Dizocilpine: Difference between revisions

'''Dizocilpine''' ([[International Nonproprietary Name|INN]]), also known as '''MK-801''', is a pore blocker of the [[NMDA receptor|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 P, Christy ME, Evans BE | assign1 = Merck & Company 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 = 395–396 | 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>{{cite 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 85 | issue = 4 | pages = 1307–1311 | date = February 1988 | pmid = 2448800 | 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 = Neuroscience Letters | volume = 80 | issue = 1 | pages = 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>{{cite journal | vauthors = Murray TK, Ridley RM, Snape MF, Cross AJ | title = The effect of dizocilpine (MK-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>{{cite journal | vauthors = Murray TK, Ridley RM | title = The effect of dizocilpine (MK-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 | s2cid = 27485569 }}</ref> and primates.<ref>{{cite journal | vauthors = Harder JA, Aboobaker AA, Hodgetts TC, Ridley RM | title = Learning impairments induced by glutamate blockade using dizocilpine (MK-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 }}</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 uncompetitive NMDA receptor antagonist in animal models to mimic psychosis for experimental purposes.

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>