N-methyl-D-aspartic acidorN-methyl-D-aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike glutamate, NMDA only binds to and regulates the NMDA receptor and has no effect on other glutamate receptors (such as those for AMPA and kainate). NMDA receptors are particularly important when they become overactive during, for example, withdrawal from alcohol as this causes symptoms such as agitation and, sometimes, epileptiform seizures.
In 1962, J.C. Watkins reported synthesizing NMDA, an isomer of the previously known N-Methyl-DL-aspartic-acid (PubChem ID 4376).[2][3] NMDA is a water-soluble D-alpha-amino acid — an aspartic acid derivative with an N-methyl substituent and D-configuration — found across Animalia from lanceletstomammals.[4][5] At homeostatic levels NMDA plays an essential role as a neurotransmitter and neuroendocrine regulator.[6] At increased but sub–toxic levels NMDA becomes neuro-protective. [citation needed] In excessive amounts NMDA is an excitotoxin. Behavioral neuroscience research utilizes NMDA excitotoxicity to induce lesions in specific regions of an animal subject's brain or spinal cord to study behavioral changes.[7]
The mechanism of action for the NMDA receptor is a specific agonist binding to its NR2 subunits, and then a non-specific cation channel is opened, which can allow the passage of Ca2+ and Na+ into the cell and K+ out of the cell. Therefore, NMDA receptors will only open if glutamate is in the synapse and concurrently the postsynaptic membrane is already depolarized - acting as coincidence detectors at the neuronal level.[8] The excitatory postsynaptic potential (EPSP) produced by activation of an NMDA receptor also increases the concentration of Ca2+ in the cell. The Ca2+ can in turn function as a second messenger in various signaling pathways.[9][10][11][12] This process is modulated by a number of endogenous and exogenous compounds and plays a key role in a wide range of physiological (such as memory) and pathological processes (such as excitotoxicity).
^"N-Methylaspartate - Compound Summary". PubChem Compound. USA: National Center for Biotechnology Information. 24 June 2005. Identification. Retrieved 9 January 2012.
^Watkins, J. C. (November 1962). "The synthesis of some acidic amino acids possessing neuropharmacological activity". Journal of Medicinal and Pharmaceutical Chemistry. 5 (6): 1187–1199. doi:10.1021/jm01241a010. ISSN1520-4804. PMID14056452.
^Johnson, Patricia I.; Parente, Mary Ann; Stellar, James R. (May 1996). "NMDA-induced lesions of the nucleus accumbens or the ventral pallidum increase the rewarding efficacy of food to deprived rats". Brain Research. 722 (1–2): 109–117. doi:10.1016/0006-8993(96)00202-8. ISSN0006-8993. PMID8813355. S2CID23002111.
