Interaction between dorsal hippocampal NMDA receptors and lithium on spatial learning consolidation in rats

• Intra-CA1 injection of lithium impaired spatial learning.
• Intra-CA1 injection of NMDA increased spatial learning.
• Intra-CA1 injection of D-AP5 decreased spatial learning.
• D-AP5 potentiated, while NMDA restored lithium-induced spatial memory deficit.

Previous investigations have shown that NMDA receptors play an important role in learning and memory process. Lithium is a primary drug for management and prophylaxis of bipolar disorder. It can regulate signal transduction pathways in several regions of the brain and alter the function of several neurotransmitter systems involved in memory processes. The present study aimed to test the interaction of NMDA glutamatergic system of the CA1 region of dorsal hippocampus and lithium on spatial learning. Spatial memory was assessed in Morris water maze task by a single training session of eight trials followed by a probe trial and visible test 24 h later. All drugs were injected into CA1 regions, 5 min after training. Our data indicated that post- training administration of lithium (20 μg/rat, intra-CA1) significantly impaired memory consolidation. Intra- CA1administration of NMDA, a glutamate receptor agonist (0.001 and 0.01 μg/rat) showed spatial learning facilitation. Infusion of D-AP5, a glutamate receptor antagonist (0.05 and 0.1 μg/rat) showed impairment of spatial memory. Our data also indicated that post- training administration of ineffective dose of NMDA (0.0001 μg/rat) significantly decreased amnesia induced by lithium in spatial memory consolidation. In addition, post-training intra-CA1 injection of ineffective dose of D-AP5 (0.01 μg/rat) could significantly increase lithium induced amnesia. It seems probable that signaling cascades of NMDA receptors that regulates synaptic plasticity are targets of anti-manic agents such as lithium. Our results suggest that NMDA receptors of the dorsal hippocampus may be involved in lithium-induced spatial learning impairment in the MWM task.