Editing NMDA receptor (section)

==Clinical significance==
NMDAR antagonists like [[ketamine]], [[esketamine]], [[tiletamine]], [[phencyclidine]], [[nitrous oxide]], and [[xenon]] are used as [[general anesthetic]]s. These and similar drugs like [[dextromethorphan]] and [[methoxetamine]] also produce [[dissociative drug|dissociative]], [[hallucinogen]]ic, and [[euphoriant]] effects and are used as [[recreational drug]]s.

NMDAR-targeted compounds, including ketamine, [[esketamine]] (JNJ-54135419), [[rapastinel]] (GLYX-13), [[apimostinel]] (NRX-1074), [[AGN-241751|zelquistinel]] (AGN-241751), [[4-chlorokynurenine]] (AV-101), and [[rislenemdaz]] (CERC-301, MK-0657), are under development for the treatment of [[mood disorder]]s, including [[major depressive disorder]] and [[treatment-resistant depression]].<ref name="Flight2013" /><ref name="VécseiSzalárdy2012" /><ref name="issn2168-9709">{{cite journal | vauthors = Wijesinghe R | year = 2014 | title = Emerging Therapies for Treatment Resistant Depression | journal = Ment Health Clin | volume = 4 | issue = 5 | page = 56 | issn = 2168-9709| doi = 10.9740/mhc.n207179 | doi-access = free }}</ref> In addition, ketamine is already employed for this purpose as an off-label therapy in some clinics.<ref name="NPR2014">{{cite web | url = https://www.npr.org/blogs/health/2014/04/03/298770933/growing-evidence-that-a-party-drug-can-help-severe-depression | vauthors = Poon L | title = Growing Evidence That A Party Drug Can Help Severe Depression | publisher = NPR | year = 2014}}</ref><ref name="ScientificAmerican2013">{{cite web | url = http://blogs.scientificamerican.com/talking-back/2013/09/11/from-club-to-clinic-physicians-push-off-label-ketamine-as-rapid-depression-treatment-part-1/ | vauthors = Stix G | title = From Club to Clinic: Physicians Push Off-Label Ketamine as Rapid Depression Treatment | publisher = Scientific American | year = 2014}}</ref>

Research suggests that [[tianeptine]] produces antidepressant effects through indirect alteration and inhibition of [[Glutamate (neurotransmitter)|glutamate]] receptor activity and release of {{abbrlink|BDNF|brain-derived neurotrophic factor}}, in turn affecting [[neural plasticity]].<ref name="mp092">{{cite journal | vauthors = McEwen BS, Chattarji S, Diamond DM, Jay TM, Reagan LP, Svenningsson P, Fuchs E | title = The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation | journal = Molecular Psychiatry | volume = 15 | issue = 3 | pages = 237–249 | date = March 2010 | pmid = 19704408 | pmc = 2902200 | doi = 10.1038/mp.2009.80 }}</ref><ref name="pmid15550348">{{cite journal | vauthors = McEwen BS, Chattarji S | title = Molecular mechanisms of neuroplasticity and pharmacological implications: the example of tianeptine | journal = European Neuropsychopharmacology | volume = 14 | issue = Suppl 5 | pages = S497–S502 | date = December 2004 | pmid = 15550348 | doi = 10.1016/j.euroneuro.2004.09.008 | s2cid = 21953270 }}</ref><ref name="pmid15753957">{{cite journal | vauthors = McEwen BS, Olié JP | title = Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine | journal = Molecular Psychiatry | volume = 10 | issue = 6 | pages = 525–537 | date = June 2005 | pmid = 15753957 | doi = 10.1038/sj.mp.4001648 | doi-access = free }}</ref><ref name="pmid18221189">{{cite journal | vauthors = Brink CB, Harvey BH, Brand L | title = Tianeptine: a novel atypical antidepressant that may provide new insights into the biomolecular basis of depression | journal = Recent Patents on CNS Drug Discovery | volume = 1 | issue = 1 | pages = 29–41 | date = January 2006 | pmid = 18221189 | doi = 10.2174/157488906775245327 | url = http://www.bentham-direct.org/pages/content.php?PRN/2006/00000001/00000001/0002PRN.SGM | access-date = 2020-04-12 | url-status = usurped | archive-url = https://archive.today/20130414074312/http://www.bentham-direct.org/pages/content.php?PRN/2006/00000001/00000001/0002PRN.SGM | archive-date = 2013-04-14 | url-access = subscription }}</ref><ref name="CNS20082">{{cite journal | vauthors = Kasper S, McEwen BS | title = Neurobiological and clinical effects of the antidepressant tianeptine | journal = CNS Drugs | volume = 22 | issue = 1 | pages = 15–26 | year = 2008 | pmid = 18072812 | doi = 10.2165/00023210-200822010-00002 | s2cid = 30330824 }}</ref> Tianeptine also acts on the NMDA and [[AMPA receptor]]s.<ref name="mp092"/><ref name="CNS20082"/> In animal models, tianeptine inhibits the pathological stress-induced changes in glutamatergic neurotransmission in the amygdala and hippocampus.

[[Memantine]], a low-trapping NMDAR antagonist, is approved in the [[United States]] and [[Europe]] for the treatment of moderate-to-severe Alzheimer's disease,<ref name=MountC2006>{{cite journal | vauthors = Mount C, Downton C | title = Alzheimer disease: progress or profit? | journal = Nature Medicine | volume = 12 | issue = 7 | pages = 780–784 | date = July 2006 | pmid = 16829947 | doi = 10.1038/nm0706-780 | doi-access = free }}</ref> and has now received a limited recommendation by the UK's [[National Institute for Health and Care Excellence]] for patients who fail other treatment options.<ref name="NICE Guidelines">NICE technology appraisal January 18, 2011 [http://www.nice.org.uk/guidance/index.jsp?action=download&o=52515 Azheimer's disease - donepezil, galantamine, rivastigmine and memantine (review): final appraisal determination]</ref>

Cochlear NMDARs are the target of intense research to find pharmacological solutions to treat [[tinnitus]]. NMDARs are associated with a rare [[autoimmune]] disease, [[anti-NMDA receptor encephalitis]] (also known as NMDAR encephalitis<ref>Todd A Hardy, Reddel, Barnett, Palace, Lucchinetti, Weinshenker, Atypical inflammatory demyelinating syndromes of the CNS, The lancet neurology, Volume 15, Issue 9, August 2016, Pages 967-981, doi: https://doi.org/10.1016/S1474-4422(16)30043-6, available at
[https://ora.ox.ac.uk/objects/uuid:49dc3a62-76a4-4b96-9900-a7cd41d5a61a/download_file?file_format=pdf&safe_filename=Atypical%2Binflammatory%2Bdemyelinating%2Bsyndromes%2Bof%2Bthe%2BCNS.pdf&type_of_work=Journal+article]</ref>), that usually occurs due to cross-reactivity of antibodies produced by the immune system against ectopic brain tissues, such as those found in [[teratoma]]. These are known as [[anti-glutamate receptor antibodies]].

Compared to [[dopaminergic]] [[stimulant]]s like [[methamphetamine]], the NMDAR antagonist phencyclidine can produce a wider range of symptoms that resemble schizophrenia in healthy volunteers, in what has led to the [[glutamate hypothesis of schizophrenia]].<ref name="pmid18395805">{{cite journal | vauthors = Lisman JE, Coyle JT, Green RW, Javitt DC, Benes FM, Heckers S, Grace AA | title = Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia | journal = Trends in Neurosciences | volume = 31 | issue = 5 | pages = 234–242 | date = May 2008 | pmid = 18395805 | pmc = 2680493 | doi = 10.1016/j.tins.2008.02.005 }}</ref> Experiments in which rodents are treated with NMDA receptor antagonist are today the most common model when it comes to testing of novel schizophrenia therapies or exploring the exact mechanism of drugs already approved for treatment of schizophrenia.

NMDAR antagonists, for instance [[eliprodil]], [[gavestinel]], [[licostinel]], and [[selfotel]] have been extensively investigated for the treatment of [[excitotoxicity]]-mediated [[neurotoxicity]] in situations like [[ischemic stroke]] and [[traumatic brain injury]], but were unsuccessful in [[clinical trial]]s used in small doses to avoid sedation, but NMDAR antagonists can block [[Cortical spreading depression|Spreading Depolarizations]] in animals and in patients with brain injury.<ref>{{cite journal | vauthors = Santos E, Olivares-Rivera A, Major S, Sánchez-Porras R, Uhlmann L, Kunzmann K, Zerelles R, Kentar M, Kola V, Aguilera AH, Herrera MG, Lemale CL, Woitzik J, Hartings JA, Sakowitz OW, Unterberg AW, Dreier JP | display-authors = 6 | title = Lasting s-ketamine block of spreading depolarizations in subarachnoid hemorrhage: a retrospective cohort study | journal = Critical Care | volume = 23 | issue = 1 | pages = 427 | date = December 2019 | pmid = 31888772 | pmc = 6937792 | doi = 10.1186/s13054-019-2711-3 | doi-access = free }}</ref> This use has not been tested in clinical trials yet.