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

Abstract

Caffeine is widely used to treat apneas of prematurity during the neonatal period; however, the potential consequences of administering a neonatal caffeine treatment (NCT) during a critical period for respiratory control development are unknown. The present study therefore determined whether NCT in rats alters the hypoxic respiratory chemoreflex measured at adulthood. Newborn rats received either caffeine (15 mg/kg) or water (control) each day from postnatal day 3 to 12. The ventilatory response to a hypoxic challenge (inspired O(2) fraction = 0.12) was first evaluated in awake adult female and male rats using whole body plethysmography. Results showed that NCT increased the initial phase of the breathing frequency response to hypoxia in males only. This result was confirmed in anesthetized and artificially ventilated adult male rats where NCT also increased the phrenic burst frequency response to hypoxia. RT-PCR assessment of mRNA encoding for adenosine A(1A) and A(2A) receptors, dopamine D(2) receptors, and tyrosine hydroxylase in the rat carotid bodies showed that NCT enhanced mRNA expression levels of adenosine A(2A), dopamine D(2) receptors, and tyrosine hydroxylase of males but not females. Subsequent experiments on awake male rats showed that injection of the adenosine A(2A) receptor antagonist ZM2413855 (1 mg/kg ip) before ventilatory measurements abolished, in NCT rats, the enhanced respiratory frequency response observed during the early phase of hypoxia. We propose that NCT elicits a sex-specific increase in the hypoxic respiratory chemoreflex, which is related, at least partially, to an enhancement in adenosine A(2A) receptors in the rat carotid body.

Influence of juvenile housing conditions on the ventilatory, thermoregulatory, and endocrine responses to hypoxia of adult male rats

“…Exposure to stress during early life has long-lasting consequences on respiratory control development (9,30,39). While the first 2 wk are currently viewed as a critical period for respiratory control development (1), elimination of the deleterious effects of NMS by triad housing indicates that this system remains substantially malleable well beyond this period.…”

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

“…Rats were vagotomised and artificially ventilated to control arterial blood gases. They breathed a hyperoxic (50% of oxygen) gas mixture to reduce the contribution of peripheral chemoreceptors since NCT alters the hypoxic respiratory response of anaesthetized and freely behaving adult rats (Montandon et al 2008 a ).…”

“…Critique of methods Resting ventilation was larger in NCT than in control animals across sleep/wake states, an effect mainly related to a greater tidal volume, except during non‐REM sleep where NCT rats present higher respiratory frequency. This result was unanticipated since such a difference was not observed in our previous studies performed on ‘awake’ adult animals, at least as judged by visual assessment of arousal state (Bairam et al 2008; Montandon et al 2006, 2008 a ). Moreover, tidal volume measurements reported here were generally lower than those reported in our previous studies (Montandon et al 2006, 2008 a ).…”

“…For example, neonatal caffeine treatment (NCT; 15 mg kg −1 day −1 ) in rats from postnatal days 3–12 persistently decreases ventilatory sensitivity to adenosine receptor antagonists when measured in the same animals when juveniles (Montandon et al 2007). NCT also produces a sex‐specific increase in the hypoxic respiratory chemoreflex that is related to an enhancement in adenosine A 2A receptor expression in the rat carotid body (Montandon et al 2008 a ). These findings, obtained in awake and anaesthetized rats, are relevant because male sex and disruption of chemoreflexes are common hallmarks of sleep‐disordered breathing in humans (Smith & Pacchia, 2007).…”

“…Animal preparation The effects of NCT on respiratory control were assessed in anaesthetized, vagotomised, neuromuscularly blocked, and artificially ventilated adult rats as previously described (Montandon et al 2008 a ). Accordingly, phrenic nerve activity was recorded in adult (8–12 weeks old) rats (control: n = 7; NCT: n = 7).…”