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

Abstract

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 A2A receptors (A1-R and A2A-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 A2A-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 A2A-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 A2A-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 A2A-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.