Objective To investigate the effect of fluoxetine on the depression-like behavior and the expression of mitogen-activated protein kinase phosphatase-1 (MKP-1),phosphorylated p38 and p38 in hippocampus of rats with depression,in order to provide clues for the molecular pathological mechanism of depression.Methods Forty Sprague Dawley rats were randomly divided into normal group,depression group,normal saline group and fluoxetine group,with ten rats in each group.The rats in the depression group,normal saline group and fluoxetine group were treated with chronic unpredictable mild stress (CUMS) for eight weeks to prepare the depression models.The rats in the normal saline group and fluoxetine group were treated with normal saline and fluoxetine by intragastric administration respectively from the fifth to eighth week,but the rats in the normal group did not give CUMS and any intervention.The behavior changes of rats in the four groups were evaluated at the time points of before modeling,after modeling and postintervention.The hippocampal tissues of rats were taken after the last the last behavioral evaluations.The expression of MKP-1,p-p38 and p38 protein in hippocampus was detected by Western blot;and the ratio of the expression of p-p38 to p38 protein (p-p38/p38) was calculated.Results There was no significant difference in the behavioral indexes of rats among the four groups (P ＞ 0.05).Compared with pre-modeling,the sucrose preference index decreased,the horizontal movement distance and vertical frequency decreased in the open field test,and the inactivity time of rats in forced swimming test increased in the depression group,normal saline group and fluoxetine group,the differences were statistically significant (P ＜ 0.05).There was no significant difference in the behavioral indexes of rats among the depression group,normal saline group and fluoxetine group (P ＞ 0.05).Compared with the normal group,the sucrose preference index decreased,the horizontal movement distance and vertical frequency of rats in open field test decreased,and the inactivity time of rats in forced swimming test increased in the depression group,normal saline group and fluoxetine group after modeling,the differences were statistically significant(P ＜0.05).Compared with the depression group and normal saline group,the sucrose preference index of rats increased,the horizontal movement distance and vertical frequency of rats in open field test increased,and the inactivity time of rats in forced swimming test shortened in fluoxetine group,the differences were statistically significant (P ＜ 0.05).The expression of MKP-1 in the hippocampus of rats in the depression group and the normal saline group was significantly higher than that in the normal group (P ＜ 0.05).The expression of MKP-1 in the hippocampus of rats in the fluoxetine group was significantly lower than that in the depression group and normal saline group (P ＜ 0.05).There was no significant difference in the expression of MKP-1 in the hippocampus of rats between the depression group and the normal saline group (P ＞ 0.05).There was no significant difference in the expression of MKP-1 in the hippocampus of rats between the fluoxetine group and normal group(P ＞ 0.05).There was no significant difference in the expression of p-p38 and p38 protein and p-p38/p38 in the hippocampus of rats among the four groups (P ＞ 0.05).Conclusions MKP-1 may be associated with the pathogenesis of depression,and p38 may not be the signaling pathway for MKP-1 to take part in the pathogenesis of depression.Fluoxetine may play a role in the treatment of depression by down-regulating MKP-1 expression.MKP-1 may play a key role in the pathogenesis of depression.Fluoxetine may play a role in the treatment of depression by down-regulating.%目的 探讨氟西汀对抑郁症大鼠行为学表现及海马内丝裂原活化蛋白激酶磷酸酶-1(MKP-1)、磷酸化p38(p-p38)和p38表达的影响,为抑郁症的分子病理学机制提供线索.方法 40只雄性Sprague Dawley大鼠随机分为正常组、抑郁症组、生理盐水组和氟西汀组,每组10只.抑郁症组、生理盐水组和氟西汀组大鼠给予8周慢性不可预见性刺激(CUMS)制备抑郁症模型,第5～8周生理盐水组和氟西汀组大鼠分别给予生理盐水和氟西汀灌胃.正常组大鼠不给予任何干预措施.分别于造模前、造模后及干预后评估4组大鼠的行为学变化;最后1次行为学评估后,取大鼠海马组织,采用Western blot法检测海马组织中MKP-1、p-p38和p38蛋白表达,并计算p-p38与p38蛋白表达的比值(p-p38/p38).结果 造模前4组大鼠行为学指标比较差异均无统计学意义(P＞0.05).与造模前比较,造模后抑郁症组、生理盐水组和氟西汀组大鼠蔗糖偏好指数降低(P＜0.05),旷场实验水平运动距离和直立次数减少(P＜0.05),强迫游泳不动时间增加(P＜0.05).造模后抑郁症组、生理盐水组和氟西汀组大鼠行为学指标比较差异均无统计学意义(P＞0.05).与正常组比较,造模后抑郁症组、生理盐水组和氟西汀组大鼠蔗糖偏好指数降低(P＜0.05),旷场实验水平运动距离和直立次数减少(P＜0.05),强迫游泳不动时间增加(P＜0.05).与抑郁症组和生理盐水组比较,干预后氟西汀组大鼠蔗糖偏好指数升高(P＜0.05),旷场实验水平运动距离和直立次数增加(P＜0.05),强迫游泳不动时间缩短(P＜0.05).抑郁症组和生理盐水组大鼠海马组织中MKP-1表达显著高于正常组(P＜0.05),氟西汀组大鼠海马组织中MKP-1表达显著低于抑郁症组和生理盐水组(P＜0.05),抑郁症组与生理盐水组大鼠海马组织中MKP-1表达比较差异无统计学意义(P＞0.05),氟西汀组与正常组大鼠海马组织中MKP-1表达比较差异无统计学意义(P＞0.05).4组大鼠海马组织中p-p38、p38蛋白表达及p-p38/p38比较差异均无统计学意义(P＞0.05).结论 MKP-1可能与抑郁症的发病机制有关,MKP-1在抑郁症的发病机制中可能不是通过p38信号通路起作用.氟西汀可能通过下调MKP-1表达而发挥治疗抑郁症的作用.
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