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.
Highlights
N-methyl-D-aspartate (NMDA) receptors, due to their role in the putative learning mechanism long-term potentiation (Bliss & Collingridge, 1993), have been proposed to be important for encoding of memories (Riedel, Platt, & Micheau, 2003)
During the test phase the novelty preference for mice that received MK-801 during the exposure phase was similar to controls (Fig. 1)
Mice that received the same drug during both the exposure and test phases showed a higher preference than mice that were tested under a drug-state that was different from that in the exposure phase, regardless of whether it was MK-801 or vehicle
Summary
N-methyl-D-aspartate (NMDA) receptors, due to their role in the putative learning mechanism long-term potentiation (Bliss & Collingridge, 1993), have been proposed to be important for encoding of memories (Riedel, Platt, & Micheau, 2003). Evidence for the role of NMDA receptors in encoding has, in part, come from studies that have examined the effects of MK-801 on tests of memory. MK-801 has been suggested to have the greatest effect when the drug is administered before the encoding phase (de Lima, Laranja, Bromberg, Roesler, & Schroder, 2005; Nilsson, Hansson, Carlsson, & Carlsson, 2007) and doses as low as 0.01 mg/kg have been found to impair performance (de Lima et al, 2005). The effect of the drug is less clear, when given after the encoding phase or prior to the test, with some studies (de Lima et al, 2005; Pichat et al, 2007) reporting impairment of performance whilst other studies reported facilitating effects of the drug (Nilsson et al, 2007) on objection recognition memory
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