MK-801 neurotoxicity in male mice: histologic effects and chronic impairment in spatial learning

• Published in: Brain research Vol. 707; no. 2; pp. 165 - 179
• Main Authors: Wozniak, D.F., Brosnan-Watters, G., Nardi, A., McEwen, M., Corso, T.D., Olney, J.W., Fix, A.S.
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 29.01.1996; Amsterdam Elsevier; New York, NY
• Subjects: Activity; Animals; Behavior, Animal - drug effects; Behavioral psychophysiology; Biological and medical sciences; Brain - pathology; Brain - ultrastructure; Cingulate cortex; Dizocilipine maleate; Dizocilpine Maleate - administration & dosage; Dizocilpine Maleate - toxicity; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; Injections, Intraperitoneal; Injections, Subcutaneous; Learning - drug effects; Male; Memory - drug effects; Mice; Mice, Inbred ICR; Microscopy, Electron; MK-801; Motor Activity - drug effects; Mouse; N-Methyl- d-aspartate antagonist; Nerve Degeneration - drug effects; Neuropathology; Neurotoxicity; Neurotransmission and behavior; Paraffin Embedding; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Rats; Sensorimotor; Space Perception - drug effects; Spatial learning and memory; MK-801; Neurotoxicity; Cingulate cortex; Mouse; Neuropathology; Dizocilipine maleate; Activity; N-Methyl- d-aspartate antagonist; Spatial learning and memory; Sensorimotor; Rodentia; Central nervous system; Male; Glutamate receptor; Space perception; Dose activity relation; Vertebrata; Mammalia; Acquisition process; Animal; Test Planches a Trous; Neurotoxin; Perception; Cytopathology; Antagonist; Perceptive learning; NMDA receptor; Brain (vertebrata)
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/0006-8993(95)01230-3

Several histological and behavioral experiments were conducted to investigate the neurotoxic effects of MK-801 in male mice. Moderate subcutaneous (s.c.) doses of MK-801 (0.5 and 1.0 mg/kg) induced the formation of intracytoplasmic vacuoles in pyramidal neurons in layers III and IV of the posterior cingulate/retrosplenial (PC/RS) cortex in 50% and 100% of the mice from the two respective treatment groups. Electron microscopic analysis of the vacuoles indicated that mitochondria and endoplasmic reticulum are the cellular organelles most prominently involved in this pathomorphological change. Treating mice with a high systemic dose of MK-801 (10 mg/kg s.c. or intraperitoneal (i.p.)) caused selective, irreversible degeneration of a small number of PC/RS cortical neurons. Compared to saline controls, the acquisition performance of mice treated i.p. with 10 mg/kg MK-801 was chronically impaired on a spatial learning task (modified hole board food search task) when tested at several posttreatment intervals (up to at least 5 months), although the groups did not differ on activity or sensorimotor tests conducted 2 weeks posttreatment. In summary, MK-801 caused histopathological changes in the mouse brain similar to those observed in the rat. Furthermore, 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 species.