Caffeine in the neonatal period induces long‐lasting changes in sleep and breathing in adult rats

Abstract

Caffeine is commonly used clinically to treat apnoeas and unstable breathing associated with premature birth. Caffeine antagonizes adenosine receptors and acts as an efficient respiratory stimulant in neonates. Owing to its persistent effects on adenosine receptor expression in the brain, neonatal caffeine administration also has significant effects on maturation of the respiratory control system. However, since adenosine receptors are critically involved in sleep regulation, and sleep also modulates breathing, we tested the hypothesis that neonatal caffeine treatment disrupts regulation of sleep and breathing in the adult rat. Neonatal caffeine treatment (15 mg kg −1 day −1 ) was administered from postnatal days 3-12. At adulthood (8-10 weeks old), sleep and breathing were measured with a telemetry system and whole-body plethysmography respectively. In adult rats treated with caffeine during the neonatal period, sleep time was reduced, sleep onset latency was increased, and non-rapid eye movement (non-REM) sleep was fragmented compared to controls. Ventilation at rest was higher in caffeine-treated adult rats compared to controls across sleep/wake states. Hypercapnic ventilatory responses were significantly reduced in caffeine-treated rats compared to control rats across sleep/wake states. Additional experiments in adult anaesthetized rats showed that at similar levels of arterial blood gases, phrenic nerve activity was enhanced in caffeine-treated rats. This study demonstrates that administration of caffeine in the neonatal period alters respiratory control system activity in awake and sleeping rats, as well as in the anaesthetized rats, and also has persistent disrupting effects on sleep that are apparent in adult rats.

Long-Term Effects of Caffeine Therapy for Apnea of Prematurity on Sleep at School Age

“…Rats who received neonatal caffeine have sleep disruption as adults, including increased sleep latency, decreased sleep time, and sleep fragmentation (13). Furthermore, long-term animal studies have shown that rats who received methylxanthines during early life had increased resting ventilation and blunted hypercapnic ventilatory responses during adulthood (13). Thus, animal studies suggest that neonatal caffeine administration can lead to permanent abnormalities in sleep regulation and ventilatory control.…”

“…In rodents, caffeine administration during early life results in permanent changes in adenosine receptor function during adulthood (30). Rats who received neonatal caffeine have sleep disruption as adults, including increased sleep latency, decreased sleep time, and sleep fragmentation (13). Furthermore, long-term animal studies have shown that rats who received methylxanthines during early life had increased resting ventilation and blunted hypercapnic ventilatory responses during adulthood (13).…”

“…Methylxanthines are also known to modulate ventilatory control, which is a determinant of upper airway collapsibility (12). Animal studies have shown that neonatal caffeine administration can chronically affect ventilation during adulthood, resulting in increased baseline ventilation and a decreased ventilatory response to hypercapnia (13). Children who were born prematurely have an elevated risk of developing OSAS (14), but it is not known whether this is due, at least in part, to the effect of neonatal caffeine exposure on ventilatory control.…”

Methylmercury: A potential environmental risk factor contributing to epileptogenesis

“…However, chronic exposure to these factors may act as risk modifiers to alter the susceptibility and to accelerate the onset of a disease or disorder caused by other pathogens or genetic defects (for review, see Sorg and Prasad, 1997; Bell et al, 1997a, 1997b; Gilbert, 2001). In some cases, effects of early developmental environmental exposure may not be expressed until later in adult life (Vathy 2001; Landrigan et al, 2005; Doherty et al, 2009; Montandon et al, 2009; Fox et al, 2010). For instance, prenatal methamphetamine or morphine exposure affects the susceptibility of adult rats to convulsive agent-induced seizures (Vathy 2001; Šlamberová et al, 2008).…”

Markers for severity of illness associated with decreased snoring in toddlers born ELGA

“…A rat study by Montandon in 2009 demonstrated that neonatal exposure to caffeine resulted in altered respiratory control both while awake and during sleep which persisted into rat adulthood (20). Interestingly, caffeine-exposed rats demonstrated an increase in baseline ventilation during sleep and wake cycles, as well as a disturbed sleep structure.…”