Disorders

What are Olney's lesions?

Answer: Olney's lesions are a form of brain damage possibly resulting from exposure to high doses of NMDA receptor antagonists.

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One of the profound questions in the field of neuroscience, medicine, and pharmacology is "how do drugs influence the brain and behavior?" Scientists are often curious about the long-lasting effect of exposure to certain chemicals.

Several drugs have their principle site of pharmacological action at the NMDA receptor. This receptor is found at several neurons in the brain, and is normally responsible for detecting the neurotransmitter glutamate. Glutamate is the main excitatory signal in the brain.

A variety of drugs act as antagonists, or blockers, of these NMDA receptors. For example, the medication amantadine is given to treat some of the symptoms of Parkinson's disease, the dyskinesia that comes with long term exposure to levodopa, and multiple sclerosis (MS). Another NMDA antagonist, memantine, is prescribed to help patients to with Alzheimer's disease. 

A few illicit drugs also have pharmacological action as NMDA receptor antagonists. For example, ketamine is a veterinary anesthetic, a misused recreational club drug, and clinically a fast-acting antidepressant that robustly inhibits the NMDA receptor. PCP, or "angel dust," is also an NMDA receptor antagonist. 

Controversially, it is not clear whether dextromethorphan (DXM), an ingredient found commonly in over-the-counter antitussives (cough medicine), produces Olney's lesions. DXM is sometimes misused for it’s psychogenic effects, including euphoria and intoxicating sensations.

In nonhuman models, such as in rats and monkeys, high exposure to NMDA receptor antagonists produce cell damage to specific parts of the brain such as the posterior cingulate and retrosplenial cortex. The cell injury appears to be a result of mitochondrial breakdown across individual neurons. The lesions are apparent after a single dose of the NMDA receptor antagonist MK-801 after 12 hours, but the extent of the injury recovered back to normal after 24 hours. The study also found that repeated doses do not cause an increase in the severity of the injury, indicating that there is not a strong cumulative effect of these drugs. 

These sites of injury came to be called Olney's lesions, after the researcher who first published the description of the injuries in 1989 in the journal Science (Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs). Alternatively, these lesions are sometimes also referred to as “NMDA receptor antagonist neurotoxicity”, or NAN. 

Although the nonhuman animal literature shows some injury, it is not entirely clear whether long term prolonged or high dose exposure to NMDA receptor antagonists lead to Olney's lesions in humans. However, the influence of these antagonists may contribute to differences in neural plasticity. The neurotransmitter glutamate is an excitatory signal that can bind to different receptor classes, such as AMPA and NMDA receptors. When both are activated, which happens regularly in the healthy brain, there are intracellular signals that lead to increased plasticity. However, in the presence of an NMDA receptor antagonist, the plasticity signals become weaker.