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% O(2), 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.