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Event: 201

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Binding of antagonist, NMDA receptors

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Binding of antagonist, NMDA receptors

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Cell term

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Binding of antagonist to NMDARs impairs cognition MolecularInitiatingEvent Anna Price (send email) Open for citation & comment TFHA/WNT Endorsed
Binding of antagonist to NMDARs can lead to neuroinflammation and neurodegeneration MolecularInitiatingEvent Florianne Tschudi-Monnet (send email) Open for citation & comment TFHA/WNT Endorsed


This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

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Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Biological state: L-glutamate (Glu) is a neurotransmitter with important role in the regulation of brain development and maturation processes. Two major classes of Glu receptors, ionotropic and metabotropic, have been identified. Due to its physiological and pharmacological properties, Glu activates three classes of ionotropic receptors named: α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA receptors), 2-carboxy-3-carboxymethyl-4-isopropenylpyrrolidine (kainate receptors) and N-methyl-D-aspartate (NMDA receptors, NMDARs), which transduce the postsynaptic signal. Ionotropic glutamate receptors are integral membrane proteins formed by four large subunits that compose a central ion channel pore. In case of NMDA receptors, two NR1 subunits are combined with either two NR2 (NR2A, NR2B, NR2C, NR2D) subunits and less commonly are assembled together with a combination of NR2 and NR3 (A, B) subunits (reviewed in Traynelis et al., 2010). To be activated NMDA receptors require simultaneous binding of both glutamate to NR2 subunits and of glycine to either NR1 or NR3 subunits that provide the specific binding sites named extracellular ligand-binding domains (LBDs). Apart from LBDs, NMDA receptor subunits contain three more domains that are considered semiautonomous: 1) the extracellular amino-terminal domain that plays important role in assembly and trafficking of these receptors; 2) the transmembrane domain that is linked with LBD and contributes to the formation of the core of the ion channel and 3) the intracellular carboxyl-terminal domain that influences membrane targeting, stabilization, degradation and post-translation modifications.

Biological compartments: The genes of the NMDAR subunits are expressed in various tissues and are not only restricted to the nervous system. The level of expression of these receptors in neuronal and non-neuronal cells depends on: transcription, chromatin remodelling, mRNA levels, translation, stabilization of the protein, receptor assembly and trafficking, energy metabolism and numerous environmental stimuli (reviewed in Traynelis et al., 2010).

In hippocampus region of the brain, NR2A and NR2B are the most abundant NR2 family subunits. NR2A-containing NMDARs are mostly expressed synaptically, while NR2B-containing NMDARs are found both synaptically and extrasynaptically (Tovar and Westbrook, 1999).

General role in biology: NMDA receptors, when compared to the other Glu receptors, are characterized by higher affinity for Glu, slower activation and desensitisation kinetics, higher permeability for calcium (Ca2+) and susceptibility to potential-dependent blockage by magnesium ions (Mg2+). NMDA receptors are involved in fast excitatory synaptic transmission and neuronal plasticity in the central nervous system (CNS). Functions of NMDA receptors:

1. They are involved in cell signalling events converting environmental stimuli to genetic changes by regulating gene transcription and epigenetic modifications in neuronal cells (Cohen and Greenberg, 2008).

2. In NMDA receptors, the ion channel is blocked by extracellular Mg2+ and Zn2+ ions, allowing the flow of Na+ and Ca2+ ions into the cell and K+ out of the cell which is voltage-dependent. Ca2+ flux through the NMDA receptor is considered to play a critical role in pre- and post-synaptic plasticity, a cellular mechanism important for learning and memory (Barria and Malinow, 2002).

3. The NMDA receptors have been shown to play an essential role in the strengthening of synapses and neuronal differentiation, through long-term potentiation (LTP), and the weakening of synapses, through long-term depression (LTD). All these processes are implicated in the memory and learning function (Barria and Malinow, 2002).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible? There is no OECD advised method for measuring NMDA receptor binding of antagonists. However, there are methods described in the scientific literature that allow measuring:

1. Ex vivo: The most common assay used is the NMDA receptor (MK801 site) radioligand competition binding assays (Reynolds, 2001; Gao et al., 2013;; This assay is based on the use of the most potent and specific antagonist of this receptor, MK801 that is used to detect and differentiate agonists and antagonists (competitive and non-competitive) that bind to this specific site of the receptor. Also radioligand competition binding assay can be performed using D, L-(E)-2-amino-4-[3H]-propyl-5-phosphono-3-pentenoic acid ([3H]-CGP 39653), a high affinity selective antagonist at the glutamate site of NMDA receptor, which is a quantitative autoradiography technique (Mugnaini et al., 1996). D-AP5, a selective N-methyl-D-aspartate (NMDA) receptor antagonist that competitively inhibits the glutamate binding site of NMDA receptors, can be studied by evoked electrical activity measurements. AP5 has been widely used to study the activity of NMDA receptors particularly with regard to researching synaptic plasticity, learning, and memory (Evans et al.,1982; Morris, 1989).

2. In silico: The prediction of NMDA receptor targeting is achievable by combining database mining, molecular docking, structure-based pharmacophore searching, and chemical similarity searching methods together (Korkut and Varnali, 2003; Koutsoukos et al., 2011; Gao et al., 2013; Mazumder and Borah, 2014; Chtitaa et al., 2015).

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

The evolution of NMDAR subunits (NR1, NR2, NR3) is well-conserved throughout different species from lower organism to mammals, including humans (Ewald and Cline, 2009; Tikhonov and Magazanik, 2009; Koo and Hampson, 2010; Teng et al., 2010; Flores-soto et al., 2012).

Many of the binding sites for the noncompetitive or competitive antagonists e.g. for binding of dizocilpine (MK-801), phencyclidine, D-2-amino-5-phosphonopentanoate (AP5) and 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (R-CPP) are also conserved in Drosophila (reviewed in Xia and Chiang, 2009).

Cellular membranes can be prepared from different brain areas of distinct species. Using [3H]MK-801, high affinity binding sites for MK-801 were detected in membranes of the rat brain (Woodruff et al., 1987). The same binding assay has been used in preparations from human brains mostly from brain of patients with neurodegenerative disorders (Slater et al., 1993) as well as from brain of different marine, avian species (Scheuhammer et al., 2008) and insects (Eldefrawi et al., 1993).

Evidence for Perturbation by Stressor

Overview for Molecular Initiating Event

When a specific MIE can be defined (i.e., the molecular target and nature of interaction is known), in addition to describing the biological state associated with the MIE, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to list stressors known to trigger the MIE and provide evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). Depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). Known stressors should be included in the MIE description, but it is not expected to include a comprehensive list. Rather initially, stressors identified will be exemplary and the stressor list will be expanded over time. For more information on MIE, please see pages 32-33 in the User Handbook.

Glu and glycine are endogenous agonists that bind to LBD of specific NMDA receptor subunits. In this binding site numerous competitive exogenous antagonists have been identified to cause closure of binding site and inhibition of NMDA receptor (reviewed in Traynelis et al., 2010). Here, are listed some known competitive antagonists for NMDA receptor, some of them are specific to NR1 subunit and some to NR2 subunit:

α-AA, α-aminoadipate;

5,7-DCKA, 5,7-dichlorokynurenic acid;

7-CKA, 7-chlorokynurenic acid;

ACEA-1011, 5-chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione;

ACEA-1021, licostinel;

AP5, 2-amino-5-phosphonopentanoate;

AP7, 2-amino-7-phosphonopentanoate;

CGP-61594, (±)-trans-4-[2-(4-azidophyenyl)acetylamino]-5,7-dichloro-1,2,3,4-tetrahydroquinoline-2-carboxylic acid;

CGP-40116, d-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid;

CGP-43487, d-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid methyl ester;

CGP-58411, 7-chloro-4-hydroxy-3-phenyl-1H-quinolin-2-one;

CGS-19755, (2R,4S)-4-(phosphonomethyl)piperidine-2-carboxylic acid;

CPP, 4-(3-phosphonopropyl) pizerazine-2-carboxylic acid;

GV150,526A, gavestinel;

GV196,771A, (E)-4,6-dichloro-3-[(2-oxo-1-phenyl-3-pyrrolidinylidene)methyl]-1H-indole-2-carboxylic acid;

L-689,560, 4-trans-2-carboxy-5,7-dichloro-4-phenylaminocarbonylamino-1,2,3,4-tetrahydroquinoline;

L-701,324, 7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(1H)-quinolone;

MDL105,519, (E)-3-(2-phenyl-2-carboxyethenyl)-4, 6-dichloro-1H-indole-2-carboxylic acid;

PBPD, (2S,3R)-1-(biphenyl-4-carbonyl)piperazine-2,3-dicarboxylic acid;

PMPA, (R,S)-4-(phosphonomethyl)-piperazine-2-carboxylic acid;

PPDA, (2S,3R)-1-(phenanthren-2-carbonyl)piperazine-2,3-dicarboxylic acid

Besides competitive antagonists, noncompetitive antagonists have also been designed like phenylethanolamine ifenprodil that interacts with the NR2B extracellular amino-terminal domain. It has been suggested that they act by stabilizing an agonist-bound state in which the receptor has a low open probability. Other more potent derivatives of ifenprodil are: α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidine propanol (Ro 25-6981), 1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol (Ro 63-1908), besonprodil (CI-1041), and traxoprodil mesylate (CP-101,606). Ethanol has been proposed to be a noncompetitive antagonist of NMDA receptors, binding to NR2 subunit (Nagy, 2008). Inhibition of NMDA receptor function by ethanol and interactions between ethanol and the noncompetitive NMDA receptor antagonist ifenprodil have been examined in neocortical neurons from rat and human embryonic kidney (HEK) 293 cells expressing recombinant NMDA receptors (Lovinger, 1995). Recently, a structural model has been suggested that predicts the presence of four sites of ethanol action on the NMDA receptor, each containing four pairs of positions in the NR1/NR2 subunits (reviewed in Chandrasekar, 2013). Some other antagonists can become trapped in the pore of the NMDA receptor after channel closure and these antagonists are called uncompetitive or trapping blockers. The most well studied NMDA receptor uncompetitive antagonists are Mg2+, polyamines, phencyclidine, ketamine, MK-801, memantine, amantadine, pentamidine, 9-tetrahydroaminoacridine, dextromethorphan, and its metabolite dextrorphan. MK-801 has been shown to prevent toluene-induced alterations in pattern-elicited visual-evoked potentials in vivo, suggesting the possibility that the binding site of toluene might be common with the one of MK-801 (Bale et al., 2007). However, another study suggests that toluene interference with the NMDA receptor might not be exclusively because of the binding to the channel pore (Smothers and Woodward, 2007) but it may involve some other binding sites. Lead (Pb2+) is considered a voltage independent antagonist of NMDA receptors and it is believed that possibly shares the same binding site with Zn2+ (reviewed in Neal and Guilarte, 2010; Traynelis et al., 2010). However, studies done in recombinant NR2A- and NR2B- containing NMDA receptors with mutated Zn2+ binding sites exhibit that additional structural elements, different from those important for Zn2+ binding are involved in Pb2+ binding site (reviewed in Neal and Guilarte, 2010). Similarly, there are contradicting experimental evidence and disagreement about Pb2+'s role as competitive or non-competitive antagonist (Neal and Guilarte, 2010). Pb2+ -induced inhibition of NMDAR during synaptogenesis in hippocampal neurons altered synaptic NMDAR composition, resulting in a decrease in NR2A-containing NMDARs at the established synapses (Neal et al., 2011).


List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide ( (OECD, 2015). More help

Bale AS, Jackson MD, Krantz QT, Benignus VA, Bushnell PJ, Shafer TJ, Boyes WK. (2007) Evaluating the NMDA-glutamate receptor as a site of action for toluene, in vivo. Toxicol Sci. 98: 159-66.

Barria A, Malinow R. (2002) Subunit-specific NMDA receptor trafficking to synapses. Neuron 35: 345-353.

Chandrasekar R. (2013) Alcohol and NMDA receptor: current research and future direction. Front Mol Neurosci. 6: 14.

Chtitaa S, Larifb M, Ghamalia M, Bouachrinec M, Lakhlifia T. (2015) DFT-based QSAR Studies of MK801 derivatives for non competitive antagonists of NMDA using electronic and topological descriptors. Journal of Taibah University for Science. 9: 143-154.

Cohen S, Greenberg ME. (2008) Communication between the synapse and the nucleus in neuronal development, plasticity, and disease. Ann Rev Cell Dev Biol 24: 183-209.

Eldefrawi ME, Anis NA, Eldefrawi AT. (1993) Glutamate receptor inhibitors as potential insecticides. Arch Insect Biochem Physiol. 22: 25-39.

Evans RH, Francis AA, Jones AW, Smith DA, Watkins JC. (1982) The Effects of a Series of ω-Phosphonic α-Carboxylic Amino Acids on Electrically Evoked and Excitant Amino Acid-Induced Responses in Isolated Spinal Cord Preparations. Br J Pharmac. 75: 65-75.

Ewald RC, Cline HT. (2009) Cloning and phylogentic analysis of NMDA receptor subunits NR1, NR2A and NR2B in Xenopus laevis tadpoles. Front Mol Neurosci. 2: 4.

Flores-soto ME, Chaparro-Huerta V, Escoto-Delgadillo M, Vazuez-Valls E, Gonzalez-Castaneda RE, Beas-Zarate C. (2012) Structure and function of NMDA-type glutamate receptor subunits. Neurologia 27: 301-310.

Gao L, Fang JS, Bai XY, Zhou D, Wang YT, Liu AL, Du GH. (2013) In silico Target Fishing for the Potential Targets and Molecular Mechanisms of Baicalein as an Antiparkinsonian Agent: Discovery of the Protective Effects on NMDA Receptor-Mediated Neurotoxicity. Chem Biol Drug Des. 81: 675-87.

Koo JCP, Hampson DR. (2010) Phylogenic and evolutionary analysis of glutamate receptor based on extant invertebrate genes. JULS 1: 42-48.

Korkut A, Varnali T. (2003) Quantitative structure activity relationship (QSAR) of competitive N-methyl-D-aspartate (NMDA) antagonists. Mol Phys 101: 3285-3291.

Koutsoukas A, Simms B, Kirchmair J, Bond PJ, Whitmore AV, Zimmer S, Young MP, Jenkins JL, Glick M, Glen RC, Bender A. (2011) From in silico target prediction to multi-target drug design: current databases, methods and applications. J Proteomics 74: 2554-2574.

Lovinger DM. (1995) Developmental decrease in ethanol inhibition of N-methyl-D-aspartate receptors in rat neocortical neurons: relation to the actions of ifenprodil. J Pharmacol Exp Ther. 274: 164-172.

Mazumder MK, Borah A. (2014) Piroxicam inhibits NMDA receptor-mediated excitotoxicity through allosteric inhibition of the GluN2B subunit: An in silico study elucidating a novel mechanism of action of the drug. Medical Hypotheses 83: 740–746.

Morris RJ. (1989) Synaptic Plasticity and Learning: Selective Impairment of Learning in Rats and Blockade of Long-Term Potentiation in vivo by the N-Methyl-D-Aspartate Receptor Antagonist AP5. J Neurosci 9: 3040-3057.

Mugnaini M, van Amsterdam FT, Ratti E, Trist DG, Bowery NG. (1996) Regionally different N-methyl-D-aspartate receptors distinguished by ligand binding and quantitative autoradiography of [3H]-CGP 39653 in rat brain. Br J Pharmacol 119: 819–828.

Nagy J. (2008) Alcohol related changes in regulation of NMDA receptor functions. Curr Neuropharmacol 6: 39-54.

Neal AP, Guilarte TR. (2010) Molecular Neurobiology of Lead (Pb2+): Effects on Synaptic Function. Mol Neurobiol. 42: 151-160.

Neal AP. Worley PF. Guilarte TR (2011) Lead exposure during synaptogenesis alters NMDA receptor targeting via NMDA receptor inhibition. Neurotoxicology. 32:281-289.

Nihei MK, Guilarte TR. (1999) NMDAR-2A subunit protein expression is reduced in the hippocampus of rats exposed to Pb2+ during development. Brain Res Mol Brain Res. 66: 42-49.

Reynolds IJ. (2001) [3H](+)MK801 radioligand binding assay at the N-methyl-D-aspartate receptor. Curr Protoc Pharmacol. Chapter 1:Unit 1.20. doi: 10.1002/0471141755.ph0120s11.

Scheuhammer AM, Basu N, Burgess NM, Elliott JE, Campbell GD, Wayland M, Champoux L, Rodrigue J. (2008) Relationships among mercury, selenium, and neurochemical parameters in common loons (Gavia immer) and bald eagles (Haliaeetus leucocephalus). Ecotoxicology 17: 93-101.

Slater P, McConnell SE, D'Souza SW, Barson AJ. (1993) Postnatal changes in N-methyl-D-aspartate receptor binding and stimulation by glutamate and glycine of [3H]-MK-801 binding in human temporal cortex. Br J Pharmacol. 108: 1143-1149.

Smothers CT, Woodward JJ. (2007) Pharmacological characterization of glycine-activated currents in HEK 293 cells expressing N-methyl-d-aspartate NR1 and NR3 subunits. J Pharmacol Exp Ther. 322: 739-748.

Teng H, Cai W, Zhou L, Zhang J, Liu Q, Wang Y, et al. (2010) Evolutionary mode of functional divergence of vertebrate NMDA receptor subunit 2 Genes. PLoS ONE. 5(10): e13342.

Tikhonov DB, Magazanik LG. (2009) Origin and molecular evolution of ionotropic glutamate receptors. Neurosci Behav Physiol. 39: 763-772.

Tovar KR, Westbrook GL. (1999) The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J Neurosci. 19: 4180–4188.

Traynelis S, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R. (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev. 62: 405-496.

Woodruff GN, Foster AC, Gill R, Kemp JA, Wong EH, Iversen LL. (1987) The interaction between MK-801 and receptors for N-methyl-D-aspartate: functional consequences. Neuropharmacology 26(7B): 903-909.

Xia S, Chiang AS. (2009) NMDA Receptors in Drosophila. In: Van Dongen AM, editor. Biology of the NMDA Receptor. Boca Raton (FL): CRC Press; Chapter 10. Available from: