Infusion of (+)-MK-801 and memantine — contrasting effects on radial maze learning in rats with entorhinal cortex lesion

Abstract

(+)-5-Methyl-10,11-dihydro-5 H-dibenzocyclohepten-5,10-imine maleate ((+)-MK-801) and 1-amino-3,5-dimethyladamantane (memantine), two uncompetitive antagonists of the NMDA receptor were tested in an allocentric version of the radial maze test (with four out of eight arms reinforced) both in normal rats and after quinolinic acid-induced entorhinal cortex lesions. Both agents were infused s.c. using Alzet osmotic minipumps in order to assure steady state drug levels in the serum and brain during the experiment. In non-lesioned rats, (+)-MK-801 (0.312 mg/kg per day) produced disturbances in learning of spatial information dependent on reference memory but not that involving working memory. In contrast, memantine (20 mg/kg per day) had no effect in normal rats. In rats with entorhinal cortex lesions, (+)-MK-801 enhanced the lesion-induced deficit in reference memory. In contrast, memantine reversed the lesion-induced increase in reference memory errors. The divergent effects of those two uncompetitive NMDA receptor antagonists could, at least partially, be due to the differences reported in their channel blocking kinetics and voltage dependence. The results indicate that under conditions of pathological impairment of brain structures such as entorhinal cortex lesion, memantine might produce beneficial effects on cognitive functions.