Picard N, Guénin S, Larnicol N, Perrin Y
DMAG, Université de Picardie Jules Verne, Amiens, 80036, France.
Neuroscience. 2008 Oct 15;156(3):630-9. doi: 10.1016/j.neuroscience.2008.07.026. Epub 2008 Jul 25.
Caffeine is a widely used psychostimulant freely crossing the placental barrier. At the doses usually absorbed, it acts as an antagonist of both A1 and A2A adenosine receptors. Pregnant women are generally not advised to limit their caffeine consumption and thus expose their progeny to the drug during the whole of gestation and lactation. The possibility that such caffeine exposure may have long-term consequences on brain development has led to several behavioral investigations on animal models. Despite the crucial role played by adenosine receptor systems in neonatal breathing control, few studies in vitro have been concerned with the consequences of maternal caffeine absorption on breathing, and none in the unrestrained intact animal. The present investigation analyzed the influence of caffeine exposure via placental and milk transfer on resting ventilation and on the response to moderate alveolar hypoxia of 0 to 2-day-old newborn rat (P0-P2) together with the possible underlying mechanisms. Dams absorbed caffeine (46+/-3 mg/kg/day) via drinking fluid (0.2 g/L) throughout gestation, in conditions mimicking moderate human consumption. Caffeine exposure did not significantly affect basal respiratory parameters. In contrast, it attenuated both the early increase and the secondary decrease in ventilation triggered by moderate alveolar hypoxia (11% O2 inhaled). The abolition of Fos protein expression evoked by hypoxia suggested that caffeine exposure may decrease the activity of O2-sensing peripheral chemoreceptor pathway. From real-time PCR data, those functional alterations were associated to increases in A2A adenosine receptor and alpha2 GABA(A) receptor subunit mRNAs in the medulla. This indicates that, even at moderate doses, maternal caffeine consumption may induce a series of subtle developmental alterations that may affect modulation of breathing control in the neonate in pathological situations such hypoxia.
咖啡因是一种广泛使用的精神兴奋剂，可自由穿过胎盘屏障。在通常吸收的剂量下，它作为A1和A2A腺苷受体的拮抗剂起作用。一般不建议孕妇限制咖啡因的摄入量，因此在整个妊娠期和哺乳期，她们的后代都会接触到这种药物。这种咖啡因暴露可能对大脑发育产生长期影响的可能性，已引发了对动物模型的多项行为学研究。尽管腺苷受体系统在新生儿呼吸控制中起着关键作用，但很少有体外研究关注母体吸收咖啡因对呼吸的影响，在不受限制的完整动物中则没有相关研究。本研究分析了通过胎盘和乳汁传递接触咖啡因对0至2日龄新生大鼠（P0 - P2）静息通气以及对中度肺泡低氧反应的影响，以及可能的潜在机制。在模拟适度人类摄入量的条件下，母鼠在整个妊娠期通过饮用含咖啡因的液体（0.2 g/L，46±3 mg/kg/天）吸收咖啡因。咖啡因暴露并未显著影响基础呼吸参数。相比之下，它减弱了由中度肺泡低氧（吸入11% O2）引发的通气早期增加和继发性降低。低氧引起的Fos蛋白表达的消除表明，咖啡因暴露可能会降低氧敏感外周化学感受器途径的活性。根据实时PCR数据，这些功能改变与延髓中A2A腺苷受体和α2 GABA(A)受体亚基mRNA的增加有关。这表明，即使在中等剂量下，母体摄入咖啡因也可能诱导一系列细微的发育改变，这些改变可能会在诸如低氧等病理情况下影响新生儿呼吸控制的调节。
