Dizocilpine

Summary

Dizocilpine, also known as MK-801, is a compound discovered by Merck in 1982, functioning as a pore blocker for the N-Methyl-D-aspartate (NMDA) receptor, which is a vital glutamate receptor in the brain. Glutamate serves as the primary excitatory neurotransmitter in the brain.
Under normal conditions, the NMDA receptor channel is blocked by a magnesium ion and necessitates neuron depolarization to remove the magnesium, enabling glutamate to open the channel. This opening leads to an influx of calcium, resulting in subsequent depolarization.
Dizocilpine binds within the ion channel of the NMDA receptor, occupying several binding sites similar to PCP, effectively preventing the flow of ions, including calcium (Ca2+), through the channel. Notably, Dizocilpine blocks NMDA receptors in a manner that relies on usage and voltage, as the track must open for the drug to bind within it.
While Dizocilpine displays potent anti-convulsant properties and likely possesses dissociative anaesthetic characteristics, it is not employed clinically for such purposes due to the discovery of brain lesions, referred to as Olney’s lesions, observed in laboratory rats. Additionally, Dizocilpine is associated with adverse effects, including cognitive disruption and reactions within the psychotic spectrum. It inhibits the induction of long-term potentiation and hinders the acquisition of challenging (but not more straightforward) learning tasks in both rats and primates.
Because of these side effects, ketamine, another NMDA receptor pore blocker, is preferred as a dissociative anaesthetic in medical procedures for humans. While ketamine may also induce transient psychosis in some individuals, its shorter half-life and lower potency make it a safer choice for clinical use. Nonetheless, Dizocilpine remains the most commonly used uncompetitive NMDA receptor antagonist in animal models for experimental purposes, especially to simulate psychosis.
Furthermore, Dizocilpine has been found to act as an antagonist for nicotinic acetylcholine receptors and has demonstrated its ability to bind to and inhibit serotonin and dopamine transporters.

Identifiers

IUPAC name
CAS Number	77086-21-6
PubChem CID	180081
IUPHAR/BPS	2403
DrugBank	?
ChemSpider	156718
UNII	7PY8KH681I
ChEBI	CHEBI:34725
ChEMBL	ChEMBL284237
CompTox Dashboard (EPA)	DTXSID3048447
Chemical and physical data
Formula	C16H15N
Molar mass	221.303 g·mol−1

An animal model of schizophrenia

Dizocilpine exhibits significant potential for research purposes in the development of animal models for schizophrenia. In contrast to dopaminergic agonists, which primarily replicate the positive symptoms of schizophrenia, a single administration of dizocilpine has proven effective in replicating both the positive and negative symptoms of this disorder.
In a separate study, it was noted that while repeated low doses of dizocilpine only managed to replicate behavioural alterations such as slight hyperactivity and reduced prepulse inhibition, repeated administration of a higher amount effectively replicated not only these behavioural changes but also the neurochemical modifications observed in individuals experiencing their first episode of schizophrenia.
Moreover, apart from its capacity to temporarily induce psychosis, prolonged administration of Dizocilpine in laboratory animals has led to the development of comparable neuropathological changes as observed in cases of schizophrenia.

Possible future medical uses

The impact of Dizocilpine on NMDA receptors is profound and noteworthy. NMDA receptors play a pivotal role in the process of excitotoxicity, which involves excessive extracellular glutamate stimulating glutamate receptors and causing harm to neurons. Consequently, NMDA receptor antagonists like Dizocilpine have been extensively explored for their potential in treating conditions marked by excitotoxic elements, including stroke, traumatic brain injury, and neurodegenerative disorders such as Huntington’s, Alzheimer’s, and amyotrophic lateral sclerosis. Dizocilpine has exhibited effectiveness in safeguarding neurons in both cell cultures and animal models experiencing excitotoxic neurodegeneration.
In experiments, Dizocilpine administration shielded the hippocampus from neurodegeneration induced by ischemia in gerbils. The effective dose for neuroprotection (ED50) was found to be 0.3 mg/kg, with the majority of animals being safeguarded against ischemia-induced damage at amounts equal to or greater than 3 mg/kg. This protection was observed when Dizocilpine was administered up to 24 hours after the ischemic event. Excitatory amino acids like glutamate and aspartate are excessively released when the brain is deprived of oxygen and blood. NMDA antagonists are believed to thwart neurodegeneration by inhibiting these receptors.
Behavioural investigations have demonstrated the involvement of NMDA receptors in the development of psychological dependence resulting from chronic morphine administration. Dizocilpine has been effective in suppressing the rewarding effects induced by morphine. It is suggested that the stimulation of NR2B subunits of the NMDA receptor, along with its associated kinases in the nucleus accumbens, is responsible for the rewarding effects of morphine. Inhibiting this receptor and its kinases through co-administration with NMDA antagonists helps prevent the development of psychological dependence linked to morphine. Research indicates that the prevention of morphine-associated psychological support is not due to state-dependency effects induced by Dizocilpine. Still, instead, it reflects the impairment of learning brought about by NMDA antagonists. This aligns with studies showing that Dizocilpine enhances the addictive potential of morphine and other substances (see below).
In animal models of depression, Dizocilpine has yielded positive results as an antidepressant. NMDA antagonists like Dizocilpine have also been found to mitigate the hearing loss caused by aminoglycosides. Aminoglycosides are believed to mimic endogenous polyamines at NMDA receptors, leading to excitotoxic damage and hair cell loss. Antagonizing NMDA receptors reduces excitotoxicity, potentially preventing hearing loss.
Furthermore, Dizocilpine has been observed to block the development of kindled seizures, although it does not impact already established kindled seizures. Intriguingly, it has been found to reduce rabies virus production, demonstrating antiviral activity. Rat cortical neuron cells infected with rabies virus and incubated with Dizocilpine experienced a roughly 1000-fold reduction in virus production. The exact mechanism for this effect has yet to be fully understood, as Dizocilpine failed to exhibit virucidal properties when tested separately from cells. It was also tested against other viruses, such as herpes simplex, vesicular stomatitis, poliovirus type I, and human immunodeficiency virus, but it did not demonstrate activity against these viruses.
Dizocilpine has been shown to potentiate the effectiveness of levodopa in alleviating akinesia and muscular rigidity in a rodent model of parkinsonism. Additionally, when administered 15 minutes after spinal trauma in rats, it improved the long-term neurological recovery following the injury.
However, NMDA antagonists like Dizocilpine have faced challenges in clinical trials, primarily due to their inhibition of NMDA receptor function, which is crucial for regular neuronal operation. Given Dizocilpine’s potent NMDA receptor antagonism, it is particularly prone to inducing psychotomimetic side effects like hallucinations stemming from NMDA receptor blockade. The once-promising future of Dizocilpine as a neuroprotective agent took a turn when neurotoxic-like effects, known as Olney’s Lesions, were observed in specific brain regions of laboratory rats. In response, Merck, the pharmaceutical company, discontinued the development of Dizocilpine.

Olney’s lesions

Dizocilpine, in conjunction with other NMDA antagonists, initiates the development of brain lesions initially observed by John W. Olney in 1989. Specifically, Dizocilpine is linked to the onset of neuronal vacuolization within the posterior cingulate/retrosplenial cortex. In response to exposure to NMDA antagonists, other neurons in the vicinity exhibit atypical heat shock protein expression and heightened glucose metabolism. The formation of vacuoles commences as early as 30 minutes following a subcutaneous dose of 1 mg/kg of Dizocilpine. Neurons in this region subsequently undergo necrosis, accompanied by a glial response that involves astrocytes and microglia.

Recreational use

Dizocilpine’s potential as a recreational substance remains a subject of limited understanding concerning its effects, dosages, and associated risks. Its notably high potency complicates the precise control of dosage in comparison to similar drugs, substantially increasing the risk of overdosing. Users report a less enjoyable experience compared to other dissociative substances, often accompanied by intense auditory hallucinations. Additionally, Dizocilpine’s effects are significantly more prolonged than those of similar dissociative agents like ketamine and phencyclidine (PCP). It also leads to more pronounced amnesia and enduring cognitive deficits, factors that have impeded its acceptance as a recreational drug.
Numerous animal studies have highlighted the addictive potential of Dizocilpine. Rats, for instance, learned to engage in lever-pressing behaviour to obtain Dizocilpine injections in the nucleus accumbens and frontal cortex. Interestingly, when administered a dopamine antagonist simultaneously, the lever-pressing behaviour remained unaltered, indicating that the rewarding effects of Dizocilpine are not solely dependent on dopamine. Intraperitoneal administration of Dizocilpine has also been shown to enhance self-stimulation response. In the case of rhesus monkeys trained to self-administer cocaine or phencyclidine, when offered Dizocilpine instead, three out of four monkeys previously using phencyclidine opted to self-administer Dizocilpine, suggesting its potential appeal as a recreational drug for individuals seeking a dissociative anaesthetic-like experience. Conditioned place preference was also elicited in animals following Dizocilpine administration, further underscoring its reinforcing properties.
Regrettably, a multiple drug fatality involving Dizocilpine, benzodiazepines, and alcohol has been documented. Additionally, Dizocilpine has been sold online as a designer drug.

FAQ

• What is Dizocilpine?
• Dizocilpine, also known as MK-801, is a compound that acts as a pore blocker for the N-Methyl-D-aspartate (NMDA) receptor, an essential receptor in the brain’s glutamate system. It was initially discovered by Merck in 1982.
• Is Dizocilpine used as a recreational drug?
• Dizocilpine has been used recreationally, but its effects, dosages, and risks are not well understood in this context. Users have reported less enjoyable experiences, including auditory solid hallucinations. Its high potency makes it challenging to control dosages, increasing the risk of overdosing.
• How does Dizocilpine compare to other dissociative drugs like ketamine and PCP?
• Dizocilpine is longer-lasting than similar dissociative drugs, such as ketamine and phencyclidine (PCP). It also tends to cause more severe amnesia and residual deficits in thinking, which has limited its acceptance as a recreational drug.
• Is Dizocilpine addictive?
• Yes, several animal studies have demonstrated the addictive potential of Dizocilpine. Rats have learned to self-administer Dizocilpine, and rhesus monkeys have shown a preference for Dizocilpine over other substances. It can lead to conditioned place preference in animals, indicating reinforcing properties.
• Are there risks associated with Dizocilpine use?
• Yes, there are significant risks associated with Dizocilpine use. These include the potential for overdose due to its high potency, as well as adverse effects like intense auditory hallucinations and long-lasting cognitive deficits. There have also been reports of fatalities involving Dizocilpine in combination with other substances.
• Is Dizocilpine available as a designer drug online?
• Yes, Dizocilpine has been sold online as a designer drug, which raises concerns about its accessibility and safety for users.
• Is Dizocilpine used for medical purposes?
• While Dizocilpine has shown potential for research in animal models, it is not used clinically due to the discovery of brain lesions associated with its use.
• What are Olney’s Lesions?
• Olney’s Lesions refer to neurotoxic-like effects observed in specific brain regions of laboratory animals, notably rats, following the administration of Dizocilpine. These lesions have raised concerns about the drug’s safety.

References

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