N-methyl-D-aspartate receptors are involved in lithium-induced state-dependent learning in mice

We have previously shown lithium-induced state-dependent learning in a step-down inhibitory avoidance task. In the present study, the effects of intracerebroventricular injections of N-methyl-D-aspartate (NMDA) receptor agents on the lithium-induced state-dependent learning have been investigated. A single-trial step-down inhibitory avoidance task was used to assess memory in male Naval Medical Research Institute (NMRI) mice. The results showed that post-training lithium (10 mg/kg) decreased the step-down latency on the test day, which was reversed by pre-test administration of the same dose of the drug; indicating state-dependent learning induced by lithium. Pre-test administration of NMDA (0.0001, 0.001 and 0.01 microg/mouse, intracerebroventricular) could also substitute for pre-test lithium to reverse the decrease of the step-down latency induced by post-training lithium. Furthermore, pre-test co-administration of an ineffective dose of NMDA (0.00001 microg/mouse, intracerebroventricular.) with lower doses of lithium (1.25, 2.5 and 5 mg/kg, intraperitoneally.) synergistically reversed the decrease of the step-down latency. On the contrary, pre-test injections of NMDA receptor antagonist D-AP5 (0.25, 0.5, 1 and 2 microg/mouse, intracerebroventricular.) disrupted state-dependent learning induced by lithium. The results suggest that NMDA receptors may be involved, at least partly, in the lithium-induced state-dependent learning.