Boulle Fabien, Pawluski Jodi L, Homberg Judith R, Machiels Barbie, Kroeze Yvet, Kumar Neha, Steinbusch Harry W M, Kenis Gunter, van den Hove Daniel L A
School for Mental Health and Neuroscience (MHeNS), Maastricht University, European Graduate School of Neuroscience (EURON), Universiteitssingel 50, P.O. box 616, 6200, MD, Maastricht, The Netherlands; Center for Psychiatry and Neuroscience, INSERM, U894, University Pierre and Marie Curie, Paris, France.
School for Mental Health and Neuroscience (MHeNS), Maastricht University, European Graduate School of Neuroscience (EURON), Universiteitssingel 50, P.O. box 616, 6200, MD, Maastricht, The Netherlands; University of Liege, GIGA-Neurosciences, 1 avenue de l'Hôpital (Bat. B36), B-4000 Liège, Belgium.
Horm Behav. 2016 Apr;80:47-57. doi: 10.1016/j.yhbeh.2016.01.017. Epub 2016 Feb 1.
A growing number of infants are exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. Perinatal exposure to SSRI medications alter neuroplasticity and increase depressive- and anxiety-related behaviors, particularly in male offspring as little work has been done in female offspring to date. The long-term effects of SSRI on development can also differ with previous exposure to prenatal stress, a model of maternal depression. Because of the limited work done on the role of developmental SSRI exposure on neurobehavioral outcomes in female offspring, the aim of the present study was to investigate how developmental fluoxetine exposure affects anxiety and depression-like behavior, as well as the regulation of hippocampal brain-derived neurotrophic factor (BDNF) signaling in the hippocampus of adult female offspring. To do this female Sprague-Dawley rat offspring were exposed to prenatal stress and fluoxetine via the dam, for a total of four groups of female offspring: 1) No Stress+Vehicle, 2) No Stress+Fluoxetine, 3) Prenatal Stress+Vehicle, and 4) Prenatal Stress+Fluoxetine. Primary results show that, in adult female offspring, developmental SSRI exposure significantly increases behavioral despair measures on the forced swim test, decreases hippocampal BDNF exon IV mRNA levels, and increases levels of the repressive histone 3 lysine 27 tri-methylated mark at the corresponding promoter. There was also a significant negative correlation between hippocampal BDNF exon IV mRNA levels and immobility in the forced swim test. No effects of prenatal stress or developmental fluoxetine exposure were seen on tests of anxiety-like behavior. This research provides important evidence for the long-term programming effects of early-life exposure to SSRIs on female offspring, particularily with regard to affect-related behaviors and their underlying molecular mechanisms.
越来越多的婴儿在围产期接触选择性5-羟色胺再摄取抑制剂（SSRI）药物。围产期接触SSRI药物会改变神经可塑性，并增加与抑郁和焦虑相关的行为，尤其是在雄性后代中，因为迄今为止在雌性后代中开展的研究很少。SSRI对发育的长期影响也可能因先前暴露于产前应激（一种母体抑郁模型）而有所不同。由于关于发育性SSRI暴露对雌性后代神经行为结果的作用的研究有限，本研究的目的是调查发育性氟西汀暴露如何影响成年雌性后代的焦虑和抑郁样行为，以及海马中脑源性神经营养因子（BDNF）信号的调节。为此，将雌性斯普拉-道利大鼠后代通过母鼠暴露于产前应激和氟西汀，总共分为四组雌性后代：1）无应激+赋形剂，2）无应激+氟西汀，3）产前应激+赋形剂，4）产前应激+氟西汀。主要结果表明，在成年雌性后代中，发育性SSRI暴露显著增加了强迫游泳试验中的行为绝望指标，降低了海马BDNF外显子IV mRNA水平，并增加了相应启动子处抑制性组蛋白3赖氨酸27三甲基化标记的水平。在强迫游泳试验中，海马BDNF外显子IV mRNA水平与不动时间之间也存在显著负相关。未观察到产前应激或发育性氟西汀暴露对焦虑样行为测试有影响。这项研究为生命早期暴露于SSRI对雌性后代的长期编程效应提供了重要证据，特别是在情感相关行为及其潜在分子机制方面。
