Graney Paige L, Chen Michael Y, Wood Ruth I, Wagner Christine K
Department of Psychology & Center for Neuroscience Research, University at Albany, Albany, NY, USA.
Department of Integrative Anatomical Sciences, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
Pharmacol Biochem Behav. 2024 Dec;245:173886. doi: 10.1016/j.pbb.2024.173886. Epub 2024 Oct 3.
The synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC), is administered to pregnant individuals with the intention of reducing preterm birth. Although there is evidence that 17-OHPC is likely transferred from mother to fetus, there is little information regarding the potential effects of 17-OHPC administration on behavioral and neural development in offspring. Neonatal 17-OHPC exposure disrupts the development of the mesocorticolimbic dopaminergic pathway and associated behaviors in rats. 17-OHPC exposure altered dopaminergic innervation of prelimbic medial prefrontal cortex (mPFC) in neonates and adolescents and altered performance in measures of decision-making, set-shifting, and reversal-learning tasks. The present study tested the effects of developmental 17-OHPC exposure on numerous cognitive behaviors mediated by the mesocorticolimbic dopaminergic system, such as decision-making in a delay discounting task, latent inhibition following conditioned taste aversion (CTA), and spatial memory in the Morris Water Maze (MWM). The present work also aimed to further investigate response omissions in rats exposed to 17-OHPC during development and the potential role of dopamine D2 receptor in altering omissions in a delay discounting task. 17-OHPC exposure rendered rats less sensitive to an Eticlopride-induced increase in omissions in a delay discounting task when compared to controls. Quinpirole flattened the discount curve in both groups but did not significantly affect omissions in 17-OHPC-exposed or control rats. Following CTA, sucrose-pre-exposed 17-OHPC-exposed rats demonstrated decreased latent inhibition when compared to controls. In Morris Water Maze testing, 17-OHPC-exposed rats did not differ from controls after the first day of testing or during probe testing. These results suggest that exposure to 17-OHPC altered aspects of decision-making and latent inhibition in adult male rats, without affecting performance in a measure of spatial learning and memory. Further, the insensitivity of 17-OHPC-exposed males to an Eticlopride-induced increase in omissions suggests a dysfunction in the D2 receptor following exposure to this clinically used synthetic progestin.
合成孕激素己酸17α-羟孕酮（17-OHPC）被用于孕妇，目的是减少早产。虽然有证据表明17-OHPC可能从母亲转移至胎儿，但关于施用17-OHPC对后代行为和神经发育的潜在影响的信息却很少。新生大鼠暴露于17-OHPC会破坏中脑边缘多巴胺能通路的发育及相关行为。17-OHPC暴露改变了新生大鼠和青少年前边缘内侧前额叶皮质（mPFC）的多巴胺能神经支配，并改变了决策、定势转换和逆向学习任务测量中的表现。本研究测试了发育过程中暴露于17-OHPC对由中脑边缘多巴胺能系统介导的多种认知行为的影响，如延迟折扣任务中的决策、条件性味觉厌恶（CTA）后的潜伏抑制以及莫里斯水迷宫（MWM）中的空间记忆。本研究还旨在进一步调查发育过程中暴露于17-OHPC的大鼠的反应遗漏情况，以及多巴胺D2受体在改变延迟折扣任务中的遗漏方面的潜在作用。与对照组相比，17-OHPC暴露使大鼠在延迟折扣任务中对埃替必利诱导的遗漏增加不太敏感。喹吡罗使两组的折扣曲线变平，但对17-OHPC暴露组或对照组的遗漏没有显著影响。CTA后，与对照组相比，预先接触蔗糖的17-OHPC暴露大鼠表现出潜伏抑制降低。在莫里斯水迷宫测试中，17-OHPC暴露大鼠在测试第一天后或探测测试期间与对照组没有差异。这些结果表明，暴露于17-OHPC会改变成年雄性大鼠的决策和潜伏抑制方面，而不影响空间学习和记忆测量中的表现。此外，17-OHPC暴露雄性大鼠对埃替必利诱导的遗漏增加不敏感，表明暴露于这种临床使用的合成孕激素后D2受体功能失调。
