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NMDA receptor antagonists are a class of anesthetics that work to antagonize, or inhibit the action of, the N-methyl d-aspartate receptor (NMDAR). They are used as anesthesia for animals and, less commonly, for humans; the state of anesthesia they induce is referred to as dissociative anesthesia. However, there is evidence that NMDA receptor antagonists can cause a certain type of brain damage referred to as Olney's Lesions (in rodents).
Some NMDA receptor antagonists, such as ketamine, Dextromethorphan (DXM), and phencyclidine (PCP), are popular as recreational drugs for their hallucinogenic properties. When used recreationally, they are classified as dissociative drugs. Because some users use them for spiritual reasons, these recreational NMDA receptor antagonists are sometimes considered entheogens.
Uses and effects
NMDA receptor antagonists induce a state called dissociative anesthesia, which is marked by catalepsy, amnesia, and analgesia. Ketamine and other NMDA receptor antagonists are most frequently used in conjunction with diazepam as anesthesia in cosmetic or reconstructive plastic surgery and in the treatment of burn victims. Ketamine is a favored anesthetic for emergency patients with unknown medical history because it depresses breathing and circulation less than other anesthetics. The NMDA receptor antagonist dextromethorphan is one of the most commonly used cough suppressants in the world.
Depressed NMDA receptor function is associated with an array of negative symptoms. For example, NMDA receptor hypofunction that occurs as the brain ages may be partially responsible for memory deficits associated with aging. Schizophrenia may also have to do with irregular NMDA receptor function (the "glutamate hypothesis" of schizophrenia). Increased levels of another NMDA antagonist, kynurenic acid, may aggravate the symptoms of schizophrenia, according to the "kynurenic hypothesis". NMDA receptor antagonists can mimic these problems; they sometimes induce "psychotomimetic" side effects, symptoms resembling psychosis. Such side effects caused by NMDA receptor inhibitors include hallucinations, paranoid delusions, confusion, difficulty concentrating, agitation, alterations in mood, nightmares, catatonia, ataxia, anaesthesia, and learning and memory deficits.
Because of these psychotomimetic effects, NMDA receptor antagonists, especially phencyclidine, ketamine, and dextromethorphan, are used as recreational drugs. At subanesthetic doses, these drugs have mild stimulant effects, and at higher doses, begin inducing dissociation and hallucinations.
Most NMDA receptor antagonists are metabolized in the liver. Frequent administration of most NMDA receptor antagonists can lead to tolerance, whereby the liver will more quickly eliminate NMDA receptor antagonists from the bloodstream.
- Main article: Olney's lesions
Exposure to NMDA receptor antagonists may cause a serious brain damage in the cingulate cortex and retrosplenial cortex regions of the brain. The experimental NMDA receptor antagonist MK-801 has been shown to cause neural vacuolization in test rodents that later develop into irreversible lesions called "Olney's Lesions." Many drugs have been found that lessen the risk of neurotoxicity from NMDA receptor antagonists. Centrally acting alpha 2 agonists such as clonidine and guanfacine are thought to most specifically target the etiology of NMDA neurotoxicity. Other drugs acting on various neurotransmitter systems known to inhibit NMDA antagonist neurotoxicity include: anticholinergics, diazepam, barbiturates, ethanol, 5-HT2A serotonin agonists, and muscimol.
Potential for treatment of excitotoxicity
Since NMDA receptors are one of the most harmful factors in excitotoxicity, antagonists of the receptors have held much promise for the treatment of conditions that involve excitotoxicity, including traumatic brain injury, stroke, and neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's. This is counterbalanced by the risk of developing Olney's lesions,  although there is evidence against Olney's lesions forming in humans, and studies have started to find agents that prevent this neurotoxicity. Most clinical trials involving NMDA receptor antagonists have failed due to unwanted side effects of the drugs; since the receptors also play an important role in normal glutamatergic function, blocking them has harmful effects. This interference with normal function could be responsible for neuronal death that sometimes results from NMDA receptor antagonist use.
Mechanism of action
The NMDA receptor is an ionotropic receptor that allows for the transfer of electrical signals between neurons in the brain and in the spinal column. For electrical signals to pass, the NMDA receptor must be open. To remain open, an NMDA receptor must bind to glutamate and to glycine. An NMDA receptor that is bound to glycine and glutamate and has an open ion channel is called "activated."
Chemicals that deactivate the NMDA receptor are called antagonists. NMDAR antagonists fall into four categories: Competitive antagonists, which bind to and block the binding site of the neurotransmitter glutamate; glycine antagonists, which bind to and block the glycine site; noncompetitive antagonists, which inhibit NMDARs by binding to allosteric sites; and uncompetitive antagonists, which block the ion channel by binding to a site within it.
Uncompetitive channel blockers include:
- Amantadine – used for treating Parkinson's disease and influenza.
- Dextromethorphan – a common antitussive found in cough medicines.
- Dextrorphan – active metabolite of dextromethorphan. Schedule I in the US.
- Ibogaine – a Schedule I controlled substance in the United States.
- Ketamine – an animal and human anesthetic and recreational drug.
- Nitrous oxide – used for anesthesia, particularly in dentistry.
- Phencyclidine, a Schedule II controlled substance in the United States.
- Riluzole – used to treat amyotrophic lateral sclerosis.
- Tiletamine – an animal anesthetic.
- Ethanol (higher dosages) – The intoxicating substance in alcoholic beverages[How to reference and link to summary or text]
- Memantine (Axura, Akatinol, Namenda, Ebixa, 1-amino-3,5-dimethylada-mantane) – moderate affinity, voltage-dependent uncompetitive antagonist. Approved in the U.S. by the Food and Drug Administration for the treatment of Alzheimer's disease.
Noncompetitive antagonists include:
- Dizocilpine (MK-801) – an experimental drug.
- Aptiganel (Cerestat, CNS-1102) – binds the Mg2+ binding site within the channel of the NMDA receptor.
- Remacimide – principle metabolite is an uncompetitive antagonist with a low affinity for the binding site.
- HU-211, an enantiomer of the potent cannabinoid HU-210 which lacks cannabinoid effects and instead acts as a potent non-competitive NMDA antagonist.
Glycine antagonists (drugs that act at the glycine binding site) include:
- DCKA (5,7-dichlorokynurenic acid)
- Kynurenic acid, a naturally occurring antagonist
- 1-Aminocyclopropanecarboxylic acid (ACPC)
- Lacosamide, an investigational drug for the treatment of epilepsy and diabetic neuropathic pain.
Competitive antagonists include:
- AP7 (2-amino-7-phosphonoheptanoic acid)
- APV (R-2-amino-5-phosphonopentanoate)
- CPPene (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid)
- Long-term potentiation
- AMPA receptor
- Calcium/calmodulin-dependent protein kinases
- ↑ Pender J (1971). Dissociative anesthesia. JAMA 215 (7): 1126–30.
- ↑ Ersek R (2004). Dissociative anesthesia for safety's sake: ketamine and diazepam--a 35-year personal experience. Plast Reconstr Surg 113 (7): 1955–9.
- ↑ Ceber M, Salihoglu T. Ketamine may be the first choice for anesthesia in burn patients. J Burn Care Res 27 (5): 760–2.
- ↑ Heshmati F, Zeinali M, Noroozinia H, Abbacivash R, Mahoori A (2003). Use of ketamine in severe status asthmaticus in intensive care unit. Iran J Allergy Asthma Immunol 2 (4): 175–80.
- ↑ Equinozzi R, Robuschi M (2006). Comparative Efficacy and Tolerability of Pholcodine and Dextromethorphan in the Management of Patients with Acute, Non-Productive Cough : A Randomized, Double-Blind, Multicenter Study. Treat Respir Med 5 (6): 509–513.
- ↑ Newcomer, JW, Krystal JH (2001). NMDA receptor regulation of memory and behavior in humans. Hippocampus 11 (5): 529–542.
- ↑ Lipina, T, Labrie V, Weiner I, Roder J (2005). Modulators of the glycine site on NMDA receptors, D-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia. Psychopharmacology 179 (1): 54–67.
- ↑ Erhardt S, Schwieler L, Nilsson L, Linderholm K, Engberg G (September 2007). The kynurenic acid hypothesis of schizophrenia. Physiol. Behav. 92 (1-2): 203–9.
- ↑ Pomarol-Clotet E, Honey GD, Murray GK, Corlett PR, Absalom AR, Lee M, McKenna PJ, Bullmore ET, Fletcher PC (August 2006). Psychological effects of ketamine in healthy volunteers. Phenomenological study. Br J Psychiatry 189: 173–9.
- ↑ Muir, KW, Lees KR (1995). Clinical experience with excitatory amino acid antagonist drugs. Stroke 26 (3): 503–513.
- ↑ Aarts, MM, Tymianski M (2003). Novel treatment of excitotoxicity: targeted disruption of intracellular signalling from glutamate receptors. Biochemical Pharmacology 66 (6): 877–886.
- ↑ 12.0 12.1 12.2 Kim AH, Kerchner GA, and Choi DW. (2002). "Blocking Excitotoxicity". In CNS Neuroproteciton. Marcoux FW and Choi DW, editors. Springer, New York. Pages 3-36.
- ↑ Kristensen, JD, Svensson B, and Gordh T Jr (1992). The NMDA-receptor antagonist CPP abolishes neurogenic 'wind-up pain' after intrathecal administration in humans. Pain 51 (2): 249–253.
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- ↑ Lim D (2003). Ketamine associated psychedelic effects and dependence. Singapore Med J 44 (1): 31–4.
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- ↑ Kharasch ED, Labroo R (1992). Metabolism of ketamine stereoisomers by human liver microsomes. Anesthesiology 77 (6): 1201–7.
- ↑ Livingston A, Waterman AE (1978). The development of tolerance to ketamine in rats and the significance of hepatic metabolism. Br. J. Pharmacol. 64 (1): 63–9.
- ↑ Olney J, Labruyere J, Price M (1989). Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 244 (4910): 1360–2.
- ↑ Hargreaves R, Hill R, Iversen L. Neuroprotective NMDA antagonists: the controversy over their potential for adverse effects on cortical neuronal morphology. Acta Neurochir Suppl (Wien) 60: 15–9.
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- ↑ 22.0 22.1 Farber, NB (2004). In the adult CNS, ethanol prevents rather than produces NMDA antagonist-induced neurotoxicity..
- ↑ Farber N, Hanslick J, Kirby C, McWilliams L, Olney J (1998). Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity. Neuropsychopharmacology 18 (1): 57–62.
- ↑ 24.0 24.1 Farber, NB (2003). Muscimol prevents NMDA antagonist neurotoxicity by activating GABAA receptors in several brain regions..
- ↑ Maas, AI (2001). Neuroprotective agents in traumatic brain injury. Expert Opinion On Investigational Drugs 10 (4): 753–767.
- ↑ Chen, HS, Lipton SA. The chemical biology of clinically tolerated NMDA receptor antagonists. Journal of Neurochemistry 97 (6): 1611–1126.
- ↑ Gardoni, F, Di Luca M (2006). New targets for pharmacological intervention in the glutamatergic synapse. European Journal of Pharmacology 545 (1): 2–10.
- ↑ "Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy", University Health Network, Toronto, September 2005
- ↑ "MedlinePlus Drug Information: Amantadine." MedlinePlus website Accessed May 29, 2007
- ↑ 30.0 30.1 Wong BY, Coulter DA, Choi DW, Prince DA (1988). Dextrorphan and dextromethorphan, common antitussives, are antiepileptic and antagonize N-methyl-D-aspartate in brain slices. Neurosci. Lett. 85 (2): 261–6.
- ↑ 31.0 31.1 31.2 Controlled Substances Act. Accessed from the US Drug Enforcement Administration website on May 29, 2007.
- ↑ Popik P, Layer RT, Skolnick P (1994): "The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex." Psychopharmacology (Berl), 114(4), 672-4. Abstract
- ↑ Harrison N, Simmonds M (1985). Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex. Br J Pharmacol 84 (2): 381–91.
- ↑ Grasshoff C, Drexler B, Rudolph U, Antkowiak B (2006). Anaesthetic drugs: linking molecular actions to clinical effects. Curr. Pharm. Des. 12 (28): 3665–79.
- ↑ Hugon J (1996). ALS therapy: targets for the future. Neurology 47 (6 Suppl 4): S251–4.
- ↑ Ko JC, Smith TA, Kuo WC, Nicklin CF (1998). Comparison of anesthetic and cardiorespiratory effects of diazepam-butorphanol-ketamine, acepromazine-butorphanol-ketamine, and xylazine-butorphanol-ketamine in ferrets. Journal of the American Animal Hospital Association 34 (5): 407–16.
- ↑ Robinson, DM, Keating GM (2006). Memantine: a review of its use in Alzheimer's disease. Drugs 66 (11): 1515–1534.
- ↑ Chawla, PS, Kochar MS (2006). What's new in clinical pharmacology and therapeutics. WMJ 105 (3): 24–29.
- ↑ Fix AS, Horn JW, Wightman KA, et al (1993). Neuronal vacuolization and necrosis induced by the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK(+)801 (dizocilpine maleate): a light and electron microscopic evaluation of the rat retrosplenial cortex. Exp. Neurol. 123 (2): 204–15.
- ↑ Muir, KW (2005). Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists. Current Opinion in Pharmacology 6 (1): 53–60.
- ↑ Nadler V, Mechoulam R, Sokolovsky M. The non-psychotropic cannabinoid (+)-(3S,4S)-7-hydroxy-delta 6- tetrahydrocannabinol 1,1-dimethylheptyl (HU-211) attenuates N-methyl-D-aspartate receptor-mediated neurotoxicity in primary cultures of rat forebrain. Neuroscience Letters. 1993 Nov 12;162(1-2):43-5. PMID 8121633
- ↑ Hartley DM, Monyer H, Colamarino SA, Choi DW (1990). 7-Chlorokynurenate Blocks NMDA Receptor-Mediated Neurotoxicity in Murine Cortical Culture. Eur J Neurosci 2 (4): 291–295.
- ↑ Frankiewicz T, Pilc A, Parsons C (2000). Differential effects of NMDA-receptor antagonists on long-term potentiation and hypoxic/hypoglycaemic excitotoxicity in hippocampal slices. Neuropharmacology 39 (4): 631–42.
- ↑ Khan MJ, Seidman MD, Quirk WS, Shivapuja BG (2000). Effects of kynurenic acid as a glutamate receptor antagonist in the guinea pig. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery 257 (4): 177–81.
- ↑ Prous Science: Molecule of the Month January 2005
- ↑ van den Bos R, Charria Ortiz G, Cools A (1992). Injections of the NMDA-antagonist D-2-amino-7-phosphonoheptanoic acid (AP-7) into the nucleus accumbens of rats enhance switching between cue-directed behaviours in a swimming test procedure. Behav Brain Res 48 (2): 165–70.
- ↑ Abizaid A, Liu Z, Andrews Z, Shanabrough M, Borok E, Elsworth J, Roth R, Sleeman M, Picciotto M, Tschöp M, Gao X, Horvath T (2006). Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Invest 116 (12): 3229–39.
- ↑ Eblen F, Löschmann P, Wüllner U, Turski L, Klockgether T (1996). Effects of 7-nitroindazole, NG-nitro-L-arginine, and D-CPPene on harmaline-induced postural tremor, N-methyl-D-aspartate-induced seizures, and lisuride-induced rotations in rats with nigral 6-hydroxydopamine lesions. Eur J Pharmacol 299 (1-3): 9–16.
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