Alleviation of cognitive deficits and high copper levels by an NMDA receptor antagonist in a rat depression model.

Major depressive disorder (MDD) is frequently associated with cognitive deficits and high copper levels. Dysfunction of N-methyl-d-aspartate (NMDA) receptors has been postulated to underlie MDD pathogenesis. This study sought to investigate the curative effect of the NMDA receptor antagonist memantine on cognitive deficits in depression and the underlying mechanisms. Adult male Sprague-Dawley rats received corticosterone (CORT) (20 mg/kg) bi-weekly via subcutaneous injection and/or copper gluconate (7 mg/kg) via daily intragastric administration. After 3 weeks, sucrose preference tests and open field tests showed anhedonia and high anxiety in both the CORT and CORT+Cu groups. Memantine intervention (20 mg/kg daily via intragastric administration for 14 days) led to recovery of anhedonia and anxiety behaviors. Memantine also remarkably suppressed serum copper ion levels. Moreover, memantine treatment effectively rescued depression-related spatial memory deficits as shown by the Morris water maze task. Compared to the pre-memantine treatment results, the results of behavioral tests and cognitive function after memantine treatment were significantly normalized, and the copper concentration was decreased in all groups. Collectively, our findings suggest that the NMDA receptor antagonist memantine may improve symptoms of anhedonia and anxiety and the cognitive deficits associated with depression, likely be related to suppress serum copper ion levels.