In this thesis, we conducted two parts of experiments. Part 1 is the preclinical research and development of new antidepressants. Part 2 we focus on the role of hippocampal long term depression (LTD) in organizing depression-like behavior in forced swim test models. Part 1：Depression is a common mental disorder, affecting 20% global population. The mortality ratios for depression and the cost of treating depression are high. The clinical antidepressants are mainly target the monoamine system. But, the ongoing antidepressants are effective in treating only 50% of depression patients, with a 2-4 weeks delay and side effects. More and more envidence suggests a depression mechanism independent on monoamine system. It is time to research and develop new antidepressants that not act at monoamine acid. We purified a component from traditional Chinese medicine and named CXZ-123. We used 4 animal models of depression which represent 3 different causing factors of depression, including behavioral despair, chronic unpredictive mild stress, reserpine induced depletion of monoamine. We also used the footshock induced freezing and elevated plusmaze to evaluate the anxiolytic effects of CXZ-123. We found that CXZ-123 produced robust antidepressant effects in different animal models of depression in a dose dependent manner. And lower doses were required to produce the same level of antidepressant effects compared with fluoxetine. CXZ-123 showed robust therapeutic effects with a short delay, as short as 30 min and a long last effect. CXZ-123 but not fluxotine is effective in treating old rat model of depression. CXZ-123 can also reduce the anxiety behavior. We also found that hippocampus, prefrontal cortex and amygdala underly the antidepressant effects of CXZ-123. CXZ-123 is a good candidate to be a new antidepressant independent of monoamine system, with fast and good therapeutic effect, anxiolytic effect and with little side effects. Part 2：We focused on the role of hippocampal long term depression in organizing depression like behavior. Retrieval of memory is the basis of a learned behavior, while this is highly sensitive to inescapable stress that impairs long-term potentiation (LTP) but facilitates long-term depression (LTD) in the hippocampus. It remains unknown whether hippocampal plasticity modulates retrieval of despair memory that may contribute to a despair-based depression-like behavior in Porsolt’s forced swim test. Here, we report that hippocampal CA1 LTD was facilitated and LTP was impaired only in rats with enhanced depression-like behavior. LTD and depression-like behavior are both decreased by the antidepressant fluoxetine or antagonists of NMDAR and NR2B-containing NMDAR or a specific inhibitor of LTD expression via AMPAR endocytosis. Remarkably, agonist of either NMDAR or mGluR I induced endogenous-like LTD in hippocampus while enhanced depression-like behavior and impaired spatial memory retrieval. Thus, hippocampal LTD alone may enhance retrieval of despair memory to confer depression-like behavior.
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