原花青素联合胡椒碱通过五羟色胺受体途径改善慢性应激小鼠抑郁焦虑样行为

目的：探讨原花青素（OPC）联合胡椒碱（PIP）对慢性不可预知应激（CUMS）小鼠的抑郁焦虑样行为的作用，通过分析海马、前额叶皮层和下丘脑中5-HT1A受体的变化探讨相关机制。方法：将ICR小鼠分为正常组、CUMS组、CUMS+PIP（5 mg/kg）+OPC（12.5、25、50 mg/kg）组、CUMS+PIP（5 mg/kg）+OPC（50 mg/kg）+NAN-190（0.1 mg/kg）组、NAN-190组（CUMS+NAN-190 0.1 mg/kg）和氟西汀组（CUMS+氟西汀 10 mg/kg），共8个组。CUMS建模后，采用强迫游泳、悬尾、新奇食物抑制摄食实验和大理石掩埋实验评估小鼠的抑郁和焦虑样行为，并采用高效液相色谱法测定海马、额叶皮层和下丘脑的单胺类神经递质含量5-羟色胺（5-HT）、去甲肾上腺素（NE）和多巴胺（DA）]。结果：与正常组相比，CUMS组小鼠强迫游泳和悬尾实验中的不动时间显著增加（P＜0.01），新奇食物抑制摄食潜伏期增加（P＜0.05），大理石掩埋实验颗粒数增加（P＜0.01）；给予OPC（25、50 mg/kg）联合PIP（5 mg/kg）可改善由CUMS引起的抑郁焦虑样行为。通过高效液相色谱法发现，OPC（25、50 mg/kg）联合PIP（5 mg/kg）用药可显著逆转由CUMS引起的海马、额叶皮层和下丘脑中的5-HT水平下降（P＜0.05），然而对NE、DA无影响（P＞0.05）。使用5-HT1A受体拮抗剂NAN-190（0.1 mg/kg）可逆转OPC和PIP的改善作用（P＜0.05）。结论：OPC和PIP联用可改善CUMS小鼠的抑郁焦虑样行为，这可能是通过激活中枢神经系统中的5-HT1A受体实现的。

Proanthocyanidins combined with piperine improved depression and anxiety-like behavior of chronic stress mice through serotonin receptor pathway

Objective: To investigate the anti-depressant and anti-anxiety effect of OPC combined with PIP on chronic unpredictable mild stress (CUMS) mice and to study the mechanism by analyzing the receptor of 5-HT1A in hippocampus, pre-frontal cortex and hypothalamus. Methods: The mice were divided into eight groups: Control group, CUMS group, CUMS+PIP 5 mg/kg+OPC (12.5, 25, 50 mg/kg) group, CUMS+PIP (5 mg/kg)+ OPC (50 mg/kg)+NAN-190 (0.1 mg/kg) group, CUMS+NAN-190 (0.1 mg/kg) group and CUMS+fluoxetine (10 mg/kg). After 21 days of chronic unpredicted mild stress, all mice were subjected to the forced swimming test, tail suspension test, novel food inhibition test and marble bury test to evaluate the depression- and anxiety-like behaviors. Then, we used high performance liquid chromatography method to detect the concentration of monoamine (5-HT, NE and DA) in the hippocampus, pre-frontal cortex and hypothalamus. Results: Compared with control group, the immobility time of forced swimming test and tail suspension test was significantly increased in CUMS group (P<0.01) and the latency to feed of CUMS in the novelty suppressed feeding also significantly increased (P<0.05). Meanwhile, the number of marbles buried of CUMS in the marble bury test obviously elevated (P<0.05, P<0.01). Given of OPC (25, 50 mg/kg) combined with PIP (5 mg/kg) improved the depression and anxiety behavior induced by CUMS (P<0.05, P<0.01). Using the HPLC method we found that OPC (25, 50 mg/kg) combined with PIP (5 mg/kg) significantly reversed the 5-HT level caused by CUMS in hippocampus, pre-frontal cortex and hypothalamus (P<0.05, P<0.01, P<0.001), however, there was no significant effect on NE and DA in the hippocampus, pre-frontal cortex and hypothalamus. Pretreatment with the 5-HT1A receptor antagonist NAN-190 prevented the improvement (P<0.05, P<0.01, P<0.001). Conclusion: OPC combined with PIP has improved the antidepressant- and anxiety-like behavior in CUMS mice probably by activating 5-HT1A receptor in the central nervous system.