Olney's lesions

Olney's lesions, also known as NMDA receptor antagonist neurotoxicity (NAT), is a form of brain damage observed in rats and certain other model animals exposed to large quantities of psychoactive drugs that inhibit the normal operation of the neuronal NMDA receptor. Such lesions are common in anesthesia, as well as certain psychiatric treatments. The visible signs of NAT are named after John Olney, who conducted a study in 1989 to investigate neurotoxicity caused by PCP and related drugs. It is unclear whether the phenomenon is relevant to the practice of modern medicine: most NMDA antagonists are co-administered with other drugs that reduce neurotoxicity, and the phenomenon is only rarely observed in human subjects who abuse the drugs. NMDA receptor antagonists include physician-prescribed drugs for therapeutic treatment of human diseases such as memantine for Alzheimer's disease and amantadine for Parkinson's disease. In anesthesiology, many general anesthetics generate their dissociative effect through NMDA receptor antagonism. These anesthetics are typically administered with positive allosteric GABAA-receptor modulators to prevent any neurotoxicity they might cause. Drugs that work to suppress NAT include anticholinergics, benzodiazepines, barbiturates and Alpha-adrenergic agonists, such as clonidine. Conversely, coadministration of NMDA-antagonists with alpha-2 adrenergic antagonists, like yohimbine, could theoretically potentiate NAT. In the late 1980s, John Olney, a researcher specializing in excitotoxicity, the phenomenon where persistently high neurotransmitter concentrations damage nerve cells, began to investigate the pharmacology of NMDA receptor antagonists. Other workers had recently begun proposing to use NMDA antagonists PCP, MK-801 (dizocilpine) and ketamine in clinical trials for various psychological effects; but the drugs' current illegality meant that scientists had no record of pharmacological response to guide safe use.