帕罗西汀对抑郁模型大鼠不同脑区环磷酸腺苷反应元件结合蛋白的影响

The effects of paroxetine on cAMP-response-element-binding-protein in different brain regions in depressed model rats

目的探讨帕罗西汀在不同用药时间对抑郁模型大鼠海马、前额叶皮质环磷酸腺苷反应元件结合蛋白(CREB)磷酸化(p-CREB)及总蛋白(t-CREB)水平的影响。方法成年雄性 Sprague-Dawley 大鼠36只,随机分为6组:对照组、抑郁模型组(以下简称模型组)、抑郁模型+用药1 d 组(以下简称用药1 d 组)、抑郁模型+用药1周组(以下简称用药1周组)、抑郁模型+用药2周组(以下简称用药2周组)和抑郁模型+用药4周组(以下简称用药4周组),每组各6只。抑郁模型的制作为强迫大鼠游泳4周,每天1次,每次15 min。帕罗西汀的剂量为10 mg/kg 体质量,灌胃给药,时间分别为1 d 和1,2,4周,每天1次,于每次游泳前用药。采用 Western blot 法检测各组大鼠海马及前额叶皮质的 p-CREB 和 t-CREB 水平。结果 (1)模型组及用药1 d、1周组大鼠海马 p-CREB 水平明显低于对照组(p<0.01),用药2,4周组大鼠海马 p-CREB 水平与对照组的差异无统计学意义(P>0.05);模型组及各用药组海马 t-CREB 水平与对照组的差异无统计学意义(P>0.05)。(2)模型组及用药1d 和1,2周组大鼠前额叶皮质 p-CREB 水平均明显低于对照组(P<0.05),用药4周组与对照组的差异无统计学意义(P>0.05)。模型组及用药1 d、1周组大鼠前额叶皮质 t-CREB 水平与对照组的差异无统计学意义(P>0.05),用药2,4周组大鼠前额叶皮质 t-CREB 水平均明显高于对照组(P<0.05或 P<0.01)。结论慢性强迫游泳导致大鼠海马及前额叶皮质 CREB 活性降低,长期使用帕罗西汀可逆转此效应,提高抑郁大鼠前额叶皮质的 CREB 水平。

Objective To explore the effects of paroxetine on the levels of p-CERB and t-CREB in hippocampus and prefrontal cortex of depressed rats in various treatment time. Methods Adult male Sprague-Dawley rats were used as experimental subjects. They were divided into six groups： control group （ Ⅰ ）, depressed model group （ Ⅱ ）, group of depressed model ＋ paroxetine once （ Ⅲ ）, group of depressed model ＋ paroxetine for one week （ Ⅳ ）, group of depressed model ＋ paroxetine for two weeks （ Ⅴ ） and group of depressed model ＋ paroxetine for four weeks （ Ⅵ）, with 6 rats in each group. The depressed model was made by forced-swimming for 4 weeks, 15 minutes per day. Paroxetine （ 10 mg/kg） was intragastricly administrated to group Ⅲ - Ⅵ everyday before swimming, with the treatment duration of one day, one week, two weeks and four weeks respectively. Western blot was used to determine the levels p-CREB and t-CREB in hippocampus and prefrontal cortex. Results （ 1 ） The hippocampal levels of p-CREB in group Ⅱ , group m, and group Ⅳ were significantly lower than that in group Ⅰ （ P 〈 0. 01 ） , and there were no significant differences in the p-CREB levels in group Ⅴ and group Ⅵ as compared to group I （ P 〉 0. 05 ）. There was no significant difference of the level of t-CREB between control group and any other group （P 〉 0. 05 ）. （2） In prefrontal cortex, the levels of p-CREB in group Ⅱ , group Ⅲ, group Ⅳ, and group V were significantly lower than that in group I respectively （P 〈 0. 05 ）, there was no significant difference of the level of p-CREB between group Ⅵ and group Ⅰ （ P 〉 0. 05 ）. The level of t-CREB in group Ⅴ or group Ⅵ was significantly higher than that in group Ⅰ （P 〈0. 05 or P 〈0. 01 ） , there was no significant difference of the level of t-CREB between any other paroxetine treatment group and control group （ P 〉 0. 05 ）. Conclusions Chronic forced-swimming could inhibit CREB phosphorylation in hippocampus and prefrontal cortex of rats , which could be reversed by chronic administration of paroxetine.