The NMDA receptor antagonist MK-801 fails to impair long-term recognition memory in mice when the state-dependency of memory is controlled

Abstract

NMDA receptor-dependent synaptic plasticity has been proposed to be important for encoding of memories. Consistent with this hypothesis, the non-competitive NMDA receptor antagonist, MK-801, has been found to impair performance on tests of memory. Interpretation of some of these findings has, however, been complicated by the fact that the drug-state of animals has differed during encoding and tests of memory. Therefore, it is possible that MK-801 may result in state-dependent retrieval or expression of memory rather than actually impairing encoding itself. We tested this hypothesis in mice using tests of object recognition memory with a 24-hour delay between the encoding and test phase. Mice received injections of either vehicle or MK-801 prior to the encoding phase and the test phase. In Experiment 1, a low dose of MK-801 (0.01 mg/kg) impaired performance when the drug-state (vehicle or MK-801) of mice changed between encoding and test, but there was no significant effect of MK-801 on encoding. In Experiment 2, a higher dose of MK-801 (0.1 mg/kg) failed to impair object recognition memory when mice received the drug prior to both encoding and test compared to mice that received vehicle. MK-801 did not affect object exploration, but it did induce locomotor hyperactivity at the higher dose. These results suggest that some previous demonstrations of MK-801 effects may reflect a failure to express or retrieve memory due to the state-dependency of memory rather than impaired encoding of memory.

Keywords: Habituation; MK-801; Memory; Mice; NMDA receptors.

Fig. 1

The effect of 0.01 mg/kg MK-801 on object recognition memory. Mice received MK-801 or vehicle prior to the exposure phase. In the test phase the drug-state of mice was either the same or different from that during the exposure phase. Left panel: Performance in the novelty preference test is shown as a difference score (mean time spent exploring the novel objects minus the mean time spent exploring the familiar objects). Scores above zero indicate a novelty preference. Right panel: Performance in the novelty preference test is shown as a discrimination ratio (difference score divided by mean total time spent exploring the objects in the test phase). Error bars indicate SEM.

Fig. 2

MK-801 (0.01 mg/kg) failed to affect levels object exploration. Left panel: Cumulative duration of object exploration in the exposure phase. Right panel: Cumulative duration of object exploration in the test phase. Error bars indicate SEM.

Fig. 3

MK-801 (0.01 mg/kg) failed to affect locomotor activity. The distance travelled was used as a measure of locomotor activity. Left panel: Path length in the exposure phase. Right panel: Path length in the test phase. Error bars indicate SEM.

Fig. 4

The effect of 0.1 mg/kg MK-801 on object recognition memory. Mice received MK-801 or vehicle prior to both the exposure and test phase. Left panel: Performance in the novelty preference test is shown as a difference score (mean time spent exploring the novel objects minus the mean time spent exploring the familiar objects). Scores above zero indicate a novelty preference. Right panel: Performance in the novelty preference test is shown as a discrimination ratio (difference score divided by mean total time spent exploring the objects in the test phase). Error bars indicate SEM.

Fig. 5

MK-801 (0.1 mg/kg) failed to affect levels object exploration. Left panel: Cumulative duration of object exploration in the exposure phase. Right panel: Cumulative duration of object exploration in the test phase. Error bars indicate SEM.

Fig. 6

MK-801 (0.1 mg/kg) increased locomotor activity. The distance travelled was used as a measure of locomotor activity. Left panel: Path length in the exposure phase. Right panel: Path length in the test phase. Error bars indicate SEM.