NMDA receptor antagonist
NMDA receptor antagonists are a class of psychoactive substances that work by antagonizing, or inhibiting the action of, the NMDA receptor (NMDAR). The NMDA receptor is one of the receptor types for glutamate which is one of the principal excitatory neurotransmitters and is involved in cognitive functions such as learning and memory.
NMDA receptor antagonists are used as anesthetics for animals and for humans; the state of anesthesia they induce is referred to as dissociative anesthesia. Some NMDA receptor antagonists, such as ketamine, dextromethorphan (DXM), phencyclidine (PCP), and nitrous oxide (N2O), are popular recreational drugs used for their dissociative, hallucinogenic, and euphoric effects. When used recreationally, they are classified as dissociative drugs.
There is evidence that NMDA receptor antagonists can cause a certain type of neurotoxicity or brain damage referred to as Olney's Lesions in rodents, although such damage has never been conclusively observed in primates like humans. Recent research conducted on primates suggests that, while very consistent and long-term ketamine use may be neurotoxic, acute use is not.
Mechanism of action
The NMDA receptor is a receptor that allows for the transfer of electrical signals between neurons in the brain and in the spinal column. For electrical signals to pass, the NMDA receptor must be open. To remain open, glutamate and glycine must bind to the NMDA receptor. An NMDA receptor that has glycine and glutamate bound to it and has an open ion channel is called "activated."
Chemicals that deactivate the NMDA receptor are called antagonists. NMDAR antagonists fall into four categories:
- Competitive antagonists, which bind to and block the binding site of the neurotransmitter glutamate
- Glycine antagonists, which bind to and block the glycine site
- Noncompetitive antagonists, which inhibit NMDARs by binding to allosteric sites
- Uncompetitive antagonists, which block the ion channel by binding to a site within it.
Once a sufficient amount of NMDA receptors have been deactivated, the result is a dosage dependent decrease in the passing of electrical signals across the brain and a disconnection of neurons. This leads to states of disconnection between conscious parts of the brain, anesthesia and its sensory organs as well as out-of-body experiences and accompanying hallucinations.
- Methoxetamine (MXE)
- Phencyclidine (PCP)
- Eticyclidine (PCE)
- Deschloroketamine (DCK)
- 2-Fluorodeschloroketamine (2F-DCK)
- 2-Oxo-PCE (O-PCE)
Toxicity and harm potential
This toxicity and harm potential section is a stub.
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Dependence and abuse potential
Dissociatives are generally considered to have moderate to high abuse potential.
- McEntee WJ, Crook TH (1993). "Glutamate: its role in learning, memory, and the aging brain". Psychopharmacology. 111 (4): 391–401. https://doi.org/10.1007/BF02253527. PMID 7870979.
- Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/23145560
- Ketamine-Induced Neuronal Cell Death in the Perinatal Rhesus Monkey | http://toxsci.oxfordjournals.org/content/98/1/145
- Kim AH, Kerchner GA, Choi DW (2002). "Blocking Excitotoxicity". In Marcoux FW, Choi DW. CNS Neuroprotection. New York: Springer. pp. 3–36.