Dizocilpine (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway. Before the advent of motorized transportation, they also provided accomm ...

), also known as MK-801, is a pore blocker of the

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...

, a

glutamate receptor Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system ...

, discovered by a team at Merck in 1982.

Glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

is the brain's primary excitatory

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

. The channel is normally blocked with a magnesium ion and requires

depolarization In biology, depolarization or hypopolarization is a change within a cell (biology), cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolar ...

of the

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

to remove the magnesium and allow the glutamate to open the channel, causing an influx of calcium, which then leads to subsequent depolarization. Dizocilpine binds inside the

ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...

of the

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

at several of PCP's binding sites thus preventing the flow of

ion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...

s, including

calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...

(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 Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatment ...

and probably has

dissociative Dissociatives, colloquially dissos, are a subclass of hallucinogens that distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of ...

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 In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neuron ...

and has been found to impair the acquisition of difficult, but not easy, learning tasks in rats and primates. Because of these effects of dizocilpine, the NMDA receptor pore blocker

ketamine Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...

is used instead as a dissociative anesthetic in human medical procedures. While ketamine may also trigger temporary

psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...

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 Nicotinic acetylcholine receptors, or nAChRs, are Receptor (biochemistry), receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the c ...

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. It has been shown to bind to and inhibit the

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

and

dopamine transporter The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...

s as well.

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. Another study found that, although repeated low doses of dizocilpine were only successful in mimicking behavioral changes such as a slight

hyperlocomotion Locomotor activity is a measure of animal behavior which is employed in scientific research. Hyperlocomotion, also known as locomotor hyperactivity, hyperactivity, or increased locomotor activity, is an effect of certain drugs in animals in whi ...

and decreased

prepulse inhibition Prepulse inhibition (PPI) is a neurological phenomenon in which a weaker prestimulus (prepulse) inhibits the reaction of an organism to a subsequent strong reflex-eliciting stimulus (pulse), often using the startle reflex. The stimuli are usually ...

, repeated administration of a higher dose mimicked both the above changes as well as the neurochemical alterations found in first-episode schizophrenic patients. Not only has temporary use been shown to mimic

but chronic administration in laboratory animals resulted in similar neuropathological changes as in

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

Possible future medical uses

The effects of dizocilpine at

s are clear and significant. NMDA receptors are key in the progression of

excitotoxicity In excitotoxicity, neuron, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamic acid, glutamate become pathologically high, resulting in excessive stimulation of cell surface recept ...

(a process in which an excessive amount of extracellular

glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

overexcites

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 Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...

traumatic brain injury A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity ranging from mild traumatic brain injury (mTBI/concussion) to severe traumati ...

, and

neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...

s such as

Huntington's Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly inherited. It typically presents as a triad of progressive psychiatric, cognitive, and motor symptoms. The earliest sympto ...

Alzheimer's Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

, and

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, Terminal illness, terminal neurodegenerative disease, neurodegenerative disorder that results i ...

. Dizocilpine has shown effectiveness in protecting neurons in

cell culture Cell culture or tissue culture is the process by which cell (biology), cells are grown under controlled conditions, generally outside of their natural environment. After cells of interest have been Cell isolation, isolated from living tissue, ...

and

animal models A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workings of other organisms. Mod ...

of excitotoxic neurodegeneration. The administration of dizocilpine 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 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 antagonist NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor ( NMDAR). They are commonly used as anesthetics for humans and animals; the state of anesthesia they ind ...

s are thought to prevent the neurodegeneration through the inhibition of these receptors. 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. An earlier study has shown that the prevention of morphine-associated psychological dependence was not due to state-dependency effects induced by dizocilpine but rather reflect the impairment of learning that is caused by NMDA antagonists. 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

animal models of depression Animal models of depression are research tools used to investigate Major depressive disorder, depression and action of antidepressant, antidepressants. They are used as a simulation to investigate the symptomatology and pathophysiology of depress ...

s like dizocilpine have been shown in animal models to attenuate the hearing loss caused by

aminoglycosides Aminoglycoside is a medicinal chemistry, medicinal and bacteriology, bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside ...

. It is thought that aminoglycosides mimic endogenous

polyamine A polyamine is an organic compound having two or more amino groups. Alkyl polyamines occur naturally, but some are synthetic. Alkylpolyamines are colorless, hygroscopic, and water soluble. Near neutral pH, they exist as the ammonium derivatives. ...

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. Dizocilpine was found to block the development of kindled

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

s, although it does not have any effect on completed kindled seizures. Oddly, it was discovered to decrease

rabies Rabies is a viral disease that causes encephalitis in humans and other mammals. It was historically referred to as hydrophobia ("fear of water") because its victims panic when offered liquids to drink. Early symptoms can include fever and abn ...

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

HIV The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...

. It did not have activity against these other viruses, however. Dizocilpine was also shown to potentiate the ability of

levodopa Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease (PD) and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. ...

to ameliorate

akinesia Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a sym ...

and muscular rigidity in a rodent model of

parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), Rigidity (neurology), rigidity, and balance disorder, postural instability. Both hypokinetic features (bradykinesia and akinesia) and hyperkinetic f ...

. When dizocilpine was administered to rats 15 minutes after a spinal trauma, the long-term neurological recovery of the trauma was improved. However, NMDA antagonists like dizocilpine have largely failed to show safety in

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s, possibly due to inhibition of

function that is necessary for normal

al function. Since dizocilpine is a particularly strong NMDA receptor antagonist, this drug is particularly likely to have

psychotomimetic A drug with psychotomimetic (also known as psychomimetic or psychotogenic) actions mimics the symptoms of psychosis, including delusions and/or delirium, as opposed to only hallucinations. Psychotomimesis is the onset of psychotic symptoms followi ...

side effects (such as

hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

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 The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

regions of lab rats. Merck, a drug company, promptly dropped development of dizocilpine.

Olney's lesions

Dizocilpine, along with other

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 The posterior cingulate cortex (PCC) is the caudal part of the cingulate cortex, located posterior to the anterior cingulate cortex. This is the upper part of the "limbic lobe". The cingulate cortex is made up of an area around the midline of the ...

/retrosplenial cortex. Other neurons in the area expressed an abnormal amount of

heat shock protein Heat shock proteins (HSPs) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including ex ...

as well as increased glucose metabolism in response to NMDA antagonist exposure. Vacuoles began to form within 30 minutes of a subcutaneous dose of dizocilpine 1 mg/kg. Neurons in this area necrotized and were accompanied by a

glial Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cell (biology), cells in the central nervous system (the brain and the spinal cord) and in the peripheral nervous system that do not produce Action potential, electrical ...

response involving

astrocytes Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of end ...

and

microglia Microglia are a type of glia, glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about around 5–10% of cells found within the brain. As the resident macrophage cells, they act as t ...

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 A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

are high. Users tend to report that the experience is not as enjoyable as other

drugs, and it is often accompanied by strong auditory hallucinations. Also, dizocilpine is much longer-lasting than similar dissociative drugs such as

and

phencyclidine Phencyclidine or phenylcyclohexyl piperidine (PCP), also known in its use as a street drug as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hall ...

(PCP), and causes far worse

amnesia Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...

and residual deficits in thinking, which have hindered its acceptance as a recreational drug. 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. Intraperitoneal administration of dizocilpine also produced an enhancement in self-stimulation responding. 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. It was found that dizocilpine administration elicited

conditioned place preference Conditioned place preference (CPP) is a form of Pavlovian conditioning used to measure the motivational effects of objects or experiences. This motivation comes from the pleasurable aspect of the experience, so that the brain can be reminded of th ...

in animals, again demonstrating its reinforcing properties. A multiple drug fatality involving dizocilpine,

benzodiazepines Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat co ...

, and

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

has been reported. Dizocilpine has been sold online as a

designer drug A designer drug is a structural or functional analog of a controlled substance that has been designed to mimic the pharmacological effects of the original drug, while avoiding classification as illegal and/or detection in standard drug tests. ...

References

External links

Erowid Dizocilpine experience vault
��includes reports from users of Dizocilpine {{Tricyclics Nicotinic antagonists Designer drugs NMDA receptor antagonists 1,2-Diarylethylamines Dissociative drugs Dibenzocycloheptenes Heterocyclic compounds with 4 rings Secondary amines

An animal model of schizophrenia

Possible future medical uses

Olney's lesions

Recreational use

See also

References

Further reading

External links