Alteration of carotid body chemoreflexes after neonatal intermittent hypoxia and caffeine treatment in rat pups

In human neonates, caffeine therapy for apnoea of prematurity, especially when associated with hypoxemia, is maintained for several weeks after birth. In the present study, we used newborn rats and whole-body plethysmography to test whether chronic exposure to neonatal caffeine treatment (NCT), alone or combined with neonatal intermittent hypoxia (n-IH) alters: (1) baseline ventilation and response to hypoxia (12% O2, 20 min); and (2) response to acute i.p. injection of caffeine citrate (20 mg/kg) or domperidone, a peripheral dopamine D2 receptor antagonist (1 mg/kg). Four groups of rats were studied as follows: raised under normal conditions with daily gavage with water (NWT) or NCT, or exposed to n-IH (n-IH + NWT and n-IH + NCT) from postnatal days 3 to 12. In n-IH + NCT rats, baseline ventilation was higher than in the other groups. Caffeine or domperidone enhanced baseline ventilation only in NWT and n-IH + NWT rats, but neither caffeine nor domperidone affected the hypoxic ventilatory response in these groups. In n-IH + NWT rats, the response during the early phase of hypoxia (<10 min) was higher than in other groups. During the late response phase to hypoxia (20 min), ventilation was lower in n-IH + NWT and n-IH + NCT rats compared to NWT or NCT, and were not affected by caffeine or domperidone injection. NCT or caffeine injection decreased baseline apnoea frequency in all groups. These data suggest that chronic exposure to NCT alters both carotid body dopaminergic and adenosinergic systems and central regulation of breathing under baseline conditions and in response to hypoxia.