目的:采用慢性束缚应激小鼠模型,研究N-棕榈酰乙醇胺(N-palmitoylethanolamide,PEA)对小鼠焦虑抑郁样行为的影响,进一步探讨PEA抗小鼠焦虑抑郁作用的可能机制.方法:小鼠分为正常对照组、模型组、氟西汀(10 mg/kg)组和PEA 2.5、5、10 mg/kg组,每天灌胃给药后30 min,将小鼠(除了正常对照组)放置于有机玻璃管内接受4 h的慢性束缚应激,持续21 d.第22天采用旷场实验和强迫应激实验观察PEA对慢性束缚应激小鼠抑郁样行为的影响;高架十字迷宫实验探讨PEA对慢性束缚应激小鼠焦虑样行为的影响;水迷宫方法分析PEA对慢性束缚应激小鼠学习、记忆、空间定向和认知功能等方面的作用;ELISA方法检测慢性束缚应激小鼠血清促肾上腺皮质激素(adrenocorticotropic hormone,ACTH)、皮质醇(cortisol,CORT)及海马5-羟色胺(5-hydroxytryptamine,5-HT)含量的变化;可见分光光度法检测海马乙酰胆碱酯酶(acetylcholinesterase,AChE)活性的改变.结果:与模型组相比,在小鼠强迫应激实验中,PEA及氟西汀组小鼠不动时间明显减少;旷场试验中,PEA及氟西汀明显增加小鼠水平移动距离及运动总时间,但只有PEA 10 mg/kg及氟西汀组增加了小鼠直立次数;在高架十字迷宫实验中,PEA及氟西汀明显增加小鼠开臂进入次数、开臂停留时间百分比及在臂总移动距离;在水迷宫实验中,PEA 5、10 mg/kg及氟西汀组明显缩短小鼠寻台潜伏期,PEA 10 mg/kg及氟西汀组明显缩短小鼠搜寻距离.与应激模型组比较,PEA 2.5~10 mg/kg及氟西汀显著降低小鼠血清中ACTH水平,PEA 5、10 mg/kg及氟西汀显著降低小鼠血清CORT水平及小鼠肾上腺指数,PEA 10 mg/kg及氟西汀显著增高海马5-HT含量,降低海马AChE活性,但PEA 2.5和5 mg/kg组海马组织中5-HT含量及AChE活性则无明显改变.结论:PEA对束缚应激模型小鼠的焦虑及抑郁样行为具有一定的拮抗作用,其具体作用机制可能与调节下丘脑-垂体-肾上腺轴功能、增加海马单胺类递质5-HT水平及参与中枢胆碱系统的调节有关.
AIM:To study the effects of N-palmitoylethanolamide ( PEA) on the anxiety-and depression-like behaviors of the mouse model induced by restraint stress , and to explore the possible mechanism of anxiolytic and antide-pressant effects of PEA .METHODS:The mice were intragastrically treated with 2.5, 5 and 10 mg/kg of PEA for 21 con-secutive days once daily .Thirty min after intragastric administration , the mice ( except the normal control group ) were placed in the glass tube to accept 4-h chronic restraint stress for 21 d.After the last administration , the mice were submit-ted to the forced stress test and the open field test (OFT) to observe the effects of PEA on the depression-like behaviors. The cumulative immobility time was recorded during the 4-min interval in the forced swimming test ( FST) or during the 5-min interval in the tail suspension test (TST).The elevated plus maze (EPM) test was used to investigate the effect of PEA on the mouse anxiety-like behaviors , and the water maze method was used to investigate the learning and memory abi-lities, spatial orientation and cognitive function of mice .After the behavior tests , the serum was collected and the hippo-campus was removed . The serum contents of adrenocorticotropic hormone ( ACTH ) , cortisol ( CORT ) and 5-hydroxytryptamine (5-HT) in the hippocampus were detected by ELISA .The changes of acetylcholinesterase ( AChE) ac-tivity in the hippocampal homogenate was measured by spectrophotometry .RESULTS:Compared with model group , in the FST or TST, the immobility time in the mice treated with PEA at 2.5~10 mg/kg and fluoxetine was significantly reduced . In the OFT, the total locomotion distance and total movement time were increased significantly in the mice , but only 10 mg/kg PEA and fluoxetine increased the numbers of rearing .In the EPM test , the percentage of the time spent in open arms, the entries into open arms and the total locomotion distance in 4 arms in the mice were significantly increased .In wa-ter maze test , PEA at 5 and 10 mg/kg and fluoxetine significantly shortened the latency to find the security zone in the mice, and PEA at 10 mg/kg and fluoxetine obviously shorten the swimming distance .Compared with model group , PEA at 10 mg/kg and fluoxetine reduced the mouse serum levels of ACTH and CORT , and the adrenal index , increased the 5-HT content and decreased the AChE activity in the hippocampus .CONCLUSION:PEA produces antagonistic effects on an-xiety-and depression-like behaviors in the mice induced by restraint stress .Its specific mechanism may be related to the re-gulation of the hypothalamic-pituitary-adrenal axis function by increasing the 5-HT level in hippocampus , thus participating in the regulation of central cholinergic system .