Dizocilpine

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Dizocilpine
Clinical data
Routes of
administration		By mouth, IM
Identifiers
  • (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine
JSmol)
Melting point68.75 °C (155.75 °F)
  • C[C@]1(C2=C(C[C@H]3N1)C=CC=C2)C4=C3C=CC=C4
  • 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 (

long term potentiation[4] and has been found to impair the acquisition of difficult, but not easy, learning tasks in rats[5][6] and primates.[7] 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.

Dizocilpine has also been found to act as a nicotinic acetylcholine receptor antagonist.[8][9][10] It has been shown to bind to and inhibit the serotonin and dopamine transporters as well.[11][12]

An animal model of schizophrenia

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.[13] 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.[14] Not only has temporary use been shown to mimic psychosis but chronic administration in laboratory animals resulted in similar neuropathological changes as in schizophrenia.[15]

Possible future medical uses

The effects of dizocilpine at

NMDA antagonists are thought to prevent the neurodegeneration through the inhibition of these receptors.[19][20]

Behavioural studies have shown that NMDA receptors are involved in the development of psychological dependence caused by chronic administration of morphine. Dizocilpine 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.[21] An earlier study has shown that the prevention of morphine-associated psychological dependence was not due to state-dependency effects induced by dizocilpine[22] but rather reflect the impairment of learning that is caused by NMDA antagonists.[23] This is consistent with studies showing that dizocilpine potentiates the addictive potential of morphine and other drugs (see below).

As an antidepressant, positive results were found in

Olney's Lesions, were seen in certain brain regions of lab rats.[31][32] Merck
, a drug company, promptly dropped development of dizocilpine.

Olney's lesions

Main article: Olney's lesions

Dizocilpine, along with other

astrocytes and microglia.[36]

Recreational use

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
] 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.[37] Intraperitoneal administration of dizocilpine also produced an enhancement in self-stimulation responding.[38] 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.[39] It was found that dizocilpine administration elicited conditioned place preference in animals, again demonstrating its reinforcing properties.[40][41]

A multiple drug fatality involving dizocilpine,

benzodiazepines, and alcohol has been reported.[42]

Dizocilpine has been sold online as a Designer drug.[43]

See also

References

  1. ^ US Patent 4399141, Anderson P, Christy ME, Evans BE, "5-Alkyl or hydroxyalkyl substituted-10,11-imines & Anticonvulsant Use Thereof", issued 1983-08-16, assigned to Merck & Company Inc 
  2. S2CID 5486568
    .
  3. PMID 2448800
    .
  4. S2CID 268615
    .
  5. S2CID 29029744
    .
  6. S2CID 27485569
    .
  7. PMID 9846639
    .
  8. PMID 1694895
    .
  9. S2CID 45243975
    .
  10. S2CID 54377970
    .
  11. S2CID 1419196
    .
  12. PMID 7881731
    .
  13. S2CID 25887719
    .
  14. S2CID 26794826
    .
  15. S2CID 22688722
    .
  16. S2CID 25943336
    .
  17. PMID 16256835
    .
  18. PMID 9337127
    .
  19. S2CID 45853861
    .
  20. PMID 3312511
    .
  21. PMID 15946694
    .
  22. S2CID 4029402
    .
  23. S2CID 4356601
    .
  24. S2CID 41078092
    .
  25. S2CID 30861122
    .
  26. S2CID 39020295
    . (Editorial)
  27. PMID 7969945
    .
  28. PMID 1674849
    .
  29. S2CID 12624754
    .
  30. PMID 3057216
    .
  31. ^
    PMID 2660263
    .
  32. S2CID 24071513
    .
  33. S2CID 19052517
    .
  34. S2CID 20604534
    .
  35. S2CID 28368130
    .
  36. S2CID 24839154
    .
  37. PMID 8622141
    .
  38. S2CID 24305644
    .
  39. PMID 2181113
    .
  40. S2CID 30742891
    .
  41. PMID 8997600
    .
  42. PMID 12742697
    .
  43. ^ "foche - premium research chemicals". 2023-06-01. Archived from the original on 2023-06-01. Retrieved 2023-06-07.

Further reading

original publications for MK-801:

External links