帕罗西汀对抑郁模型大鼠空间学习记忆和海马ERK-CREB通路的效应

Effects of Paroxetine on Hippocampus-Dependent Learning and Memory and ERK-CREB Pathway in Depressed Model Rats

目的探讨帕罗西汀对应激抑郁模型大鼠海马依赖性学习记忆和细胞外信号调节激酶CAMP反应序列结合蛋白(ERK-CREB)通路的效应。方法将成年雄Sprague Dawley(SD)大鼠随机分为6组:对照组(Ⅰ)、抑郁模型组(Ⅱ)、抑郁模型+给药1次组(Ⅲ)、抑郁模型+给药1周组(Ⅳ)、抑郁模型+给药2周组(Ⅴ)和抑郁模型+给药4周组(Ⅵ),每组动物12只,抑郁模型为强迫大鼠游泳。帕罗西汀的剂量为10mg·kg-1,给药方式为灌胃。应用Morris水迷宫测试大鼠的空间学习记忆情况。采用Western blot检测各组大鼠海马ERK和CREB的磷酸化及总蛋白(p-ERK和ERK,p-CREB和t-CREB)水平。结果在Morris水迷宫定位航行实验中,各组的平均逃避潜伏期(EL)比较无统计学差异(P>0.05);记忆保留实验中,Ⅱ组和Ⅲ组EL显著大于对照组(P<0.05);Ⅳ、Ⅴ和Ⅵ组平均EL与对照组比较无统计学差异(P>0.05),各用药组EL随用药时间的延长呈现缩短趋势;各组空间探索实验和可见平台实验的成绩比较无统计学差异(P>0.05)。Ⅱ、Ⅲ、Ⅳ和Ⅴ组大鼠海马pERK44和pERK42水平显著低于Ⅰ组和Ⅵ组(P<0.05),后两组比较无统计学差异(P>0.05)。各组之间ERK44和ERK42比较均无统计学差异(P>0.05)。Ⅱ、Ⅲ和Ⅳ组大鼠海马p-CREB水平明显低于对照组(P<0.01),Ⅴ和Ⅵ组大鼠海马p-CREB水平与对照组比较无统计学差异(P>0.05);各组t-CREB水平比较无统计学差异(P>0.05)。结论帕罗西汀长期用药明显改善抑郁模型大鼠长时记忆的损害,逆转抑郁模型大鼠海马降低的ERK和CREB磷酸化水平。

OBJECTIVE To explore the effects of paroxetine on hippocampus-dependent learning and memory and ERK-CREB pathway of depressed model rats. METHODS Adult male Sprague dawley （SD） rats were used as experimental subjects. They were divided into six groups： control group （ Ⅰ ）, depressed model group （ Ⅱ ）, group of depressed model treated with single dose of paroxetine once（ Ⅲ）, group of depressed model treated with paroxetine for one week （Ⅳ ）, group of depressed model treated with paroxetine for two weeks （ Ⅴ ） and group of depressed model treated with paroxetine for four weeks （ Ⅵ）, twelve rats in each group. Except control group, others were subjected to forced-swimming for four weeks, 15 min a day. Paroxetine （10 mg · kg^-1） was given intragastricly to group Ⅲ- Ⅵ everyday before swimming. Morris water maze （MWM） was used to measure the spatial learning and memory of rats. Western blot was used to determine the levels of p-ERK, ERK and p-CREB and t-CREB. RESULTS In the hiding platform test of MWM, there was no significant difference of escape latency（EL） between any two groups （P 〉 0. 05 ）. In the retention test, the excape latencyl （EL） in group Ⅱ or group Ⅲ was significantly longer than that in group Ⅰ （P 〈 0. 05）. There was no significant difference of EL between group Ⅳ, or group Ⅴ, or groupⅥ and group Ⅰrespectively（P 〉0. 05）. And the EL in all groups treated with paroxetine became shorter with the prolonging of treatment. In the probe test and visible platform test, there were no significant differences of EL among all groups（ P 〉0. 05）. In hippocampus, the levels of pERK44 and pERK42 in group Ⅱ , or group Ⅲ,or group Ⅳ, or group Ⅴ were all significantly lower than that in group Ⅰ or group Ⅵ respectively （P 〈 0. 05）. There were no significant differences between group Ⅵ and group Ⅰ （P 〉0. 05）. There were no significant differences of the levels of ERK44 and ERK42 between any two groups respectively（P 〉0. 05）. The level of p-CREB in group Ⅱ,or group m ,or group Ⅳ was significantly lower than that in group Ⅰ respectively（P 〈0.01 ）. There were no significant differences of the level of p-CREB between group Ⅴandgroup Ⅰ , and between group Ⅵ and group Ⅰ （ P 〉 0. 05 ）. There was no significant difference of the level of t-CREB between any two groups（ P 〉 0.05 ）. CONCLUSION Chronic administration of paroxetin could improve the impairment of long-term memory and reverse the inhibition of ERK and CREB phosphorylation in hippocampus of depressed model rats.