Consequences of In Utero Caffeine Exposure on Respiratory Output in Normoxic and Hypoxic Conditions and Related Changes of Fos Expression: A Study on Brainstem-Spinal Cord Preparations Isolated From Newborn Rats

Abstract

Several aspects of the central regulation of respiratory control have been investigated on brainstem-spinal cord preparations isolated from newborn rats whose dam was given 0.02% caffeine in water as drinking fluid during the whole period of pregnancy. Analysis of the central respiratory drive estimated by the recording of C4 ventral root activity was correlated to Fos pontomedullary expression. Under normoxic conditions, preparations obtained from the caffeine-treated group of animals displayed a higher respiratory frequency than observed in the control group (9.2 Ϯ 0.5 versus 7.2 Ϯ 0.6 burst/min). A parallel Fos detection tends to indicate that the changes of the respiratory rhythm may be due to a decrease in neuronal activity of medullary structures such as the ventrolateral subdivision of the solitary tract, the area postrema, and the nucleus raphe obscurus. Under hypoxic conditions, the preparations displayed a typical hypoxic respiratory depression associated with changes in the medullary Fos expression pattern. In addition, the hypoxic respiratory depression is clearly emphasized after in utero exposure to caffeine and coincides with an increased Fos expression in the area postrema and nucleus raphe obscurus, two structures in which it is not increased in the absence of caffeine. Taken together, these results support the idea that in utero caffeine exposure could affect central respiratory control. Caffeine, which belongs to the methylxanthine family, is commonly ingested in various beverages such as coffee, tea, or cola drink (1). It interacts with adenosine neuronal transmitter system as an A 1 and A 2A receptor antagonist (2) and has been shown to alter the adenosinergic transmission upon chronic administration (3-5).In rats, a positive correlation has been established between exposure to caffeine during gestation and a reduction of the fetal cerebral weight (6). Such an observation could lead to propose that caffeine modifies maturational neuronal processes. Moreover, various studies reported that a sustained maternal caffeine intake induces harmful physiologic effects on human newborns (for review, see 7). Among these effects, respiratory perturbations have been described (8 -10). Nevertheless, the existence of a relation between exposure to caffeine during pregnancy and the occurrence of respiratory perturbations in

Developmental Consequences of Fetal Exposure to Drugs: What We Know and What We Still Must Learn

“…Gressens et al (2001) have documented caffeine-induced acceleration of the evagination of neuroepithelium into telencephalic vesicles (Sahir et al, 2000) and upregulation of sonic hedgehog (Sahir et al, 2004). Gestational caffeine also downregulates central adenosine receptors (Leon et al, 2005;Lorenzo et al, 2010), reduces NMDA antagonist-induced locomotor activity (da Silva et al, 2005), and affects respiratory control (Bodineau et al, 2003;Saadani-Makki et al, 2004). Cognitive and motor deficits have also been reported in adult rodents exposed in caffeine during gestation and/or early postnatal life (Bjorklund et al, 2008;Soellner et al, 2009), although some impairments may be paradigm specific (Soellner et al, 2009).…”

Níveis plasmáticos de cafeína no cordão umbilical e apneia da prematuridade

“…22 Under conditions of normoxia, animals treated with caffeine presented higher breathing frequency than a control group, and under conditions of hypoxia, the resulting respiratory depression was emphasized by intrauterine exposure to caffeine. 22,23 Such data are in agreement with the tachypnea found in neonates of women who reported an important consumption of caffeine during pregnancy.…”

“…22 Under conditions of normoxia, animals treated with caffeine presented higher breathing frequency than a control group, and under conditions of hypoxia, the resulting respiratory depression was emphasized by intrauterine exposure to caffeine. 22,23 Such data are in agreement with the tachypnea found in neonates of women who reported an important consumption of caffeine during pregnancy. 24 Preterm infants with birth weight of 500 to 1,250 g treated with caffeine during the first 10 days have a reduced rate of bronchopulmonary dysplasia, and present a better neurodevelopmental outcome at 18 to 21 months than a control group.…”

The effects of prenatal exposure to methylxanthines

“…Hence, this analysis has allowed a positive correlation between the alterations in RF and changed neuronal activity in both the medial parabrachial nucleus and the ventrolateral reticular neurons to be found. In addition, the analysis of consequences of in utero caffeine exposure on respiratory output based on C4 ventral root activity and its correlation with c-fos expression has also been extended to normoxic and hypoxic conditions (Bodineau et al 2003). Interestingly, in rats ponto-medullary respiratory disturbances caused by in utero caffeine exposure can be prevented by the presence of caffeine in the milk ).…”