NMDA antagonist MK-801 impairs acquisition but not performance of spatial working and reference memory

Abstract

To assess the effects of NMDA receptor blockade on memory tasks that require the hippocam-pal system, rats were injected with either MK-801, a noncompetitive NMDA antagonist known to block induction of long-term potentiation in vitro, or normal saline before daily behavioral testing in both working-memory (WM) and reference-memory (RM) procedures on an eight-arm radial maze. Even after 64 days of testing, rats given MK-801 performed poorly on both RM and WM tasks relative to rats given saline. The same dose of MK-801 that impaired memory acquisition affected neither WM nor RM performance in trained rats that had been given saline. In these rats, combined MK-801 and naloxone affected neither WM nor RM, larger doses of MK-801 produced slight ataxia and both WM and RM deficits, but none of the doses produced a selective WM impairment. Interposing a 2-h delay between the first two and the last two correct WM choices produced a small increase in both WM and RM errors, which demonstrates that MK-801 does not selectively impair long-term WM. Finally, rats given MK-801 chronically and then withdrawn from the drug learned both the WM and the RM tasks, and were subsequently affected only mildly by low doses of MK-801. The results show that functioning NMDA receptors are necessary for learning spatial WM and RM tasks, but not for performing WM or RM tasks after training, and imply that two mechanisms may be required for storing relational (e.g., spatial) memory: an NMDA-dependent mechanism for long-term storage of spatial representations, and a second, non-NMDA mechanism for operating upon those representations.