Age has a similar influence on the susceptibility to NMDA antagonist-induced neurodegeneration in most brain regions

Abstract

NMDA antagonists are of potential therapeutic benefit for several conditions. However, their ability to produce neurotoxicity and psychosis has hampered their clinical use. A better understanding of these side effects and the mechanism underlying them could result in their safer use and in improving our understanding of psychotic illnesses. By disinhibiting certain multisynaptic circuits, moderate doses of NMDA antagonists produce reversible neurotoxicity in the retrosplenial cortex in rats older than 1 month. Higher doses of these same agents result in the death of neurons in the retrosplenial cortex and several other brain regions. It is unknown whether susceptibility to this irreversible neurodegeneration has a similar age dependency profile. We, therefore, examined the sensitivity of rats of various ages (PND20-60) to the irreversible neurodegenerative effect of the selective NMDA antagonist, MK-801. Quantification of the severity of neurodegeneration with stereology revealed that the retrosplenial cortex, induseum griseum, and dentate gyrus had decreasing amounts of damage with decreasing age and onset of sensitivity around PND30. The piriform cortex also displayed a decreased amount of degeneration in younger age groups. However, a low level of degeneration continued to occur in the posterior piriform cortex in the PND20-25 animals. The stage of degeneration appeared to be more advanced, suggesting that these neurons were dying by a different mechanism. We conclude that for most neuronal populations, susceptibility to the irreversible and reversible neurodegenerative effects of NMDA antagonists has a similar age dependency profile, consistent with the proposal that the same disinhibitory mechanism underlies both neurotoxicities.