The Effects Of Fluoxetine Exposure During Pregnancy On Offspring' Behavior And 5-HT System

Objective(s):The study aimed to evaluate the effects of prenatal fluoxetine exposure on the behaviors and 5-HT system of offspring.By measuring the change of behaviors to find the possible pathophysiological mechanism of prenatal fluoxetine exposure,so as to provide theoretical basis of antidepressant use in pregnancy.Methods:Healthy adult rats were mated overnight(1 male and 3 females per cage)at 9:00 pm.And gestational day 0(GD 0)was determined through vaginal smear and the presence of spermatozoids.Dams were housed singly after pregnancy and randomly divided into experimental group and control group.From GD11 until birth(postnatal day(PND)1)dams were injected subcutaneously daily with 12 mg/kg fluoxetine(experimental group)or with equal volumes of normal saline(control group).At delivery day,marked as PND1,after weaning(PND 21),pups were maintained in the same environmental conditions described above and were housed separated according to sex.In this study,developmental index and behaviors were measured in different time,and 5-HT levels in prefrontal cortex and raphe nucleus were detected by ELISA,TPH and SERT levels in prefrontal cortex and raphe nucleus were detected by western blot and IF.Results:1.The effects of prenatal fluoxetine exposure on physical development of offspring1.1 Weight:the weight were delayed in fluoxetine group,no matter male and female offspring(P<0.05).1.2 Fur length:the fur length were delayed in fluoxetine group,no matter male and female offspring(P<0.05).1.3 Eye opening:there were no significant differences in eye opening between fluoxetine group and control group,no matter male and female offspring(P>0.05).1.4 Incisor eruption:there were no significant differences in incisor eruption between fluoxetine group and control group,no matter male and female offspring(P>0.05).2.The effects of prenatal fluoxetine exposure on neurological development of offspring2.1 Cliff avoidance:in male offspring,significant difference were found in cliff avoidance between fluoxetine group and control group at 6d;there were no significant differences in female offspring(P>0.05).2.2 Righting reflex:in male offspring,significant differences were found in righting reflex between fluoxetine group and control group at 4d?5d?6d?7d(P<0.05);in female offspring,there were significant differences in righting reflex between fluoxetine group and control group at 3d?4d?6d?7d(P<0.05).2.3 Buried food pellet test:in male offspring,the time of finding the food pellet in fluoxetine were increased at 27d(P<0.05);there were no significant difference in female offspring(P>0.05).3.The effects of prenatal fluoxetine exposure on upper limb movement of offspring3.1 Free suspension test:in male offspring,the duration of free suspension were reduced in fluoxetine group at 14d(P<0.05);in female offspring,the duration of suspension were reduced in fluoxetine group at 14d?18d?20d(P<0.05).4.The effects of prenatal fluoxetine exposure on anxiety-like behavior and social behavior4.1 Open field test:in male offspring,the time spent in centre areas in fluoxetine group were reduced(P<0.05),there were no significant difference in female offspring(P>0.05).4.2 Social behavior:in male offspring,the distance walked in the compartment containing a stranger rat in fluoxetine group were reduced(P<0.05),there were no significant difference in female offspring(P>0.05).5.The effects of prenatal fluoxetine exposure on the level of 5-HT?SERT and TPH5.1 In male offspring,the levels of 5-HT in prefrontal cortex were decreased in fluoxetine group at 7d and 35d(P<0.05);the levels of SERT in prefrontal cortex were decreased in fluoxetine group at 35d(P<0.05);the levels of TPH in prefrontal cortex were increased in fluoxetine group at 7d and 35d(P<0.05);5.2 There were no significant differences in female offspring(P>0.05).Conclusion(s):1.Prenatal fluoxetine exposure had significant impact on growth and development and behaviors,lead to austisic behavior in offspring,especially in male offspring.2.Prenatal fluoxetine exposure might influence the function of 5-HT system in male offspring.It might be the reason of abnormal physicial development and behaviors in male offspring.