普萘洛尔抗焦虑作用与脑内四氢孕酮相关性研究

Correlation Study Between Anxiolytic Effect of Propranolol and Allopregnanolone in Brain

目的探讨普萘洛尔抗焦虑效应的作用机制。方法选用昆明小鼠50只,单次腹腔注射左旋-丁硫氨酸-亚砜亚胺(BSO)5 mg/kg建立焦虑症动物模型,并按用药的不同分为模型组(不额外用药),普萘洛尔低剂量组(10 mg/kg)、中剂量组(20 mg/kg)、高剂量组(40 mg/kg)及舍曲林阳性药组(10 mg/kg),各10只。另取10只小鼠作为正常对照组。各组小鼠给予相应剂量药物,药物质量浓度均为100 g/mL,正常对照组给予等体积的溶剂(生理盐水),每天1次,连续灌胃7 d后开始抗焦虑药效学评价。选用经典焦虑模型试验(Vogel饮水冲突试验、高架十字迷宫试验和明暗箱穿梭试验)评价普萘洛尔的抗焦虑作用;采用酶联免疫吸附试验测定法(ELISA)分别检测小鼠前额皮质和海马四氢孕酮的水平和血清皮质酮的浓度。行为学评价期间,每天给药1 h后再进行试验。结果 Vogle饮水冲突试验中,普萘洛尔连续给药显著性增加焦虑症小鼠饮水次数;高架十字迷宫试验中,普萘洛尔中、高剂量(20,40 mg/kg)显著性增加焦虑症小鼠在开臂的停留时间百分比和开臂次数百分比;明暗穿梭箱试验中,普萘洛尔中、高剂量明显增加焦虑症小鼠明暗箱的穿梭次数及明箱的停留时间百分比;ELISA检测结果显示,与正常对照组比较,BSO注射小鼠海前额皮质和海马的四氢孕酮含量显著减少而血清皮质酮浓度明显升高,普萘洛尔各剂量均能不同程度逆转BSO引起的变化。结论普萘洛尔改善小鼠焦虑样行为与脑内前额皮质和海马的四氢孕酮有关,其可能通过升高前额皮质和海马四氢孕酮的水平,进而抑制血清皮质酮的分泌。

Objective To investigate the mechanism of anxiolytic effect of propranolol. Methods Totally 50 Kunming mice were given single intraperitoneal injection of 5 mg/kg BSO for establishing anxiety animal models,and they were divided into model group （no ad-ditional medication）,propranolol low-dose group （10 mg/kg）,medium dose group （20 mg/kg）,high dose group （40 mg/kg）and ser-traline positive drug group （10 mg/kg）,10 cases in each group. Another 10 mice were selected as normal control group. Each group of mice was given the corresponding dose of medicine,the normal control group was given equal volume of solvent （physiological saline）,1 time a day,after continuous intragastric administration of 7 d,the anti anxiety pharmacodynamics was evaluated. The anxiolytic effects of propranolol were evaluated by the classic anxiety model test （Vogel′s conflict test,elevated plus maze test and light-dark box test）. The level of allopregnanolone and concentration of serum corticosterone in the prefrontal cortex and hippocampus of mice were detected by ELISA. During the behavioral evaluation,the test was done after the medication of 1 h every day. Results Vogel′s conflict test showed that continuous administration of propranolol could significantly increase the number of drinking water in anxiety mice. Elevated plus maze test showed that the median and high doses of propranolol （20,40 mg/kg）significantly increased the anxiety mice′s per-centage of residence time and the number of open arm entering. In light-dark box test,median and high dose of propranolol signifi-cantly increased the anxiety mice′s percentage of residence time in the light box and the shuttle number in light-dark box. In the ELISA test,compared with the normal control group,the level of allopregnanolone in the prefrontal cortex and hippocampus of mice in-jected with BSO were significantly decreased,while the concentration of serum corticosterone was significantly increased. Each dose of propranolol can reverse the change induced by BSO in different degrees. Conclusion The effect of propranolol on anxiety-like behavior in mice is related to allopregnanolone in the prefrontal cortex and hippocampus of the brain,which may increase the level of allo-pregnanolone in prefrontal cortex and hippocampus and then inhibit the secretion of corticosterone in serum.