NMDA Receptor Antagonist - Neurotoxicity

Neurotoxicity

Exposure to NMDA receptor antagonists may cause serious brain damage in the cingulate cortex and retrosplenial cortex regions of the brain, but evidence towards this hypothesis is not very strong at the moment. The correlation observed, however, does make sense given the profound bilateral communication abnormalities observed in NMDA antagonist intoxication. In high doses, almost no glutaminergic activity is observed within the corpus callosum, naturally a region primarily GABAergic. Given a sufficiently long duration of action of the ligand, abnormalities develop in hemisphere communication. The cingulate cortex shifts its balance towards the posterior, where hemispheric communication is much more deeply ingrained, due to depth perception. Through long-term potentiation (LTP) and long-term depression (LTD), this can become permanent with regular administration. While gross structural abnormalities are yet to be observed in humans, likely due to the lack of studies with people under continuous administration, significant cognitive deficits are observed in those who regularly abuse dissociatives. Constant antagonism of NMDA, the primary neurotransmitter involved in LTP, and a major contributor to LTD, results in profound, permanent synaptic abnormalities, even in relatively low doses. The experimental NMDA and nicotinic acetylcholine receptor antagonist MK-801 has been shown to cause neural vacuolization in test rodents that later develop into irreversible lesions called "Olney's Lesions." 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 specifically target the etiology of NMDA neurotoxicity. Other drugs acting on various neurotransmitter systems known to inhibit NMDA antagonist neurotoxicity include: anticholinergics, diazepam, barbiturates, ethanol, 5-HT_2A serotonin agonists, and muscimol.