Excitatory amino acid antagonists and memory: effect of drugs acting at N-methyl-D-aspartate receptors in learning and memory tasks.

The role of N-methyl-D-aspartate (NMDA) receptors in memory processes was examined using a Y-shaped maze and a step-through passive avoidance task in mice. In the Y-maze, the total number of arm entries, which represents locomotor activity and alternation behaviour, thought to reflect working memory, were measured. Competitive NMDA antagonists, CGS 19755 (cis-4-phosphonomethyl-2-piperidine-carboxylate) and CPP (3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphate), impaired spontaneous alternation at doses which reduced locomotion of mice. N-Methyl-D-aspartate prevented the impairment of alternation and decrease of locomotor activity produced by CGS 19755 and CPP. These results suggest that NMDA-dependent processes are involved in the mechanisms of working memory. In contrast, the non-competitive NMDA antagonist, MK 801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate) dramatically enhanced the total number of arm entries, while reducing alternation behaviour, N-Methyl-D-aspartate had no effect on MK 801-induced enhancement of locomotor activity and impairment of alternation. In the passive avoidance task, mice were trained to avoid entry into the dark compartment. At doses which impaired working memory in the alternation task, CPP, CGS 19755 and MK-801 reduced acquisition, when administered before training. N-Methyl-D-aspartate antagonized the effect of CPP, CGS 19755 and MK-801. Neither CPP nor MK-801 affected retention, when administered immediately after training or before testing retention. N-Methyl-D-aspartate had no effect on retention with high-intensity shock, but facilitated retention with low-intensity shock.(ABSTRACT TRUNCATED AT 250 WORDS)