Sexually dimorphic effects of prenatal diazepam exposure on respiratory control and the monoaminergic system of neonate and young rats
Sexually dimorphic effects of prenatal diazepam exposure on respiratory control and the monoaminergic system of neonate and young rats
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DOI：
10.1007/s00424-022-02730-7
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发表时间：
2022-07-25
影响因子：
4.5
通讯作者：
Gargaglioni, Luciane H.
中科院分区：
文献类型：
--
作者：
da Silva Junior, Carlos Aparecido;Patrone, Luis Gustavo A.;Gargaglioni, Luciane H.
怀孕受到焦虑症的影响很大，可以用苯二氮卓类药物治疗，尤其是地西泮 (DZP)，它可以穿过胎盘屏障并与胎儿 GABA 能系统相互作用。我们测试了产前接触 DZP 是否会促进大鼠呼吸控制的性别特异性产后变化。我们评估了妊娠期间接受 DZP 治疗的母亲的新生 [产后 (P) 0-1 和 (P12-13)] 大鼠和幼鼠 (P21-22) 在静息条件下以及高碳酸血症 (7% CO2) 和缺氧 (10% O-2) 下的通气量 ((V) 超过点 (E)) 和耗氧量 ((V) 超过点 O-2)。我们还分析了同一年龄的脑干单胺。 DZP 暴露对雌性室内空气呼吸变量影响极小，但导致 P12-13 雄性通气不足（(V)Over dot(E)/(V)Over dot O-2 下降），持续到 P21-22。在 P0-1 和 P12-13 DZP 治疗的雌性中，高碳酸血症通气反应减弱，主要是由于潮气量 (V-T) 减少，而雄性在 P12-13 时呼吸频率 (f(R)) 降低。在缺氧情况下观察到微小变化，但在 P12-13 雄性中观察到 (V) 相对于点 (E) 的减弱。在女性脑干中，DZP 在 P0-1 时增加多巴胺浓度并降低 5-羟基吲哚-3-乙酸 (5-HIAA) 和 3,4-二羟基苯乙酸 (DOPAC)/多巴胺比率，并在 P12-13 时降低 DOPAC 浓度。在男性中，DZP 在 P0-1 时降低脑干去甲肾上腺素。我们的结果表明，产前 DZP 暴露仅在产后女性中减少 CO2 化学反射，并且不会影响两性缺氧引起的过度换气。此外，产前 DZP 在雄性和雌性大鼠的整个发育过程中以不同方式改变脑干单胺浓度。
Pregnancy is highly affected by anxiety disorders, which may be treated with benzodiazepines, especially diazepam (DZP), that can cross the placental barrier and interact with the fetal GABAergic system. We tested whether prenatal exposure to DZP promotes sex-specific postnatal changes in the respiratory control of rats. We evaluated ventilation ((V)over dot(E)) and oxygen consumption ((V)over dot O-2) in resting conditions and under hypercapnia (7% CO2) and hypoxia (10% O-2) in newborn [postnatal day (P) 0-1 and (P12-13)] and young (P21-22) rats from mothers treated with DZP during pregnancy. We also analyzed brainstem monoamines at the same ages. DZP exposure had minimal effects on room air-breathing variables in females, but caused hypoventilation (drop in (V)Over dot(E)/(V)Over dot O-2) in P12-13 males, lasting until P21-22. The hypercapnic ventilatory response was attenuated in P0-1 and P12-13 DZP-treated females mainly by a decrease in tidal volume (V-T), whereas males had a reduction in respiratory frequency (f(R)) at P12-13. Minor changes were observed in hypoxia, but an attenuation in (V)over dot(E) was seen in P12-13 males. In the female brainstem, DZP increased dopamine concentration and decreased 5-hydroxyindole-3-acetic acid (5-HIAA) and the 3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine ratio at P0-1, and reduced DOPAC concentration at P12-13. In males, DZP decreased brainstem noradrenaline at P0-1. Our results demonstrate that prenatal DZP exposure reduces CO2 chemoreflex only in postnatal females and does not affect hypoxia-induced hyperventilation in both sexes. In addition, prenatal DZP alters brainstem monoamine concentrations throughout development differently in male and female rats.