Amantadine Impeded The Cognition Deficit In A Rat Model Of Depression

Depression is a mood disorder that caused by a variety of reasons and with a significant and persistent depressive state as the main clinical features. Patients are often associated with significant cognitive dysfunction, including executive function disorders, memory deficit and attention disorders. The pathogenesis of depression is complex, and the researchers reported that exposure to excessive stimulation and frustration in the life experience could induce depression. Based on this observation, the chronic unpredictable stress (CUS) animal model has been developed to mimic the development and progress of clinical depression. It is one of the most widely used and reliable animal model of depression and it mainly simulates anhedonia, which is a core symptom of depression. Studies has suggest that CUS could induce spatial learning and cognitive flexibility deficit, which is closely related to the atrophy and death of CA3 pyramidal neurons, the deficit of synaptic plasticity and the decreased neurogenesis of dentate granule cells.Amantadine (AMA) is a derivative of tricyclodecane amino, it is originally applied as an antiviral agent in the treatment of influenza infection and later found to be effective in treating Parkinsonism. The possible mechanism is that it could enhance the release of dopamine (DA) from the nerve ending of corpus striatum. Additionally, as the same as menmantine (MEM), it is a low-affinity non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist which has a neuroprotective effect. Our previous study reported that memantine exhibited an antidepressant effect and improved the performance of the reversal learning in the Morris Water Maze (MWM) and repaired the synaptic plasticity with the possible mechanism by mediating NR2B receptor. AMA as a historic clinical drug whose structure is similar to menmantine is cheap for purchase. So in this study, we focused on exploring the potential therapeutic effects of amantadine in depression rats model, especially on the cognition and synaptic plasticity deficit caused by chronic stress.We chose adult male Wistar rat and used CUS with isolation rearing for modeling, then arbitrarily assigned to four groups:Control group (CON), Control treated with amantadine group (CON+AMA), CUS+isolation group (STRESS) and STRESS treated with amantadine group (STRESS+AMA). Weight and sucrose Consumption were used to assess the model. Spatial learning and memory was evaluated using the MWM test. Long-term potentiation (LTP) and depotentiation (DP) from the Schaffer collaterals to CA1 region were recorded by electrophysiological technique. NR2B and PSD-95 proteins were measured by the Western blotting to explore the possible mechanism.The mainly results as follows:(1) The body weight and sucrose Consumption percentage were significant lower in CUS group than those in CON one. After amantadine administration, both the weight and sucrose preference were increased.(2) In the place navigation test, the escape latency of STRESS group was significant longer than those in CON and STRESS+AMA group. In the spatial exploring text, the platform crossings and NW quadrant dwell time were decreased in STRESS group compared to that in CON group. However, these values were all significant increased after amantadine administrating.(3) In the spatial reversal training text, the STRESS group need longer time to find the platform compared to CON group. However, amantadine treatment group spent shorter time than the STRESS group. Additionally, the platform crossings and SE quadrant dwell time of STRESS group in the reversal exploring text were significant decreased compared to that in CON group. After amantadine administrating, both the values were increased.(4) Compared to CON group, the LTP of STRESS rats were obvious reduced but the DP was increased. After amantadine treatment, the LTP in STRESS+AMA group was significant increased and DP was decreased.(5) Western blot test showed that the relative expression of NR2B and PSD-95 in STRESS group were significant lower than those in CON group and STRESS+AMA group.Based on above results, we can draw the Conclusion that:(1) Chronic amantadine administered significantly alleviated depressant-like behavior in chronic unpredictable stress-exposed rats.(2) Amantadine impeded the deficit of spatial cognition and re-acquisition in reversal learning caused by STRESS. The possible mechanism is the ability to prevent the alterations of NR2B receptor and PSD-95 levels in hippocampus, then restore the bidirectional synaptic plasticity deficits as shown by increasing the LTP and facilitating DP from the Schaffer collaterals to CA1 region.