Caffeine is commonly used to treat respiratory instabilities related to prematurity. However, the role of adenosinergic modulation and the potential long term effect of neonatal caffeine treatment (NCT) on respiratory control are poorly understood. To address these shortcomings, we tested the following hypotheses: 1) Adenosine A₁ and A_2A 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 3-12. At day 20, rats received ip injection with vehicle, DPCPX (A₁ antagonist, 4 mg/kg), or ZM241385 (A_2A antagonist, 1 mg/kg) prior to plethysmographic measurements of resting ventilation, hypercapnic ventilatory response (5% CO₂), 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=0.003). A₁ antagonist increased the hypercapnic response by 60% (P<0.001), whereas A_2A antagonist increased the hypercapnic response by 42% (P=0.033). In NCT rats, A1 antagonist increased resting ventilation by 27% (P=0.02), but the increase of the hypercapnic response was blunted in comparison with controls. A₁ antagonist enhanced the occurrence of spontaneous apneas in NCT rats only (P=0.005). Finally, A_2A antagonist injected in NCT rats had no effect on ventilation. These data show that hypercapnia activates adenosinergic pathways which attenuates responsiveness (and/or sensitivity) to CO₂ via A₁ receptors. NCT elicits developmental plasticity of adenosinergic modulation, since neonatal caffeine persistently decreases ventilatory sensitivity to adenosine blockers.