A single dose of the non-competitive NMDA receptor antagonist MK-801 (dizocilpine maleate) induces neuronal necrosis in the posterior cingulate/retrosplenial (PC/RS) cortex of adult rats. The present studies further characterized this effect and evaluated several variables that affect its expression. Male and female rats of two strains (Sprague-Dawley and Fischer 344) and two ages (70 and 127 days) were given a single subcutaneous injection of vehicle (water) or MK-801 (0.5, 1.0 or 5.0 mg/kg). A simple behavioral response (recumbency) and number of necrotic neurons in the PC/RS cortex were evaluated. MK-801 induced dose-dependent recumbency which was more severe and of longer duration in females of either strain or age. In addition, female rats (regardless of strain, dose, or age) consistently had significantly more necrotic PC/RS neurons than male rats. In a second study, a high dose of MK-801 was given intraperitoneally (10 mg/kg) to male and female Sprague-Dawley rats (90-120 days of age). Necrotic neuron counts were determined at 5 separate rostrocaudal levels of the PC/RS cortex. At levels where neuronal necrosis occurred, the magnitude of the effect was significantly greater in females than males and the number of necrotic neurons increased along a rostral to caudal gradient. Our findings indicate that (1) MK-801 dose dependently induces recumbency and necrosis of PC/RS cortical neurons in both Sprague-Dawley and Fischer 344 rats, (2) female rats of either strain are more sensitive than their male counterparts, and (3) the extent of necrosis of PC/RS cortical neurons increases along a rostral to caudal gradient.