MK-801-induced neuronal damage in rats.

The non-competitive N-methyl-D-aspartate antagonist MK-801 has been frequently used to attenuate neurotoxicity mediated by excessive release of glutamate. However, doses of MK-801, effective to prevent cell loss in some areas have been reported to induce pathological changes in retrosplenial cortex [32]. In the present study, we examined the extent of the MK-801-induced damage. Silver staining techniques were used to label damaged neurons, axon terminals and activated microglia. In addition to the retrosplenial cortex, we observed silver-impregnated neurons in the pyriform, and entorhinal cortices, in amygdala in tenia tecti, and in the temporal two thirds of the dentate gyrus. With the exception of the dentate gyrus, signs of early degeneration appeared in the first 4 days in all observed regions. Activated microglia have been found 1 and 3 weeks after the lesion in the same areas. The time course and dose dependence of the damage was also investigated. The distribution of labeled neurons resembled the pattern observed after certain epileptic states. Our data suggest that irreversible cell damage occurred in the affected regions. These findings confirm and extend previous suggestions that, besides its protective effect, MK-801 may lead to neuronal degeneration.