Olney's lesions Olney's lesions, also known as NMDA receptor antagonist neurotoxicity (NAN), are a potential form of brain

damage. They are named after John Olney, who conducted a study investigating neurotoxicity caused by PCP and related drugs in 1989. History In 1989, John Olney et al. conducted tests wherein high doses of the experimental dissociative substance MK-801 were injected into rats. Shortly after dosage, the rats' brains were examined, revealing the development of tiny holes, or vacuoles, primarily in the posterior cingulate cortex and retrosplenial cortex. These vacuoles lead to a concentration of microglia and Heat-Shock Protein 70 (Hsp70), which formed irreversible lesions. The dissociatives also seemed to form antecedents of other forms of brain damage in the test subjects. Researcher Roland N. Auer conducted similar studies to look at the correlation between age and sex and the development of NMDA receptor antagonist neurotoxicity in test rats. Older rats experienced a much higher mortality rate after the development of NAN. Female rats were found, at all ages, to have a higher incidence of necrotic (dead) neurons as a result of NAN. Nitrous oxide, a common anesthetic for humans (especially in dentistry), has also been shown to cause vacuolization in rats' brains, but caused no irreversible lesions. Dextromethorphan, a common antitussive often found in cough medicines, has been shown to cause vacuolization in rats' brains. However, oral administration of dextromethorphan has been found to not cause vacuolization in rats' brains. Olney's Lesions have not yet been proven or disproven to manifest in humans. No tests have been conducted to test the validity of post-dissociative development of vacuolization in human brain tissue, and critics claim that animal testing is not a reliable predictor of the effects of dissociative substances on humans: The evidence is that ketamine and many other NMDA-receptor antagonists that have been tested in humans, cause an acute disturbance in neural circuitry that leads to psychotic manifestations. These same drugs cause the same disturbance in neural circuitry in rats and when we look at their brains we see evidence for physical neuronal injury. Since no one has looked at the brains of humans immediately after administering these drugs, we do not know whether the physical neuronal injury occurs. John Olney, Private correspondence Prevention In medical settings, NMDA receptor antagonists are used as anesthetics, so GABA-A receptor agonists are used to effectively prevent any neurotoxicity caused by them.Drugs that work to suppress NAN include anticholinergics, benzodiazepines, barbiturates and agonists at the alpha-2 adrenergic receptor in the brain, such as clonidine. Conversely, coadministration of NMDA-antagonists with alpha-2 adrenergic antagonists, like yohimbine could theoretically potentiate NAN.