The synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC), is administered to women at risk for preterm birth during a critical period of fetal development for mesocortical pathways. Yet, little information is available regarding the potential effects of 17-OHPC on the developing fetal brain. In rat models, the mesocortical serotonin pathway is sensitive to progestins. Progesterone receptor (PR) is expressed in layer 3 pyramidal neurons of medial prefrontal cortex (mPFC) and in serotonergic neurons of the dorsal raphe. The present study tested the hypothesis that exposure to 17-OHPC during development disrupts serotonergic innervation of the mPFC in adolescence and impairs behavior mediated by this pathway in adulthood. Administration of 17-OHPC from postnatal days 1–14 decreased the density of SERT-ir fibers within superficial and deep layers and decreased the density of synaptophysin-ir boutons in all layers of prelimbic mPFC at postnatal day 28. In addition, rats exposed to 17-OHPC during development were less likely to make impulsive choices in the Delay Discounting task, choosing the larger, delayed reward more often than controls at moderate delay times. Interestingly, 17-OHPC exposed rats were more likely to fail to make any choice (i.e., increased omissions) compared to controls at longer delays, suggesting disruptions in decision-making. These results suggest that further investigation is warranted in the clinical use of 17-OHPC to better inform a risk/benefit analysis of progestin use in pregnancy.

中文翻译：

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发育过程中接触合成孕激素 17α-羟基孕酮己酸酯会扰乱中皮质血清素途径并改变大鼠的冲动决策


合成黄体酮 17α-羟基黄体酮己酸酯 (17-OHPC) 在胎儿中皮质通路发育的关键时期给予有早产风险的女性。然而，关于 17-OHPC 对胎儿大脑发育的潜在影响的信息很少。在大鼠模型中，中皮质血清素途径对孕激素敏感。黄体酮受体 (PR) 在内侧前额皮质 (mPFC) 的第 3 层锥体神经元和中缝背侧的血清素能神经元中表达。本研究检验了以下假设：发育过程中暴露于 17-OHPC 会扰乱青春期 mPFC 的血清素神经支配，并损害成年期由该途径介导的行为。出生后第 1-14 天给予 17-OHPC 降低了浅层和深层内 SERT-ir 纤维的密度，并降低了出生后第 28 天前边缘 mPFC 所有层中突触素-ir 纤维的密度。此外，暴露于开发期间的 17-OHPC 在延迟贴现任务中不太可能做出冲动选择，与适度延迟时间的对照相比，更频繁地选择较大的延迟奖励。有趣的是，与对照组相比，暴露于 17-OHPC 的大鼠在较长的延迟时间内更有可能无法做出任何选择（即遗漏增加），这表明决策受到干扰。这些结果表明，有必要在 17-OHPC 的临床使用中进行进一步的研究，以便更好地为怀孕期间使用孕激素的风险/效益分析提供信息。