一氧化氮合酶抑制剂N-硝基-L-精氨酸甲酯对大鼠恐惧消退的影响

Effect of nitric oxide synthase inhibitor L-NAME on fear extinction in rats

目的研究一氧化氮合酶（NOS）抑制剂N-硝基-L-精氨酸甲酯（L·NAME）对两种不同模式恐惧消退的影响。方法AAA模式，恐惧条件化、消退训练和消退检测在相同场景进行。AAB模式，恐惧条件化、消退训练在场景A进行，消退检测在场景B进行。每个任务中，利用随机数字表法将40只大鼠随机分成4组（10只／组），消退训练前30min分别注射L—NAME（10，20，40mg／kg）和生理盐水。以大鼠僵直时间作为评价恐惧记忆指标。对差异有统计学意义的组，进一步进行药物状态依赖效应和活动度检测。结果AAA模式中，消退检测阶段，生理盐水组和10，20，40mg／kg组的僵直百分比分别为（27．42±6．52）％，（30．83±7．15）％，（32．49±8．55）％，（38．94±11．48）％。各L—NAME组大鼠僵直水平与生理盐水组相比差异均无统计学意义（F：0．451，P〉0．05）；AAB模式中，消退检测阶段，生理盐水组和10，20，40mg／kg组的僵直百分比分别为（30．32±6．15）％，（32．83±6．64）％，（39．49±8．74）％，（49．94±10．83）％。与生理盐水组相比，仅40mg／kg组大鼠的僵直水平明显增加（F=5．154，P〈0．01）。状态依赖效应检测中，与生理盐水-生理盐水（消退和消退检测前30min都注射生理盐水，以后类推）组相比[（26．73±5．62）％]，L—NAME-生理盐水组[（48．44±10．46）％]和L—NAME—L—NAME组[（61．25±13．24）％]大鼠的僵直水平都显著增高，差异均有统计学意义（均P〈0．01）。结论L—NAME对恐惧消退损伤具有任务依赖性，提示一氧化氮信号通路选择性参与某些恐惧消退学习过程。

Objective To investigate the effects of nitric oxide synthase inhibitor L-NAME on two tone fear extinction design in rats. Methods In AAA design, the rats received fear conditioning, extinction training and extinction test in the same context. In AAB design, the rats received fear conditioning and extinction training in context A ,extinction test in context B. In each task ,40 male rats were randomly divided into 4 groups（ n = 10 per group ） , and L-NAME （10,20 and 40 mg/kg） or saline was injected intraperitoneally （i. p） 30 mix prior to extinc- tion training. Percent freezing was used as an index for fear memory during extinction test phases. Further experi- ments were used to test state-dependency effects or nonspecific changes of locomotor activity that followed L-NAME injection. Results In AAA design, percent freezing was （ 27.42 ±6.52 ） % in saline group, and （ 30.83 ±7.15 ） % , （ 32.49 ± 8.55 ） % , （ 38.94 ± 11.48 ） % in 10,20,40 mg/kg L-NAME group respectively. There was no significant difference in the level of percent freezing among the four groups （P 〉 0.05 ）. In AAB design, percent freezing was （ 30.32 ± 6.15 ） % in saline group, and （ 32.83 ± 6.64） %, （ 39.49 ± 8.74 ） %, （49.94 ± 10.83 ） % in 10,20,40 mg/kg L-NAME group respectively. Compared with saline ,only rats with L-NAME 40 mg/kg showed more levels of freezing （P 〈 0.01 ）. In state-dependency effects test, compared with Sal-Sal group （ （ 26.73 ± 5.62） % ） which received both saline injections 30 rain before extinction training and extinction test, respectively, both NAME-Sal group（ （48.44 ± 10.46 ） % ） and NAME-NAME group （ （61.25 ± 13.24） % ） showed more levels of freezing （P 〈 0.01, respectively）. Conclusion These results show that L-NAME produces a task-dependent impairment of fear extinction, and implies that nitric oxide signaling is involved in memory process of certain extinc- tion tasks.