Neonatal caffeine treatment up-regulates adenosine receptors in brainstem and hypothalamic cardio-respiratory related nuclei of rat pups.

While neonatal caffeine treatment is commonly used to alleviate apnea of prematurity in neonates and to improve neurological outcomes, its effects on adenosine A₁ and A(2A) receptors (A₁-R and A(2A)-R) are poorly known. We hypothesized that the central pharmacological action of caffeine is mediated by modification of the postnatal development of the adenosinergic system during a critical period. On postnatal days 2-6 (P2-P6) two groups of newborn rats were orally administered water plus glucose and/or caffeine at therapeutic doses to mimic the clinical use of caffeine in human neonates. Cardio-respiratory parameters were measured and the presence of A₁-R and A(2A)-R and c-Fos protein was identified immunohistochemically in animals sacrificed from P2 to P11. % Haemoglobin saturation, and hearth and breath rates were significantly increased in caffeine-treated group (P5-P6). Significant differences were identified in the relative gene expression of A₁-R and A(2A)-R, with an increase of A₁-R labeling in the anterior hypothalamic area, ventromedial hypothalamic nucleus, parabrachial complex and ventrolateral medulla of the caffeine-treated group at P6. A moderate increase in A(2A)-R labeling was observed in ponto-medullary nuclei and other hypothalamic areas. An increase in c-Fos-positive labeled cells was found in the caffeine-treated group at P5-P6 within the same areas described above, with the most clear-cut increase seen in the arcuate nucleus. Indeed, increased A₁-R and A(2A)-R gene expression was observed in both the brainstem and hypothalamus at P5. Up-regulation of adenosinergic maturation in central cardio-respiratory areas in caffeine-treated neonatal rats could explain the pharmacological effects of caffeine observed in premature infants.