NEONATA THERAPEUTIC CAFFEINE & NEURAL DEVELOPMENT

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Apnea of prematurity is a significant problem in the under 2500gm birth-weight neonate. Current treatment involves administration of caffeine for periods of weeks, at plasma levels 5-10 times that found in the normal adult population. Although acute toxicity is minimal, there is insufficient data to ensure the absence of long- term toxicity. Exposure to exogenous chemicals at developmentally- sensitive time periods is known to result in significant, long- lasting neural and behavioral effects. This proposal aims to establish an animal model for the therapeutic use of caffeine and its possible effects on brain receptor systems and functional correlates. Precise pharmacokinetic data will be obtained initially to allow better correlation with infant drug regimens in use. Adenosine and benzodiazepine receptors will be characterized by binding parameters as a function of age and drug exposure. The functional correlates of early caffeine exposure as a consequence of drug-receptor interactions will be assessed as alterations in locomotor activity and seizure thresholds and susceptibilities. Animal's locomotor activity will be tested both in their baseline state and following challenge with exposure to a known stimulant (caffeine) or depressant (L-phenylisopropyladenosine) to assess adenosine receptor-effector integrity. The susceptibility to and threshold for hyperthermic and chemically-induced seizures, as well as the efficacy of anti-convulsant therapy (diazepam) will assess benzodiazepine receptor-effector integrity. Concomitantly developing neurochemical systems will also be examined because of their interrelationships with the adenosine and benzodiazepine receptor-effector systems. High performance liquid chromatography determination of norepinephrine levels and turnover rates will be performed. Finally, the possible interactions between early caffeine exposure and other environmental insults will be examined. The consequences for neural development of the combination of undernutrition or hypoxemia with therapeutic caffeine exposure will be assessed. These studies will provide information on neural developmental implications for human premature neonates of chronic exposure to therapeutic levels of caffeine.