氟哌啶醇对小鼠在避暗实验中学习记忆获得、巩固和再现过程的影响

Influence of haloperidol on memory acquisition, consolidation and retrieval processes in step-through test in mice

目的:考察抗精神病药氟哌啶醇对小鼠在避暗实验中学习记忆的获得、巩固和再现过程的影响。方法:实验于2003-09/2004-01在沈阳药科大学药学院神经药理实验室完成。选择健康雄性昆明种小鼠200只。①氟哌啶醇对小鼠运动能力的影响:首先将50只小鼠随机均分5组,氟哌啶醇0.01mg/kg组、0.03mg/kg组、0.1mg/kg组、0.3mg/kg组、空白对照组。应用自主活动测定仪记录10min内小鼠自主活动次数。②避暗实验:训练前将小鼠头背着洞口放入明室,先适应环境3min,然后给暗室铜栅通以36V电流,小鼠一进入暗室即受电击,其正确反应是回到明室,铜栅通电持续5min,此为训练过程。24h后对小鼠进行记忆测验,记录小鼠第一次进入暗室的时间,此为避暗潜伏期,并记录5min内小鼠进入暗室的次数(即避暗错误次数),5min内未进入暗室的小鼠其潜伏期按300s计算。③应用避暗法考察氟哌啶醇对小鼠学习记忆的获得、巩固和再现过程的各实验中,每50只小鼠随机均分5组,空白对照组,氟哌啶醇0.01mg/kg组、0.03mg/kg组、0.1mg/kg组、阳性药物对照组。训练前50min各组皮下注射氟哌啶醇或溶媒,阳性药对照组在训练前10min腹腔注射东莨菪碱3mg/kg,此种给药方案测定小鼠记忆的获得过程;训练后各组立即给予受试药物或溶媒的给药方案为测定记忆的巩固过程,阳性对照组皮下注射亚硝酸钠125mg/kg;测验前50min各组给予受试药物或溶媒的给药方案为测定小鼠记忆的再现过程,阳性对照组在测验前30min灌胃300mL/L乙醇10mL/kg。结果:200只小鼠均进入结果分析。①氟哌啶醇在0.01～0.1mg/kg剂量范围内,与空白对照组比较小鼠自主活动无明显变化;而在0.3mg/kg剂量下,小鼠自主活动明显减少(P<0.001)。因此,在以下避暗实验中,氟哌啶醇采用0.01～0.1mg/kg剂量范围。②与空白对照组比较,训练前给予氟哌啶醇0.01～0.1mg/kg对小鼠错误潜伏期和错误次数无明显影响。阳性药东莨菪碱能明显增加小鼠避暗错误次数并缩短错误潜伏期。③训练后给予氟哌啶醇0.01mg/kg或0.1mg/kg,能明显缩短小鼠错误潜伏期(P<0.05),对小鼠错误次数无明显影响。阳性药亚硝酸钠能明显增加小鼠避暗错误次数(P<0.01),并缩短错误潜伏期(P<0.01)。④与空白对照组比较,测试前给予氟哌啶醇0.01～0.1mg/kg对小鼠错误潜伏期和错误次数无明显影响。阳性药乙醇能明显增加小鼠避暗错误次数(P<0.001),并缩短错误潜伏期(P<0.01)。结论:氟哌啶醇(0.01mg/kg,0.1mg/kg)损伤了避暗实验过程中小鼠记忆的巩固过程,而对记忆获得和再现过程没有明显影响。

AIM： To investigate the effects of antipsychotic drug haloperidol on memory acquisition, consolidation and retrieval processes of mice in stepthrough test. METHODS： The experiment was carried out in the laboratory of Neuroscience Program, Department of Pharmacology, Shenyang Pharmaceutical University from September 2003 to January 2004. Two hundred healthy male Kunming mice were selected. ①Effect of haloperidol on motor ability of mice： Fifty mice were randomly divided into 5 groups： haloperidol 0.01, 0.03, 0.1 and 0.3 mg/kg groups and control group. The locomotor activity of mice were recorded by a locomotor monitoring cage. ②Step-through test： The mouse was placed in the illuminated compartment to adapt the environment for 3 minutes. Then the 36 V electric current was delivered through the grid floor of the dark compartment. Once the mouse entered the dark compartment through the door, a scrambled foot shock was delivered through the grid floor. The mouse could escape from the shock only by stepping back into the safe illuminated compartment. The grid was given the current for 5 minutes. This was the training section. Twenty-four hours after the training, the mouse was again placed in the safe illuminated compartment. The response latency to enter the dark compartment and numbers of errors （enter the dark compartment） in 5 minutes were measured. The latency of not entering the dark room during the 5-minute observation period was regarded as 300 s.③The effects of haloperidol on memory acquisition, consolidation and retrieval processes in mice were investigated by using step-through test. For each process, every fifty mice were randomly divided into 5 groups： control group, haloperidol 0.01, 0.03 and 0.1 mg/kg groups and positive control group. Haloperidol or vehicle was injected subcutaneously into the mice of each group 50 minutes before the training; the positive drug was injected 3 mg/kg scopolamine 10 minutes before training for testing acquisition of memory; haloperidol or vehicle was administered immediately after the training for testing memory consolidation. The positive drug was injected with 125 mg/kg NANO2 immediately after the training. Haloperidol was administered 50 minutes before the test for memory retrieval. The positive group was administered 300 mL/L alcohol 10 mL/kg 30 minutes before the test. RESULTS： Totally 200 mice entered the result analysis. ①There was no obvious change in locomotor activity between the haloperidol-treated group at doses of 0.01, 0.03 and 0.1 mg/kg and the control group; but the activities were significantly decreased at dose of 0.3 mg/kg （P 〈 0.001）.Therefore, haloperidol at doses of 0.01, 0.03 and 0.1 mg/kg was used in the following tests. ②Compared with the control group, haloperidol of 0.01-0.1 mg/kg administrated before training had no significant effect on the number of errors nor the latency. The positive drug hyoscine could significantly increase the number of errors and shorten the escaping la tency. ③ Haloperidol of 0.01 or 0.1 mg/kg given after training could markedly shorten the escaping latency of mice （P 〈 0.05）, but had no effect on the number of errors. The positive drug NANO2 could significantly increase the number of errors （P 〈 0.01） and shorten the escaping latency （P 〈 0.01）. ④Compared with the control group, haloperidol of 0.01-0.1 mg/kg administrated before test did not have significant effect on the number of errors nor the latency. The positive drug alcohol could significantly increase the number of errors （P 〈 0.001）, and shorten the escaping latency （P 〈 0.01）. CONCLUSION： Haloperidol （0.01 and 0.1 mg,/kg） impairs the memory consolidation process in step-through test, while has no effect on the acquisition or retrieval process.