强啡肽/kappa受体(KOR)系统参与情绪调控，激活KOR介导动物表现抑郁样行为，调控机制尚不清楚。应激是导致抑郁症发生的重要原因。社交失败应激可良好地建立与人类抑郁症相符的动物模型。我们前期研究发现社交失败应激介导动物表现明显的社交逃避抑郁样行为，伴随前额叶皮层KOR内源性配体强啡肽表达增加，谷氨酸转运体（GLT-1，Xc-系统）表达降低。阻断前额叶皮层prelimbic而非infralimbic区KOR激活可以逆转Xc-系统的下调，改善动物抑郁样表现。谷氨酸转运体表达降低可能会介导谷氨酸清除障碍致胞外谷氨酸浓度过高，过度激活突触后膜NMDA受体导致抑郁的发生。因此我们将从社交失败应激-KOR激活-谷氨酸转运体表达减少-谷氨酸递质系统异常的角度，结合药理学和基因学手段，阐述强啡肽/KOR系统调控抑郁样行为的分子机制。本项目有助深入理解抑郁发病机理和KOR功能，为临床抑郁治疗提供新靶点。

Accumulating evidence suggests that dynorphin and its cognate kappa opioid receptor (KOR) play an important role in regulating stress responsiveness including depression, however, the underlying mechanism is unclear. Exposure to stress can trigger debilitating psychiatric illness, in particular depressive disorders. Our preliminary data showed that social defeat stress induced social avoidance, with significantly increased endogenous dynorphin expression and decreased glutamate transporters (GLT-1, cystine/glutamate exchange) expression in the medial prefrontal cortex. Blocking KOR activation in the prelimbic, but not infralimbic subregion of the medial prefrontal cortex restored glutamate transporter expression and ameliorated depressive-like behaviors. Thus, we hypothesized that the activation of KOR in the prelimbic cortex induced by social defeat stress mediated depressive-like behavior by decreasing glutamate transporter expression and thereby increasing extracellular glutamate concentration and activating NMDA receptor. Pharmacological and genetic approaches will be used to reveal the role of dynorphin/KOR system in regulating depressive-like behaviors. The present study will give insights into the mechanism of depression and provide new strategies for treating depression.