DRUGS AND DEVELOPMENT OF THE ADRENERGIC NERVOUS SYSTEM

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Catecholamines serve a dual role in the perinatal period, mediating vital physiological responses which are necessary to survive the adaptation to extrauterine life, as well as serving as potential trophic factors regulating cellular development in adrenergic target tissues. The current proposal examines both of these roles in the developing lung, a tissue where we have already shown that beta-receptor-mediated responses are critical to survival. Three basic questions will be addressed: 1. How do catecholamines derived from sympathetic innervation or the adrenal medulla influence the adaptation of the lung to air- breathing in the perinatal period? 2. How do catecholamines influence the replication and differentiation of lung tissue during development? 3. How do pharmacological treatments designed to promote neonatal respiratory function, influence development of catecholamine targets elsewhere in the body, with particular attention to the central nervous system? In all these cases, we will examine normal development and five perturbation models: peripheral sympathectomy (neonatal treatment with 6-hydroxydopamine s.c.), interference with central catecholaminergic development (intracisternal 6- hydroxydopamine), prenatal exposure to agents used to promote respiratory function in the newborn (late gestational maternal treatment with a beta 2-agonist, terbutaline, or a glucocorticoid, betamethasone), or prenatal exposure to beta-receptor blockade (late gestational maternal infusion of propranolol). For each model, biochemical profiles will be evaluated which assess development of tissue responsiveness to catecholamines (beta- receptor binding sites, beta-receptor-mediated responses), development of sympathetic innervation (nerve terminals, biosynthetic enzymes, norepinephrine release capabilities, sympathetic reflex competence), and onset of tonic regulation of lung sympathetics by the CNS. This will be followed by studies of the normal ontogenetic pattern and responsiveness to catecholamines and sympathetic stimulation of biochemical indices of cellular maturation of lung tissue (ornithine decarboxylase, polyamines, nucleic acid and protein synthesis and levels); for each perturbation model, we will assess the impact of altered adrenergic input on cellular development in the lung, as well as comparing these with adrenergic targets in the CNS, where catecholamines have been postulated to play a trophic role in differentiation and synaptogenesis.