebroventricularly in the mouse produces two independent behavioral effects: (1) a norbinaltorphimine (kappa opioid antagonist)-reversible analgesia in the acetic acid-induced writhing test and (2) motor dysfunction characterized by wild running, pop-corn jumping, hindlimb jerking and barrel rolling and antagonized by the irreversible phencyclidine (PCP) and sigma (sigma) receptor antagonist, metaphit and the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, dextromethorphan and ketamine. The specific involvement of the PCP receptor in the motor effects of Dyn Ia is supported by the direct competitive interaction of the peptide with the binding of [3H]MK-801 (Ki: 0.63 microM) and [3H]TCP (Ki: 4.6 microM) to mouse brain membrane preparations.

  13. Scavenging ROS dramatically increase NMDA receptor whole-cell currents in painted turtle cortical neurons.

    Science.gov (United States)

    Dukoff, David James; Hogg, David William; Hawrysh, Peter John; Buck, Leslie Thomas

    2014-09-15

    Oxygen deprivation triggers excitotoxic cell death in mammal neurons through excessive calcium loading via over-activation of N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This does not occur in the western painted turtle, which overwinters for months without oxygen. Neurological damage is avoided through anoxia-mediated decreases in NMDA and AMPA receptor currents that are dependent upon a modest rise in intracellular Ca(2+) concentrations ([Ca(2+)]i) originating from mitochondria. Anoxia also blocks mitochondrial reactive oxygen species (ROS) generation, which is another potential signaling mechanism to regulate glutamate receptors. To assess the effects of decreased intracellular [ROS] on NMDA and AMPA receptor currents, we scavenged ROS with N-2-mercaptopropionylglycine (MPG) or N-acetylcysteine (NAC). Unlike anoxia, ROS scavengers increased NMDA receptor whole-cell currents by 100%, while hydrogen peroxide decreased currents. AMPA receptor currents and [Ca(2+)]i concentrations were unaffected by ROS manipulation. Because decreases in [ROS] increased NMDA receptor currents, we next asked whether mitochondrial Ca(2+) release prevents receptor potentiation during anoxia. Normoxic activation of mitochondrial ATP-sensitive potassium (mKATP) channels with diazoxide decreased NMDA receptor currents and was unaffected by subsequent ROS scavenging. Diazoxide application following ROS scavenging did not rescue scavenger-mediated increases in NMDA receptor currents. Fluorescent measurement of [Ca(2+)]i and ROS levels demonstrated that [Ca(2+)]i increases before ROS decreases. We conclude that decreases in ROS concentration are not linked to anoxia-mediated decreases in NMDA/AMPA receptor currents but are rather associated with an increase in NMDA receptor currents that is prevented during anoxia by mitochondrial Ca(2+) release.

  14. Glycine Potentiates AMPA Receptor Function through Metabotropic Activation of GluN2A-containing NMDA Receptors

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    Li-Jun Li

    2016-10-01

    Full Text Available NMDA receptors are Ca2+-permeable ion channels. The activation of NMDA receptors requires agonist glutamate and co-agonist glycine. Recent evidence indicates that NMDA receptor also has metabotropic function. Here we report that in cultured mouse hippocampal neurons, glycine increases AMPA receptor-mediated currents independent of the channel activity of NMDA receptors and the activation of glycine receptors. The potentiation of AMPA receptor function by glycine is antagonized by the inhibition of ERK1/2. In the hippocampal neurons and in the HEK293 cells transfected with different combinations of NMDA receptors, glycine preferentially acts on GluN2A-containing NMDA receptors (GluN2ARs, but not GluN2B-containing NMDA receptors (GluN2BRs, to enhance ERK1/2 phosphorylation independent of the channel activity of GluN2ARs. Without requiring the channel activity of GluN2ARs, glycine increases AMPA receptor-mediated currents through GluN2ARs. Thus, these results reveal a metabotropic function of GluN2ARs in mediating glycine-induced potentiation of AMPA receptor function via ERK1/2 activation.

  15. Glycine Potentiates AMPA Receptor Function through Metabotropic Activation of GluN2A-Containing NMDA Receptors

    Science.gov (United States)

    Li, Li-Jun; Hu, Rong; Lujan, Brendan; Chen, Juan; Zhang, Jian-Jian; Nakano, Yasuko; Cui, Tian-Yuan; Liao, Ming-Xia; Chen, Jin-Cao; Man, Heng-Ye; Feng, Hua; Wan, Qi

    2016-01-01

    NMDA receptors are Ca2+-permeable ion channels. The activation of NMDA receptors requires agonist glutamate and co-agonist glycine. Recent evidence indicates that NMDA receptor also has metabotropic function. Here we report that in cultured mouse hippocampal neurons, glycine increases AMPA receptor-mediated currents independent of the channel activity of NMDA receptors and the activation of glycine receptors. The potentiation of AMPA receptor function by glycine is antagonized by the inhibition of ERK1/2. In the hippocampal neurons and in the HEK293 cells transfected with different combinations of NMDA receptors, glycine preferentially acts on GluN2A-containing NMDA receptors (GluN2ARs), but not GluN2B-containing NMDA receptors (GluN2BRs), to enhance ERK1/2 phosphorylation independent of the channel activity of GluN2ARs. Without requiring the channel activity of GluN2ARs, glycine increases AMPA receptor-mediated currents through GluN2ARs. Thus, these results reveal a metabotropic function of GluN2ARs in mediating glycine-induced potentiation of AMPA receptor function via ERK1/2 activation.

  16. N-methyl-D-aspartate receptor blockade is neuroprotective in experimental autoimmune optic neuritis.

    Science.gov (United States)

    Sühs, Kurt-Wolfram; Fairless, Richard; Williams, Sarah K; Heine, Katrin; Cavalié, Adolfo; Diem, Ricarda

    2014-06-01

    Optic neuritis is a common clinical manifestation of the chronic inflammatory CNS disease multiple sclerosis that can result in persistent visual impairment caused by degeneration of optic nerve axons and apoptosis of retinal ganglion cells (RGCs). Using a model of experimental autoimmune encephalomyelitis with optic neuritis (Brown Norway rats), we show that administration of the N-methyl-D-aspartate (NMDA) receptor antagonists memantine or MK801 results in RGC protection, axon protection, and reduced demyelination of optic nerves. Calcium imaging revealed that RGC responses to glutamate stimulation predominantly occurred via NMDA receptors and were inhibited by memantine in a dose-dependent manner. In contrast, oligodendrocytes were mainly responsive through the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor. This suggests that NMDA receptor blockade protected RGCs directly and that the protection was independent of effects on oligodendrocytes. Moreover, increased RGC survival was observed before the onset of optic nerve demyelination--when RGC degeneration had already started. These results indicate an important pathophysiologic role for NMDA receptor-mediated glutamate toxicity during the induction phase of this disease model and highlight a potential target for therapeutic neuroprotection in human optic neuritis.

  17. Nonopioid motor effects of dynorphin A and related peptides: structure dependence and role of the N-methyl-D-aspartate receptor.

    Science.gov (United States)

    Shukla, V K; Prasad, J A; Lemaire, S

    1997-11-01

    Dynorphin (Dyn) A and related opioid and nonopioid peptides were tested for their ability to produce motor effects in mice. Central (intracerebroventricular) administration of Dyn A in mice produced marked motor effects characterized by wild running, jumping, circling and/or barrel rolling with an ED50 value of 14.32 (95% confidence limits, 10.09-20.32) nmol/mouse. The order of potency of the various Dyn A-related peptides and fragments in producing motor effects was Dyn A approximately Dyn A-(1-13) > [Ala1]Dyn A-(1-13) approximately Dyn A-(2-13) > alpha-Neo-End > Dyn A-(1-8) approximately Dyn B approximately Dyn A-(2-8) > Dyn A-(3-8). Dyn A-(1- 5) (or Leu-Enk) and Dyn A-(6-10) displayed no motor effect at doses up to 100 nmol/mouse. The potencies of Dyn A and Dyn A-(2-13) were not affected by preadministration of naloxone (5 mg/kg s.c.), but the motor effects of Dyn A-(1-13) (20 nmol/mouse i.c.v.) were significantly reduced by coadministration of low doses (0.2-0.6 nmol/mouse) of the N-methyl-D-aspartate (NMDA) receptor antagonists dextrorphan, MK-801 and CPP. Dyn A was also a potent inhibitor of the binding of the phencyclidine receptor ligand, [3H]MK-801, to rat brain membranes, with a Ki value of 0.41 microM. However, the order of potency of the various Dyn A-related peptides and fragments in inhibiting [3H]MK-801 binding did not correlate with their ability to produce motor effects. On the other hand, Dyn A and related peptides produced a significant potentiation of the binding of the competitive NMDA antagonist [3H]CGP-39653 to rat brain membranes, an effect that correlated well (r = 0.91) with their potency in producing motor effects. These results indicate that the nonopioid motor effects of Dyn A and related peptides are structure dependent, with Dyn A-(2-8) being the minimal core peptide for motor activity. In addition, these effects most likely involve the participation of the excitatory amino acid binding domain on the NMDA receptor complex.

  18. Functional heterogeneity of NMDA receptors in rat substantia nigra pars compacta and reticulata neurones.

    Science.gov (United States)

    Suárez, F; Zhao, Q; Monaghan, D T; Jane, D E; Jones, S; Gibb, A J

    2010-08-01

    The nigra substantia nigra pars compacta (SNc) and substantia pars reticulata (SNr) form two major basal ganglia components with different functional roles. SNc dopaminergic (DA) neurones are vulnerable to cell death in Parkinson's disease, and NMDA receptor activation is a potential contributing mechanism. We have investigated the sensitivity of whole-cell and synaptic NMDA responses to intracellular ATP and GTP application in the SNc and SNr from rats on postnatal day (P) 7 and P28. Both NMDA current density (pA/pF) and desensitization to prolonged or repeated NMDA application were greater in the SNr than in the SNc. When ATP levels were not supplemented, responses to prolonged NMDA administration desensitized in P7 SNc DA neurones but not at P28. At P28, SNr neurones desensitized more than SNc neurones, with or without added ATP. Responses to brief NMDA applications and synaptic NMDA currents were not sensitive to inclusion of ATP in the pipette solution. To investigate these differences between the SNc and SNr, NR2 subunit-selective antagonists were tested. NMDA currents were inhibited by ifenprodil (10 microM) and UBP141 (4 microM), but not by Zn(2+) (100 nm), in both the SNr and SNc, suggesting that SNc and SNr neurones express similar receptor subunits; NR2B and NR2D, but not NR2A. The different NMDA response properties in the SNc and SNr may be caused by differences in receptor modulation and/or trafficking. The vulnerability of SNc DA neurones to cell death is not correlated with NMDA current density or receptor subtypes, but could in part be related to inadequate NMDA receptor desensitization.

  19. MK-801与抗癫痫药合用对大鼠杏仁核点燃的影响%Effect of combination of dizocilpine with general antiepileptic drugs on amygdala kindling models in rats

    Institute of Scientific and Technical Information of China (English)

    仲伟珍; 赵永娟; 高桂梅; 杨志宏; 岳旺

    2004-01-01

    目的在大鼠杏仁核点燃模型研究MK-801(地佐西平)及其联合用药的抗癫痫作用.方法建立大鼠杏仁核慢性电刺激点燃模型,测定不同剂量的MK-801对点燃模型各项指标的影响,探讨MK-801与其他抗癫痫药的协同作用,用氨基脲诱发的小鼠惊厥模型测定MK-801抗惊厥作用. 结果 MK-801(0.1~0.25 mg·kg-1)可剂量依赖性抑制杏仁核点燃,缩短后放电时程,降低Racine's分级;在对点燃均无明显影响的剂量下,MK-801(0.05 mg·kg-1)与抗癫痫药(苯巴比妥、丙戊酸及尼卡地平)合用可缩短后放电时程或降低Racine's分级.MK-801(0.1~0.25 mg·kg-1)显著降低小鼠氨基脲诱发的发作潜伏期、惊厥发生率和死亡率.结论 MK-801具有抑制大鼠杏仁核点燃的作用,增强苯巴比妥、丙戊酸及尼卡地平的抗癫痫活性,为临床的合并用药提供实验依据.%Aim To investigate the antiepileptic effect of dizocilpine (MK-801) on amygdala kindling models in rats and the effects of its combination with general antiepileptic drugs. Methods To establish amygdala kindling models in rats and observe the effect of dizocilpine on kindling models and its combination with general antiepileptic drugs (phenobarbital, valproate and nicardipine) at ineffective dose. The influence of dizocilpine on convulsions induced by semicarbazide (SCZ) in mice were also observed. Results Dizocilpine (0.1-0.25 mg·kg-1, ip) was shown to dose-dependently inhibit amygdala kindled seizure, shorten the after discharge duration (ADD) and reduce the Racine's stage (P<0.01). The combination of dizocilpine with phenobarbital, valproate, nicardipine at ineffective dose shortened ADD or reduced Racine's stages (P<0.01). Dizocilpine (0.1-0.25 mg·kg-1, ip) significantly prolonged the latency and reduced the rate of convulsions and death in mice. Conclusion Dizocilpine inhibits the seizure of the amygdala kindling and improve the antiepileptic activity of phenobarbital

  20. Role of ionotropic GABA, glutamate and glycine receptors in the tonic and reflex control of cardiac vagal outflow in the rat

    Directory of Open Access Journals (Sweden)

    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.

  1. 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.

  2. MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction

    DEFF Research Database (Denmark)

    Kocerha, Jannet; Faghihi, Mohammad Ali; Lopez-Toledano, Miguel A

    2009-01-01

    N-methyl-D-aspartate (NMDA) glutamate receptors are regulators of fast neurotransmission and synaptic plasticity in the brain. Disruption of NMDA-mediated glutamate signaling has been linked to behavioral deficits displayed in psychiatric disorders such as schizophrenia. Recently, noncoding RNA m...

  3. 大鼠孤束核内谷氨酸受体亚型对心脏伤害性感受信息的调控作用%Role of glutamate receptor subtypes in cardiac nociception in nucleus tractus solitarius in rats

    Institute of Scientific and Technical Information of China (English)

    刘晓华; 韩曼; 杜剑青

    2014-01-01

    Objective To study the role of glutamate receptor subtypes in nucleus tractus solitarius(NTS)in cardiac-somatic motor reflex (CMR)induced by intrapericardial administration of capsaicin,and to clarify the modulation mechanism of NTS to cardiac nociceptoion.Methods 60 SD rats were randomly divided into ibotenic (IBO)group, glutamate group, MK-801 group, MCGP group, MK-801 + MCPG group and DNQX group. The NTS microinjected with 130 mmol·L-1 IBO 100 nL,100,200,500 mmol·L-1 L-glutamate 100 nL,NMDA receptor antagonist 40 and 60 mmol · L-1 MK-801 100 nL, metabotropic glutamate receptors antagonist 25 and 50 mmol·L-1 MCPG 100 nL,25 mmol· L-1 MCPG 50 nL plus 40 mmol· L-1 MK-801 50 nL,non-NMDA receptor antagonist 20 and 50 mmol·L-1 DNQX 100 nL,respectively.The changes of CMR of the rats in various groups were observed.Results Compared with control group,the CMR of the rats in IBO group was decreased (P0.05).Conclusion NTS play an facilictory role in cardiac nociception,and the NMDA receptors and mGluRs receptors mediate this facilitory modulation.%目的:探讨大鼠孤束核(NTS)内谷氨酸受体亚型对心包内注射辣椒素诱发的心脏-躯体运动反射(CMR)的影响,阐明 NTS对心脏伤害性信息调控的作用机制。方法:SD大鼠60只随机分为鹅膏蕈氨酸(IBO)组、谷氨酸组、5-甲基二氢丙环庚烯亚胺马来酸(MK-801)组、α-甲基,4-羧基苯丙氨酸(MCPG)组、MCPG联合MK-801组和6,7-二硝基喹喔啉-2,3-二酮(DNQX)组;各组大鼠孤束核内分别微量注射13 mmol·L-1 IBO 100 nL,100、200、500 mmol·L-1谷氨酸100 nL,NMDA受体拮抗剂40和60 mmol·100-1 MK-801100 nL,代谢型谷氨酸受体拮抗剂25和50 mmol·L-1 MCPG 100 nL,25 mmol·L-1 MCPG 50 nL联合40 mmol·L-1 MK-80150 nL,非 NMDA 受体拮抗剂20和50 mmol · L-1 DNQX 100 nL;观察各组大鼠 CMR 的变化。结果:与对照组比较,IBO组大鼠CMR减少(P<0.05);谷氨酸组随着谷氨

  4. NMDA receptors in dopaminergic neurons are crucial for habit learning.

    Science.gov (United States)

    Wang, Lei Phillip; Li, Fei; Wang, Dong; Xie, Kun; Wang, Deheng; Shen, Xiaoming; Tsien, Joe Z

    2011-12-22

    Dopamine is crucial for habit learning. Activities of midbrain dopaminergic neurons are regulated by the cortical and subcortical signals among which glutamatergic afferents provide excitatory inputs. Cognitive implications of glutamatergic afferents in regulating and engaging dopamine signals during habit learning, however, remain unclear. Here, we show that mice with dopaminergic neuron-specific NMDAR1 deletion are impaired in a variety of habit-learning tasks, while normal in some other dopamine-modulated functions such as locomotor activities, goal-directed learning, and spatial reference memories. In vivo neural recording revealed that dopaminergic neurons in these mutant mice could still develop the cue-reward association responses; however, their conditioned response robustness was drastically blunted. Our results suggest that integration of glutamatergic inputs to DA neurons by NMDA receptors, likely by regulating associative activity patterns, is a crucial part of the cellular mechanism underpinning habit learning.

  5. Scopolamine administration modulates muscarinic, nicotinic and NMDA receptor systems.

    Directory of Open Access Journals (Sweden)

    Soheil Keihan Falsafi

    Full Text Available Studies on the effect of scopolamine on memory are abundant but so far only regulation of the muscarinic receptor (M1 has been reported. We hypothesized that levels of other cholinergic brain receptors as the nicotinic receptors and the N-methyl-D-aspartate (NMDA receptor, known to be involved in memory formation, would be modified by scopolamine administration.C57BL/6J mice were used for the experiments and divided into four groups. Two groups were given scopolamine 1 mg/kg i.p. (the first group was trained and the second group untrained in the multiple T-maze (MTM, a paradigm for evaluation of spatial memory. Likewise, vehicle-treated mice were trained or untrained thus serving as controls. Hippocampal levels of M1, nicotinic receptor alpha 4 (Nic4 and 7 (Nic7 and subunit NR1containing complexes were determined by immunoblotting on blue native gel electrophoresis.Vehicle-treated trained mice learned the task and showed memory retrieval on day 8, while scopolamine-treatment led to significant impairment of performance in the MTM. At the day of retrieval, hippocampal levels for M1, Nic7 and NR1 were higher in the scopolamine treated groups than in vehicle-treated groups.The concerted action, i.e. the pattern of four brain receptor complexes regulated by the anticholinergic compound scopolamine, is shown. Insight into probable action mechanisms of scopolamine at the brain receptor complex level in the hippocampus is provided. Scopolamine treatment is a standard approach to test cognitive enhancers and other psychoactive compounds in pharmacological studies and therefore knowledge on mechanisms is of pivotal interest.

  6. Caldendrin-Jacob: a protein liaison that couples NMDA receptor signalling to the nucleus.

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    Daniela C Dieterich

    2008-02-01

    Full Text Available NMDA (N-methyl-D-aspartate receptors and calcium can exert multiple and very divergent effects within neuronal cells, thereby impacting opposing occurrences such as synaptic plasticity and neuronal degeneration. The neuronal Ca2+ sensor Caldendrin is a postsynaptic density component with high similarity to calmodulin. Jacob, a recently identified Caldendrin binding partner, is a novel protein abundantly expressed in limbic brain and cerebral cortex. Strictly depending upon activation of NMDA-type glutamate receptors, Jacob is recruited to neuronal nuclei, resulting in a rapid stripping of synaptic contacts and in a drastically altered morphology of the dendritic tree. Jacob's nuclear trafficking from distal dendrites crucially requires the classical Importin pathway. Caldendrin binds to Jacob's nuclear localization signal in a Ca2+-dependent manner, thereby controlling Jacob's extranuclear localization by competing with the binding of Importin-alpha to Jacob's nuclear localization signal. This competition requires sustained synapto-dendritic Ca2+ levels, which presumably cannot be achieved by activation of extrasynaptic NMDA receptors, but are confined to Ca2+ microdomains such as postsynaptic spines. Extrasynaptic NMDA receptors, as opposed to their synaptic counterparts, trigger the cAMP response element-binding protein (CREB shut-off pathway, and cell death. We found that nuclear knockdown of Jacob prevents CREB shut-off after extrasynaptic NMDA receptor activation, whereas its nuclear overexpression induces CREB shut-off without NMDA receptor stimulation. Importantly, nuclear knockdown of Jacob attenuates NMDA-induced loss of synaptic contacts, and neuronal degeneration. This defines a novel mechanism of synapse-to-nucleus communication via a synaptic Ca2+-sensor protein, which links the activity of NMDA receptors to nuclear signalling events involved in modelling synapto-dendritic input and NMDA receptor-induced cellular degeneration.

  7. Dopamine D2/D3 but not dopamine D1 receptors are involved in the rapid antidepressant-like effects of ketamine in the forced swim test.

    Science.gov (United States)

    Li, Yan; Zhu, Zhuo R; Ou, Bao C; Wang, Ya Q; Tan, Zhou B; Deng, Chang M; Gao, Yi Y; Tang, Ming; So, Ji H; Mu, Yang L; Zhang, Lan Q

    2015-02-15

    Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses. The traditional antidepressants often take several weeks, even months, to obtain clinical effects. However, recent clinical studies have shown that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects within 2h and are long-lasting. The aim of the present study was to investigate whether dopaminergic system was involved in the rapid antidepressant effects of ketamine. The acute administration of ketamine (20 mg/kg) significantly reduced the immobility time in the forced swim test. MK-801 (0.1 mg/kg), the more selective NMDA antagonist, also exerted rapid antidepressant-like effects. In contrast, fluoxetine (10 mg/kg) did not significantly reduced the immobility time in the forced swim test after 30 min administration. Notably, pretreatment with haloperidol (0.15 mg/kg, a nonselective dopamine D2/D3 antagonist), but not SCH23390 (0.04 and 0.1 mg/kg, a selective dopamine D1 receptor antagonist), significantly prevented the effects of ketamine or MK-801. Moreover, the administration of sub-effective dose of ketamine (10 mg/kg) in combination with pramipexole (0.3 mg/kg, a dopamine D2/D3 receptor agonist) exerted antidepressant-like effects compared with each drug alone. In conclusion, our results indicated that the dopamine D2/D3 receptors, but not D1 receptors, are involved in the rapid antidepressant-like effects of ketamine.

  8. Antagonistas de los receptores glutamatérgicos NMDA en el tratamiento del dolor crónico NMDA glutamatergic receptor antagonists for the management of chronic pain

    Directory of Open Access Journals (Sweden)

    F. Neira

    2004-05-01

    Full Text Available Los receptores NMDA están asociados con los procesos de aprendizaje y memoria, el desarrollo y la plasticidad neural, así como con los estados de dolor agudo y crónico. Intervienen en el inicio y mantenimiento de la sensibilización central asociada a daño o inflamación de los tejidos periféricos. El glutamato es el principal aminoácido excitatorio del SNC, puede participar en los procesos de transmisión nociceptiva a nivel espinal, siendo el principal responsable de la transmisión sináptica rápida. La acción del glutamato en las vías del dolor está mediada en su mayor parte a través de receptores ionotrópicos (AMPA, NMDA y kaínicos. La activación de los receptores NMDA juega un papel importante en la neurotransmisión excitatoria y la plasticidad sináptica del SNC. El glutamato o sus agonistas (NMDA, AMPA o ácido kaínico están involucrados en los procesos de generación y mantenimiento de los estados de hiperalgesia (respuesta exacerbada al estímulo nocivo y alodinia (disminución del umbral doloroso. Se analiza la eficacia clínica de los antagonistas de los receptores NMDA (ketamina, memantina, amantadina, dextrometorfano y metadona. Entre sus posibles indicaciones se encuentran: dolor neuropático oncológico, neuralgia postherpética, traumatismo crónico, amputación, lesión de la médula espinal, dolor de origen central secundario a accidente cerebrovascular, dolor de miembro fantasma, síndrome de piernas inquietas, dolor crónico orofacial, fibromialgia y cirugía, entre otros. La efectividad de la ketamina por vía oral y parenteral ha sido estudiada en el dolor disestésico central, el dolor neuropático en el síndrome de cola de caballo traumático, la alodinia y la hiperalgesia. El dextrometorfano es un antitusígeno no opioide y un bloqueante no competitivo de los receptores NMDA. Entre sus indicaciones se encuentra el tratamiento de la neuropatía diabética. La metadona se une fundamentalmente a los

  9. mGluR5 positive modulators both potentiate activation and restore inhibition in NMDA receptors by PKC dependent pathway

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    Liao Pei-Fei

    2011-02-01

    Full Text Available Abstract Background In order to understand the interaction between the metabotropic glutamate subtype 5 (mGluR5 and N-methyl-D-aspartate (NMDA receptors, the influence of mGluR5 positive modulators in the inhibition of NMDA receptors by the noncompetitive antagonist ketamine, the competitive antagonist D-APV and the selective NR2B inhibitor ifenprodil was investigated. Methods This study used the multi-electrode dish (MED system to observe field potentials in hippocampal slices of mice. Results Data showed that the mGluR5 agonist (RS-2-chloro-5-hydroxyphenylglycine (CHPG, as well as the positive allosteric modulators 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl benzamide (CDPPB and 3,3'-difluorobenzaldazine (DFB alone did not alter the basal field potentials, but enhanced the amplitude of field potentials induced by NMDA. The inhibitory action of ketamine on NMDA-induced response was reversed by CHPG, DFB, and CDPPB, whereas the blockade of NMDA receptor by D-APV was restored by CHPG and CDPPB, but not by DFB. Alternatively, activation of NMDA receptors prior to the application of mGluR5 modulators, CHPG was able to enhance NMDA-induced field potentials and reverse the suppressive effect of ketamine and D-APV, but not ifenprodil. In addition, chelerythrine chloride (CTC, a protein kinase C (PKC inhibitor, blocked the regulation of mGluR5 positive modulators in enhancing NMDA receptor activation and recovering NMDA receptor inhibition. The PKC activator (PMA mimicked the effects of mGluR5 positive modulators on enhancing NMDA receptor activation and reversing NMDA antagonist-evoked NMDA receptor suppression. Conclusion Our results demonstrate that the PKC-dependent pathway may be involved in the positive modulation of mGluR5 resulting in potentiating NMDA receptor activation and reversing NMDA receptor suppression induced by NMDA antagonists.

  10. Computationally Discovered Potentiating Role of Glycans on NMDA Receptors

    Science.gov (United States)

    Sinitskiy, Anton V.; Stanley, Nathaniel H.; Hackos, David H.; Hanson, Jesse E.; Sellers, Benjamin D.; Pande, Vijay S.

    2017-01-01

    N-methyl-D-aspartate receptors (NMDARs) are glycoproteins in the brain central to learning and memory. The effects of glycosylation on the structure and dynamics of NMDARs are largely unknown. In this work, we use extensive molecular dynamics simulations of GluN1 and GluN2B ligand binding domains (LBDs) of NMDARs to investigate these effects. Our simulations predict that intra-domain interactions involving the glycan attached to residue GluN1-N440 stabilize closed-clamshell conformations of the GluN1 LBD. The glycan on GluN2B-N688 shows a similar, though weaker, effect. Based on these results, and assuming the transferability of the results of LBD simulations to the full receptor, we predict that glycans at GluN1-N440 might play a potentiator role in NMDARs. To validate this prediction, we perform electrophysiological analysis of full-length NMDARs with a glycosylation-preventing GluN1-N440Q mutation, and demonstrate an increase in the glycine EC50 value. Overall, our results suggest an intramolecular potentiating role of glycans on NMDA receptors. PMID:28378791

  11. NMDA receptor blockade alters the intracellular distribution of neuronal nitric oxide synthase in the superficial layers of the rat superior colliculus

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    R.E. de Bittencourt-Navarrete

    2009-02-01

    Full Text Available Nitric oxide (NO is a molecular messenger involved in several events of synaptic plasticity in the central nervous system. Ca2+ influx through the N-methyl-D-aspartate receptor (NMDAR triggers the synthesis of NO by activating the enzyme neuronal nitric oxide synthase (nNOS in postsynaptic densities. Therefore, NMDAR and nNOS are part of the intricate scenario of postsynaptic densities. In the present study, we hypothesized that the intracellular distribution of nNOS in the neurons of superior colliculus (SC superficial layers is an NMDAR activity-dependent process. We used osmotic minipumps to promote chronic blockade of the receptors with the pharmacological agent MK-801 in the SC of 7 adult rats. The effective blockade of NMDAR was assessed by changes in the protein level of the immediate early gene NGFI-A, which is a well-known NMDAR activity-dependent expressing transcription factor. Upon chronic infusion of MK-801, a decrease of 47% in the number of cells expressing NGFI-A was observed in the SC of treated animals. Additionally, the filled dendritic extent by the histochemical product of nicotinamide adenine di-nucleotide phosphate diaphorase was reduced by 45% when compared to the contralateral SC of the same animals and by 64% when compared to the SC of control animals. We conclude that the proper intracellular localization of nNOS in the retinorecipient layers of SC depends on NMDAR activation. These results are consistent with the view that the participation of NO in the physiological and plastic events of the central nervous system might be closely related to an NMDAR activity-dependent function.

  12. Effects of Repeated Ethanol Exposures on NMDA Receptor Expression and Locomotor Sensitization in Mice Expressing Ethanol Resistant NMDA Receptors

    Science.gov (United States)

    den Hartog, Carolina R.; Gilstrap, Meghin; Eaton, Bethany; Lench, Daniel H.; Mulholland, Patrick J.; Homanics, Gregg. E.; Woodward, John J.

    2017-01-01

    Evidence from a large number of preclinical studies suggests that chronic exposure to drugs of abuse, such as psychostimulants or ethanol induces changes in glutamatergic transmission in key brain areas associated with reward and control of behavior. These changes include alterations in the expression of ionotropic glutamate receptors including N-methyl-D-aspartate receptors (NMDAR) that are important for regulating neuronal activity and synaptic plasticity. NMDA receptors are inhibited by ethanol and reductions in NMDA-mediated signaling are thought to trigger homestatic responses that limit ethanol's effects on glutamatergic transmission. Following repeated exposures to ethanol, these homeostatic responses may become unstable leading to an altered glutamatergic state that contributes to the escalations in drinking and cognitive deficits observed in alcohol-dependent subjects. An important unanswered question is whether ethanol-induced changes in NMDAR expression are modulated by the intrinsic sensitivity of the receptor to ethanol. In this study, we examined the effects of ethanol on NMDAR subunit expression in cortical (orbitofrontal, medial prefrontal), striatal (dorsal and ventral striatum) and limbic (dorsal hippocampus, basolateral amygdala) areas in mice genetically modified to express ethanol-resistant receptors (F639A mice). These mice have been previously shown to drink more ethanol than their wild-type counterparts and have altered behavioral responses to certain actions of ethanol. Following long-term voluntary drinking, F639A mice showed elevations in GluN2A but not GluN1 or GluN2B expression as compared to wild-type mice. Mice treated with repeated injections with ethanol (2–3.5 g/kg; i.p.) showed changes in NMDAR expression that varied in a complex manner with genotype, brain region, subunit type and exposure protocol all contributing to the observed response. F639A mice, but not wild-type mice, showed enhanced motor activity following repeated

  13. Anti-NMDA Receptor Encephalitis in the Polar Bear (Ursus maritimus) Knut.

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    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.

  14. [Clinical diagnosis and treatment of anti-NMDA (N-methyl-D-aspartate) receptor encephalitis].

    Science.gov (United States)

    Kamei, Satoshi

    2013-05-01

    Recent clinical management of anti-NMDA receptor encephalitis is reviewed. This illness is required the management of the neurological emergency. Typical symptoms of anti-NMDA receptor encephalitis develop in several stages that progresses from psychosis, memory deficits, seizures, and language disintegration into a state of unresponsiveness with catatonic features often associated with abnormal movements, and autonomic and respiratory instability. The diagnosis is depended on the detection of the NMDA receptor antibody in CSF or serum under the above characteristic symptoms of encephalitis. The disorder predominantly affects children and young adults, occurs with or without tumor association. The presence of a tumor (usually an ovarian teratoma) is dependent on age and sex, being more frequent in women older than 18 years. Anti-NMDA receptor encephalitis should be treated with tumor resection and immunotherapy (corticosteroids, intravenous immunoglobulin, or plasma exchange) responded faster to treatment and less frequently needed second-line immunotherapy (cyclophosphamide or rituximab, or both).

  15. EXTREME DELTA BRUSH EEG PATTERN IN A CASE WITH ANTI-NMDA RECEPTOR ENCEPHALITIS.

    Science.gov (United States)

    Söylemez, Elif; Güveli, Betül Tekin; Atakli, Dilek; Yatmazoğlu, Merve; Atay, Turan; Dayan, Cengiz

    2015-09-30

    Anti-N-methyl-D-aspartate receptor NMDA-R encephalitis is caused by antibodies against the NMDA-R and characterized by a severe encephalopathy with psychosis, epileptic seizures and autonomic disturbances. This disorder is often accompanied with malignancies, especially ovarian teratoma. Some patients' EEGs show a different pattern similar to the waveforms of premature infants and this pattern is specifically named as extreme delta brush (EDB). We report a 24-year-old female having anti-NMDA receptor encephalitis and EDB patern.

  16. 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.

  17. Role of motor cortex NMDA receptors in learning-dependent synaptic plasticity of behaving mice

    OpenAIRE

    Mazahir T Hasan; Hernández-González, Samuel; Dogbevia, Godwin; Treviño, Mario; Bertocchi, Ilaria; Gruart, Agnès; Delgado-García, José M.

    2013-01-01

    The primary motor cortex has an important role in the precise execution of learned motor responses. During motor learning, synaptic efficacy between sensory and primary motor cortical neurons is enhanced, possibly involving long-term potentiation and N-methyl-D-aspartate (NMDA)-specific glutamate receptor function. To investigate whether NMDA receptor in the primary motor cortex can act as a coincidence detector for activity-dependent changes in synaptic strength and associative learning, her...

  18. Facilitation of neocortical presynaptic terminal development by NMDA receptor activation

    Directory of Open Access Journals (Sweden)

    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.

  19. Scribble1/AP2 Complex Coordinates NMDA Receptor Endocytic Recycling

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    Nicolas H. Piguel

    2014-10-01

    Full Text Available The appropriate trafficking of glutamate receptors to synapses is crucial for basic synaptic function and synaptic plasticity. It is now accepted that NMDA receptors (NMDARs internalize and are recycled at the plasma membrane but also exchange between synaptic and extrasynaptic pools; these NMDAR properties are also key to governing synaptic plasticity. Scribble1 is a large PDZ protein required for synaptogenesis and synaptic plasticity. Herein, we show that the level of Scribble1 is regulated in an activity-dependent manner and that Scribble1 controls the number of NMDARs at the plasma membrane. Notably, Scribble1 prevents GluN2A subunits from undergoing lysosomal trafficking and degradation by increasing their recycling to the plasma membrane following NMDAR activation. Finally, we show that a specific YxxR motif on Scribble1 controls these mechanisms through a direct interaction with AP2. Altogether, our findings define a molecular mechanism to control the levels of synaptic NMDARs via Scribble1 complex signaling.

  20. In vitro neuronal network activity in NMDA receptor encephalitis

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    Jantzen Sabine U

    2013-02-01

    Full Text Available Abstract Background Anti-NMDA-encephalitis is caused by antibodies against the N-methyl-D-aspartate receptor (NMDAR and characterized by a severe encephalopathy with psychosis, epileptic seizures and autonomic disturbances. It predominantly occurs in young women and is associated in 59% with an ovarian teratoma. Results We describe effects of cerebrospinal fluid (CSF from an anti-N-methyl-D-aspartate receptor (NMDAR encephalitis patient on in vitro neuronal network activity (ivNNA. In vitro NNA of dissociated primary rat cortical populations was recorded by the microelectrode array (MEA system. The 23-year old patient was severely affected but showed an excellent recovery following multimodal immunomodulatory therapy and removal of an ovarian teratoma. Patient CSF (pCSF taken during the initial weeks after disease onset suppressed global spike- and burst rates of ivNNA in contrast to pCSF sampled after clinical recovery and decrease of NMDAR antibody titers. The synchrony of pCSF-affected ivNNA remained unaltered during the course of the disease. Conclusion Patient CSF directly suppresses global activity of neuronal networks recorded by the MEA system. In contrast, pCSF did not regulate the synchrony of ivNNA suggesting that NMDAR antibodies selectively regulate distinct parameters of ivNNA while sparing their functional connectivity. Thus, assessing ivNNA could represent a new technique to evaluate functional consequences of autoimmune encephalitis-related CSF changes.

  1. Partial genetic deletion of neuregulin 1 and adolescent stress interact to alter NMDA receptor binding in the medial prefrontal cortex

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    Tariq Waseem Chohan

    2014-09-01

    Full Text Available Schizophrenia is thought to arise due to a complex interaction between genetic and environmental factors during early neurodevelopment. We have recently shown that partial genetic deletion of the schizophrenia susceptibility gene neuregulin 1 (Nrg1 and adolescent stress interact to disturb sensorimotor gating, neuroendocrine activity and dendritic morphology in mice. Both stress and Nrg1 may have converging effects upon N-methyl-D-aspartate receptors (NMDARs which are implicated in the pathogenesis of schizophrenia, sensorimotor gating and dendritic spine plasticity. Using an identical repeated restraint stress paradigm to our previous study, here we determined NMDAR binding across various brain regions in adolescent Nrg1 heterozygous (HET and wild-type (WT mice using [3H] MK-801 autoradiography. Repeated restraint stress increased NMDAR binding in the ventral part of the lateral septum (LSV and the dentate gyrus (DG of the hippocampus irrespective of genotype. Partial genetic deletion of Nrg1 interacted with adolescent stress to promote an altered pattern of NMDAR binding in the infralimbic (IL subregion of the medial prefrontal cortex. In the IL, whilst stress tended to increase NMDAR binding in WT mice, it decreased binding in Nrg1 HET mice. However in the DG, stress selectively increased the expression of NMDAR binding in Nrg1 HET mice but not WT mice. These results demonstrate a Nrg1-stress interaction during adolescence on NMDAR binding in the medial prefrontal cortex.

  2. Treatment with dehydroepiandrosterone sulfate increases NR1 and NR2 subunits of NMDA receptors in rat hippocampus.

    Institute of Scientific and Technical Information of China (English)

    E.DARTOIS; W.PINOTEAU; M.VINCENS

    2004-01-01

    Neurosteroids are present in the central nervous system (CNS) and can be allosteric modulators of neurotransmitter receptors. One of them, the dehydroepiandrosterone sulfate (DHEAS) has been shown to modulate the NMDA receptor, a subtype of glutamate receptor. These NMDA receptors are known to be involved in long-term potentiation and in learning and memory (Tsien 2000). Moreover, DHEAS has been reported

  3. Effects of NMDA receptor on glucocorticoid receptor mRNA levels in hippocampus of rats after scald burn stress%NMDA受体对烫伤应激大鼠海马糖皮质激素受体基因表达的影响

    Institute of Scientific and Technical Information of China (English)

    陆建华; 党健; 黎海蒂; 高京生; 熊加祥

    2003-01-01

    目的观察烫伤应激后海马糖皮质激素受体(GR)基因表达的变化,探讨N-甲基-D-天冬氨酸(N-methyl-D-aspartate, NMDA)受体在这种变化中的作用.方法利用RT-PCR技术,检测烫伤前腹腔注射NMDA受体拮抗剂MK-801及激动剂NMDA对烫伤应激后2 h GR mRNA水平的影响.结果烫伤应激后2 h海马GR mRNA水平明显降低 (P<0.01);应激前腹腔注射MK-801使烫伤后降低的GR mRNA水平明显恢复(P<0.01),注射NMDA使其进一步降低(P<0.05),注射生理盐水无明显变化.结论 NMDA受体介导了烫伤应激导致的海马GR转录水平基因表达的下降.

  4. NMDA and AMPA receptors contribute to the maintenance of substance P-induced thermal hyperalgesia.

    Science.gov (United States)

    Nakayama, Tomohiro; Naono, Rumi; Ikeda, Tetsuya; Nishimori, Toshikazu

    2010-05-01

    It is well known that intrathecal administration of substance P (SP) induces thermal hyperalgesia, but the mechanisms underlying the maintenance of SP-induced thermal hyperalgesia remain to be clarified. Thus, to clarify the receptors involved in the maintenance of SP-induced thermal hyperalgesia, the effect of administering SP or glutamate receptor agonists, NMDA or AMPA, under SP-induced thermal hyperalgesia was investigated. Also, the effect of pretreatment with protein kinase inhibitors on scratching behavior by NMDA or AMPA under SP-induced thermal hyperalgesia was examined. Under SP-induced thermal hyperalgesia, the number of scratchings following SP administration was time-dependently suppressed, whereas the number of scratchings after NMDA or AMPA administration was markedly enhanced and SP-induced thermal hyperalgesia was attenuated by pretreatment with NMDA or AMPA receptor antagonist. Furthermore, pretreatment with kinase inhibitors significantly attenuated the enhancement of scratching behavior by NMDA or AMPA under SP-induced thermal hyperalgesia. These findings indicate that SP-induced thermal hyperalgesia may be maintained through the enhanced responsiveness of NMDA or AMPA receptors, but not the receptor of SP, mediated by kinases.

  5. Cardiac sympathetic dysfunction in anti-NMDA receptor encephalitis.

    Science.gov (United States)

    Byun, Jung-Ick; Lee, Soon-Tae; Moon, Jangsup; Jung, Keun-Hwa; Shin, Jung-Won; Sunwoo, Jun-Sang; Lim, Jung-Ah; Shin, Yong-Won; Kim, Tae-Joon; Lee, Keon-Joo; Park, Kyung-Il; Jung, Ki-Young; Lee, Sang Kun; Chu, Kon

    2015-12-01

    Patients with anti-NMDA receptor (anti-NMDAR) encephalitis frequently suffer from autonomic dysfunctions, which can cause substantial morbidity. This study assessed cardiac autonomic functions in patients with anti-NMDAR encephalitis using heart rate variability (HRV) analysis. This was a retrospective single-center case-control study. Eleven patients with anti-NMDAR encephalitis and 15 age- and sex-matched controls were included in this study. To ensure that autonomic dysfunction does not occur in any encephalitis, we additionally analyzed HRV of 9 patients with herpes encephalitis (HSE) and compared with that of NMDAR encephalitis patients and controls. Five minute resting stationary electrocardiogram was collected from each subject, and HRV was analyzed. Total power and low frequency (LF) power were lower in anti-NMDAR encephalitis patients than those in controls (p=0.005, 0.001 respectively), indicating cardiac autonomic dysfunction especially in sympathetic system. Patients with HSE showed no significant difference in HRV parameters compared with that of controls. Cardiac autonomic dysfunction was associated with 3 month functional outcome in anti-NMDAR encephalitis patients.

  6. Schizophrenia, dissociative anaesthesia and near-death experience; three events meeting at the NMDA receptor.

    Science.gov (United States)

    Bonta, Iván L

    2004-01-01

    The three events, viz. schizophrenia, dissociative anaesthesia and Near-Death Experience, despite their seemingly unrelated manifestation to each other, have nevertheless similar functional basis. All three events are linked to the glutamate sensitive N-methyl-D-aspartate (NMDA) receptor complex, which serves as their common functional denominator. Arguments and speculations are presented in favor of the view that, the three events might be considered as functional models of each other. Antagonism to the recognition NMDA-site of the receptor induces dissociative anaesthesia and precipitates Near-Death Experience. Agonist reinforcement at the modulatory glycine-site of the receptor counteracts negative symptoms of schizophrenia. Both types of challenges towards the receptor are compatible with a glutamate deficiency concept which underlies the meeting of the three events at the NMDA receptor.

  7. Glutamatergic synaptic inputs activate neurons in the subfornical organ through non-NMDA receptors.

    Science.gov (United States)

    Xu, S H; Inenaga, K; Honda, E; Yamashita, H

    2000-01-14

    The subfornical organ (SFO) plays an important role in central regulation of the autonomic nervous system. The synaptic transmission properties of neurons in the SFO were studied with intracellular and whole-cell patch clamp recordings in the rat slice preparations. Both the spontaneous and evoked excitatory postsynaptic potentials (EPSPs) and currents (EPSCs) were almost completely suppressed by the glutamate receptor antagonist kynurenic acid and the non-NMDA (N-methyl-D-aspartic acid) antagonist CNQX. The non-NMDA agonist kainic acid depolarized the membrane most potently, compared with NMDA and quisqualic acid. These suggest that glutamate is a main excitatory neurotransmitter in the SFO and that its action is at least partly mediated through non-NMDA receptors.

  8. Activation of nucleus accumbens NMDA receptors differentially affects appetitive or aversive taste learning and memory

    Directory of Open Access Journals (Sweden)

    Luis eNuñez-Jaramillo

    2012-04-01

    Full Text Available Taste memory depends on motivational and post-ingestional consequences; thus, it can be aversive (e.g., conditioned taste aversion, CTA if a novel, palatable taste is paired with visceral malaise, or it can be appetitive if no intoxication appears after novel taste consumption, and a taste preference is developed. The nucleus accumbens (NAc plays a role in hedonic reactivity to taste stimuli, and recent findings suggest that reward and aversion are differentially encoded by the activity of NAc neurons. The present study examined whether the requirement for NMDA receptors in the NAc core during rewarding appetitive taste learning differs from that during aversive taste conditioning, as well as during retrieval of appetitive versus aversive taste memory, using the taste preference or CTA model, respectively. Bilateral infusions of NMDA (1 μg/μl, 0.5 μl into the NAc core were performed before acquisition or before retrieval of taste preference or CTA. Activation of NMDA receptors before taste preference training or CTA acquisition did not alter memory formation. Furthermore, NMDA injections before aversive taste retrieval had no effect on taste memory; however, 24 h later, CTA extinction was significantly delayed. Also, NMDA injections, made before familiar appetitive memory retrieval, interrupted the development of taste preference and produced a preference delay 24 h later. These results suggest that memory formation for a novel taste produces neurochemical changes in the NAc core that have differential requirements for NMDA receptors during retrieval of appetitive or aversive memory.

  9. Evolution of NMDA receptor cytoplasmic interaction domains: implications for organisation of synaptic signalling complexes

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    Emes Richard D

    2008-01-01

    Full Text Available Abstract Background Glutamate gated postsynaptic receptors in the central nervous system (CNS are essential for environmentally stimulated behaviours including learning and memory in both invertebrates and vertebrates. Though their genetics, biochemistry, physiology, and role in behaviour have been intensely studied in vitro and in vivo, their molecular evolution and structural aspects remain poorly understood. To understand how these receptors have evolved different physiological requirements we have investigated the molecular evolution of glutamate gated receptors and ion channels, in particular the N-methyl-D-aspartate (NMDA receptor, which is essential for higher cognitive function. Studies of rodent NMDA receptors show that the C-terminal intracellular domain forms a signalling complex with enzymes and scaffold proteins, which is important for neuronal and behavioural plasticity Results The vertebrate NMDA receptor was found to have subunits with C-terminal domains up to 500 amino acids longer than invertebrates. This extension was specific to the NR2 subunit and occurred before the duplication and subsequent divergence of NR2 in the vertebrate lineage. The shorter invertebrate C-terminus lacked vertebrate protein interaction motifs involved with forming a signaling complex although the terminal PDZ interaction domain was conserved. The vertebrate NR2 C-terminal domain was predicted to be intrinsically disordered but with a conserved secondary structure. Conclusion We highlight an evolutionary adaptation specific to vertebrate NMDA receptor NR2 subunits. Using in silico methods we find that evolution has shaped the NMDA receptor C-terminus into an unstructured but modular intracellular domain that parallels the expansion in complexity of an NMDA receptor signalling complex in the vertebrate lineage. We propose the NR2 C-terminus has evolved to be a natively unstructured yet flexible hub organising postsynaptic signalling. The evolution of

  10. Early Use of the NMDA Receptor Antagonist Ketamine in Refractory and Superrefractory Status Epilepticus

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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.

  11. 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

  12. Current Evidence of Chinese Herbal Constituents with Effects on NMDA Receptor Blockade

    Directory of Open Access Journals (Sweden)

    David T. Yew

    2013-08-01

    Full Text Available NMDA receptor (NMDA-R is an important molecular entity governing a wide range of functions in the central nervous system. For example, the NMDA-R is involved in memory and cognition, and impairment of both (as in Alzheimer’s Disease is attributed to NMDA-mediated neurotoxicity. With greater understanding of the NMDA-R structure, antagonists with varying degrees of binding-site and subtype selectivity have been developed and put into clinical use. Discovery of target-specific Chinese herbs have also been made in parallel. This article provides an overview of the known active sites on the NMDA-R, followed by a discussion of the relevant herbs and their constituents. Experimental evidence supporting the inhibitory role of the herbal compounds on the NMDA-R is highlighted. For some of the compounds, potential research directions are also proposed to further elucidate the underlying mechanisms of the herbs. It is envisaged that future investigations based on the present data will allow more clinically relevant herbs to be identified.

  13. Role of ventral hippocampal NMDA receptors in anxiolytic-like effect of morphine.

    Science.gov (United States)

    Motevasseli, Tahmineh; Rezayof, Ameneh; Zarrindast, Mohammad-Reza; Nayer-Nouri, Touraj

    2010-12-02

    The possible role of ventral hippocampal N-methyl-d-aspartate (NMDA) receptors on morphine-induced anxiolytic-like behavior in an elevated plus maze (EPM) task was investigated in the present study. Adult male mice (7 per group) with cannulas aimed at the ventral hippocampus (VH) received NMDA or a competitive NMDA receptor antagonist D-AP5 with or without morphine and 30min later were subjected to an EPM task. Intraperitoneal injection (i.p.) of morphine (3-9mg/kg) increased the percentage of open arm time (%OAT) and open arm entries (%OAE), which suggested an anxiolytic-like effect. Intra-VH microinjection of NMDA (0.5-1μg/mouse) with an ineffective dose of morphine (3mg/kg, i.p.) significantly increased %OAT and %OAE. However, microinjections of the same doses of NMDA into the VH in the absence of morphine had no effect on %OAT and %OAE. Intra-VH microinjection of D-AP5 (0.5-2μg/mouse) decreased the anxiolytic-like effect of morphine, while intra-VH microinjection of the same doses of D-AP5 alone increased %OAT and %OAE, which indicated an anxiolytic response. Furthermore, intra-VH microinjection of D-AP5 reversed the effect of NMDA response to the administration of a lower morphine dose as seen in the EPM task. It should be noted that intra-VH microinjection of D-AP5 plus NMDA, 5min before morphine increased locomotor activity, while other treatments had no effect on this parameter. The results suggest that VH-NMDA receptors participate in the mediation of morphine-induced anxiolytic-like behavior.

  14. The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus.

    Science.gov (United States)

    Ninan, Ipe; Bath, Kevin G; Dagar, Karishma; Perez-Castro, Rosalia; Plummer, Mark R; Lee, Francis S; Chao, Moses V

    2010-06-30

    The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene results in a defect in regulated release of BDNF and affects episodic memory and affective behaviors. However, the precise role of the BDNF Val66Met polymorphism in hippocampal synaptic transmission and plasticity has not yet been studied. Therefore, we examined synaptic properties in the hippocampal CA3-CA1 synapses of BDNF(Met/Met) mice and matched wild-type mice. Although basal glutamatergic neurotransmission was normal, both young and adult mice showed a significant reduction in NMDA receptor-dependent long-term potentiation. We also found that NMDA receptor-dependent long-term depression was decreased in BDNF(Met/Met) mice. However, mGluR-dependent long-term depression was not affected by the BDNF Val66Met polymorphism. Consistent with the NMDA receptor-dependent synaptic plasticity impairment, we observed a significant decrease in NMDA receptor neurotransmission in the CA1 pyramidal neurons of BDNF(Met/Met) mice. Thus, these results show that the BDNF Val66Met polymorphism has a direct effect on NMDA receptor transmission, which may account for changes in synaptic plasticity in the hippocampus.

  15. Induction of Increased Intraceilular Calcium in Astrocytes by Glutamate through Activating NMDA and AMPA Receptors

    Institute of Scientific and Technical Information of China (English)

    张蕲; 胡波; 孙圣刚; 童萼塘

    2003-01-01

    To study the effect of glutamate on the intracellular calcium signal of pure cultured ratastrocytes and the role of NMDA and AMPA receptors in the procedure, the change of calcium sig-nal was investigated by monitoring the fluctuation of intracellular Ca2+ concentration ([Ca2+]i) onthe basis of Fura-2 single cell fluorescent ratio (F345/F380). The changes in the effect of glutamateon the intracellular calcium signal were observed after blockage of NMDA and(or) AMPA recep-tors. It was found that L-glutamate could induce an increased [Ca2+]i in most of the cells in concen-tration- and time-dependent manner. D-(-)-2-amino-5-phosphonopentanoic acid (D-AP-5, a selec-tive antagonist of the NMDA receptor) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, a selec-tive antagonist of the AMPA receptor) could abolish the effects of NMDA and AMPA respectively.Th.e treatment of D-AP-5 and CNQX simultaneously or respectively could attenuate the effect of L-glutamate at varying degrees. All these indicated that glutamate could modulate intracellular Ca2+of pure cultured rat astrocytes through different pathways. The activation of NMDA and AMPA re-ceptors took part in the complex mechanisms.

  16. Noncompetitive antagonists and agonists of glutamate receptor regulate filopodia formation in epidermal cells and melanosome transfer: an experimental study%谷氨酸受体非竞争性拮抗剂及激动剂调节表皮细胞伪足形成及黑素小体转运的观察

    Institute of Scientific and Technical Information of China (English)

    王楠; 宋智琦

    2013-01-01

    Objective To investigate the regulatory effect of glutamate signaling pathway on filopodia formation in epidermal cells and on melanosome transfer.Methods Epidermal melanocytes and keratinocytes were isolated from human foreskin and subjected to subculture.After two to three passages of subculture,the melanocytes and keratinocytes were cultured alone or in combination with or without the presence of MK801 (an antagonist of N-methyl-D-aspartic acid (NMDA) receptor) of 100 μmol/L,or NMDA (the activator of NMDA receptor) of 100 μmol/L,for 24 hours.The melanocytes irradiated with UVB at 311 nm served as the control.Scanning electron microscopy was used to observe the appearance of filopodia and dendrites of melanocytes and keratinocytes.Melanosome transfer was visualized under confocal laser scanning microscopy after double immunofluorescent staining.Results Although no obvious changes were observed in the number of dendrites in monocultured melanocytes after treatment with MK801 or NMDA for 24 hours,dendrites became thinner at the terminus and longer with a decrease in the number and length of filopodia after MK801 treatment,but thicker and shorter with an increase in the number and length of filopodia after NMDA treatment compared with untreated monocultured melanocytes.In the coculture system,filopodia were observed between the untreated melanocytes and keratinocytes,and the number of filopodia in melanocytes was larger in the side adjacent to keratinocytes than in the opposite side.Compared with the untreated coculture system,the number of both filopodia connecting melanocytes and keratinocytes and filopodia extending from melanocytes to keratinocytes decreased in the coculture system after treatment with MK801 of 100 μmol/L,but increased after treatment with NMDA of 100 μmol/L,for 24 hours.Melanosomes were found in keratinocytes cocultured with melanocytes without treatment,which were decreased in number after 24-hour treatment with MK801 of 100

  17. Novel 3-carboxy- and 3-phosphonopyrazoline amino acids as potent and selective NMDA receptor antagonists

    DEFF Research Database (Denmark)

    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...

  18. Adolescent social defeat alters N-methyl-D-aspartic acid receptor expression and impairs fear learning in adulthood.

    Science.gov (United States)

    Novick, Andrew M; Mears, Mackenzie; Forster, Gina L; Lei, Yanlin; Tejani-Butt, Shanaz M; Watt, Michael J

    2016-05-01

    Repeated social defeat of adolescent male rats results in adult mesocortical dopamine hypofunction, impaired working memory, and increased contextual anxiety-like behavior. Given the role of glutamate in dopamine regulation, cognition, and fear and anxiety, we investigated potential changes to N-methyl-D-aspartic acid (NMDA) receptors following adolescent social defeat. As both NMDA receptors and mesocortical dopamine are implicated in the expression and extinction of conditioned fear, a separate cohort of rats was challenged with a classical fear conditioning paradigm to investigate whether fear learning is altered by adolescent defeat. Quantitative autoradiography was used to measure 3H-MK-801 binding to NMDA receptors in regions of the medial prefrontal cortex, caudate putamen, nucleus accumbens, amygdala and hippocampus. Assessment of fear learning was achieved using an auditory fear conditioning paradigm, with freezing toward the auditory tone used as a measure of conditioned fear. Compared to controls, adolescent social defeat decreased adult NMDA receptor expression in the infralimbic region of the prefrontal cortex and central amygdala, while increasing expression in the CA3 region of the hippocampus. Previously defeated rats also displayed decreased conditioned freezing during the recall and first extinction periods, which may be related to the observed decreases and increases in NMDA receptors within the central amygdala and CA3, respectively. The alteration in NMDA receptors seen following adolescent social defeat suggests that dysfunction of glutamatergic systems, combined with mesocortical dopamine deficits, likely plays a role in the some of the long-term behavioral consequences of social stressors in adolescence seen in both preclinical and clinical studies.

  19. NMDA and AMPA receptors mediate intracellular calcium increase in rat cortical astrocytes

    Institute of Scientific and Technical Information of China (English)

    Bo HU; Sheng-gang SUN; E-tang TONG

    2004-01-01

    AIM: To study the effect of glutamate on the intracellular calcium signal of pure cultured rat astrocytes and the role of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors in the procedure. METHODS: The fluorescence of calcium was measured by Fura-2/AM (F345/F380).RESULTS: L-Glutamate induced [Ca2+]i increase in most of the cells in concentration- and time-dependent manner.NMDA 50 mmol/L induced the fluorescence increase by almost three to four times, while the effect of AMPA 50mmol/L was just half of that of D-(-)-2-amino-5-phosphonopentanoic acid (D-AP-5; a selective antagonist of the NMDA receptor). 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX, a selective antagonist of the AMPA receptor)abolished the effects of NMDA and AMPA, respectively. D-AP-5 and CNQX simultaneously or respectively attenuated the effect of L-glutamate at different degrees, but could not abolish it entirely. CONCLUSION: Glutamate modulated intracellular Ca2+ of pure cultured rat astrocytes through different pathways. The activation of NMDA and AMPA receptors took part in the complex mechanisms.

  20. Heterogeneity of clinical features and corresponding antibodies in seven patients with anti-NMDA receptor encephalitis.

    Science.gov (United States)

    Sühs, Kurt-Wolfram; Wegner, Florian; Skripuletz, Thomas; Trebst, Corinna; Tayeb, Said Ben; Raab, Peter; Stangel, Martin

    2015-10-01

    Anti-N-methyl D-aspartate (NMDA) receptor encephalitis is the most common type of encephalitis in the spectrum of autoimmune encephalitis defined by antibodies targeting neuronal surface antigens. In the present study, the clinical spectrum of this disease is presented using instructive cases in correlation with the anti-NMDA receptor antibody titers in the cerebrospinal fluid (CSF) and serum. A total of 7 female patients admitted to the hospital of Hannover Medical School (Hannover, Germany) between 2008 and 2014 were diagnosed with anti-NMDA receptor encephalitis. Among these patients, 3 cases were selected to illustrate the range of similar and distinct clinical features across the spectrum of the disease and to compare anti-NMDA antibody levels throughout the disease course. All patients received immunosuppressive treatment with methylprednisolone, intravenous immunoglobulin and/or plasmapheresis, followed in the majority of patients by second-line therapy with rituximab and cyclophosphamide. The disease course correlated with NMDA receptor antibody titers, and to a greater extent with the ratio between antibody titer and protein concentration. A favorable clinical outcome with a modified Rankin Scale (mRS) score of ≤1 was achieved in 4 patients, 1 patient had an mRS score of 2 after 3 months of observation only, whereas 2 patients remained severely impaired (mRS score 4). Early and aggressive immunosuppressive treatment appears to support a good clinical outcome; however, the clinical signs and symptoms differ distinctively and treatment decisions have to be made on an individual basis.

  1. Inhibition of glutamate receptors reduces the homocysteine-induced whole blood platelet aggregation but does not affect superoxide anion generation or platelet membrane fluidization.

    Science.gov (United States)

    Karolczak, Kamil; Pieniazek, Anna; Watala, Cezary

    2017-01-01

    Homocysteine (Hcy) is an excitotoxic amino acid. It is potentially possible to prevent Hcy-induced toxicity, including haemostatic impairments, by antagonizing glutaminergic receptors. Using impedance aggregometry with arachidonate and collagen as platelet agonists, we tested whether the blockade of platelet NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainate receptors with their inhibitors: MK-801 (dizocilpine hydrogen maleate, [5R,10S]-[+]-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine), CNQX (7-nitro-2,3-dioxo-1,4-dihydroquinoxaline-6-carbonitrile) and UBP-302 (2-{[3-[(2S)-2-amino-2-carboxyethyl]-2,6-dioxo-3,6-dihydropyrimidin 1(2H)-yl]methyl}benzoic acid) may hamper Hcy-dependent platelet aggregation. All the tested compounds significantly inhibited Hcy-augmented aggregation of blood platelets stimulated either with arachidonate or collagen. Hcy stimulated the generation of superoxide anion in whole blood samples in a concentration-dependent manner; however, this process appeared as independent on ionotropic glutamate receptors, as well as on NADPH oxidase and protein kinase C, and was not apparently associated with the extent of either arachidonate- or collagen-dependent platelet aggregation. Moreover, Hcy acted as a significant fluidizer of surface (more hydrophilic) and inner (more hydrophobic) regions of platelet membrane lipid bilayer, when used at the concentration range from 10 to 50 µmol/l. However, this effect was independent on the Hcy action through glutamate ionotropic receptors, since there was no effects of MK-801, CNQX or UBP-302 on Hcy-mediated membrane fluidization. In conclusion, Hcy-induced changes in whole blood platelet aggregation are mediated through the ionotopic excitotoxic receptors, although the detailed mechanisms underlying such interactions remain to be elucidated.

  2. IRSp53/BAIAP2 in dendritic spine development, NMDA receptor regulation, and psychiatric disorders.

    Science.gov (United States)

    Kang, Jaeseung; Park, Haram; Kim, Eunjoon

    2016-01-01

    IRSp53 (also known as BAIAP2) is a multi-domain scaffolding and adaptor protein that has been implicated in the regulation of membrane and actin dynamics at subcellular structures, including filopodia and lamellipodia. Accumulating evidence indicates that IRSp53 is an abundant component of the postsynaptic density at excitatory synapses and an important regulator of actin-rich dendritic spines. In addition, IRSp53 has been implicated in diverse psychiatric disorders, including autism spectrum disorders, schizophrenia, and attention deficit/hyperactivity disorder. Mice lacking IRSp53 display enhanced NMDA (N-methyl-d-aspartate) receptor function accompanied by social and cognitive deficits, which are reversed by pharmacological suppression of NMDA receptor function. These results suggest the hypothesis that defective actin/membrane modulation in IRSp53-deficient dendritic spines may lead to social and cognitive deficits through NMDA receptor dysfunction. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.

  3. A Case of Anti-NMDA Receptor Encephalitis Treated with ECT.

    Science.gov (United States)

    Jones, Kristin C; Schwartz, Ann C; Hermida, Adriana P; Kahn, David A

    2015-09-01

    We describe the case of a 17-year-old male who presented with acute onset of seizures and malignant catatonia with psychosis, agitation, and hypermetabolism, who responded to electroconvulsive therapy (ECT). Soon after he began to respond, he was diagnosed with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis and then given immunosuppressive therapy. Anti-NMDA receptor encephalitis is an increasingly recognized autoimmune disorder that often presents with neuropsychiatric symptoms. The mainstays for treatment have been early diagnosis, tumor work-up and removal if found, and initiation of immunosuppressive therapy. Treatment response is often slow and residual symptoms common. In this case, ECT produced clinical stabilization before the underlying diagnosis of anti-NMDA receptor encephalitis was made and standard treatment initiated. We suggest that ECT may be highly beneficial for stabilizing life-threatening neuropsychiatric symptoms in this syndrome and should be considered as a potentially additive treatment to immunotherapy when rapid relief is sought.

  4. Anti-NMDA receptor encephalitis presenting as atypical anorexia nervosa: an adolescent case report.

    Science.gov (United States)

    Mechelhoff, David; van Noort, Betteke Maria; Weschke, Bernhard; Bachmann, Christian J; Wagner, Christiane; Pfeiffer, Ernst; Winter, Sibylle

    2015-11-01

    Since 2007, more than 600 patients have been diagnosed with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, with almost 40 % of those affected being children or adolescents. In early phases of the illness, this life-threatening disease is characterized by psychiatric symptoms, such as depression, anxiety, obsessions, hallucinations or delusions. Consequently, a high percentage of patients receive psychiatric diagnoses at first, hindering the crucial early diagnosis and treatment of the anti-NMDA receptor encephalitis. We report on a 15-year-old girl initially presenting with pathological eating behaviour and significant weight loss resulting in an (atypical) anorexia nervosa (AN) diagnosis. Her early course of illness, diagnostic process, treatment and short-term outcome are described. This case report aims to raise awareness about the association between anorectic behaviour and anti-NMDA receptor encephalitis and highlight the importance of multidisciplinary teams in child and adolescent services.

  5. EVALUATING THE NMDA-GLUTAMATE RECEPTOR AS A SITE OF ACTION FOR TOLUENE USING PATTERN ELICITED VISUAL EVOKED POTENTIALS.

    Science.gov (United States)

    In vitro studies have demonstrated that toluene disrupts the function of NMDA-glutamate receptors, as well as other channels. This has led to the hypothesis that effects on NMDA receptor function may contribute to toluene neurotoxicity, CNS depression, and altered visual evoked ...

  6. A role of periaqueductal grey NR2B-containing NMDA receptor in mediating persistent inflammatory pain

    Directory of Open Access Journals (Sweden)

    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.

  7. Isolated NMDA receptor-mediated synaptic responses express both LTP and LTD.

    Science.gov (United States)

    Xie, X; Berger, T W; Barrionuevo, G

    1992-04-01

    1. The possibility of use-dependent, long-lasting modifications of pharmacologically isolated N-methyl-D-aspartate (NMDA) receptor-mediated synaptic transmission was examined by intracellular recordings from granule cells of the hippocampal dentate gyrus in vitro. In the presence of the non-NMDA receptor antagonist 6-cyano-7-nitroquinaxaline-2,3-dione (CNQX, 10 microM) robust, long-term potentiation (LTP) of NMDA receptor-mediated synaptic potentials was induced by brief, high (50 Hz) and lower (10 Hz) frequency tetanic stimuli of glutamatergic afferents (60 +/- 6%, n = 8, P less than 0.001 and 43 +/- 12%, n = 3, P less than 0.05, respectively). 2. Hyperpolarization of granule cell membrane potential to -100 mV during 50-Hz tetanic stimuli reversibly blocked the induction of LTP (-6 +/- 2%, n = 6, P greater than 0.05) indicating that simultaneous activation of pre- and postsynaptic elements is a prerequisite for potentiation of NMDA receptor-mediated synaptic transmission. In contrast, hyperpolarization of the granule cell membrane potential to -100 mV during 10-Hz tetanic stimuli resulted in long-term depression (LTD) of NMDA receptor-mediated synaptic potentials (-34 +/- 8%, n = 8, P less than 0.01). 3. We also studied the role of [Ca2+]i in the induction of LTP and LTD of NMDA receptor-mediated synaptic responses. Before tetanization, [Ca2+]i was buffered by iontophoretic injections of bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA). BAPTA completely blocked the induction of LTP (3 +/- 5%, n = 13) and partially blocked LTD (-14.8 +/- 6%, n = 10).(ABSTRACT TRUNCATED AT 250 WORDS)

  8. [The influence of piracetam on behavior and brain receptors in C57BL/6 and BALB/c mice: nootropic and anxiolytic effects].

    Science.gov (United States)

    Kovalev, G I; Kondrakhin, E A; Salimov, R M; Neznamov, G G

    2013-01-01

    The influence of acute and long-term piracetam administration on the dynamics of rapid (non-specific, anxiolytic) and slow (specific, nootropic) behavioral drug effects, as well as on their interrelation with NMDA- and BDZ-receptors was studied in inbred mice strains differing in cognitive and emotional status--C57BL/6 and BALB/c. The BALB/c strain contained 17% less [3H]-flunitrazepam binding sites in frontal cortex and 22% less [3H]-MK801 binding sites in hippocampus as compared to those in C57BL/6 mice. Based on these data, BALB/c strain was used as a model of psychopathology, combining increased anxiety and cognitive deficit. Under the action of single, 7-fold, and 14-fold piracetam i.p. injections (200 mg/kg body weight, daily), a fast increase in NMDA-receptor density and slow escalation of the specific nootropic effect was observed in BALB/c mice. Non-specific anxiolytic effects in these mice increased for the first 1 - 7 days without any changes in BDZ-binding and then decreased to initial values accompanied by decrement of brain receptor concentration. Thus, in BALB/c mice, a slowly manifested specific nootropic action of piracetam develops, following an increase in NMDA receptor density, whereas the non-specific anxiolytic effect precedes the fast-paced changes in BDZ-binding site density.

  9. Alpha-synuclein promotes clathrin-mediated endocytosis of NMDA receptors in dopaminergic cells

    Institute of Scientific and Technical Information of China (English)

    Shun Yu; Furong Cheng; Xin Li; Yaohua Li; Tao Wang; Guangwei Liu; Andrius Baskys

    2012-01-01

    Loss of dopaminergic i a compensatory increase in nput to the striatum associated with Parkinson' s disease brings about glutamate release onto the dopaminergic cell bodies in the substantia nigra pars compacta (SNpc)[1] Glutamate over-activation of NMDA receptors on these cells can cause excitotoxicity and contribute to their further loss. NMDA receptor-mediated neuronal death is reduced by group I mGluR-mediated up-regulation of endocytosis protein RAB5B[2.3] Among proteins shown to interact with RAB5 proteins is a-synuclein

  10. Unilateral predominance of abnormal movements: A characteristic feature of the pediatric anti-NMDA receptor encephalitis?

    Science.gov (United States)

    Benjumea-Cuartas, Vanessa; Eisermann, Monika; Simonnet, Hina; Hully, Marie; Nabbout, Rima; Desguerre, Isabelle; Kaminska, Anna

    2017-01-01

    Anti-NMDA receptor encephalitis is a treatable autoimmune disease characterized by cognitive, motor and psychiatric features that primarily affects young adults and children. We present a case of a 7-year-old boy with asymmetrical (mainly right hemibody) and abnormal polymorphic movements without concomitant scalpictal EEG changes but had background slowing predominating over the left hemisphere. This report illustrates previous descriptions of asymmetric presentation of abnormal movements in pediatric anti-NMDA receptor encephalitis and emphasizes the importance of video-EEG interpreted within the overall clinical context, to differentiate epileptic from non-epileptic abnormal movements in patients with autoimmune encephalitis.

  11. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis in a young Lebanese girl.

    Science.gov (United States)

    Safadieh, Layal; Dabbagh, Omar

    2013-10-01

    Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a recently recognized autoimmune neurologic disorder that presents with severe neuropsychiatric symptoms in previously healthy children. A 4-year-old Lebanese girl presented with new-onset behavioral changes, orofacial dyskinesias, fluctuation in consciousness, inability to walk, and mutism. Antibodies directed against NMDA receptors were detected in the patient's serum and cerebrospinal fluid. Prompt treatment with a single course of intravenous immunoglobulin resulted in early complete recovery. This is the first case report of a Middle Eastern child affected with this condition.

  12. Anti-NMDA receptor encephalitis: psychiatric presentation and diagnostic challenges from psychosomatic medicine perspective.

    Science.gov (United States)

    Gulyayeva, Nataliya A; Massie, Mary Jane; Duhamel, Katherine N

    2014-04-01

    We describe two cases of confirmed anti-NMDA receptor encephalitis; one patient initially presented with a clinical picture that resembled delirium and later appeared to present with a conversion reaction and the second patient presented with a first psychotic break followed by the clinical picture of neuroleptic malignant syndrome with catatonia. Neither patient had a previous history of psychiatric illness or recreational drug use. These cases illustrate the diagnostic and treatment challenges associated with this neuropsychiatric condition and underscore the role of psychosomatic medicine psychiatrists in diagnosing anti-NMDA receptor encephalitis.

  13. Anti-NMDA receptor encephalitis: a neurological disease in psychiatric disguise.

    Science.gov (United States)

    Sharma, Bhawna; Handa, Rahul; Prakash, Swayam; Nagpal, Kadam; Gupta, Pankaj

    2014-02-01

    Anti-NMDA receptor encephalitis was first described in 2005 when psychiatric features, memory loss and altered consciousness were found in four women with ovarian teratoma. We report a case of anti-NMDA receptor encephalitis in a 16-year-old female who presented with psychiatric features followed by autonomic dysfunction and orofacial dyskinesias that showed drastic improvement to intravenous immunoglobulin. As many patients of anti-NMDAR encephalitis initially present with psychiatric features, it is important for psychiatrists to have high index of suspicion for this disease and thus avoid the delay in diagnosing this treatable condition which may be otherwise fatal.

  14. [Anti-NMDA receptor encephalitis: two paediatric cases].

    Science.gov (United States)

    González-Toro, M Cristina; Jadraque-Rodríguez, Rocío; Sempere-Pérez, Ángela; Martínez-Pastor, Pedro; Jover-Cerdá, Jenaro; Gómez-Gosálvez, Francisco

    2013-12-01

    Introduccion. La encefalitis asociada a anticuerpos antirreceptores de N-metil-D-aspartato (NMDA) es una patologia neurologica autoinmune documentada en la poblacion pediatrica de manera creciente en los ultimos años. Se presentan dos casos de nuestra experiencia con clinica similar. Casos clinicos. Caso 1: niña de 5 años que inicia un cuadro de convulsiones y alteracion de conciencia, asociando trastornos del movimiento y regresion de habilidades previamente adquiridas que evoluciona a autismo. Caso 2: niña de 13 años que presenta hemiparesia izquierda, movimientos anomalos, trastorno de conducta y disautonomia. En ambos casos se obtienen anticuerpos antirreceptores de NMDA positivos en el liquido cefalorraquideo y se diagnostican de encefalitis antirreceptor de NMDA. En el primer caso se inicia el tratamiento con perfusion intravenosa de corticoides e inmunoglobulinas y es necesario asociar rituximab. En el segundo, corticoides e inmunoglobulinas. La evolucion fue favorable en ambas pacientes, con una leve alteracion del lenguaje como secuela en el primer caso y una recaida en el segundo caso, con resolucion completa. Conclusion. La encefalitis antirreceptor de NMDA es un trastorno tratable y es importante el diagnostico y tratamiento precoz, ya que mejora el pronostico y disminuye las recaidas.

  15. CB1 receptor activation in the rat paraventricular nucleus induces bi-directional cardiovascular effects via modification of glutamatergic and GABAergic neurotransmission.

    Science.gov (United States)

    Grzęda, Emilia; Schlicker, Eberhard; Toczek, Marek; Zalewska, Iwona; Baranowska-Kuczko, Marta; Malinowska, Barbara

    2017-01-01

    We have shown previously that the cannabinoid receptor agonist CP55940 microinjected into the paraventricular nucleus of the hypothalamus (PVN) of urethane-anaesthetized rats induces depressor and pressor cardiovascular effects in the absence and presence of the CB1 antagonist AM251, respectively. The aim of our study was to examine whether the hypotension and/or hypertension induced by CP55940 given into the PVN results from its influence on glutamatergic and GABAergic neurotransmission. CP55940 was microinjected into the PVN of urethane-anaesthetized rats twice (S1 and S2, 20 min apart). Antagonists of the following receptors, NMDA (MK801), β2-adrenergic (ICI118551), thromboxane A2-TP (SQ29548), angiotensin II-AT1 (losartan) or GABAA (bicuculline), or the NO synthase inhibitor L-NAME were administered intravenously 5 min before S2 alone or together with AM251. The CP55940-induced hypotension was reversed into a pressor response by AM251, bicuculline and L-NAME, but not by the other antagonists. The CP55940-induced pressor effect examined in the presence of AM251 was completely reversed by losartan, reduced by about 50-60 % by MK801, ICI118551 and SQ29548, prevented by bilateral adrenalectomy but not modified by bicuculline and L-NAME. Parallel, but smaller, changes in heart rate accompanied the changes in blood pressure. The bi-directional CB1 receptor-mediated cardiovascular effects of cannabinoids microinjected into the PVN of anaesthetized rats depend on stimulatory glutamatergic and inhibitory GABAergic inputs to the sympathetic tone; the glutamatergic input is related to AT1, TP and β2-adrenergic receptors and catecholamine release from the adrenal medulla whereas the GABAergic input is reinforced by NO.

  16. S-Nitrosoglutathione and glutathione act as NMDA receptor agonists in cultured hippocampal neurons

    Institute of Scientific and Technical Information of China (English)

    Ting-yu CHIN; Sheau-huei CHUEH; Pao-luh TAO

    2006-01-01

    Aim: To characterize the effect of combined pre- and postnatal morphine exposure on Af-methyl-D-aspartate receptor (NMDA) receptor signaling in hippocampal neurons of the offspring of morphine-addicted female rats. Methods: Cultured hippocampal neurons and synaptosomes were prepared from neonatal and 2-week-old offspring, respectively, of control or morphine-addicted female rats. The increase in the cytosolic Ca2+ concentration ([Ca2+]i) of cultured cells was measured using Fura-2, and glutamate release from synaptosomes was measured enzymatically. Results: Both glutamate and NMDA caused a dose-dependent increase in the [Ca2+]i. The nitric oxide (NO) donor, S-nitrosoglutathione (GSNO), but not 3-morpholinosydnonimine, sodium nitroprusside, and S-nitroso-N-acetylpenicillamine, also induced a [Ca2+]i increase. GSNO and glutathione caused a dose-dependent increase in the [Ca2+]i with respective EC50 values of 56 and 414 μmol/L. Both effects were inhibited by Mg2+ or an NMDA receptor antagonist and were unaffected by the presence of a glutamate scavenger. The other glutathione derivatives, oxidized glutathione, S-methylglutathione, S-ethylglutathione, S-propylglutathione, and S-butylglutathione, the dipeptides, Glu-Cys and Cys-Gly, and the antioxidants, dithiothreitol and mercaptoethanol, failed to induce a [Ca2+]i increase. In addition, glutathione caused a dose-dependent increase in glutamate release from synaptosomes. The maximal responses and the EC50 values for the glutamate-, NMDA-, GSNO-, and glutathione-induced [Ca2+]i increases and the glutathione-induced glutamate release were indistinguishable in the neurons of the offspring from control and morphine-addicted female rats. Conclusion: GSNO and glutathione act as NMDA receptor agonists and, in contrast to hippocampal brain slice, combined pre- and postnatal morphine exposure does not modulate NMDA receptor signaling in the cultured hippocampal neurons.

  17. Potentiation of NMDA receptor-mediated transmission in striatal cholinergic interneurons

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    Manfred eOswald

    2015-04-01

    Full Text Available Pauses in the tonic firing of striatal cholinergic interneurons (CINs emerge during reward-related learning in response to conditioning of a neutral cue. We have previously reported that augmenting the postsynaptic response to cortical afferents in CINs is coupled to the emergence of a cell-intrinsic afterhyperpolarisation (AHP underlying pauses in tonic activity. Here we investigated in a bihemispheric rat-brain slice preparation the mechanisms of synaptic plasticity of excitatory afferents to CINs and the association with changes in the AHP. We found that high frequency stimulation (HFS of commissural corticostriatal afferents from the contralateral hemisphere induced a robust long-term depression (LTD of postsynaptic potentials (PSP in CINs. Depression of the PSP of smaller magnitude and duration was observed in response to HFS of the ipsilateral white matter or cerebral cortex. In Mg2+-free solution HFS induced NMDA receptor-dependent potentiation of the PSP, evident in both the maximal slope and amplitude of the PSP. The increase in maximal slope corroborates previous findings, and was blocked by antagonism of either D1-like dopamine receptors with SCH23390 or D2-like dopamine receptors with sulpiride during HFS in Mg2+-free solution. Potentiation of the slower PSP amplitude component was due to augmentation of the NMDA receptor-mediated potential as this was completely reversed on subsequent application of the NMDA receptor antagonist AP5. HFS similarly potentiated NMDA receptor currents isolated by blockade of AMPA/kainate receptors with CNQX. The plasticity-induced increase in the slow PSP component was directly associated with an increase in the subsequent AHP. Thus plasticity of cortical afferent synapses is ideally suited to influence the cue-induced firing dynamics of CINs, particularly through potentiation of NMDA receptor-mediated synaptic transmission.

  18. Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action.

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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.

  19. Mechanisms for Antagonistic Regulation of AMPA and NMDA-D1 Receptor Complexes at Postsynaptic Sites

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    Schumann, Johann; Scheler, Gabriele

    2004-01-01

    From the analysis of these pathways we conclude that postsynaptic processes that regulate synaptic transmission undergo significant cross-talk with respect to glutamatergic and neuromodulatory (dopamine) signals. The main hypothesis is that of a compensatory regulation, a competitive switch between the induction of increased AMPA conductance by CaMKII-dependent phosphorylation and reduced expression of PP2A, and increased D1 receptor sensitivity and expression by increased PKA, PP2A and decreased PP-1/calcineurin expression. Both types of plasticity are induced by NMDA receptor activation and increased internal calcium, they require different internal conditions to become expressed. Specifically we propose that AMPA regulation and D1 regulation are inversely coupled;The net result may be a bifurcation of synaptic state into predominantly AMPA or NMDA-D1 synapses. This could have functional consequences: stable connections for AMPA and conditional gating for NMDA-D1 synapses.

  20. Relief learning is dependent on NMDA receptor activation in the nucleus accumbens

    Science.gov (United States)

    Mohammadi, Milad; Fendt, Markus

    2015-01-01

    Background and Purpose Recently, we demonstrated that the nucleus accumbens (NAC) is required for the acquisition and expression of relief memory. The purpose of this study was to investigate the role of NMDA receptors within the NAC in relief learning. Experimental Approach The NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) was injected into the NAC. The effects of these injections on the acquisition and expression of relief memory, as well as on the reactivity to aversive electric stimuli, were tested. Key Results Intra-accumbal AP-5 injections blocked the acquisition but not the expression of relief memory. Furthermore, reactivity to aversive electric stimuli was not affected by the AP-5 injections. Conclusion and Implication The present data indicate that NMDA-dependent plasticity within the NAC is crucial for the acquisition of relief memory. PMID:25572550

  1. Enhancement of NMDA receptor-mediated excitatory postsynaptic currents by gp120-treated macrophages: implications for HIV-1-associated neuropathology.

    Science.gov (United States)

    Yang, Jianming; Hu, Dehui; Xia, Jianxun; Liu, Jianuo; Zhang, Gang; Gendelman, Howard E; Boukli, Nawal M; Xiong, Huangui

    2013-09-01

    A plethora of prior studies has linked HIV-1-infected and immune activated brain mononuclear phagocytes (MP; blood borne macrophages and microglia) to neuronal dysfunction. These are modulated by N-methyl-D-aspartate receptor (NMDAR) antagonists and supporting their relevance for HIV-1-associated nervous system disease. The role of NMDAR subsets in HIV-1-induced neuronal injury, nonetheless, is poorly understood. To this end, we investigated conditioned media from HIV-1gp120-treated human monocyte-derived-macrophages (MDM) for its abilities to affect NMDAR-mediated excitatory postsynaptic currents (EPSC(NMDAR)) in rat hippocampal slices. Bath application of gp120-treated MDM-conditioned media (MCM) produced an increase of EPSC(NMDAR). In contrast, control (untreated) MCM had limited effects on EPSC(NMDAR). Testing NR2A NMDAR (NR2AR)-mediated EPSC (EPSC(NR2AR)) and NR2B NMDAR (NR2BR)-mediated EPSC (EPSC(NR2BR)) for MCM showed significant increased EPSC(NR2BR) when compared to EPSC(NR2AR) enhancement. When synaptic NR2AR-mediated EPSC was blocked by bath application of MK801 combined with low frequency stimulations, MCM retained its ability to enhance EPSC(NMDAR) evoked by stronger stimulations. This suggested that increase in EPSC(NMDAR) was mediated, in part, through extra-synaptic NR2BR. Further analyses revealed that the soluble factors with low (NR2BR but not NR2AR blockers. Taken together, these results indicate that macrophage secretory products induce neuronal injury through extra-synaptic NR2BRs.

  2. The A3 adenosine receptor attenuates the calcium rise triggered by NMDA receptors in retinal ganglion cells.

    Science.gov (United States)

    Zhang, Mei; Hu, Huiling; Zhang, Xiulan; Lu, Wennan; Lim, Jason; Eysteinsson, Thor; Jacobson, Kenneth A; Laties, Alan M; Mitchell, Claire H

    2010-01-01

    The A(3) adenosine receptor is emerging as an important regulator of neuronal signaling, and in some situations receptor stimulation can limit excitability. As the NMDA receptor frequently contributes to neuronal excitability, this study examined whether A(3) receptor activation could alter the calcium rise accompanying NMDA receptor stimulation. Calcium levels were determined from fura-2 imaging of isolated rat retinal ganglion cells as these neurons possess both receptor types. Brief application of glutamate or NMDA led to repeatable and reversible elevations of intracellular calcium. The A(3) agonist Cl-IB-MECA reduced the response to both glutamate and NMDA. While adenosine mimicked the effect of Cl-IB-MECA, the A(3) receptor antagonist MRS 1191 impeded the block by adenosine, implicating a role for the A(3) receptor in response to the natural agonist. The A(1) receptor antagonist DPCPX provided additional inhibition, implying a contribution from both A(1) and A(3) adenosine receptors. The novel A(3) agonist MRS 3558 (1'S,2'R,3'S,4'R,5'S)-4-(2-chloro-6-(3-chlorobenzylamino)-9H-purin-9-yl)-2,3-dihydroxy-N-methylbicyclo [3.1.0] hexane-1-carboxamide and mixed A(1)/A(3) agonist MRS 3630 (1'S,2'R,3'S,4'R,5'S)-4-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-2,3-dihydroxy-N-methylbicyclo [3.1.0] hexane-1-carboxamide also inhibited the calcium rise induced by NMDA. Low levels of MRS 3558 were particularly effective, with an IC(50) of 400 pM. In all cases, A(3) receptor stimulation inhibited only 30-50% of the calcium rise. In summary, stimulation of the A(3) adenosine receptor by either endogenous or synthesized agonists can limit the calcium rise accompanying NMDA receptor activation. It remains to be determined if partial block of the calcium rise by A(3) agonists can modify downstream responses to NMDA receptor stimulation.

  3. Opposite modulation of brain stimulation reward by NMDA and AMPA receptors in the ventral tegmental area.

    Science.gov (United States)

    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

  4. Opposite modulation of brain stimulation reward by NMDA and AMPA receptors in the ventral tegmental area.

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    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

  5. Rapid effect of stress concentration corticosterone on glutamate receptor and its subtype NMDA receptor activity in cultured hippocampal neurons

    Institute of Scientific and Technical Information of China (English)

    刘玲; 孙继虎; 王春安

    2003-01-01

    Objective:To study the rapid effect of glucocorticoids(GCs)on NMDA receptor activity in hippocampal neurons in stress and to elucidate its underlying probable membrane mechanisms.Methods:Whole-cell patch-clamp recording was used to assess the effect of stress concentration corticosterone(B)on the responses of cultured hippocampal neurons to glutamate and NMDA(N-methy-D-asparatic acid).To make clear the target of B,intracellular dialysis of B(10 μ mol/L)through patch pipette and extracellular application of bovine serum albumin-conjugated corticosterone(B-BSA,10 μmol/L)were carried out to observe their influence on peak amplitude of NMDA-evoked current.Results:B had a rapid,reversible and inhibitory effect on peak amplitude of GLU- or NMDA-evoked current in cultured hippocampal neurons.Furthermore,B-BSA had the inhibitory effect on INMDA as that of B,but intracellularly dialyzed B had no significant effect on INMDA.Conclusion:These results suggest that under the condition of stress,GCs may rapidly,negatively regulate excitatory synaptic receptors-glutamate receptors(GluRs),especially NMDA receptor(NMDAR)in central nervous system,which is mediated by rapid membrane mechanisms,but not by classical,genomic mechanisms.

  6. Ethanol-withdrawal seizures are controlled by tissue plasminogen activator via modulation of NR2B-containing NMDA receptors.

    Science.gov (United States)

    Pawlak, Robert; Melchor, Jerry P; Matys, Tomasz; Skrzypiec, Anna E; Strickland, Sidney

    2005-01-11

    Chronic ethanol abuse causes up-regulation of NMDA receptors, which underlies seizures and brain damage upon ethanol withdrawal (EW). Here we show that tissue-plasminogen activator (tPA), a protease implicated in neuronal plasticity and seizures, is induced in the limbic system by chronic ethanol consumption, temporally coinciding with up-regulation of NMDA receptors. tPA interacts with NR2B-containing NMDA receptors and is required for up-regulation of the NR2B subunit in response to ethanol. As a consequence, tPA-deficient mice have reduced NR2B, extracellular signal-regulated kinase 1/2 phosphorylation, and seizures after EW. tPA-mediated facilitation of EW seizures is abolished by NR2B-specific NMDA antagonist ifenprodil. These results indicate that tPA mediates the development of physical dependence on ethanol by regulating NR2B-containing NMDA receptors.

  7. Differential Involvement of Amygdala and Cortical NMDA Receptors Activation upon Encoding in Odor Fear Memory

    Science.gov (United States)

    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…

  8. Involvement of ERK in NMDA receptor-independent cortical neurotoxicity of hydrogen sulfide

    Energy Technology Data Exchange (ETDEWEB)

    Kurokawa, Yuko; Sekiguchi, Fumiko; Kubo, Satoko; Yamasaki, Yoshiko; Matsuda, Sachi; Okamoto, Yukari; Sekimoto, Teruki; Fukatsu, Anna; Nishikawa, Hiroyuki [Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502 (Japan); Kume, Toshiaki [Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501 (Japan); Fukushima, Nobuyuki [Division of Molecular Neurobiology, Department of Life Sciences, Kinki University School of Science and Engineering, 3-4-1 Kowakae, Higashi-Osaka 577-8502 (Japan); Akaike, Akinori [Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501 (Japan); Kawabata, Atsufumi, E-mail: kawabata@phar.kindai.ac.jp [Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502 (Japan)

    2011-11-04

    Highlights: Black-Right-Pointing-Pointer Hydrogen sulfide causes NMDA receptor-independent neurotoxicity in mouse fetal cortical neurons. Black-Right-Pointing-Pointer Activation of ERK mediates the toxicity of hydrogen sulfide. Black-Right-Pointing-Pointer Apoptotic mechanisms are involved in the hydrogen-induced cell death. -- Abstract: Hydrogen sulfide (H{sub 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{sub 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{sub 2}S involves activation of the MEK/ERK pathway and some apoptotic mechanisms.

  9. Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade

    Directory of Open Access Journals (Sweden)

    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.

  10. Differential Involvement of Amygdala and Cortical NMDA Receptors Activation upon Encoding in Odor Fear Memory

    Science.gov (United States)

    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…

  11. Neuregulin and BDNF induce a switch to NMDA receptor-dependent myelination by oligodendrocytes.

    Directory of Open Access Journals (Sweden)

    Iben Lundgaard

    2013-12-01

    Full Text Available Myelination is essential for rapid impulse conduction in the CNS, but what determines whether an individual axon becomes myelinated remains unknown. Here we show, using a myelinating coculture system, that there are two distinct modes of myelination, one that is independent of neuronal activity and glutamate release and another that depends on neuronal action potentials releasing glutamate to activate NMDA receptors on oligodendrocyte lineage cells. Neuregulin switches oligodendrocytes from the activity-independent to the activity-dependent mode of myelination by increasing NMDA receptor currents in oligodendrocyte lineage cells 6-fold. With neuregulin present myelination is accelerated and increased, and NMDA receptor block reduces myelination to far below its level without neuregulin. Thus, a neuregulin-controlled switch enhances the myelination of active axons. In vivo, we demonstrate that remyelination after white matter damage is NMDA receptor-dependent. These data resolve controversies over the signalling regulating myelination and suggest novel roles for neuregulin in schizophrenia and in remyelination after white matter damage.

  12. Fear memory in a neurodevelopmental model of schizophrenia based on the postnatal blockade of NMDA receptors.

    Science.gov (United States)

    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.

  13. Recent Progress in Understanding Subtype Specific Regulation of NMDA Receptors by G Protein Coupled Receptors (GPCRs

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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.

  14. Anti-NMDA receptor encephalitis: an easily missed diagnosis in older patients.

    Science.gov (United States)

    Rainey, Katie; Gholkar, Bethan; Cheesman, Mark

    2014-09-01

    Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an important, treatable cause of encephalitis which remains under-recognised despite a growing body of the literature [1]. It is an immune-mediated syndrome which presents with a variety of neurological symptoms including headache, fever, personality change and seizures. Most case reports to date are of young adults, it is much less frequently reported in older adults. The syndrome has been associated with ovarian teratomas. The prognosis is good with early recognition and treatment, though may relapse. We present a case of NMDA encephalitis in an elderly patient who responded well to immunosuppressive therapy.

  15. Nerve growth factor alters the sensitivity of rat masseter muscle mechanoreceptors to NMDA receptor activation.

    Science.gov (United States)

    Wong, Hayes; Dong, Xu-Dong; Cairns, Brian E

    2014-11-01

    Intramuscular injection of nerve growth factor (NGF) into rat masseter muscle induces a local mechanical sensitization that is greater in female than in male rats. The duration of NGF-induced sensitization in male and female rats was associated with an increase in peripheral N-methyl-d-aspartate (NMDA) receptor expression by masseter muscle afferent fibers that began 3 days postinjection. Here, we investigated the functional consequences of increased NMDA expression on the response properties of masseter muscle mechanoreceptors. In vivo extracellular single-unit electrophysiological recordings of trigeminal ganglion neurons innervating the masseter muscle were performed in anesthetized rats 3 days after NGF injection (25 μg/ml, 10 μl) into the masseter muscle. Mechanical activation threshold was assessed before and after intramuscular injection of NMDA. NMDA injection induced mechanical sensitization in both sexes that was increased significantly following NGF injection in the male rats but not in the female rats. However, in female but not male rats, further examination found that preadministration of NGF induced a greater sensitization in slow Aδ-fibers (2-7 m/s) than fast Aδ-fibers (7-12 m/s). This suggests that preadministration of NGF had a different effect on slowly conducting mechanoreceptors in the female rats compared with the male rats. Although previous studies have found an association between estrogenic tone and NMDA activity, no correlation was observed between NMDA-evoked mechanical sensitization and plasma estrogen level. This study suggests NGF alters NMDA-induced mechanical sensitization in the peripheral endings of masseter mechanoreceptors in a sexually dimorphic manner.

  16. [NMDA receptor encephalitis in the course of recurrent CNS demyelinating disorders: a case report].

    Science.gov (United States)

    Yamamoto, Masanari; Kokubun, Norito; Watanabe, Yuka; Okabe, Ryuta; Nakamura, Toshiki; Hirata, Koichi

    2013-01-01

    We present the case of a 31-year-old woman who developed N-methyl-d-aspartate (NMDA) receptor encephalitis during the course of relapsing and remitting multiple brain lesions. The patient developed a tingling sensation in the left upper and lower extremities, and was first admitted to our hospital at age 27. She was tentatively diagnosed with multiple sclerosis on the basis of multiple lesions with Gd-enhancement in the brainstem, and 2 separate clinical relapses by age 28. At age 31, she developed a headache and pyrexia, followed by confusion and abnormal behavior. Her symptoms acutely progressed to stupor, and subsequently, she developed oral dyskinesia and athetosis-like involuntary movement of the left arm. The stupor state continued over 2 months. However, she had completely recovered by 3 months after the onset of psychiatric symptoms. Her serum and CSF samples tested positive for anti-NMDA receptor antibodies, and she was diagnosed with NMDA receptor encephalitis. Her serum was negative for anti-AQP4 antibody, but showed weak positivity for antinuclear antibody. Between ages 32 and 34, she experienced 2 clinical relapses, including right-hand clumsiness, confusion, aphasia, and dysphagia. FLAIR images showed a high-intensity area in the brain stem, thalamus, and subcortical white matter. No tumors were found throughout the course. A clinical entity of NMDA receptor encephalitis can include various neurologic disorders, such as the development of recurrent demyelinating brain lesions. Further investigation is required to clarify the pathophysiological role of anti-NMDA receptor antibody in our patient.

  17. GHB-Induced Cognitive Deficits During Adolescence and the Role of NMDA Receptor.

    Science.gov (United States)

    Sircar, R; Wu, L-C; Reddy, K; Sircar, D; Basak, A K

    2011-03-01

    We have earlier reported that γ-hydroxybutyric acid (GHB) disrupts the acquisition of spatial learning and memory in adolescent rats. GHB is known to interact with several neurotransmitter systems that have been implicated in cognitive functioning. The N-methyl-D-aspartate receptor (NR) -type of glutamate receptor is considered to be an important target for spatial learning and memory. Molecular mechanisms governing the neuroadptations following repeated GHB treatment in adolecent rats remain unknown. We examined the role of NMDA receptor in adolescent GHB-induced cognitive deficit. Adolescent rats were administered with GHB on 6 consecutive days, and surface-expressed NMDA receptor subunits levels were measured. GHB significantly decreased NR1 levels in the frontal cortex. Adolescent GHB also significantly reduced cortical NR2A subunit levels. Our findings support the hypothesis that adolescent GHB-induced cogntive deficits are associated with neuroadaptations in glutamatergic transmission, particulaly NR functioning in the frontal cortex.

  18. Fast cortical oscillation after thalamic degeneration: pivotal role of NMDA receptor.

    Science.gov (United States)

    Kyuhou, Shin-ichi; Gemba, Hisae

    2007-04-27

    We examined electrophysiological and molecular changes of the thalamocortical system after thalamic degeneration in Purkinje cell degeneration (pcd) mice. In pcd mice, neurons in specific thalamic nuclei including the ventral medial geniculate nucleus began to degenerate around postnatal day 50, whereas the visual thalamic nucleus and nonspecific thalamic nuclei remained almost intact. In association with the morphological changes, auditory evoked potentials in the primary auditory cortex (AC) began to decrease gradually. Fast Fourier transform analysis of spontaneous cortical field potentials revealed that fast oscillation (FO) around 25 Hz occurred in the AC but not in the visual cortex. Quantitative mRNA analysis demonstrated that expression of the N-methyl-D-aspartate (NMDA) receptor was up-regulated in the AC but not in the visual cortex. Systemic administration of an NMDA antagonist abolished the FO in the AC. These results indicate that increased NMDA activity may cause the FO in the AC of pcd mice.

  19. NMDA receptors are the basis for persistent network activity in neocortex slices.

    Science.gov (United States)

    Castro-Alamancos, Manuel A; Favero, Morgana

    2015-06-01

    During behavioral quiescence the neocortex generates spontaneous slow oscillations that consist of Up and Down states. Up states are short epochs of persistent activity, but their underlying source is unclear. In neocortex slices of adult mice, we monitored several cellular and network variables during the transition between a traditional buffer, which does not cause Up states, and a lower-divalent cation buffer, which leads to the generation of Up states. We found that the resting membrane potential and input resistance of cortical cells did not change with the development of Up states. The synaptic efficacy of excitatory postsynaptic potentials mediated by non-NMDA receptors was slightly reduced, but this is unlikely to facilitate the generation of Up states. On the other hand, we identified two variables that are associated with the generation of Up states: an enhancement of the intrinsic firing excitability of cortical cells and an enhancement of NMDA-mediated responses evoked by electrical or optogenetic stimulation. The fact that blocking NMDA receptors abolishes Up states indicates that the enhancement in intrinsic firing excitability alone is insufficient to generate Up states. NMDA receptors have a crucial role in the generation of Up states in neocortex slices.

  20. NMDA receptor subunit expression and PAR2 receptor activation in colospinal afferent neurons (CANs during inflammation induced visceral hypersensitivity

    Directory of Open Access Journals (Sweden)

    Caudle Robert M

    2009-09-01

    Full Text Available Abstract Background Visceral hypersensitivity is a clinical observation made when diagnosing patients with functional bowel disorders. The cause of visceral hypersensitivity is unknown but is thought to be attributed to inflammation. Previously we demonstrated that a unique set of enteric neurons, colospinal afferent neurons (CANs, co-localize with the NR1 and NR2D subunits of the NMDA receptor as well as with the PAR2 receptor. The aim of this study was to determine if NMDA and PAR2 receptors expressed on CANs contribute to visceral hypersensitivity following inflammation. Recently, work has suggested that dorsal root ganglion (DRG neurons expressing the transient receptor potential vanilloid-1 (TRPV1 receptor mediate inflammation induced visceral hypersensitivity. Therefore, in order to study CAN involvement in visceral hypersensitivity, DRG neurons expressing the TRPV1 receptor were lesioned with resiniferatoxin (RTX prior to inflammation and behavioural testing. Results CANs do not express the TRPV1 receptor; therefore, they survive following RTX injection. RTX treatment resulted in a significant decrease in TRPV1 expressing neurons in the colon and immunohistochemical analysis revealed no change in peptide or receptor expression in CANs following RTX lesioning as compared to control data. Behavioral studies determined that both inflamed non-RTX and RTX animals showed a decrease in balloon pressure threshold as compared to controls. Immunohistochemical analysis demonstrated that the NR1 cassettes, N1 and C1, of the NMDA receptor on CANs were up-regulated following inflammation. Furthermore, inflammation resulted in the activation of the PAR2 receptors expressed on CANs. Conclusion Our data show that inflammation causes an up-regulation of the NMDA receptor and the activation of the PAR2 receptor expressed on CANs. These changes are associated with a decrease in balloon pressure in response to colorectal distension in non-RTX and RTX lesioned

  1. N-Methyl D-Aspartic Acid (NMDA Receptors and Depression

    Directory of Open Access Journals (Sweden)

    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

  2. Modulation of NMDA receptor function by inhibition of D-amino acid oxidase in rodent brain.

    Science.gov (United States)

    Strick, Christine A; Li, Cheryl; Scott, Liam; Harvey, Brian; Hajós, Mihály; Steyn, Stefanus J; Piotrowski, Mary A; James, Larry C; Downs, James T; Rago, Brian; Becker, Stacey L; El-Kattan, Ayman; Xu, Youfen; Ganong, Alan H; Tingley, F David; Ramirez, Andres D; Seymour, Patricia A; Guanowsky, Victor; Majchrzak, Mark J; Fox, Carol B; Schmidt, Christopher J; Duplantier, Allen J

    2011-01-01

    Observations that N-Methyl-D-Aspartate (NMDA) antagonists produce symptoms in humans that are similar to those seen in schizophrenia have led to the current hypothesis that schizophrenia might result from NMDA receptor hypofunction. Inhibition of D-amino acid oxidase (DAAO), the enzyme responsible for degradation of D-serine, should lead to increased levels of this co-agonist at the NMDA receptor, and thereby provide a therapeutic approach to schizophrenia. We have profiled some of the preclinical biochemical, electrophysiological, and behavioral consequences of administering potent and selective inhibitors of DAAO to rodents to begin to test this hypothesis. Inhibition of DAAO activity resulted in a significant dose and time dependent increase in D-serine only in the cerebellum, although a time delay was observed between peak plasma or brain drug concentration and cerebellum D-serine response. Pharmacokinetic/pharmacodynamic (PK/PD) modeling employing a mechanism-based indirect response model was used to characterize the correlation between free brain drug concentration and D-serine accumulation. DAAO inhibitors had little or no activity in rodent models considered predictive for antipsychotic activity. The inhibitors did, however, affect cortical activity in the Mescaline-Induced Scratching model, produced a modest but significant increase in NMDA receptor-mediated synaptic currents in primary neuronal cultures from rat hippocampus, and resulted in a significant increase in evoked hippocampal theta rhythm, an in vivo electrophysiological model of hippocampal activity. These findings demonstrate that although DAAO inhibition did not cause a measurable increase in D-serine in forebrain, it did affect hippocampal and cortical activity, possibly through augmentation of NMDA receptor-mediated currents. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. NR2 subunits and NMDA receptors on lamina II inhibitory and excitatory interneurons of the mouse dorsal horn

    Directory of Open Access Journals (Sweden)

    MacDermott Amy B

    2010-05-01

    Full Text Available Abstract Background NMDA receptors expressed by spinal cord neurons in the superficial dorsal horn are involved in the development of chronic pain associated with inflammation and nerve injury. The superficial dorsal horn has a complex and still poorly understood circuitry that is mainly populated by inhibitory and excitatory interneurons. Little is known about how NMDA receptor subunit composition, and therefore pharmacology and voltage dependence, varies with neuronal cell type. NMDA receptors are typically composed of two NR1 subunits and two of four NR2 subunits, NR2A-2D. We took advantage of the differences in Mg2+ sensitivity of the NMDA receptor subtypes together with subtype preferring antagonists to identify the NR2 subunit composition of NMDA receptors expressed on lamina II inhibitory and excitatory interneurons. To distinguish between excitatory and inhibitory interneurons, we used transgenic mice expressing enhanced green fluorescent protein driven by the GAD67 promoter. Results Analysis of conductance ratio and selective antagonists showed that lamina II GABAergic interneurons express both the NR2A/B containing Mg2+ sensitive receptors and the NR2C/D containing NMDA receptors with less Mg2+ sensitivity. In contrast, excitatory lamina II interneurons express primarily NR2A/B containing receptors. Despite this clear difference in NMDA receptor subunit expression in the two neuronal populations, focally stimulated synaptic input is mediated exclusively by NR2A and 2B containing receptors in both neuronal populations. Conclusions Stronger expression of NMDA receptors with NR2C/D subunits by inhibitory interneurons compared to excitatory interneurons may provide a mechanism to selectively increase activity of inhibitory neurons during intense excitatory drive that can provide inhibitory feedback.

  4. AMPA receptor mediated excitotoxicity in neocortical neurons is developmentally regulated and dependent upon receptor desensitization

    DEFF Research Database (Denmark)

    Jensen, J B; Schousboe, A; Pickering, D S;

    1998-01-01

    was blocked was seen as early as 5 DIV since 10 microM MK-801 did not completely block the response whereas 10 microM NBQX did. The 2,3-benzodiazepine GYKI compounds, which have been reported to be selective non-competitive AMPA receptor antagonists, were here observed to block the AMPA toxicity...

  5. Design, synthesis, and pharmacological characterization of novel, potent NMDA receptor antagonists

    DEFF Research Database (Denmark)

    Conti, Paola; De Amici, Marco; Grazioso, Giovanni

    2004-01-01

    acids were tested at ionotropic and metabotropic glutamate receptors. None of the compounds was active, neither as agonists nor as antagonists, at 1 mM on metabotropic receptors (mGluR1, -2, -4, and -5 expressed in CHO cell lines). Conversely, the pair of stereoisomers 8A/8B showed a remarkable affinity......, antagonist potency, and selectivity for NMDA receptors, when tested on ionotropic glutamate receptors. The affinity of 8A proved to be 5 times higher than that of diastereomer 8B (K(i) values 0.21 and 0.96 microM, respectively). Furthermore, compounds 8A and 8B exhibited a noteworthy anticonvulsant activity...

  6. Mapping of the human NMDA receptor subunit (NMDAR1) and the proposed NMDA receptor glutamate-binding subunit (NMDARA1) to chromosomes 9q34.3 and chromosome 8, respectively

    DEFF Research Database (Denmark)

    Collins, C; Duff, C; Duncan, A M;

    1993-01-01

    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...... subunit (NMDAR1) and a proposed glutamate-binding subunit of the NMDA receptor (NMDARA1) have provided an opportunity to test the hypothesis that either of these genes might be directly involved in the causation of HD. We have mapped NMDAR1 to 9q34.3 using in situ hybridization studies and NMDARA1...... that the gene for torsion dystonia has also been localized by genetic studies to 9q34.3, the same regional map location as NMDAR1....

  7. Prenatal protein deprivation in rats induces changes in prepulse inhibition and NMDA receptor binding.

    Science.gov (United States)

    Palmer, Abraham A; Printz, David J; Butler, Pamela D; Dulawa, Stephanie C; Printz, Morton P

    2004-01-23

    Epidemiological studies suggest that prenatal malnutrition increases the risk of developing schizophrenia. Animal models indicate that prenatal protein deprivation (PPD) affects many aspects of adult brain function. We tested the hypothesis that PPD in rats would alter prepulse inhibition (PPI), which is an operational measure of sensorimotor gating that is deficient in schizophrenia patients. Additionally, we examined dopaminergic and glutaminergic receptor binding in the striatum and hippocampus, which have been suggested to play a role in the etiology of schizophrenia. Rat dams were fed normal (25%) or low (6%) protein diets beginning 5 weeks prior to, and throughout pregnancy. The pups were tested at postnatal days (PND) 35 and 56 for PPI. Striatal and hippocampal NMDA receptor, and striatal dopamine receptor binding were quantified post-mortem in a subset of these rats. Female rats exposed to PPD had reduced levels of PPI at PND 56, but not PND 35, suggesting the emergence of a sensorimotor gating deficit in early adulthood. Striatal NMDA receptor binding was increased in PPD females. A decrease in initial startle response (SR) was also observed in all PPD rats relative to control rats. These results suggest that PPD causes age- and sex-dependent decreases in PPI and increases in NMDA receptor binding. This animal model may be useful for the investigation of neurodevelopmental changes that are associated with schizophrenia in humans.

  8. Antagonistas de los receptores glutamatérgicos NMDA en el tratamiento del dolor crónico NMDA glutamatergic receptor antagonists for the management of chronic pain

    OpenAIRE

    F. Neira; J. L. Ortega

    2004-01-01

    Los receptores NMDA están asociados con los procesos de aprendizaje y memoria, el desarrollo y la plasticidad neural, así como con los estados de dolor agudo y crónico. Intervienen en el inicio y mantenimiento de la sensibilización central asociada a daño o inflamación de los tejidos periféricos. El glutamato es el principal aminoácido excitatorio del SNC, puede participar en los procesos de transmisión nociceptiva a nivel espinal, siendo el principal responsable de la transmisión sináptica r...

  9. Synaptic NMDA receptor-mediated currents in anterior piriform cortex are reduced in the adult fragile X mouse.

    Science.gov (United States)

    Gocel, James; Larson, John

    2012-09-27

    Fragile X syndrome is a neurodevelopmental condition caused by the transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. The Fmr1 knockout (KO) mouse exhibits age-dependent deficits in long term potentiation (LTP) at association (ASSN) synapses in anterior piriform cortex (APC). To investigate the mechanisms for this, whole-cell voltage-clamp recordings of ASSN stimulation-evoked synaptic currents were made in APC of slices from adult Fmr1-KO and wild-type (WT) mice, using the competitive N-methyl-D-aspartate (NMDA) receptor antagonist, CPP, to distinguish currents mediated by NMDA and AMPA receptors. NMDA/AMPA current ratios were lower in Fmr1-KO mice than in WT mice, at ages ranging from 3-18months. Since amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs) mediated by AMPA receptors were no different in Fmr1-KO and WT mice at these ages, the results suggest that NMDA receptor-mediated currents are selectively reduced in Fmr1-KO mice. Analyses of voltage-dependence and decay kinetics of NMDA receptor-mediated currents did not reveal differences between Fmr1-KO and WT mice, suggesting that reduced NMDA currents in Fmr1-KO mice are due to fewer synaptic receptors rather than differences in receptor subunit composition. Reduced NMDA receptor signaling may help to explain the LTP deficit seen at APC ASSN synapses in Fmr1-KO mice at 6-18months of age, but does not explain normal LTP at these synapses in mice 3-6months old. Evoked currents and mEPSCs were also examined in senescent Fmr1-KO and WT mice at 24-28months of age. NMDA/AMPA ratios were similar in senescent WT and Fmr1-KO mice, due to a decrease in the ratio in the WT mice, without significant change in AMPA receptor-mediated mEPSCs.

  10. [Studying specific effects of nootropic drugs on glutamate receptors in the rat brain].

    Science.gov (United States)

    Firstova, Iu Iu; Vasil'eva, E V; Kovalev, G I

    2011-01-01

    The influence of nootropic drugs of different groups (piracetam, phenotropil, nooglutil, noopept, semax, meclofenoxate, pantocalcine, and dimebon) on the binding of the corresponding ligands to AMPA, NMDA, and mGlu receptors of rat brain has been studied by the method of radio-ligand binding in vitro. It is established that nooglutil exhibits pharmacologically significant competition with a selective agonist of AMPA receptors ([G-3H]Ro 48-8587) for the receptor binding sites (with IC50 = 6.4 +/- 0.2 microM), while the competition of noopept for these receptor binding sites was lower by an order of magnitude (IC50 = 80 +/- 5.6 microM). The heptapeptide drug semax was moderately competitive with [G-3H]LY 354740 for mGlu receptor sites (IC50 = 33 +/- 2.4 microM). Dimebon moderately influenced the specific binding of the ligand of NMDA receptor channel ([G-3H]MK-801) at IC50 = 59 +/- 3.6 microM. Nootropic drugs of the pyrrolidone group (piracetam, phenotropil) as well as meclofenoxate, pantocalcine (pantogam) in a broad rage of concentrations (10(-4)-10(-10) M) did not affect the binding of the corresponding ligands to glutamate receptors (IC50 100 pM). Thus, the direct neurochemical investigation was used for the first time to qualitatively characterize the specific binding sites for nooglutil and (to a lower extent) noopept on AMPA receptors, for semax on metabotropic glutamate receptors, and for dimebon on the channel region of NMDA receptors. The results are indicative of a selective action of some nootropes on the glutamate family.

  11. Rhythmic delta activity represents a form of nonconvulsive status epilepticus in anti-NMDA receptor antibody encephalitis.

    Science.gov (United States)

    Kirkpatrick, McNeill P; Clarke, Charles D; Sonmezturk, Hasan H; Abou-Khalil, Bassel

    2011-02-01

    Anti-NMDA receptor antibody encephalitis is a limbic encephalitis with psychiatric manifestations, abnormal movements, coma, and seizures. The coma and abnormal movements are not typically attributed to seizure activity, and slow activity is the most common EEG finding. We report drug-resistant nonconvulsive status epilepticus as the basis for coma in a 19-year-old woman with anti-NMDA receptor antibodies and a mediastinal teratoma. The EEG showed generalized rhythmic delta activity, with evolution in morphology, frequency, and field typical of nonconvulsive status epilepticus. The status was refractory to antiepileptic drugs, repeated drug-induced coma, resection of the tumor, intravenous steroids, rituximab, and plasmapheresis. She awoke after the addition of felbamate, and the rhythmic delta activity ceased. The rhythmic delta activity described with coma in anti-NMDA receptor antibody encephalitis may represent a pattern of status epilepticus in some patients. Felbamate, which has NMDA receptor antagonist activity, should be studied as a therapeutic agent in this condition.

  12. Kalirin-7 is necessary for normal NMDA receptor-dependent synaptic plasticity

    KAUST Repository

    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.

  13. 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.

  14. Stress-induced changes of hippocampal NMDA receptors: modulation by duloxetine treatment.

    Directory of Open Access Journals (Sweden)

    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.

  15. Computational study of the evolutionary relationships of the ionotropic receptors NMDA, AMPA and kainate in four species of primates.

    OpenAIRE

    Moreno-Pedraza, Francy Johanna; Grupo de Bioquímica Molecular Computacional y Bioinformática, Departamento de Bioquímica, Facultad de Ciencias. Pontificia Universidad Javeriana, Carrera 7 No. 43-82 Ed. 52, Bogotá,; Lareo, Leonardo René; Grupo de Bioquímica Molecular Computacional y Bioinformática, Departamento de Bioquímica, Facultad de Ciencias. Pontificia Universidad Javeriana, Carrera 7 No. 43-82 Ed. 52, Bogotá,; Reyes-Montaño, Edgar Antonio; Grupo de Investigación en Proteínas (GRIP) Departamento de Química, Universidad Nacional de Colombia, Ciudad Universitaria, Edificio 451, Bogotá

    2010-01-01

    Objective. To identify the influence of changes on the secondary structure and evolutionary relationship of NMDA, AMPA and kainate receptors in Homo sapiens, Pan troglodytes, Pongo pygmaeus and Macaca mulatta. Materials and methods. We identified 91 sequences 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 s...

  16. Neural activation deficits in a mouse genetic model of NMDA receptor hypofunction in tests of social aggression and swim stress

    OpenAIRE

    Duncan, Gary E.; Inada, Ken; Farrington, Joseph S.; Koller, Beverly H.; Moy, Sheryl S.

    2009-01-01

    Mice with reduced expression of the NR1 subunit of the NMDA receptor (NR1 hypomorphic mice) display altered behavioral phenotypes that may relate to behavioral characteristics of schizophrenia. Altered phenotypes in the NR1 hypomorphs include marked deficits in species-typical behavioral interactions in tests of social aggression and social affiliation. To gain insight into neuroanatomical circuits disrupted by reduced NMDA receptor function, the present work compared regional brain activatio...

  17. On the Role of Glutamate in Presynaptic Development: Possible Contributions of Presynaptic NMDA Receptors

    Directory of Open Access Journals (Sweden)

    Karlie N. Fedder

    2015-12-01

    Full Text Available Proper formation and maturation of synapses during development is a crucial step in building the functional neural circuits that underlie perception and behavior. It is well established that experience modifies circuit development. Therefore, understanding how synapse formation is controlled by synaptic activity is a key question in neuroscience. In this review, we focus on the regulation of excitatory presynaptic terminal development by glutamate, the predominant excitatory neurotransmitter in the brain. We discuss the evidence that NMDA receptor activation mediates these effects of glutamate and present the hypothesis that local activation of presynaptic NMDA receptors (preNMDARs contributes to glutamate-dependent control of presynaptic development. Abnormal glutamate signaling and aberrant synapse development are both thought to contribute to the pathogenesis of a variety of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability, epilepsy, anxiety, depression, and schizophrenia. Therefore, understanding how glutamate signaling and synapse development are linked is important for understanding the etiology of these diseases.

  18. NMDA receptor NR2B subunits contribute to PTZ-kindling-induced hippocampal astrocytosis and oxidative stress.

    Science.gov (United States)

    Zhu, Xinjian; Dong, Jingde; Shen, Kai; Bai, Ying; Zhang, Yuan; Lv, Xuan; Chao, Jie; Yao, Honghong

    2015-05-01

    The N-methyl-d-aspartate (NMDA) receptor plays an important role in the pathophysiology of several neurological diseases, including epilepsy. The present study investigated the effect of NMDA receptor NR2B subunits on pentylenetetrazole (PTZ)-kindling-induced pathological and biochemical events in mice. Our results showed that PTZ-kindling up-regulates the expression of NMDA receptor NR2B subunits in the hippocampus and that kindled mice were characterized by significant astrocytosis and neuron loss in the hippocampus. Oxidative stress, including excessive malondialdehyde (MDA) production and decreased enzymatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), were detected in the hippocampus after the mice were fully kindled. Additionally, expression of brain-derived neurotrophic factor (BDNF) in the hippocampus was found to be up-regulated in PTZ-kindled mice. However, selectively blocking NMDA receptor NR2B subunits by ifenprodil significantly suppressed PTZ-kindling-induced hippocampal astrocytosis, oxidative stress and neuron loss. Furthermore, blocking NMDA receptor NR2B subunits also abolished PTZ-kindling-induced BDNF expression. These results indicate that NMDA receptor NR2B subunits contribute to epilepsy-associated pathological and biochemical events, including hippocampal astrocytosis, oxidative stress and neuron loss, and these events might be correlated with up-regulation of BDNF expression.

  19. The role of NR2B containing NMDA receptor in place preference conditioned with morphine and natural reinforcers in rats.

    Science.gov (United States)

    Ma, Yao-Ying; Guo, Chang-Yong; Yu, Peng; Lee, David Yue-Wei; Han, Ji-Sheng; Cui, Cai-Lian

    2006-08-01

    It has been reported that N-methyl-D-aspartate (NMDA) receptor is implicated in drug addiction and antagonists of the NMDA receptor complex can inhibit the development and expression of conditioned place preference (CPP) induced by several addictive drugs, implying that this class of compounds might be considered as candidate for the treatment of substance abuse. To explore this possibility, it is important to evaluate whether the inhibitory effect of NMDA receptor antagonists would be confined to behaviors produced by drugs of abuse only, but not by natural reinforcers. According to the quantitative changes of NMDA receptor subunits, including NR1, NR2A, and NR2B, induced by diverse types of reinforcers, we chose NR2B subunit as the target of research. Experimental results showed that (1) an augmented expression of NR2B subunit was revealed by Western blotting in the nucleus accumbens (NAc) and the hippocampus in rats with CPP induced by morphine, but not by natural rewards such as food, novel environment and social interaction. (2) Ifenprodil, an antagonist highly selective for NR2B subunit of the NMDA receptor, produced a dose-dependent reduction in CPP induced by morphine and novel environment, but not that by food consumption and social interaction. Taking together, these findings suggested that NR2B containing NMDA receptor may be more involved with morphine reward rather than natural rewards, and that antagonism of NR2B may have a potential for the treatment of morphine abuse.

  20. Anti-NMDA receptor antibodies in patients with a first episode of schizophrenia

    Directory of Open Access Journals (Sweden)

    Masopust J

    2015-03-01

    Full Text Available Jirí Masopust,1,2 Ctirad Andrýs,3 Jan Bažant,1 Oldrich Vyšata,4 Kamil Kuca,5 Martin Vališ4 1Department of Psychiatry, Faculty of Medicine in Hradec Kralové, Charles University in Prague, University Hospital Hradec Králové, Hradec Králové, Czech Republic; 2National Institute of Mental Health, Klecany, Czech Republic; 3Institute of Clinical Immunology and Allergology, Charles University in Prague, Faculty of Medicine in Hradec Králové, and University Hospital Hradec Králové, Hradec Králové, Czech Republic; 4Department of Neurology, Charles University in Prague, Faculty of Medicine in Hradec Králové, and University Hospital Hradec Králové, Hradec Králové, Czech Republic; 5Biomedical Research Centrum, University Hospital Hradec Králové, Hradec Králové, Czech Republic Background: Encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDA-R is classified as an autoimmune disorder with psychotic symptoms, which are frequently dominant. However, it remains unclear how frequently NMDA-R antibodies lead to a condition that mimics psychosis and first-episode schizophrenia. In our work, we investigated the presence of antibodies against NMDA-R in patients with first-episode psychosis (FEP in comparison with healthy volunteers.Methods: This study included 50 antipsychotic-naïve patients with FEP (including 21 women and 50 healthy volunteers (including 21 women. The mean age of the patients was 27.4 (±7.4 years and that of the healthy controls was 27.0 (±7.3 years. Antibodies against NMDA-R in the serum were detected by immunofluorescence.Results: None of the investigated patients with an FEP and none of the healthy controls showed positive antibodies against NMDA-Rs.Conclusion: According to results of studies, a small proportion of patients with an FEP possess antibodies against NMDA-R. However, the extent to which this finding contributes to the etiopathogenesis of the response to antipsychotic medication and

  1. Characterising seizures in anti-NMDA-receptor encephalitis with dynamic causal modelling.

    Science.gov (United States)

    Cooray, Gerald K; Sengupta, Biswa; Douglas, Pamela; Englund, Marita; Wickstrom, Ronny; Friston, Karl

    2015-09-01

    We characterised the pathophysiology of seizure onset in terms of slow fluctuations in synaptic efficacy using EEG in patients with anti-N-methyl-d-aspartate receptor (NMDA-R) encephalitis. EEG recordings were obtained from two female patients with anti-NMDA-R encephalitis with recurrent partial seizures (ages 19 and 31). Focal electrographic seizure activity was localised using an empirical Bayes beamformer. The spectral density of reconstructed source activity was then characterised with dynamic causal modelling (DCM). Eight models were compared for each patient, to evaluate the relative contribution of changes in intrinsic (excitatory and inhibitory) connectivity and endogenous afferent input. Bayesian model comparison established a role for changes in both excitatory and inhibitory connectivity during seizure activity (in addition to changes in the exogenous input). Seizures in both patients were associated with a sequence of changes in inhibitory and excitatory connectivity; a transient increase in inhibitory connectivity followed by a transient increase in excitatory connectivity and a final peak of excitatory-inhibitory balance at seizure offset. These systematic fluctuations in excitatory and inhibitory gain may be characteristic of (anti NMDA-R encephalitis) seizures. We present these results as a case study and replication to motivate analyses of larger patient cohorts, to see whether our findings generalise and further characterise the mechanisms of seizure activity in anti-NMDA-R encephalitis.

  2. NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia

    OpenAIRE

    Anticevic, Alan; Repovš, Grega

    2015-01-01

    however, cognition involves large-scale brain systems with multiple interacting regions. A prominent feature of the human brainʼs global architecture is the anticorrelation of default-mode vs. task-positive systems. Here, we show that administration of an NMDA glutamate receptor antagonist, ketamine, disrupted the reciprocal relationship between these systems in terms of task-dependent activation and connectivity during performance of delayed working memory. Furthermore, the degree of this di...

  3. Effect of Electroacupuncture on Chronic Visceral Pain and Involvement of Spinal NMDA Receptor in IBS Rats

    Institute of Scientific and Technical Information of China (English)

    王智君; 李为民; 周娟; 陈颖波

    2009-01-01

    Objective:To clarify effect of electroacupuncture (EA) on relieving chronic visceral pain and the underlying neurobiological mechanism for such an effect,we observed the effect of EA on the Irritable bowel syndrome (IBS) rat and then examined spinal expression of N-methyl-D-aspartate (NMDA)receptor-1 in rats.Methods:Daily mechanical colon distention was performed on male Sprague-Dawley neonatal rats to produce IBS model.EA was applied at acupoints of Zusanli (ST 36) and Shangjuxu (ST 37)in each hind leg.Abdominal withdrawal reflex (AWR) assessment or rectus abdominis electromyograms (AEMG) recordings were then performed after EA treatment.The mRNA expression of the NMDA subtype of glutamate receptors in the spinal dorsal horn (L4-5) before and after EA was investigated by RT-PCR analysis in IBS rats.Results:The results demonstrated that EA could significantly decreased both AWR scores from behavioral test and AEMG discharges from electrophysiological recording in IBS model rats elicited by colorectal distension (CRD) stimuli with strengths of 20,40,60 and 80 mmHg,respectively (P<0.05).Meanwhile there was a significant decrease in mRNA expression of NMDA receptor-1 in the spinal dorsal horn of IBS rats treated by EA (P<0.05),but no such effect was observed in IBS rats treated by sham EA (inserting needles without electrical stimulation).Conclusion:These results indicate that EA can relieve chronic visceral hyperalgesia in IBS rats and this effect might be correlated with the down-regulation of NMDA receptor-1 in the dorsal hom of the spinal cord.

  4. Effect of Electroacupuncture on Chronic Visceral Pain and Involvement of Spinal NMDA Receptor in IBS Rats

    Institute of Scientific and Technical Information of China (English)

    王智君; 李为民; 周娟; 陈颖波

    2008-01-01

    Objective: To clarify effect of electroacupuncture (EA) on relieving chronic visceral pain and the underlying neurobiological mechanism for such an effect, we observed the effect of EA on the Irritable bowel syndrome (IBS) rat and then examined spinal expression of N-methyl-D-aspartate (NMDA) receptor-1 in rats. Methods: Daily mechanical colon distention was performed on male Sprague-Dawley neonatal rats to produce IBS model. EA was applied at acupoints of Zusanli (ST 36) and Shangjuxu (ST 37) in each hind leg. Abdominal withdrawal reflex (AWR) assessment or rectus abdominis electromyograms (AEMG) recordings were then performed after EA treatment. The mRNA expression of the NMDA subtype of glutamate receptors in the spinal dorsal horn (L4-5) before and after EA was investigated by RT-PCR analysis in IBS rats. Results: The results demonstrated that EA could significantly decreased both AWR scores from behavioral test and AEMG discharges from electrophysiological recording in IBS model rats elicited by colorectal distension (CRD) stimuli with strengths of 20, 40, 60 and 80 mmHg, respectively (P<0.05). Meanwhile there was a significant decrease in mRNA expression of NMDA receptor-1 in the spinal dorsal horn of IBS rats treated by EA (P<0.05), but no such effect was observed in IBS rats treated by sham EA (inserting needles without electrical stimulation). Conclusion: These results indicate that EA can relieve chronic visceral hyperalgesia in IBS rats and this effect might be correlated with the down-regulation of NMDA receptor- 1 in the dorsal horn of the spinal cord.

  5. INVOLVEMENT OF PRE- AND POSTSYNAPTIC NMDA RECEPTORS AT LOCAL CIRCUIT INTERNEURON CONNECTIONS IN RAT NEOCORTEX

    OpenAIRE

    De-May, C.L.; Ali, A.B.

    2013-01-01

    To investigate the involvement of N-Methyl-D-aspartate (NMDA) receptors in local neocortical synaptic transmission, dual whole-cell recordings – combined with biocytin labelling – were obtained from bitufted adapting, multipolar adapting or multipolar non-adapting interneurons and pyramidal cells in layers II–V of rat (postnatal days 17–22) sensorimotor cortex. The voltage dependency of the amplitude of Excitatory postsynaptic potentials (EPSPs) received by the three types of interneuron appe...

  6. Involvement of hippocampal NMDA receptors in retention of shuttle avoidance conditioning in rats

    Directory of Open Access Journals (Sweden)

    Roesler R.

    1998-01-01

    Full Text Available The purpose of this research was to evaluate the role of hippocampal N-methyl-D-aspartate (NMDA receptors in acquisition and consolidation of memory during shuttle avoidance conditioning in rats. Adult male Wistar rats were surgically implanted with cannulae aimed at the CA1 area of the dorsal hippocampus. After recovery from surgery, animals were trained and tested in a shuttle avoidance apparatus (30 trials, 0.5-mA footshock, 24-h training-test interval. Immediately before or immediately after training, animals received a bilateral intrahippocampal 0.5-µl infusion containing 5.0 µg of the NMDA competitive receptor antagonist aminophosphonopentanoic acid (AP5 or vehicle (phosphate-buffered saline, pH 7.4. Infusion duration was 2 min per side. Pre-training infusion of AP5 impaired retention test performance (mean ± SEM number of conditioned responses (CRs during retention test session was 16.47 ± 1.78 in the vehicle group and 9.93 ± 1.59 in the AP5 group; P<0.05. Post-training infusion of AP5 did not affect retention (mean ± SEM number of conditioned responses during retention test session was 18.46 ± 1.94 in the vehicle group and 20.42 ± 2.38 in the AP5 group; P>0.10. This impairment could not be attributed to an effect on acquisition, motor activity or footshock sensitivity since AP5 affected neither training session performance measured by the number of CRs nor the number of intertrial crossings during the training session. These data suggest that NMDA receptors in the hippocampus are critical for retention of shuttle avoidance conditioning, in agreement with previous evidence showing a role of NMDA receptors in fear memory.

  7. Heterotopic ossification following anti-NMDA receptor encephalitis: a case report

    OpenAIRE

    Wang, Dongmei; Wang, Shengnan; Huang, Xiaoxian; Wang, Qun

    2016-01-01

    Background Heterotopic ossification (HO) is defined as the formation of true bone tissue in non-osseous tissues. HO may occur under several conditions such as soft tissue injury, central nervous system injury and many other diseases like arthopathies, and vasculopathies. The underlying mechanisms of HO are not well elucidated. Anti-NMDA receptor encephalitis is a newly recognized autoimmune mediated disease which is predominant in young female patients with ovarian teratomas. Encephalitis com...

  8. Involvement of pre- and postsynaptic NMDA receptors at local circuit interneuron connections in rat neocortex

    OpenAIRE

    De-May, C.L.; Ali, A. B.

    2013-01-01

    To investigate the involvement of N-Methyl-D-aspartate (NMDA) receptors in local neocortical synaptic transmission, dual whole-cell recordings – combined with biocytin labelling – were obtained from bitufted adapting, multipolar adapting or multipolar non-adapting interneurons and pyramidal cells in layers II–V of rat (postnatal days 17–22) sensorimotor cortex. The voltage dependency of the amplitude of Excitatory postsynaptic potentials (EPSPs) received by the three types of interneuron appe...

  9. Role of AMPA and NMDA receptors and back-propagating action potentials in spike timing-dependent plasticity.

    Science.gov (United States)

    Fuenzalida, Marco; Fernández de Sevilla, David; Couve, Alejandro; Buño, Washington

    2010-01-01

    The cellular mechanisms that mediate spike timing-dependent plasticity (STDP) are largely unknown. We studied in vitro in CA1 pyramidal neurons the contribution of AMPA and N-methyl-d-aspartate (NMDA) components of Schaffer collateral (SC) excitatory postsynaptic potentials (EPSPs; EPSP(AMPA) and EPSP(NMDA)) and of the back-propagating action potential (BAP) to the long-term potentiation (LTP) induced by a STDP protocol that consisted in pairing an EPSP and a BAP. Transient blockade of EPSP(AMPA) with 7-nitro-2,3-dioxo-1,4-dihydroquinoxaline-6-carbonitrile (CNQX) during the STDP protocol prevented LTP. Contrastingly LTP was induced under transient inhibition of EPSP(AMPA) by combining SC stimulation, an imposed EPSP(AMPA)-like depolarization, and BAP or by coupling the EPSP(NMDA) evoked under sustained depolarization (approximately -40 mV) and BAP. In Mg(2+)-free solution EPSP(NMDA) and BAP also produced LTP. Suppression of EPSP(NMDA) or BAP always prevented LTP. Thus activation of NMDA receptors and BAPs are needed but not sufficient because AMPA receptor activation is also obligatory for STDP. However, a transient depolarization of another origin that unblocks NMDA receptors and a BAP may also trigger LTP.

  10. Cytisine confers neuronal protection against excitotoxic injury by down-regulating GluN2B-containing NMDA receptors.

    Science.gov (United States)

    Li, Yu-Jiao; Yang, Qi; Zhang, Kun; Guo, Yan-Yan; Li, Xu-Bo; Yang, Le; Zhao, Ming-Gao; Wu, Yu-Mei

    2013-01-01

    Cytisine (CYT), one of the principal bioactive components derived from the seeds of Cytisus laborinum L, has been widely used for central nervous system (CNS) diseases treatment. The present study investigated the protective effect of CYT on cultured cortical neural injury induced by N-methyl-d-aspartate (NMDA). Our data showed that CYT conferred protective effect against loss of cellular viability induced by brief exposure to 200 μM NMDA in a concentration-dependent manner. CYT significantly inhibited the neuronal apoptosis induced by NMDA exposure by reversing intracellular Ca(2+) overload and balancing Bcl-2 and Bax expression levels. Furthermore, CYT significantly reversed the up-regulation of GluN2B-containing NMDA receptors by exposure to NMDA, but it did not affect the level of GluN2A-containing NMDA receptors. These findings suggest that CYT protects cortical neurons, at least partially, by inhibiting the level of GluN2B-containing NMDA receptors and regulating Bcl-2 family.

  11. NMDA receptor activity and the transmission of sensory input into motor output in introverts and extraverts.

    Science.gov (United States)

    Rammsayer, Thomas H

    2003-05-01

    Recent research suggests that individual differences in brain dopamine functioning may be related to the personality dimension of extraversion. The major goal of the present study was to answer the question of whether a pharmacologically induced change in glutamatergic NMDA receptor activity would also differentially affect the transmission of sensory input into motor out-put in introverts and extraverts. Therefore, in a double-blind within-subjects design, either 30 mg of the NMDA receptor antagonist memantine or placebo were administered to 48 healthy male volunteers before performing a choice reaction-time task. In introverts, memantine caused a pronounced increase in lift-off time (i.e., the time required to lift the finger from a home button) compared to that in extraverts, whereas movement time (i.e., the time required to move the finger from the home button to a response button) was decreased in both groups. The pattern of results suggests that extraversion-related differential sensitivity to pharmacologically induced changes in NMDA receptor activity is limited to functions that involve an interaction between the glutamatergic and dopaminergic systems.

  12. Cochlear NMDA Receptors as a Therapeutic Target of Noise-Induced Tinnitus

    Directory of Open Access Journals (Sweden)

    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.

  13. Steroid unresponsive anti-NMDA receptor encephalitis during pregnancy successfully treated with plasmapheresis.

    Science.gov (United States)

    Shahani, Lokesh

    2015-04-29

    Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is an autoimmune disorder resulting in neurological and psychiatric symptoms. It is rare during pregnancy and treatment is extremely challenging as little data exist to guide management. A 26-year-old woman presented at 22 weeks of gestation with intermittent headache and an acute episode of bizarre behaviour and grandiose delusions resulting in hospitalisation. The patient was worked up for encephalitis and was found to have anti-NMDA receptor antibody in cerebrospinal fluid as well as in serum. She was initially treated with high-dose steroids but failed to improve clinically and serologically. She was then treated with plasmapheresis and showed clinical and serological response. She had a successful delivery at 37 weeks and the baby did not show serological evidence of disease. This case adds to the sparse literature of anti-NMDA receptor encephalitis during pregnancy and adds to the differential diagnosis of new onset psychiatric symptoms during pregnancy.

  14. The hippocampal NMDA receptors may be involved in acquisition, but not expression of ACPA-induced place preference.

    Science.gov (United States)

    Nasehi, Mohammad; Sharaf-Dolgari, Elmira; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

    2015-12-01

    Numerous studies have investigated the functional interactions between the endocannabinoid and glutamate systems in the hippocampus. The present study was made to test whether N-methyl-D-aspartate (NMDA) receptors of the CA1 region of the dorsal hippocampus (CA1) are implicated in ACPA (a selective cannabinoid CB1 receptor agonist)-induced place preference. Using a 3-day schedule of conditioning, it was found that intraperitoneal (i.p.) administration of ACPA (0.02mg/kg) caused a significant conditioned place preference (CPP) in male albino NMRI mice. Intra-CA1 microinjection of the NMDA or D-[1]-2-amino-7-Phosphonoheptanoic acid (D-AP7, NMDA receptor antagonist), failed to induce CPP or CPA (condition place aversion), while NMDA (0.5μg/mouse) potentiated the ACPA (0.01mg/kg)-induced CPP; and D-AP7 (a specific NMDA receptor antagonist; 0.5 and 1μg/mouse) reversed the ACPA (0.02mg/kg)-induced CPP. Moreover, microinjection of different doses of glutamatergic agents on the testing day did not alter the expression of ACPA-induced place preference. None of the treatments, with the exception of ACPA (0.04mg/kg), had an effect on locomotor activity. In conclusion, these observations provide evidence that glutamate NMDA receptors of the CA1 may be involved in the potentiation of ACPA rewarding properties in the acquisition, but not expression, of CPP in mice.

  15. Blockade of cannabinoid CB receptor function protects against in vivo disseminating brain damage following NMDA-induced excitotoxicity

    DEFF Research Database (Denmark)

    Hansen, H.H.; Ramos, J.A.; Fernández-Ruiz, J.

    2002-01-01

    The ability of cannabinoid CB, receptors to influence glutamatergic excitatory neurotransmission has fueled interest in how these receptors and their endogenous ligands may interact in conditions of excitotoxic insults. The present study characterized the impact of stimulated and inhibited CB...... 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......-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...

  16. Non-tumor-Associated Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis in Chinese Girls With Positive Anti-thyroid Antibodies.

    Science.gov (United States)

    Guan, Wenjuan; Fu, Zhenqiang; Zhang, Hui; Jing, Lijun; Lu, Jingjing; Zhang, Jing; Lu, Hong; Teng, Junfang; Jia, Yanjie

    2015-10-01

    Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a new category of autoimmune encephalitis associated with anti-NMDA receptor antibodies. The disease was first described in 2007, and it predominantly affects young women with or without ovarian teratomas. Most patients typically present with seizures, a decreased consciousness level, dyskinesia, autonomic dysfunction, and psychiatric symptoms. The presence of anti-thyroid antibodies in non-tumor-associated anti-NMDA receptor encephalitis was first described in 2010. Additionally, anti-thyroid antibodies were found in teratoma-associated anti-NMDA receptor encephalitis. We report the cases of 3 Chinese girls with non-tumor-associated anti-NMDA receptor encephalitis with positive anti-thyroid antibodies. We followed up the details of their titers and suggest that anti-thyroid antibodies were an indicator of autoimmune predisposition in the development of non-tumor-associated anti-NMDA receptor encephalitis.

  17. Pathological reorganization of NMDA receptors subunits and postsynaptic protein PSD-95 distribution in Alzheimer's disease.

    Science.gov (United States)

    Leuba, Genevieve; Vernay, Andre; Kraftsik, Rudolf; Tardif, Eric; Riederer, Beat Michel; Savioz, Armand

    2014-01-01

    In Alzheimer's disease (AD), synaptic alterations play a major role and are often correlated with cognitive changes. In order to better understand synaptic modifications, we compared alterations in NMDA receptors and postsynaptic protein PSD-95 expression in the entorhinal cortex (EC) and frontal cortex (FC; area 9) of AD and control brains. We combined immunohistochemical and image analysis methods to quantify on consecutive sections the distribution of PSD-95 and NMDA receptors GluN1, GluN2A and GluN2B in EC and FC from 25 AD and control cases. The density of stained receptors was analyzed using multivariate statistical methods to assess the effect of neurodegeneration. In both regions, the number of neuronal profiles immunostained for GluN1 receptors subunit and PSD-95 protein was significantly increased in AD compared to controls (3-6 fold), while the number of neuronal profiles stained for GluN2A and GluN2B receptors subunits was on the contrary decreased (3-4 fold). The increase in marked neuronal profiles was more prominent in a cortical band corresponding to layers 3 to 5 with large pyramidal cells. Neurons positive for GluN1 or PSD-95 staining were often found in the same localization on consecutive sections and they were also reactive for the anti-tau antibody AD2, indicating a neurodegenerative process. Differences in the density of immunoreactive puncta representing neuropile were not statistically significant. Altogether these data indicate that GluN1 and PSD-95 accumulate in the neuronal perikarya, but this is not the case for GluN2A and GluN2B, while the neuropile compartment is less subject to modifications. Thus, important variations in the pattern of distribution of the NMDA receptors subunits and PSD-95 represent a marker in AD and by impairing the neuronal network, contribute to functional deterioration.

  18. Selective 5-HT7 Receptor Activation May Enhance Synaptic Plasticity Through N-methyl-D-aspartate (NMDA) Receptor Activity in the Visual Cortex.

    Science.gov (United States)

    Xiang, Kangjian; Zhao, Xuefei; Li, Youjun; Zheng, Liang; Wang, Jue; Li, Yan-Hai

    2016-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that modulates N-methyl-D-aspartate (NMDA) receptor activity by binding to several different 5-HT receptor subtypes. In the present study, we used whole-cell patch-clamp recordings in transverse slice preparations to test the role of 5-HT receptors in modulating the NMDA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in layer II/III pyramidal neurons of the rat visual cortex. We found that the NMDA receptor-mediated component of mEPSCs could be potentiated by exogenously applied 5-HT. Similar results were obtained by exogenously applied 5-CT or 8-OH-DPAT (the 5-HT1A and 5-HT7 receptor agonist). A specific antagonist for the 5-HT7 receptor, SB-269970, completely blocked the increase in NMDA receptor-mediated component of mEPSCs by 5-CT or 8- OH-DPAT. Moreover, the selective 5-HT1A receptor antagonist, WAY-100135, displayed no influence on the enhancement in NMDA receptor-mediated component of mEPSCs by 5-CT or 8-OHDPAT. These results indicated that the increase in NMDA receptor-mediated component of mEPSCs by 5-HT in layer II/III pyramidal neurons of the young rat visual cortex requires activation of 5-HT7 receptors, but not 5-HT1A receptors. These observations might be clinically relevant to schizophrenia and Alzheimer's disease (AD), where enhancing NMDA receptor-mediated neurotransmission is considered to be a promising strategy for treatment of these diseases.

  19. NMDA Receptor Antagonist Ketamine Distorts Object Recognition by Reducing Feedback to Early Visual Cortex.

    Science.gov (United States)

    van Loon, Anouk M; Fahrenfort, Johannes J; van der Velde, Bauke; Lirk, Philipp B; Vulink, Nienke C C; Hollmann, Markus W; Scholte, H Steven; Lamme, Victor A F

    2016-05-01

    It is a well-established fact that