Porcu Patrizia, Lallai Valeria, Locci Andrea, Catzeddu Sandro, Serra Valeria, Pisu Maria Giuseppina, Serra Mariangela, Dazzi Laura, Concas Alessandra
Neuroscience Institute, National Research Council of Italy (CNR), Cittadella Universitaria, Monserrato, 09042, Cagliari, Italy.
Department of Life and Environment Sciences, Section of Neuroscience and Anthropology, University of Cagliari, Cagliari, Italy.
Psychopharmacology (Berl). 2017 Mar;234(5):749-760. doi: 10.1007/s00213-016-4511-7. Epub 2016 Dec 24.
Allopregnanolone plays a role in the stress response and homeostasis. Alterations in the estrogen milieu during the perinatal period influence brain development in a manner that persists into adulthood. Accordingly, we showed that a single administration of estradiol benzoate (EB) on the day of birth decreases brain allopregnanolone concentrations in adult female rats.
We examined whether the persistent decrease in allopregnanolone concentrations, induced by neonatal EB treatment, might affect sensitivity to stress during adulthood.
Female rats were treated with 10 μg of EB or vehicle on the day of birth. During adulthood, the response to acute foot shock stress was assessed by measuring changes in brain allopregnanolone and corticosterone levels, as well as extracellular dopamine output in the medial prefrontal cortex (mPFC).
Neonatal EB treatment enhanced stress-stimulated allopregnanolone levels in the hypothalamus, as well as extracellular dopamine output in the mPFC; this latest effect is reverted by subchronic progesterone treatment. By contrast, neonatal EB treatment did not alter stress-induced corticosterone levels, sensitivity to hypothalamic-pituitary-adrenal (HPA) axis negative feedback, or abundance of glucocorticoid and mineralocorticoid receptors.
The persistent decrease in brain allopregnanolone concentrations, induced by neonatal EB treatment, enhances stress-stimulated allopregnanolone levels and extracellular dopamine output during adulthood. These effects are not associated to an impairment in HPA axis activity. Heightened sensitivity to stress is a risk factor for several neuropsychiatric disorders; these results suggest that exposure to estrogen during development may predispose individuals to such disorders.
别孕烯醇酮在应激反应和体内平衡中发挥作用。围产期雌激素环境的改变会以持续至成年期的方式影响大脑发育。因此，我们发现出生当天单次注射苯甲酸雌二醇（EB）会降低成年雌性大鼠大脑中的别孕烯醇酮浓度。
我们研究了新生期EB处理诱导的别孕烯醇酮浓度持续降低是否会影响成年期对应激的敏感性。
雌性大鼠在出生当天接受10μg EB或溶剂处理。成年期，通过测量大脑别孕烯醇酮和皮质酮水平的变化以及内侧前额叶皮质（mPFC）细胞外多巴胺的释放来评估对急性足部电击应激的反应。
新生期EB处理可增强下丘脑应激刺激的别孕烯醇酮水平以及mPFC细胞外多巴胺的释放；亚慢性孕酮处理可逆转这一最新效应。相比之下，新生期EB处理并未改变应激诱导的皮质酮水平、下丘脑-垂体-肾上腺（HPA）轴负反馈敏感性或糖皮质激素和盐皮质激素受体的丰度。
新生期EB处理诱导的大脑别孕烯醇酮浓度持续降低会增强成年期应激刺激的别孕烯醇酮水平和细胞外多巴胺的释放。这些效应与HPA轴活性受损无关。对应激的敏感性增强是几种神经精神疾病的危险因素；这些结果表明，发育过程中接触雌激素可能使个体易患此类疾病。
