Department of Physiology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland.
Department of Physiology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland.
Pharmacol Biochem Behav. 2024 Nov;244:173849. doi: 10.1016/j.pbb.2024.173849. Epub 2024 Aug 13.
Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are commonly prescribed to women during pregnancy and breastfeeding despite posing a risk of adverse cognitive outcomes and affective disorders for the child. The consequences of SSRI-induced excess of 5-HT during development for the brain neuromodulatory 5-HT system remain largely unexplored. In this study, an SSRI - fluoxetine (FLX) - was administered to C57BL/6 J mouse dams during pregnancy and lactation to assess its effects on the offspring. We found that maternal FLX decreased field potentials, impaired long-term potentiation, facilitated long-term depression and tended to increase the density of 5-HTergic fibers in the medial prefrontal cortex (mPFC) of female but not male adolescent offspring. These effects were accompanied by deteriorated performance in the temporal order memory task and reduced sucrose preference with no change in marble burying behavior in FLX-exposed female offspring. We also found that maternal FLX reduced the axodendritic tree complexity of 5-HT dorsal raphe nucleus (DRN) neurons in female but not male offspring, with no changes in the excitability of DRN neurons of either sex. While no effects of maternal FLX on inhibitory postsynaptic currents (sIPSCs) in DRN neurons were found, we observed a significant influence of FLX exposure on kinetics of spontaneous excitatory postsynaptic currents (sEPSCs) in DRN neurons. Finally, we report that no changes in field potentials and synaptic plasticity were evident in the mPFC of the offspring after maternal exposure during pregnancy and lactation to a new antidepressant, vortioxetine. These findings show that in contrast to the mPFC, long-term consequences of maternal FLX exposure on the structure and function of DRN 5-HT neurons are mild and suggest a sex-dependent, distinct sensitivity of cortical and brainstem neurons to FLX exposure in early life. Vortioxetine appears to exert fewer side effects with regards to the mPFC when compared with FLX.
选择性 5-羟色胺（5-HT）再摄取抑制剂（SSRIs）在怀孕期间和哺乳期通常被开给女性，但会给孩子带来认知障碍和情感障碍的风险。SSRI 在发育过程中引起的 5-HT 过多对大脑神经调质 5-HT 系统的影响在很大程度上仍未得到探索。在这项研究中，我们在妊娠和哺乳期向 C57BL/6J 母鼠给予 SSRI - 氟西汀（FLX），以评估其对后代的影响。我们发现，母鼠 FLX 降低了场电位，损害了长时程增强，促进了长时程抑制，并倾向于增加雌性但不是雄性青春期后代内侧前额叶皮质（mPFC）中 5-HT 能纤维的密度。这些影响伴随着在时间顺序记忆任务中的表现恶化和蔗糖偏好减少，而在暴露于 FLX 的雌性后代中，大理石埋藏行为没有变化。我们还发现，母鼠 FLX 降低了雌性后代但不降低雄性后代 5-HT 中脑背侧缝核（DRN）神经元的轴突树突复杂性，而对两性 DRN 神经元的兴奋性没有影响。虽然没有发现母鼠 FLX 对 DRN 神经元抑制性突触后电流（sIPSCs）的影响，但我们观察到 FLX 暴露对 DRN 神经元自发性兴奋性突触后电流（sEPSCs）动力学有显著影响。最后，我们报告说，在妊娠和哺乳期母体暴露于新型抗抑郁药文拉法辛后，mPFC 中的场电位和突触可塑性没有变化。这些发现表明，与 mPFC 相反，母鼠 FLX 暴露对 DRN 5-HT 神经元结构和功能的长期影响是轻微的，并表明皮质和脑干神经元对生命早期 FLX 暴露的敏感性存在性别依赖性差异。与 FLX 相比，文拉法辛似乎对 mPFC 的副作用较少。
