Dizocilpine: Difference between revisions

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'''Dizocilpine''' ([[International Nonproprietary Name|INN]]), also known as '''MK-801''', is a noncompetitivepore [[NMDA receptor antagonist|antagonistblocker of the ''N''-Methyl-<small>D</small>-aspartate ([[NMDA) receptor]], a [[glutamate receptor]], discovered by a team at Merck in 1982.<ref>{{ cite patent | country = US | status = Patent | number = 4399141 | title = 5-Alkyl or hydroxyalkyl substituted-10,11-imines & Anticonvulsant Use Thereof | gdate = 1983-08-16 | inventor = ANDERSON,Anderson P.; CHRISTY, M.Christy E.; EVANSME, B.Evans BE E. | assign1 = MERCKMerck & COCompany Inc INC}}</ref> [[Glutamate]] is the brain's primary excitatory [[neurotransmitter]]. The channel is normally blocked with a magnesium ion and requires [[depolarization]] of the [[neuron]] to remove the magnesium and allow the glutamate to open the channel, causing an influx of calcium, which then leads to subsequent depolarization.<ref>{{cite journal | vauthors = Foster AC, Fagg GE | title = Neurobiology. Taking apart NMDA receptors | journal = Nature | volume = 329 | issue = 6138 | pages =395–6 395–396 | year = 1987 | pmid = 2443852 | doi = 10.1038/329395a0 | s2cid = 5486568 }}</ref> Dizocilpine binds inside the [[ion channel]] of the [[receptor (biochemistry)|receptor]] at several of [[phencyclidine|PCP]]'s binding sites thus preventing the flow of [[ion]]s, including [[calcium]] (Ca²⁺), through the channel. Dizocilpine blocks NMDA receptors in a use- and voltage-dependent manner, since the channel must open for the drug to bind inside it.<ref>{{Citecite journal | vauthors = Huettner JE, Bean BP | title = Block of N-methyl-D-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels |last1 journal = Huettner|first1Proceedings =of Jamesthe E|dateNational =Academy Octoberof 16,Sciences 1987|journalof =the United States of America PNAS|doi volume = 10.1073/pnas.85.4.1307 |pmid issue = 24488004 |last2 pages = Bean1307–1311 |first2 date = BruceFebruary 1988 P|volume=85|issue pmid = 4|pages=1307–13112448800 | pmc = 279756 | doi = 10.1073/pnas.85.4.1307 | doi-access = free }}</ref> The drug acts as a potent [[anti-convulsant]] and probably has [[dissociative]] anesthetic properties, but it is not used clinically for this purpose because of the discovery of brain lesions, called [[Olney's lesions]] (see below), in laboratory rats. Dizocilpine is also associated with a number of negative side effects, including cognitive disruption and psychotic-spectrum reactions. It inhibits the induction of [[long term potentiation]]<ref>{{cite journal | vauthors = Coan EJ, Saywood W, Collingridge GL | title = MK-801 blocks NMDA receptor-mediated synaptic transmission and long term potentiation in rat hippocampal slices | journal =Neurosci. Lett.Neuroscience Letters | volume = 80 | issue = 1 | pages =111–4 111–114 | date = September 1987 | pmid = 2821457 | doi = 10.1016/0304-3940(87)90505-2 | s2cid = 268615 }}</ref> and has been found to impair the acquisition of difficult, but not easy, learning tasks  in rats<ref>{{Citecite journal |last vauthors = Murray, T.K.TK, Ridley, R.M.RM, Snape MF, M.F.Cross andAJ Cross,| A.J.|date=1995|title = The effect of dizocilpine (MK801MK-801) on spatial and visual discrimination tasks in the rat. | journal = Behavioural Pharmacology | volume = 6 | issue = 5 And 6 | pages = 540–549 | date = August 1995 | pmid = 11224361 | doi = 10.1097/00008877-199508000-00014 | s2cid = 29029744 }}</ref><ref>{{Citecite journal |last vauthors = Murray TK, T.K.Ridley andRM Ridley,| R.M.|date=1997|title = The effect of dizocilpine (MK801MK-801) on conditional discrimination learning in the rat. | journal = Behavioural Pharmacology | volume = 8 | issue = 5 | pages = 383–388 | date = October 1997 | pmid = 9832977 | doi = 10.1097/00008877-199710000-00002 |pmid=9832977| s2cid = 27485569 }}</ref> and primates.<ref>{{Citecite journal |last vauthors = Harder, J.A.JA, Aboobaker, A.A.AA, Hodgetts TC, T.C.Ridley andRM Ridley, R.M.|date=1998| title = Learning impairmentimpairments induced by glutamate blockade using dizocilpine (MK801MK-801) in monkeys. | journal = British Journal of Pharmacology | volume = 125 | issue = 5 | pages = 1013–1018 | date = November 1998 | pmid = 9846639 | pmc = 1565679 | doi = 10.1038/sj.bjp.0702178|pmid=9846639|pmc=1565679 }}</ref> Because of these effects of dizocilpine, the NMDA receptor pore- blocker [[ketamine]] is used instead as a dissociative anesthetic in human medical procedures. While ketamine may also trigger temporary [[psychosis]] in certain individuals, its short half-life and lower potency make it a much safer clinical option. However, dizocilpine is the most frequently used non-competitiveuncompetitive NMDA receptor antagonist in animal models to mimic psychosis for experimental purposes.

Dizocilpine has also been found to act as a [[nicotinic acetylcholine receptor]] [[nicotinic antagonist|antagonist]].<ref name="pmid1694895">{{cite journal |vauthors=Ramoa AS, Alkondon M, Aracava Y | title = The anticonvulsant MK-801 interacts with peripheral and central nicotinic acetylcholine receptor ion channels | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 254 | issue = 1 | pages = 71–82 |date=July 1990 | pmid = 1694895 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=1694895|display-authors=etal}}</ref><ref name="pmid1715611">{{cite journal |vauthors=Amador M, Dani JA | title = MK-801 inhibition of nicotinic acetylcholine receptor channels | journal = Synapse | volume = 7 | issue = 3 | pages = 207–15 |date=March 1991 | pmid = 1715611 | doi = 10.1002/syn.890070305 | s2cid = 45243975 }}</ref><ref name="pmid8793902">{{cite journal |vauthors=Briggs CA, McKenna DG | title = Effect of MK-801 at the human alpha 7 nicotinic acetylcholine receptor | journal = Neuropharmacology | volume = 35 | issue = 4 | pages = 407–14 |date=April 1996 | pmid = 8793902 | doi = 10.1016/0028-3908(96)00006-8| s2cid = 54377970 }}</ref> It has been shown to bind to and [[reuptake inhibitor|inhibit]] the [[serotonin transporter|serotonin]] and [[dopamine transporter]]s as well.<ref name="pmid10340631">{{cite journal |vauthors=Iravani MM, Muscat R, Kruk ZL | title = MK-801 interaction with the 5-HT transporter: a real-time study in brain slices using fast cyclic voltammetry | journal = Synapse | volume = 32 | issue = 3 | pages = 212–24 |date=June 1999 | pmid = 10340631 | doi = 10.1002/(SICI)1098-2396(19990601)32:3<212::AID-SYN7>3.0.CO;2-M | s2cid = 1419196 }}</ref><ref name="pmid">{{cite journal |vauthors=Clarke PB, Reuben M | title = Inhibition by dizocilpine (MK-801) of striatal dopamine release induced by MPTP and MPP+: possible action at the dopamine transporter | journal = British Journal of Pharmacology | volume = 114 | issue = 2 | pages = 315–22 |date=January 1995 | pmid = 7881731| pmc = 1510234 | doi = 10.1111/j.1476-5381.1995.tb13229.x}}</ref>

Dizocilpine has a great deal of potential to be used in research in creating [[animal models of schizophrenia]]. Unlike dopaminergic agonists, which mimic only the positive symptoms of schizophrenia, a single injection of dizocilpine was successful in modelling both the positive and negative symptoms of schizophrenia.<ref>{{cite journal |vauthors=Rung JP, Carlsson A, Rydén Markinhuhta K, Carlsson ML |title=(+)-MK-801 induced social withdrawal in rats; a model for negative symptoms of schizophrenia |journal=Prog. Neuropsychopharmacol. Biol. Psychiatry |volume=29 |issue=5 |pages=827–32 |date=June 2005 |pmid=15916843 |doi=10.1016/j.pnpbp.2005.03.004 |s2cid=25887719 }}</ref> Another study found that, although repeated low doses of dizocilpine were only successful in mimicking behavioral changes such as a slight [[hyperlocomotion]] and decreased [[prepulse inhibition]], repeated administration of a higher dose mimicked both the above changes as well as the neurochemical alterations found in first-episode schizophrenic patients.<ref>{{cite journal |vauthors=Eyjolfsson EM, Brenner E, Kondziella D, Sonnewald U |title=Repeated injection of MK801: an animal model of schizophrenia? |journal=Neurochem. Int. |volume=48 |issue=6–7 |pages=541–6 |year=2006 |pmid=16517016 |doi=10.1016/j.neuint.2005.11.019 |s2cid=26794826 }}</ref> Not only has temporary use been shown to mimic [[psychosis]] but chronic administration in laboratory animals resulted in similar neuropathological changes as in [[schizophrenia]].<ref>{{cite journal |vauthors=Braun I, Genius J, Grunze H, Bender A, Möller HJ, Rujescu D |title=Alterations of hippocampal and prefrontal GABAergic interneurons in an animal model of psychosis induced by NMDA receptor antagonism |journal=Schizophr. Res. |volume=97 |issue=1–3 |pages=254–63 |date=December 2007 |pmid=17601703 |doi=10.1016/j.schres.2007.05.005 |s2cid=22688722 }}</ref>

The effects of dizocilpine at [[NMDA receptorsreceptor]]s are clear and significant. NMDA receptors are key in the progression of [[excitotoxicity]] (a process in which an excessive amount of extracellular [[glutamate]] overexcites [[glutamate receptor]]s and harms neurons). Thus NMDA receptor antagonists including dizocilpine have been extensively studied for use in treatment of diseases with excitotoxic components, such as [[stroke]], [[traumatic brain injury]], and [[neurodegenerative disease]]s such as [[Huntington's disease|Huntington's]], [[Alzheimer's disease|Alzheimer's]], and [[amyotrophic lateral sclerosis]]. Dizocilpine has shown effectiveness in protecting neurons in [[cell culture]] and [[animal experimentation|animal models]] of excitotoxic neurodegeneration.<ref name="Ayala">{{cite journal |vauthors=Ayala GX, Tapia R |title=Late N-methyl-D-aspartate receptor blockade rescues hippocampal neurons from excitotoxic stress and death after 4-aminopyridine-induced epilepsy |journal=Eur. J. Neurosci. |volume=22 |issue=12 |pages=3067–76 |date=December 2005 |pmid=16367773 |doi=10.1111/j.1460-9568.2005.04509.x |s2cid=25943336 }}</ref><ref name="Kocaeli">{{cite journal |vauthors=Kocaeli H, Korfali E, Oztürk H, Kahveci N, Yilmazlar S |title=MK-801 improves neurological and histological outcomes after spinal cord ischemia induced by transient aortic cross-clipping in rats |journal=Surg Neurol |volume=64 |issue=Suppl 2|pages=S22–6; discussion S27 |year=2005 |pmid=16256835 |doi=10.1016/j.surneu.2005.07.034 }}</ref><ref name="Mukhin">{{cite journal |vauthors=Mukhin AG, Ivanova SA, Knoblach SM, Faden AI |title=New in vitro model of traumatic neuronal injury: evaluation of secondary injury and glutamate receptor-mediated neurotoxicity |journal=J. Neurotrauma |volume=14 |issue=9 |pages=651–63 |date=September 1997 |pmid=9337127 |doi=10.1089/neu.1997.14.651 }}</ref> The administration of dizocilpine protected the hippocampus from ischemia-induced neurodegeneration in the gerbil. The ED₅₀ (effective dose 50) for neuroprotection was 0.3&nbsp;mg/kg and the majority of the animals were protected against the ischemia-induced damage at doses greater than or equal to 3&nbsp;mg/kg, when dizocilpine was given one hour prior to the occlusion of the carotid arteries, although other studies have shown protection up to 24 hours post-insult. Excitatory amino acids, such as glutamate and aspartate, are released in toxic amounts when the brain is deprived of blood and oxygen and [[NMDA antagonistsantagonist]]s are thought to prevent the neurodegeneration through the inhibition of these receptors.<ref>{{cite journal |author=Barnes DM |title=Drug may protect brains of heart attack victims |journal=Science |volume=235 |issue=4789 |pages=632–3 |date=February 1987 |pmid=3027893 |doi=10.1126/science.3027893|bibcode=1987Sci...235..632B |s2cid=45853861 }}</ref><ref>{{cite journal |vauthors=Gill R, Foster AC, Woodruff GN |title=Systemic administration of MK-801 protects against ischemia-induced hippocampal neurodegeneration in the gerbil |journal=J. Neurosci. |volume=7 |issue=10 |pages=3343–9 |date=October 1987 |pmid=3312511 |pmc=6569187 |doi=10.1523/JNEUROSCI.07-10-03343.1987 }}</ref>

As an antidepressant, positive results were found in [[animal models of depression]].<ref>{{cite journal |author=Berk M |title=Depression therapy: future prospects |journal=Int J Psychiatry Clin Pract |volume=4 |issue=4 |pages=281–6 |year=2000 |doi=10.1080/13651500050517830|pmid=24926578 |s2cid=41078092 }}</ref> [[NMDA antagonistsantagonist]]s like dizocilpine have been shown in animal models to attenuate the hearing loss caused by [[aminoglycosides]] It is thought that aminoglycosides mimic endogenous polyamines[[polyamine]]s at NMDA receptors and produce excitotoxic damage, leading to hair cell loss. Antagonizing NMDA receptors to reduce the excitotoxicity would prevent that hearing loss.<ref>{{cite journal |vauthors=Basile AS, Huang JM, Xie C, Webster D, Berlin C, Skolnick P |title=N-methyl-D-aspartate antagonists limit aminoglycoside antibiotic-induced hearing loss |journal=Nat. Med. |volume=2 |issue=12 |pages=1338–43 |date=December 1996 |pmid=8946832 |doi=10.1038/nm1296-1338 |s2cid=30861122 }}</ref><ref>{{cite journal |vauthors=Ernfors P, Canlon B |title=Aminoglycoside excitement silences hearing |journal=Nat. Med. |volume=2 |issue=12 |pages=1313–4 |date=December 1996 |pmid=8946827 |doi=10.1038/nm1296-1313 |s2cid=39020295 }} (Editorial)</ref> Dizocilpine was found to block the development of kindled [[seizure]]s, although it does not have any effect on completed kindled seizures.<ref>{{cite journal |vauthors=Post RM, Silberstein SD |title=Shared mechanisms in affective illness, epilepsy, and migraine |journal=Neurology |volume=44 |issue=10 Suppl 7 |pages=S37–47 |date=October 1994 |pmid=7969945 }}</ref> Oddly, it was discovered to decrease [[rabies]] virus production and is believed to be the first neurotransmitter antagonist to present with antiviral activity. Rat cortical neuron cells were infected with the rabies virus and those incubated with dizocilpine had virus produced reduced about 1000-fold. It is not known how MK-801 has this effect; the rabies virus suspension, without cells, was inoculated with dizocilpine and the drug failed to produce a virucidal effect, indicated that the mechanism of action is something other than direct discontinuation of virus reproduction. It was also tested against herpes simplex, vesicular stomatitis, poliovirus type I, and human immunodeficiency virus[[HIV]]. It did not have activity against these other viruses, however.<ref>{{cite journal |vauthors=Tsiang H, Ceccaldi PE, Ermine A, Lockhart B, Guillemer S |title=Inhibition of rabies virus infection in cultured rat cortical neurons by an N-methyl-D-aspartate noncompetitive antagonist, MK-801 |journal=Antimicrob. Agents Chemother. |volume=35 |issue=3 |pages=572–4 |date=March 1991 |pmid=1674849 |pmc=245052 |doi=10.1128/AAC.35.3.572}}</ref> Dizocilpine was also shown to potentiate the ability of [[levodopa]] to ameliorate [[akinesia]] and muscular rigidity in a rodent model of [[parkinsonism]].<ref>{{cite journal |vauthors=Klockgether T, Turski L |title=NMDA antagonists potentiate antiparkinsonian actions of L-dopa in monoamine-depleted rats |journal=Ann. Neurol. |volume=28 |issue=4 |pages=539–46 |date=October 1990 |pmid=2252365 |doi=10.1002/ana.410280411 |s2cid=12624754 }}</ref> When dizocilpine was administered to rats 15 minutes after a spinal trauma, the long-term neurological recovery of the trauma was improved.<ref>{{cite journal |vauthors=Faden AI, Lemke M, Simon RP, Noble LJ |title=N-methyl-D-aspartate antagonist MK801 improves outcome following traumatic spinal cord injury in rats: behavioral, anatomic, and neurochemical studies |journal=J. Neurotrauma |volume=5 |issue=1 |pages=33–45 |year=1988 |pmid=3057216 |doi=10.1089/neu.1988.5.33 }}</ref> However, NMDA antagonists like dizocilpine have largely failed to show safety in [[clinical trial]]s, possibly due to inhibition of [[NMDA receptor]] function that is necessary for normal [[neuron]]al function. Since dizocilpine is a particularly strong NMDA receptor antagonist, this drug is particularly likely to have [[psychotomimetic]] side effects (such as [[hallucination]]s) that result from NMDA receptor blockade. Dizocilpine had a promising future as a neuroprotective agent until neurotoxic-like effects, called [[Olney's Lesions]], were seen in certain [[brain]] regions of lab rats.<ref name="Olney89">{{cite journal |vauthors=Olney JW, Labruyere J, Price MT |title=Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs |journal=Science |volume=244 |issue=4910 |pages=1360–2 |date=June 1989 |pmid=2660263 |doi=10.1126/science.2660263|bibcode=1989Sci...244.1360O }}</ref><ref name="ellison">{{cite journal |author=Ellison G |title=The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias |journal=Brain Res. Brain Res. Rev. |volume=20 |issue=2 |pages=250–67 |date=February 1995 |pmid=7795658 |doi=10.1016/0165-0173(94)00014-G|s2cid=24071513 }}</ref> [[Merck & Co.|Merck]], a drug company, promptly dropped development of dizocilpine.

Dizocilpine, along with other [[NMDA antagonistsantagonist]]s, induce the formation of brain lesions first discovered by John W. Olney in 1989. Dizocilpine leads to the development of neuronal vacuolization in the [[posterior cingulate]]/retrosplenial cortex.<ref name="Olney89"/> Other neurons in the area expressed an abnormal amount of [[heat shock protein]]<ref>{{cite journal |vauthors=Sharp FR, Jasper P, Hall J, Noble L, Sagar SM |title=MK-801 and ketamine induce heat shock protein HSP72 in injured neurons in posterior cingulate and retrosplenial cortex |journal=Ann. Neurol. |volume=30 |issue=6 |pages=801–9 |date=December 1991 |pmid=1838680 |doi=10.1002/ana.410300609 |s2cid=19052517 }}</ref> as well as increased glucose metabolism<ref>{{cite journal |vauthors=Hargreaves RJ, Rigby M, Smith D, Hill RG, Iversen LL |title=Competitive as well as uncompetitive N-methyl-D-aspartate receptor antagonists affect cortical neuronal morphology and cerebral glucose metabolism |journal=Neurochem. Res. |volume=18 |issue=12 |pages=1263–9 |date=December 1993 |pmid=7903796 |doi=10.1007/BF00975046 |s2cid=20604534 }}</ref> in response to NMDA antagonist exposure. Vacuoles began to form within 30 minutes of a subcutaneous dose of dizocilpine 1&nbsp;mg/kg.<ref>{{cite journal |vauthors=Fix AS, Horn JW, Truex LL, Smith RA, Gomez E |title=Neuronal vacuole formation in the rat posterior cingulate/retrosplenial cortex after treatment with the N-methyl-D-aspartate (NMDA) antagonist MK-801 (dizocilpine maleate) |journal=Acta Neuropathol. |volume=88 |issue=6 |pages=511–9 |year=1994 |pmid=7879597 |doi=10.1007/BF00296487 |s2cid=28368130 }}</ref> Neurons in this area necrotized and were accompanied by a [[glial]] response involving [[astrocytes]] and [[microglia]].<ref>{{cite journal |vauthors=Fix AS, Horn JW, Wightman KA |title=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 |journal=Exp. Neurol. |volume=123 |issue=2 |pages=204–15 |date=October 1993 |pmid=8405286 |doi=10.1006/exnr.1993.1153 |s2cid=24839154 |display-authors=etal}}</ref>

{{refimprovemore citations needed section|date=February 2015}}

Dizocilpine may be effective as a recreational drug. Little is known in this context about its effects, dosage, and risks. The high potency of dizocilpine makes its dosage more difficult to accurately control when compared to other similar drugs. As a result, the chances of [[overdosing]] are high. Users tend to report that the experience is not as enjoyable as other [[dissociative]] drugs, and it is often accompanied by strong auditory hallucinations. Also, dizocilpine is much longer-lasting than similar dissociative drugs such as [[ketamine]] and [[phencyclidine]] (PCP), and causes far worse [[amnesia]] and residual deficits in thinking, which have hindered its acceptance as a recreational drug.{{Citation needed|date=November 2007}}

Several animal studies have demonstrated the addictive potential of dizocilpine. Rats learned to lever-press in order to obtain injections of dizocilpine into the nucleus accumbens and frontal cortex, however, when given a dopamine antagonist at the same time, the lever-pressing was not altered, which shows that the rewarding effect of dizocilpine is not dependent on dopamine.<ref>{{cite journal |vauthors=Carlezon WA, Wise RA |title=Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex |journal=J. Neurosci. |volume=16 |issue=9 |pages=3112–22 |date=May 1996 |pmid=8622141 |pmc=6579051 |doi=10.1523/JNEUROSCI.16-09-03112.1996 }}</ref> Intraperitoneal administration of dizocilpine also produced an enhancement in self-stimulation responding.<ref>{{cite journal |vauthors=Herberg LJ, Rose IC |title=The effect of MK-801 and other antagonists of NMDA-type [[glutamate]] receptors on brain-stimulation reward |journal=Psychopharmacology |volume=99 |issue=1 |pages=87–90 |year=1989 |pmid=2550989 |doi=10.1007/BF00634458 |s2cid=24305644 }}</ref> Rhesus monkeys were trained to self-administer cocaine or phencyclidine, then were offered dizocilpine instead. None of the four monkeys who were used to cocaine chose to self-administer dizocilpine but three out of the four monkeys who had been using phencyclidine self-administered dizocilpine, suggesting again that dizocilpine has potential as a recreational drug for those seeking a dissociative anaesthetic type of experience.<ref>{{cite journal |vauthors=Beardsley PM, Hayes BA, Balster RL |title=The self-administration of MK-801 can depend upon drug-reinforcement history, and its discriminative stimulus properties are phencyclidine-like in rhesus monkeys |journal=J. Pharmacol. Exp. Ther. |volume=252 |issue=3 |pages=953–9 |date=March 1990 |pmid=2181113 |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2181113}}</ref> It was found that dizocilpine administration elicited [[conditioned place preference]] in animals, again demonstrating its reinforcing properties.<ref>{{cite journal |vauthors=Layer RT, Kaddis FG, Wallace LJ |title=The NMDA receptor antagonist M-801 elicits conditioned place preference in rats |journal=Pharmacology Biochemistry and Behavior |volume=44 |issue=1 |pages=245–7 |date=January 1993 |doi=10.1016/0091-3057(93)90306-E|pmid=8430127 |s2cid=30742891 }}</ref><ref>{{cite journal |vauthors=Papp M, Moryl E, Maccecchini ML |title=Differential effects of agents acting at various sites of the NMDA receptor complex in a place preference conditioning model |journal=Eur. J. Pharmacol. |volume=317 |issue=2–3 |pages=191–6 |date=December 1996 |pmid=8997600 |doi=10.1016/S0014-2999(96)00747-9}}</ref>