Research On The Mechanism Of The Impacts Of NMDA Receptor Antagonist In Depression Rats Induced By High Level Of Copper

ObjectiveIn this study, we adopt corticosterone (CORT) and copper gluconate to build the model of depression. The both depression models CORT and Copper gluconate administration group are treated by the NMDA receptor antagonist memantine. This study sought to investigate the possible mechanism between copper and NMDA in depression, and to lay the foundation for the pathogenesis and the treatment of NMDA receptor antagonists in depression.MethodsExperiments were performed on adult male Sprague-Dawley rats. Rats were exposed to saline, copper gluconate and corticosterone for 3 weeks.Group A were treated with corticosterone 20mg/kg · bw by subcutaneous injection(s.c), and treated with normal saline lml/kg by intragastric (i.g) administration, Group B were treated with corticosterone 20mg/kg · bw s.c and copper gluconate 7mg/kg · bw i.g.Group C were treated with copper gluconate 7mg/kg · bw i.g. Group D just accepted by normal saline lml/kg i.g. After 3 weeks, there were series of tests for all rats:weight, sucrose consumption, Open-field test and Morris water maze task.5 rats of each group were immediately killed and tissue was collected for real time PCR (Q-PCR), and the level of copper in the serum and cerebrospinal fluid were tested. The rest of group were administrated with memantine (20mg/kg, intragastric (i.g) administration for 14 days, then measured the weight, sucrose consumption, Open-field test and Morris water maze task. After that, the levels of NMDAR1 protein and Grinl gene were measured and the level of copper in the serum and cerebrospinal fluid were tested.Results1. The body weight of rats treated by corticosterone were decreased gradually,especially CORT+Cu.Rats’weight of Cu have no difference to Healthy control.The food consumption and sucrose preference of CORT,CORT+Cu and Cu were significantly decreased (F=21.945,p=0.000;F=52.159,p=0.000). At Open-Field test,distance and mean velocity of CORT and CORT+Cu were lower than HC (F=4.23,p=0.000;F=5.73,p=0.002).At the Morris water maze test,all rats performed differences from the third day,CORT+Cu’s Escape Latency were significantly longer than others,at the fourth and fifth day, CORT+Cu’s Escape Latency were significantly longer than CORT and Cu,meanwhile, CORT and Cu’s Escape Latency were significantly longer than HC(F=7.249,p=0.001; F=11.873,p=0.000).as to the times of cross platform,HC was significantly more than other groups(F=17.526,p=0.000).2. Compared to the results of pre-memantine treatment, we found differences in the results of after memantine treatment as below:the food consumption of CORT and CORT+Cu were significantly increased(t=-2.509, p=0.046;t=-4.75,p=0.005);the sucrose preference of CORT was significantly increased (t=-6.959,p=0.000);at the Open-Field test, CORT,CORT+Cu and Cu’s distance were significantly increased (t=-3.764,p=0.009,t=-4.872,p=0.005, t=-4.915,p=0.004); CORT+Cu and Cu’s mean velocity were significantly increased (t=-4.23,p=0.008,t=-4.635,p=0.006); At the Morris water maze test,CORT+Cu’s Escape Latency in each day were significantly decreased,and the times of cross platform was significantly increased (t=2.843,p=0.036; t=2.786,p=0.039;t=5.073,p=0.004;t=3.465,p=0.018; t=3.807,p=0.013;t=-6.5, p=0.001).3. The level of serum copper in CORT,CORT+Cu were significantly higher than Cu and HC,the difference of serum copper between Cu and HC was not significant(F=11.7,p=0.000). Every group’s level of serum copper were significantly decreased after memantine treatment(t=9.625,p=0.025;t=3.207, p=0.000;t=0.003,p=0.003;t=1.943,p=0.003).4.The expression of NMDA receptor and Grinl gene had no significant differences after treatment of corticosterone and copper(F=3.168,p=0.053; F=1.041,p=0.401).There were also no differences in expressions of NMDA receptor(t=0.681,p=0.077;t=0.817,p=0.329;t=0.012,p=0.561;t=0.765,p=0.873) and Grin1 gene(t=0.565,p=0.619;t=2.388,p=0.121;t=4.339,p=0.211;t=0.476, p=0.112) after treatment by memantine.Conclusion1.Cu2+ may aggravate the depressive symptoms such as losing of pleasure,which were caused by corticosterone. Adding intake of copper may aggravate the cognitive dysfunctions caused by corticosterone.2.NMDA receptor Antagonist may improve those symptoms of appetite,ppleasurement and cognitive dysfunctions of depressive rats.3.NMDA receptor Antagonist may significantly decrease the level of serum copper which had increased in depressive rats.4.NMDA receptor Antagonist may has no influence in NMDA receptor’s expression in protein and gene level.