Question

1. We previously suggested that administering glutamate antagonists immediately after a stroke might reduce the damage produced by that insult. If these antagonists were antagonists at the NMDA receptor, might their administration have other cognitive effects? Why or why not?

Answer 1

Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists (competitive receptor antagonists, ion channel blockers, and glycine antagonists)--such as selfotel, aptiganel, eliprodil, licostinel and gavestinel--failed to show efficacy in clinical trials of stroke or traumatic brain injury. This failure has been attributed to the deficient properties of the molecules that entered human trials and to inappropriate design of clinical studies. In this article we hypothesise that glutamate may be involved in the acute neurodestructive phase that occurs immediately after traumatic or ischaemic injury (excitotoxicity), but that, after this period, it assumes its normal physiological functions, which include promotion of neuronal survival. We propose that NMDA receptor antagonists failed stroke and traumatic brain injury trials in human beings because blockade of synaptic transmission mediated by NMDA receptors hinders neuronal survival.

NMDA receptor antagonists induce a state called dissociative anesthesia, marked by catalepsy, amnesia, and analgesia. Ketamine is a favored anesthetic for emergency patients with unknown medical history and in the treatment of burn victims because it depresses breathing and circulation less than other anesthetics.Dextrorphan, a metabolite of dextromethorphan (one of the most commonly used cough suppressants in the world is known to be an NMDA receptor antagonist.

Depressed NMDA receptor function is associated with an array of negative symptoms. For example, NMDA receptor hypofunction that occurs as the brain ages may be partially responsible for memory deficits associated with aging.Schizophrenia may also have to do with irregular NMDA receptor function (the glutamate hypothesis of schizophrenia).Increased levels of another NMDA antagonist, kynurenic acid, may aggravate the symptoms of schizophrenia, according to the "kynurenic hypothesis".NMDA receptor antagonists can mimic these problems; they sometimes induce "psychotomimetic" side effects, symptoms resembling psychosis. Such side effects caused by NMDA receptor inhibitors include hallucinations, paranoid delusions, confusion, difficulty concentrating, agitation, alterations in mood, nightmares,catatonia,ataxia, anesthesia, and learning and memory deficits.

Because of these psychotomimetic effects, NMDA receptor antagonists, especially phencyclidine, ketamine, and dextromethorphan, are used as recreational drugs. At subanesthetic doses, these drugs have mild stimulant effects and, at higher doses, begin inducing dissociation and hallucinations, though these effects and the strength thereof vary from drug to drug.

Most NMDA receptor antagonists are metabolized in the liver.Frequent administration of most NMDA receptor antagonists can lead to tolerance, whereby the liver will more quickly eliminate NMDA receptor antagonists from the bloodstream.

NMDA receptor antagonists are also under investigation as antidepressants.

Neurotoxicity

Although NMDA antagonists were once thought to reliably cause neurotoxicity in humans in the form of Olney's lesions, recent research suggests otherwise. Olney's lesions involve mass vacuolization of neurons observed in rodents. However, many suggest that this is not a valid model of human use, and studies conducted on primates have shown that use must be heavy and chronic to cause neurotoxicity. A 2009 review found no evidence of ketamine-induced neuron death in humans.However, temporary and permanent cognitive impairments have been shown to occur in long-term or heavy human users of the NMDA antagonists PCP and ketamine. A large-scale, longitudinal study found that current frequent ketamine users have modest cognitive deficits, while infrequent or former heavy users do not. Many drugs have been found that lessen the risk of neurotoxicity from NMDA receptor antagonists. Centrally acting alpha 2 agonists such as clonidine and guanfacine are thought to most directly target the etiology of NMDA neurotoxicity. Other drugs acting on various neurotransmitter systems known to inhibit NMDA antagonist neurotoxicity include: anticholinergics, diazepam, barbiturates,ethanol, serotonin receptor agonists,anticonvulsants, and muscimol.