MK-801 NEUROTOXICITY IN MALE-MICE - HISTOLOGIC EFFECTS AND CHRONIC IMPAIRMENT IN SPATIAL-LEARNING

Several histological and behavioral experiments were conducted to inve stigate the neurotoxic effects of MK-801 in male mice. Moderate subcut aneous (s.c.) doses of MK-801 (0.5 and 1.0 mg/kg) induced the formatio n of intracytoplasmic vacuoles in pyramidal neurons in layers In: and TV of the posterior cingulate/retrosplenial (PC/RS) cortex in 50% and 100% of the mice from the two respective treatment groups. Electron mi croscopic analysis of the vacuoles indicated that mitochondria and end oplasmic reticulum are the cellular organelles most prominently involv ed in this pathomorphological change. Treating mice with a high system ic dose of MK-801 (10 mg/kg s.c. or intraperitoneal (i.p.)) caused sel ective, irreversible degeneration of a small number of PC/RS cortical neurons. Compared to saline controls, the acquisition performance of m ice treated i.p. with 10 mg/kg MK-801 was chronically impaired on a sp atial learning task (modified hole board food search task) when tested at several posttreatment intervals (up to at least 5 months), althoug h the groups did not differ on activity or sensorimotor tests conducte d 2 weeks posttreatment. In summary, MK-801 caused histopathological c hanges in the mouse brain similar to those observed in the rat. Furthe rmore, high dose MK-801 treatment that killed a small number of mouse PC/RS cortical neurons resulted in a chronic acquisition impairment in spatial learning, an effect not previously demonstrated in any specie s.