Neonatal caffeine exposure alters developmental sensitivity to adenosine receptor ligands

Studies were done to determine whether the apparent changes in behavioral sensitivity to adenosine receptor ligands that occur with age and with neonatal caffeine exposure were due to a change in sensitivity of the receptor for the ligand or to a more fundamental change in the receptor. Using an animal model that mimics the brain developmental period and level of caffeine exposure in human premature neonates treated with caffeine for apnea of prematurity, behavioral and neurochemical investigations were undertaken. The locomotor responses to acute challenge with caffeine (15, 30 and 60 mg/kg) and with D-phenylisopropyladenosine (D-PIA) (0.038 and 0.38 mg/kg), an adenosine receptor agonist, were measured in control and neonatally caffeine-exposed rats at 12, 15, 18, and 28 days of age. The dissociation constants (Kd) and maximal binding densities (Bmax) for agonist binding at the adenosine A1 receptor site were determined over a similar time period. Caffeine displacement of an adenosine A1 agonist was also measured to examine in vitro sensitivity to caffeine as a function of age and neonatal caffeine exposure. Our studies demonstrated that the differential responses to adenosine receptor ligands seen as a function of both age and neonatal caffeine exposure could not be overcome by merely increasing the doses of ligand administered. In addition, the results of the binding studies indicated that changes in the adenosine receptor are occurring as a function of age in different regions of the brain of control animals and that this development is influenced by neonatal caffeine exposure.