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Role of NMDA and Dopamine Receptor against Neurodegenerative Disease: A Comprehensive Review

Prashant Tiwari, G. V. Mohan Das, Mahesh Rachamalla, Jyotirmaya Sahoo, Shweta Shrivastava


Neurodegenerative disease is the illness that encompasses the death of the certain parts of the brain. Irregularities of neurotransmitters like NMDA and dopamine receptors may attributes Huntington’s disease, Alzheimer’s disease and Parkinson’s disease that are most severe and common movement disorders. Neurodegenerative disease is characterized by the memory loss, apathy, anxiety, agitation, forgetfulness, tremor and bradykinesia. About ten million people across the globe are being affected from neurological disorders. NMDA and dopamine receptors and their interaction control numerous function in the brain. Due to the lack of dopamine causes pathological changes in the basal ganglia. Glutamate receptor modulate neurotransmission may slow the disease progression by delaying dopamine neuron degeneration. NMDA receptors may improve motor symptoms and neurodegeneration.  Most of the pathological activity is associated with neurotransmitter receptors. However, many drugs failed due to their poor therapeutic utility. So there is necessity to develop new drugs that can target the specific pathways. There are additional challenges and opportunities for future studies that are beyond the scope of this review. Further studies are also needed to elucidate the multifaceted cross-talk between neurotransmitters, their receptors and signalling cascade.  

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Tsuiji H, Yamanaka K. (2013), “Animal Models for Neurodegenerative Disorders. In: Animal Biotechnology: Models in Discovery and Translation”, Elsevier Inc., pp. 39-56, DOI:

Villoslada P, Baeza-Yates R, Masdeu JC. (2020), “Reclassifying neurodegenerative diseases”, Nat. Biomed. Eng., Volume 4, Issue 8, pp. 759-760, DOI:

Soria Lopez JA, González HM, Léger GC. (2019), “Alzheimer’s disease”, Handb. Clin. Neurol., Elsevier B.V., Volume 167, pp. 231-255, DOI:

Butler PM, Chiong W. (2019), “Neurodegenerative disorders of the human frontal lobes”, Handb. Clin. Neurol., Elsevier B.V.; Volume 163, pp. 391-410, DOI:

Kovacs GG. (2019), “Are comorbidities compatible with a molecular pathological classification of neurodegenerative diseases?”, Curr. Opin. Neurol., Volume 32, Issue 2, pp. 279-291, Avaiable at:

Alafuzoff I, Hartikainen P. (2018), “Alpha-synucleinopathies”, Handb. Clin. Neurol., Elsevier B.V.; Volume 145, pp. 339-353, DOI:

Peng C, Trojanowski JQ, Lee VMY. (2020), “Protein transmission in neurodegenerative disease”, Nat. Rev. Neurol., Volume 16, Issue 4, pp. 199-212, DOI:

Elahi FM, Miller BL. (2017), “A clinicopathological approach to the diagnosis of dementia”, Nat. Rev. Neurol., Volume 13, Issue 8, pp. 457. DOI:

Karanth S, Nelson PT, Katsumata Y, Kryscio RJ, Schmitt FA, Fardo DW, Cykowski MD, Jicha GA, Van Eldik LJ, Abner EL. “Prevalence and Clinical Phenotype of Quadruple Misfolded Proteins in Older Adults”, JAMA neurol., DOI:

Tosun A, Khan S. (2015), “Antioxidant Actions of Spices and Their Phytochemicals on Age-Related Diseases” Bioactive Nutraceut. Dietary Supplements Neurol. Brain Dis.: Prevention and Therapy. Elsevier Inc., pp. 311-318, DOI:

Zahra W, Rai SN, Birla H, Singh SS, Dilnashin H, Rathore AS, Singh SP. (2020), “The global economic impact of neurodegenerative diseases: Opportunities and challenges”, Bioecono. Sustainable Development, pp. 333-345, DOI:

Rothman SM, Olney JW. (1987), “Excitotoxity and the NMDA receptor”, Trends neurosci., Volume 10, Issue 7, pp. 299-302, DOI:

Kutsuwada T, Kashiwabuchi N, Mori H, Sakimura K, Kushiya E, Araki K, Meguro H, Masaki H, Kumanishi T, Arakawa M, Mishina M. (1992), “Molecular diversity of the NMDA receptor channel”, Nature, Volume 358, pp. 36-41, DOI:

Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P. (2005), “Regulation of NMDA receptor trafficking by amyloid-β”, Nature neurosci., Volume 8, Issue 8, pp. 1051-1058, DOI:

Mori H, Mishina M. (1995), “Structure and function of the NMDA receptor channel”, Neuropharmacol., Volume 34, Issue 10, pp. 1219-1237, DOI:

Cull-Candy S, Brickley S, Farrant M. (2001), “NMDA receptor subunits: diversity, development and disease”, Curr. Opin. Neurol., Volume 1, Issue 3, pp. 327-335, DOI:

Paoletti P, Neyton J. (2007), “NMDA receptor subunits: function and pharmacology” Curr. Opin. Pharmacol., Volume 7, Issue 1, pp. 39-47,

Paoletti P, Bellone C, Zhou Q. (2013), “NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease”, Nat. Rev. Neurosci., Volume 14, Issue 6, pp. 383-400, DOI:

Malenka RC, Nicoll RA. (1993), “NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms” Trends neurosci., Volume 16, Issue 12, pp. 521-527, DOI:

Kemp JA, McKernan RM. (2002), “NMDA receptor pathways as drug targets”, Nat. neurosci., Volume 5, Issue 11, pp. 1039-1042, DOI:

Barria A. (2007), “Subunit-specific NMDA receptor trafficking to synapses”, Protein Trafficking in Neurons, Academic Press., pp. 203-221, DOI:

Hardingham GE, Bading H. (2003), “The Yin and Yang of NMDA receptor signalling”, Trends in neurosci., Volume 26, Issue 2, pp. 81-89, DOI:

Bading H, Greenberg ME. (1991), “Stimulation of protein tyrosine phosphorylation by NMDA receptor activation”, Sci., Volume 253, pp. 912-914, DOI:

Grant KA, Valverius P, Hudspith M, Tabakoff B. (1990), “Ethanol withdrawal seizures and the NMDA receptor complex”, Euro. J. pharmacol., Volume 176, Issue 3, pp. 289-296, DOI:

Cull-Candy SG, Leszkiewicz DN. (2004), “Role of distinct NMDA receptor subtypes at central synapses”, Science's STKE, Volume 2004, Issue 255, DOI:

Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB, Charney DS. (1994), “Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses”, Archives of general psychiatry, Volume 51, Issue 3, pp. 199-214, Available at:

Caramanos Z, Shapiro ML. (1994), “Spatial memory and N-methyl-D-aspartate receptor antagonists APV and MK-801: memory impairments depend on familiarity with the environment, drug dose, and training duration”, Behavioral neurosci.,Volume 108, Issue 1, pp. 30, DOI:

Verma A, Moghaddam B. (1996), “NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine”, J. Neurosci., Volume 16, Issue 1, pp. 373-379, DOI:

Javitt DC, Steinschneider M, Schroeder CE, Arezzo JC. (1996), “Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia”, Proceedings of the National Academy of Sci.,Volume 93, Issue 21, pp. 11962-11967, DOI:

Fingelkurts AA, Fingelkurts AA, Bagnato S, Boccagni C, Galardi G. (2012), “Toward operational architectonics of consciousness: basic evidence from patients with severe cerebral injuries”, Cognitive processing, Volume 13, Issue 2, pp. 111-131, DOI:

Adler C, Goldberg T, Malhotra A, Pickar D, Breier A. (1998), “Effects of ketamine on thought disorder, working memory, and semantic memory in healthy volunteers”, Biol. psychiat., Volume 43, Issue 11, pp. 811-816, DOI:

Funahashi S, Bruce CJ, Goldman-Rakic PS. (1989), “Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex”, J, neurophysiol., Volume 61, Issue 2, pp. 331-349, DOI:

Daw NW, Stein PS, Fox K. (1993), “The role of NMDA receptors in information processing”, Ann. rev. neurosci., Volume 16, Issue 1, pp. 207-222, DOI:

Lisman JE, Fellous JM, Wang XJ. (1998), “A role for NMDA-receptor channels in working memory”, Nat. neurosci., Volume 1, Issue 4, pp. 273-275, DOI:

Salter MW, Kalia LV. (2004), “Src kinases: a hub for NMDA receptor regulation”, Nat. Rev. Neurosci., Volume 5, Issue 4, pp. 317-328, DOI:

Hughes EG, Peng X, Gleichman AJ, Lai M, Zhou L, Tsou R, Parsons TD, Lynch DR, Dalmau J, Balice-Gordon RJ. (2010), “Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis”, J. Neurosci. Volume 30, Issue 17, pp. 5866-5878, DOI:

Wyszynski M, Lin J, Rao A, Nigh E, Beggs AH, Craig AM, Sheng M. (1997), “Competitive binding of α-actinin and calmodulin to the NMDA receptor”, Nat., Volume 385, Issue 6615, pp. 439-442, DOI:

Dingledine R, Borges K, Bowie D, Traynelis SF. (1995), “The glutamate receptor ion channels”, Pharmacol. rev., Volume 51, Issue 1, pp. 7-62, Available at:

Johnson JW, Ascher P. (1987), “Glycine potentiates the NMDA response in cultured mouse brain neurons”, Nat., Volume 325, Issue 6104, pp. 529-531, DOI:

Kleckner NW, Dingledine R. (1988), “Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes”, Sci., Volume 241, Issue 4867, pp. 835-837, DOI:

Nong Y, Huang YQ, Ju W, Kalia LV, Ahmadian G, Wang YT, Salter MW. (2003), “Glycine binding primes NMDA receptor internalization”, Nat., Volume 422, Issue 6929, pp. 302-307, DOI:

Wang M, Wong AH, Liu F. (2012), “Interactions between NMDA and dopamine receptors: a potential therapeutic target”, Brain res., Volume 1476, pp. 154-163, DOI:

Seeman P, Van Tol HH. (1994), “Dopamine receptor pharmacology”, Trend. pharmacol. sci., Volume 15, Issue 7, pp. 264-270, DOI:

Rondou P, Haegeman G, Van Craenenbroeck K. (2010), “The dopamine D4 receptor: biochemical and signalling properties”, Cellul. Molecular life sci., Volume 67, Issue 12, pp. 1971-1986, DOI:

Ferré S, Fuxe K, Fredholm BB, Morelli M, Popoli P. (1997), “Adenosine–dopamine receptor–receptor interactions as an integrative mechanism in the basal ganglia”, Trend neurosci., Volume 20, Issue 10, pp. 482-487, DOI:

Gerfen CR, Engber TM, Mahan LC, Susel ZV, Chase TN, Monsma FJ, Sibley DR. (1990), “D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons”, Sci., Volume 250, Issue 4986, pp. 142-432, DOI:

Burt DR, Creese I, Snyder SH. (1977), “Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain”, Sci., Volume 196, Issue 4287, pp. 326-328, DOI:

Creese I, Sibley DR, Hamblin MW, Leff SE. (1983), “The classification of dopamine receptors: relationship to radioligand binding”, Ann. rev. neurosci., Volume 6, Issue 1, pp. 43-71, DOI:

Seeman P. (1980), “Brain dopamine receptors”, Pharmacol. Rev., Volume 32, Issue 3, pp. 229-313, Available at:

Lee T, Seeman P, Rajput A, FARLEY IJ, Hornykiewicz O. (1987), “Receptor basis for dopaminergic super sensitivity in Parkinson's disease”, Nat., Volume 273, Issue 5657, pp. 59-61, DOI:

Seeman P, Ulpian C, Bergeron C, Riederer P, Jellinger K, Gabriel E, Reynolds GP, Tourtellotte WW. (1984), “Bimodal distribution of dopamine receptor densities in brains of schizophrenics”, Sci., Volume 225, Issue 4663, pp. 728-731, DOI:

Barnes DM. (1988), “The biological tangle of drug addiction”, Sci., Volume 241, Issue 4864, pp. 415, Available at:

Cote TE, Frey EA, Grewe CW, Kebabian JW. (1983), “Evidence that the D-2 dopamine receptor in the intermediate lobe of the rat pituitary gland is associated with an inhibitory guanyl nucleotide component”, In Basic Aspects of Receptor Biochem., pp. 139-147, DOI:

Senogles SE, Benovic JL, Amlaiky N, Unson C, Milligan G, Vinitsky R, Spiegel AM, Caron MG. (1987), “The D2-dopamine receptor of anterior pituitary is functionally associated with a pertussis toxin-sensitive guanine nucleotide binding protein”, J. Biol. Chem., Volume 262, Issue 10, pp. 4860-4867, Available at:

Dohlman HG, Caron MG, Lefkowitz RJ. 91987), “A family of receptors coupled to guanine nucleotide regulatory proteins”, Biochem., Volume 26, Issue 10, pp. 2657-2664, DOI:

Bunzow JR, Van Tol HH, Grandy DK, Albert P, Salon J, Christie M, Machida CA, Neve KA, Civelli O. (1988), “Cloning and expression of a rat D 2 dopamine receptor cDNA”, Nat., Volume 336, Issue 6201, pp. 783-787, DOI:

Creese I, Burt DR, Snyder SH. (1977), “Dopamine receptor binding enhancement accompanies lesion-induced behavioral supersensitivity”, Sci., Volume 197, Issue 4303, pp. 596-598, DOI:

Surmeier DJ, Eberwine J, Wilson CJ, Cao Y, Stefani A, Kitai ST. (1992), “Dopamine receptor subtypes colocalize in rat striatonigral neurons”, Proceedings of the National Academy of Sci. (PNAS), Volume 89, Issue 21, pp. 10178-10182, DOI:

Andersen PH, Gingrich JA, Bates MD, Dearry A, Falardeau P, Senogles SE, Caron MG. (1990), “Dopamine receptor subtypes: beyond the D1/D2 classification”, Trends pharmacol. sci., Volume 11, Issue 6, pp. pp. 231-236, DOI:

Weiner DM, Levey AI, Sunahara RK, Niznik HB, O'Dowd BF, Seeman P, Brann MR. (1991), “D1 and D2 dopamine receptor mRNA in rat brain”, Proceedings of the national academy of sci. (PNAS), Volume 88, Issue 5, pp. 1859-1863, DOI:

Ben-Jonathan N, Hnasko R. (2001), “Dopamine as a prolactin (PRL) inhibitor”, Endocr. Rev., Volume 22, Issue 6, pp. 724-763, DOI:

Jackson DM, Westlind-Danielsson A. “Dopamine receptors: Molecular biology, biochemistry and behavioural aspects”, Pharmacol. Ther., Volume 64, Issue 2, pp. 291-370, DOI:

Mishra A, Singh S, Shukla S. (2018), “Physiological and Functional Basis of Dopamine Receptors and Their Role in Neurogenesis: Possible Implication for Parkinson’s disease”, J. Exp. Neurosci., Volume 12, Issue , DOI:

Beaulieu J-M, Espinoza S, Gainetdinov RR. (2015), “Dopamine receptors - IUPHAR Review 13”, Br. J. Pharmacol., Volume 172, Issue 1, pp. 1-23, DOI:

Penney JBJ, Young AB. (1983), “Speculations on the functional anatomy of basal ganglia disorders”, Annu. Rev. Neurosci., Volume 6, pp. 73-94, DOI:

Albin RL, Young AB, Penney JB. (1989), “The Functional Anatomy of Basal Ganglia Disorders”, Trend Neuro., Volume 12, issue 10, pp. 366-375, DOI:

Gerfen CR, Engber TM, Mahan LC, et al. (1990), “D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons”, Sci., Volume 250, pp. 1429-1432, DOI:

Floran B, Aceves J, Sierra A, Martinez-Fong D. (1990), “Activation of D1 dopamine receptors stimulates the release of GABA in the basal ganglia of the rat”, Neurosci. Lett.”, Volume 116, Issue 1-2, pp.136-140, DOI:

Floran B, Floran L, Sierra A, Aceves J. (1997), “D2 receptor-mediated inhibition of GABA release by endogenous dopamine in the rat globus pallidus”, Neurosci. Lett., Volume 237, Issue 1, pp. 1-4, DOI:

Cooper AJ, Stanford IM. (2001), “Dopamine D2 receptor mediated presynaptic inhibition of striatopallidal GABA(A) IPSCs in vitro”, Neuropharmacol., Volume 41, Issue 1, pp. 62-71, DOI:

Gutekunst CA, Li SH, Yi H, et al. (1999), “Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology”, J. Neurosci., Volume 19, Issue 7, pp. 2522-2534, DOI:

Quarrell O, O’Donovan KL, Bandmann O, Strong M. (2012), “The Prevalence of Juvenile Huntington’s Disease: A Review of the Literature and Meta-Analysis”, PLoS Curr., pp. 20-24, DOI:

Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EPJ. (1985), “Neuropathological classification of Huntington’s disease” J. Neuropathol. Exp. Neurol., Volume 44, Issue 6, pp. 559-577, DOI:

Cowan CM, Fan MMY, Fan J, et al. (2008), “Polyglutamine-modulated striatal calpain activity in YAC transgenic huntington disease mouse model: Impact on NMDA receptor function and toxicity”, J. Neurosci., Volume 28, Issue 48, pp. 12725-12735, DOI:

Duncan GE, Inada K, Koller BH, Moy SS. (2010), “Increased sensitivity to kainic acid in a genetic model of reduced NMDA receptor function”, Brain Res., Volume 1307, pp. 166-176, DOI:

Brito VI, Rozanski VE, Beyer C, Küppers E. (2009), “Dopamine regulates the expression of the glutamate transporter GLT1 but not GLAST in developing striatal astrocytes”, J. Mol. Neurosci., Volume 39, Issue 3, pp. 372-379, DOI:

Bałkowiec-Iskra E, Kurkowska-Jastrzebska I, Joniec I, Ciesielska A, Członkowska A, Członkowski A. (2007), “Dopamine, serotonin and noradrenaline changes in the striatum of C57BL mice following myelin oligodendrocyte glycoprotein (MOG) 35-55 and complete Freund adjuvant (CFA) administration”, Acta Neurobiol. Exp. (Wars), Volume 67, Issue 4, pp. 379-388, Available at:

Giorelli M, Livrea P, Trojano M. (2005), “Dopamine fails to regulate activation of peripheral blood lymphocytes from multiple sclerosis patients: effects of IFN-beta.”, J. Interf. Cytokine. Res. Off. J. Int. Soc. Interf. Cytokine Res., Volume: 25, Issue 7, pp. 395-406, DOI:

Johnson KA, Conn PJ, Niswender CM. (2009), “Glutamate receptors as therapeutic targets for Parkinson's disease”, CNS Neurol. Disorders-Drug Targets (Formerly Curr. Drug Targets-CNS & Neurol. Disorders), Volume 8, Issue 6, pp. 475-491, DOI:

Fischer F, Matthisson M, Herrling P. (2004), “List of drugs in development for neurodegenerative diseases”, Neurodeg. Dis., Volume 1, Issue 1, pp. 50-70, Available at:

Waldmeier PC. (2003), “Prospects for antiapoptotic drug therapy of neurodegenerative diseases”, Progress in Neuro-Psychopharmacol. Biol. Psych., Volume 27, Issue 2, pp. 303-321, DOI:

Marchetti B, Abbracchio MP. (2005), “To be or not to be (inflamed)–is that the question in anti-inflammatory drug therapy of neurodegenerative disorders?”, Trends pharmacol. sci., Volume 26, Issue 10, pp. 517-525, DOI:

Markowicz-Piasecka M, Sikora J, Szydłowska A, Skupień A, Mikiciuk-Olasik E, Huttunen KM. (2017), “Metformin–a future therapy for neurodegenerative diseases”, Pharmaceut. res., Volume 34, Issue 12, pp. 2614-2627, DOI:

Das MK, Tiwari P, Prusty SK, Sahu PK. (2018), “Neuroprotective Potential of Metformin against Forced Swimming Induced Neurodegeneration Wistar Albino Rats”, Asian J. Biol. Sci. Volume 11, Issue 2, pp. 89-97, DOI:


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