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Dizocilpine may be effective as a recreational drug, and may have an active dose in the 50-100 μg range. 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}}
Dizocilpine may be effective as a recreational drug, and may have an active dose in the 50-100 μg range. 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 MK-801 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 MK-801 is not dependent on dopamine.<ref>{{cite journal |author=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 |year=1996 |month=May |pmid=8622141 |url=http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=8622141}}</ref> Intraperitoneal administration of MK-801 also produced an enhancement in self-stimulation responding.<ref>{{cite journal |author=Herberg LJ, Rose IC |title=The effect of MK-801 and other antagonists of NMDA-type glutamate receptors on brain-stimulation reward |journal=Psychopharmacology (Berl.) |volume=99 |issue=1 |pages=87–90 |year=1989 |pmid=2550989 |doi=10.1007/BF00634458 }}</ref> Rhesus monkeys were trained to self-administer cocaine or phencyclidine, then were offered MK-801 instead. None of the four monkeys who were used to cocaine chose to self-administer MK-801 but three out of the four monkeys who had been using phencyclidine self-administered MK-801, suggesting again that MK-801 has potential as a recreational drug for those seeking a dissociative anaesthetic type of experience.<ref>{{cite journal |author=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 |year=1990 |month=March |pmid=2181113 |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2181113}}</ref> It was found that MK-801 administration elicited conditioned place preference in animals, again demonstrating its reinforcing properties.<ref>{{cite journal |author=Layer RT, Kaddis FG, Wallace LJ |title=The NMDA receptor antagonist M-801 elicits conditioned place preference in rats |journal=Pharmacology, Biochemistry and Behaviour |volume=44 |issue=1 |pages=245–7 |year=1993 |month=January |doi=10.1016/0091-3057(93)90306-E}}</ref><ref>{{cite journal |author=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 |year=1996 |month=December |pmid=8997600 |url=http://linkinghub.elsevier.com/retrieve/pii/S0014-2999(96)00747-9 |doi=10.1016/S0014-2999(96)00747-9}}</ref>
Several animal studies have demonstrated the addictive potential of dizocilpine. Rats learned to lever-press in order to obtain injections of MK-801 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 MK-801 is not dependent on dopamine.<ref>{{cite journal |author=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 |year=1996 |month=May |pmid=8622141 |url=http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=8622141}}</ref> Intraperitoneal administration of MK-801 also produced an enhancement in self-stimulation responding.<ref>{{cite journal |author=Herberg LJ, Rose IC |title=The effect of MK-801 and other antagonists of NMDA-type glutamate receptors on brain-stimulation reward |journal=Psychopharmacology (Berl.) |volume=99 |issue=1 |pages=87–90 |year=1989 |pmid=2550989 |doi=10.1007/BF00634458 }}</ref> Rhesus monkeys were trained to self-administer cocaine or phencyclidine, then were offered MK-801 instead. None of the four monkeys who were used to cocaine chose to self-administer MK-801 but three out of the four monkeys who had been using phencyclidine self-administered MK-801, suggesting again that MK-801 has potential as a recreational drug for those seeking a dissociative anaesthetic type of experience.<ref>{{cite journal |author=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 |year=1990 |month=March |pmid=2181113 |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2181113}}</ref> It was found that MK-801 administration elicited [[conditioned place preference]] in animals, again demonstrating its reinforcing properties.<ref>{{cite journal |author=Layer RT, Kaddis FG, Wallace LJ |title=The NMDA receptor antagonist M-801 elicits conditioned place preference in rats |journal=Pharmacology, Biochemistry and Behaviour |volume=44 |issue=1 |pages=245–7 |year=1993 |month=January |doi=10.1016/0091-3057(93)90306-E}}</ref><ref>{{cite journal |author=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 |year=1996 |month=December |pmid=8997600 |url=http://linkinghub.elsevier.com/retrieve/pii/S0014-2999(96)00747-9 |doi=10.1016/S0014-2999(96)00747-9}}</ref>


A multiple drug fatality involving MK-801, [[benzodiazepines]], and [[ethanol|alcohol]] has been reported.<ref>{{cite journal|last=Mozayani|first=A|coauthors=Schrode, P, Carter, J, Danielson, TJ|title=A multiple drug fatality involving MK-801 (dizocilpine), a mimic of phencyclidine.|journal=Forensic Science International|date=2003 Apr 23|volume=133|issue=1-2|pages=113–7|pmid=12742697|doi=10.1016/S0379-0738(03)00070-7}}</ref>
A multiple drug fatality involving MK-801, [[benzodiazepines]], and [[ethanol|alcohol]] has been reported.<ref>{{cite journal|last=Mozayani|first=A|coauthors=Schrode, P, Carter, J, Danielson, TJ|title=A multiple drug fatality involving MK-801 (dizocilpine), a mimic of phencyclidine.|journal=Forensic Science International|date=2003 Apr 23|volume=133|issue=1-2|pages=113–7|pmid=12742697|doi=10.1016/S0379-0738(03)00070-7}}</ref>

Revision as of 13:23, 4 November 2012

Dizocilpine
Clinical data
Pregnancy
category
  • AU: ?
Routes of
administration		Oral, IM
ATC code
Pharmacokinetic data
Bioavailability?
Metabolism?
Elimination half-life?
Excretion?
Identifiers
  • [5R,10S]-[+]-5-methyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC16H15N
Molar mass221.297 g/mol g·mol−1
3D model (JSmol)
Melting point68.75 °C (155.75 °F)
  • c1c3c(ccc1)[C@@]4(c2c(cccc2)C[C@H]3N4)C
  • InChI=1S/C16H15N/c1-16-13-8-4-2-6-11(13)10-15(17-16)12-7-3-5-9-14(12)16/h2-9,15,17H,10H2,1H3/t15-,16+/m1/s1 checkY
  • Key:LBOJYSIDWZQNJS-CVEARBPZSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Dizocilpine (INN), also known as MK-801, is a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, a glutamate receptor. 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.[1] MK-801 binds inside the ion channel of the receptor at several of PCP's binding sites thus preventing the flow of ions, including an influx of 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. The drug acts as a potent anti-convulsant and likely has dissociative anesthetic properties, but it is not used clinically for this purpose due to the discovery of brain lesions, called Olney's lesions (see below), in test rats. MK-801 is also associated with a number of negative side effects, including cognitive disruption and psychotic-spectrum reactions. It also inhibited the induction of long term potentiation.[2] Instead, the NMDA receptor pore-blocker ketamine is used 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-competitive NMDA receptor antagonist in animal models to mimic psychosis for experimental purposes.

Dizocilpine has also been found to act as a nicotinic acetylcholine receptor antagonist.[3][4][5] It has been shown to bind to and inhibit the serotonin and dopamine transporters as well.[6][7]

An animal model of schizophrenia

MK-801 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 MK801 was successful in modelling both the positive and negative symptoms of schizophrenia.[8] Another study found that, although repeated low doses of MK-801 were only successful in mimicking behavioural changes such as a slight hyperlocomotion and increased 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.[9] Not only has temporary use been shown to mimic psychosis but chronic administration in laboratory animals resulted in similar neuropathological changes as in schizophrenia.[10]

Possible future medical uses

The effects of MK-801 at NMDA receptors 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 receptors and harms neurons). Thus NMDA receptor antagonists including MK-801 have been extensively studied for use in treatment of diseases with excitotoxic components, such as stroke, traumatic brain injury, and neurodegenerative diseases such as Huntington's, Alzheimer's, and amyotrophic lateral sclerosis. MK-801 has shown effectiveness in protecting neurons in cell culture and animal models of excitotoxic neurodegeneration.[11][12][13] The administration of MK-801 protected the hippocampus from ischemia-induced neurodegeneration in the gerbil. The ED50 (effective dose 50) for neuroprotection was 0.3 mg/kg and the majority of the animals were protected against the ischemia-induced damage at doses greater than or equal to 3 mg/kg, when MK-801 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 receptors are thought to prevent the neurodegeneration through the inhibition of these receptors.[14][15]

Behavioural studies have shown that NMDA receptors are involved in the development of psychological dependence caused by chronic administration of morphine. MK-801 suppressed the morphine-induced rewarding effect. It is suggested that stimulating NR2B subunits of the NMDA receptor and its associated kinases in the nucleus accumbens leads to the rewarding effect caused by morphine. Inhibition of this receptor and its kinases in the nucleus accumbens by co-treatment with NMDA antagonists prevents morphine-associated psychological dependence.[16] An earlier study has show that the prevention of morphine-associated psychological dependence was not due to state-dependency effects induced by MK-801[17] but rather reflect the impairment of learning that is caused by NMDA antagonists.[18] This is consistent with studies showing that MK-801 potentiates the addictive potential of morphine and other drugs (see below).

3-D molecular model

As an antidepressant, positive results were found in animal models of depression.[19] NMDA antagonists like MK-801 have been shown in animal models to attenuate the hearing loss caused by aminoglycosides It is thought that aminoglycosides mimic endogenous polyamines at NMDA receptors and produce excitotoxic damage, leading to hair cell loss. Antagonizing NMDA receptors to reduce the excitotoxicity would prevent that hearing loss.[20][21] MK-801 was found to block the development of kindled seizures, although it does not have any effect on completed kindled seizures.[22] 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 MK-801 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 MK-801 and the drug failed to produce a virucidal effect, indicated that the mechanism of action is something other than direct killing of the virus. It was also tested against herpes simplex, vesicular stomatitis, poliovirus type I, and human immunodeficiency virus. It did not have activity against these other viruses, however.[23] MK-801 was also shown to potentiate the ability of levodopa to ameliorate akinesia and muscular rigidity in a rodent model of parkinsonism.[24] When MK-801 was administered to rats 15 minutes after a spinal trauma, the long-term neurological recovery of the trauma was improved.[25] However, NMDA antagonists like MK-801 have largely failed to show safety in clinical trials, possibly due to inhibition of NMDA receptor function that is necessary for normal neuronal function. Since MK-801 is a particularly strong NMDA receptor antagonist, this drug is particularly likely to have psychotomimetic side effects (such as hallucinations) that result from NMDA receptor blockade. MK-801 had a promising future as a neuroprotective agent until neurotoxic-like effects, called Olney's Lesions, were seen in certain brain regions of test rats.[26][27] Merck, a drug company, promptly dropped development of MK-801.

Olney's lesions

Main article: Olney's lesions

MK-801, along with other NMDA antagonists, induce the formation of brain lesions first discovered by John W. Olney in 1989. MK-801 leads to the development of neuronal vacuolization in the posterior cingulate/retrosplenial cortex.[26] Other neurons in the area expressed an abnormal amount of heat shock protein[28] as well as increased glucose metabolism[29] in response to NMDA antagonist exposure. Vacuoles began to form within 30 minutes of a subcutaneous dose of MK-801 1 mg/kg.[30] Neurons in this area necrotized and were accompanied by a glial response involving astrocytes and microglia.[31]

However, it may be necessary to point out that Ketamine was also found in animal models to produce Olney's Lesions, but not in humans.[citation needed]

Recreational use

Dizocilpine may be effective as a recreational drug, and may have an active dose in the 50-100 μg range. 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] Several animal studies have demonstrated the addictive potential of dizocilpine. Rats learned to lever-press in order to obtain injections of MK-801 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 MK-801 is not dependent on dopamine.[32] Intraperitoneal administration of MK-801 also produced an enhancement in self-stimulation responding.[33] Rhesus monkeys were trained to self-administer cocaine or phencyclidine, then were offered MK-801 instead. None of the four monkeys who were used to cocaine chose to self-administer MK-801 but three out of the four monkeys who had been using phencyclidine self-administered MK-801, suggesting again that MK-801 has potential as a recreational drug for those seeking a dissociative anaesthetic type of experience.[34] It was found that MK-801 administration elicited conditioned place preference in animals, again demonstrating its reinforcing properties.[35][36]

A multiple drug fatality involving MK-801, benzodiazepines, and alcohol has been reported.[37]

See also

References

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  2. ^ Coan EJ, Saywood W, Collingridge GL (1987). "MK-801 blocks NMDA receptor-mediated synaptic transmission and long term potentiation in rat hippocampal slices". Neurosci. Lett. 80 (1): 111–4. doi:10.1016/0304-3940(87)90505-2. PMID 2821457. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Ramoa AS, Alkondon M, Aracava Y; et al. (1990). "The anticonvulsant MK-801 interacts with peripheral and central nicotinic acetylcholine receptor ion channels". The Journal of Pharmacology and Experimental Therapeutics. 254 (1): 71–82. PMID 1694895. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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  27. ^ Ellison G (1995). "The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias". Brain Res. Brain Res. Rev. 20 (2): 250–67. doi:10.1016/0165-0173(94)00014-G. PMID 7795658. {{cite journal}}: Unknown parameter |month= ignored (help)
  28. ^ Sharp FR, Jasper P, Hall J, Noble L, Sagar SM (1991). "MK-801 and ketamine induce heat shock protein HSP72 in injured neurons in posterior cingulate and retrosplenial cortex". Ann. Neurol. 30 (6): 801–9. doi:10.1002/ana.410300609. PMID 1838680. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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  33. ^ Herberg LJ, Rose IC (1989). "The effect of MK-801 and other antagonists of NMDA-type glutamate receptors on brain-stimulation reward". Psychopharmacology (Berl.). 99 (1): 87–90. doi:10.1007/BF00634458. PMID 2550989.
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Further reading

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