Disruption of adenosinergic modulation of ventilation at rest and during hypercapnia by neonatal caffeine in young rats: role of adenosine A₁and A_2Areceptors

Abstract

feine is commonly used to treat respiratory instabilities related to prematurity. However, the role of adenosinergic modulation and the potential long-term effects of neonatal caffeine treatment (NCT) on respiratory control are poorly understood. To address these shortcomings, we tested the following hypotheses: 1) adenosine A 1-and A2A-receptor antagonists modulate respiratory activity at rest and during hypercapnia; 2) NCT has long-term consequences on adenosinergic modulation of respiratory control. Rat pups received by gavage either caffeine (15 mg/kg) or water (control) once a day from postnatal days 3 to 12. At day 20, rats received intraperitoneal injection with vehicle, DPCPX (A 1 antagonist, 4 mg/kg), or ZM-241385 (A2A antagonist, 1 mg/kg) before plethysmographic measurements of resting ventilation, hypercapnic ventilatory response (5% CO 2), and occurrence of apneas in freely behaving rats. In controls, data show that A 2A, but not A1, antagonist decreased resting ventilation by 31% (P ϭ 0.003). A 1 antagonist increased the hypercapnic response by 60% (P Ͻ 0.001), whereas A 2A antagonist increased the hypercapnic response by 42% (P ϭ 0.033). In NCT rats, A 1 antagonist increased resting ventilation by 27% (P ϭ 0.02), but the increase of the hypercapnic response was blunted compared with controls. A 1 antagonist enhanced the occurrence of spontaneous apneas in NCT rats only (P ϭ 0.005). Finally, A 2A antagonist injected in NCT rats had no effect on ventilation. These data show that hypercapnia activates adenosinergic pathways, which attenuate responsiveness (and/or sensitivity) to CO 2 via A1 receptors. NCT elicits developmental plasticity of adenosinergic modulation, since neonatal caffeine persistently decreases ventilatory sensitivity to adenosine blockers.control of breathing; carbon dioxide chemosensitivity; ventilation; plasticity; hypercapnic ventilatory response AT BIRTH, THE RESPIRATORY control system of mammals is immature, and respiratory instabilities, such as apneas, are frequently observed (1, 43). Caffeine, an adenosine-receptor blocker, is commonly used as a respiratory stimulant in infants born prematurely to treat respiratory instabilities. However, the use of caffeine during a critical period of development is always a matter of concern given the potential impact on central nervous system maturation and respiratory functions (19). In utero chronic caffeine administration induced changes in respiratory activity (5, 28) and in Fos expression in brain stem respiratory nuclei of newborn rats (5). Exposure to caffeine during the early postnatal period enhanced the ventilatory response to hypercapnia in 20-day-old young male rats (47) and modified the distribution of adenosine A 1 receptors in respiratory nuclei of the newborn rat brain stem (23). Young rats showed the largest sensitivity to neonatal caffeine treatment (NCT), and from a developmental standpoint it has been proposed that this age group is comparable to infants (10) for which respiratory instabilities, such as apneas (42), ca...

Neonatal caffeine induces sex-specific developmental plasticity of the hypoxic respiratory chemoreflex in adult rats

“…Previous studies demonstrate that exaggerated ventilatory responses to hypoxia or hypercapnia are initiators and perpetuators of breathing instabilities, such as obstructive (64) and central sleep apneas (30). We demonstrated that neonatal caffeine increases hypoxic chemosensitivity, and we previously showed that it modifies the pattern of the hypercapnic ventilatory response (45,46). Cumulative, long-term changes of chemosensitivities due to neonatal caffeine might therefore predispose to respiratory instabilities, especially during sleep.…”

“…Before intraperitoneal injection, the solution was diluted into saline with final concentration of 1 mg/kg, 5%, and 5% for ZM241385, DMSO, and Cremophor EL, respectively. This ZM241385 concentration was sufficient to modify ventilation in freely behaving juvenile rats (46). Measurements of the hypoxic ventilatory response were identical to study 1.…”

“…ZM241385 was first diluted into DMSO and Cremophor EL (46). Before intraperitoneal injection, the solution was diluted into saline with final concentration of 1 mg/kg, 5%, and 5% for ZM241385, DMSO, and Cremophor EL, respectively.…”

“…This effect changed with maturation since, in adult rats, NCT no longer augments the magnitude of the hypercapnic ventilatory response but modifies its pattern (tidal volume vs. frequency) in males but not in females (45). Subsequent results showed that NCT decreases ventilatory responsiveness to selective adenosine receptor antagonists, thereby suggesting that changes in adenosinergic neurotransmission are involved (46). However, our understanding of the persistent effects of NCT on respiratory control development remains limited since other functional and mechanistic aspects of this system have not been explored.…”

Sleep fragmentation attenuates the hypercapnic (but not hypoxic) ventilatory responses via adenosine A1 receptors in awake rats

“…One recent study demonstrated that systemic injection of the A1 receptor antagonist DPCPX (4 mg/kg, i.p.) increased HCVR by 60% in awake 20-day-old rats (Montandon et al, 2007). In the present study, however, the injection of 8-CPT (2.5 mg/kg, i.p.)…”