DRUGS AND DEVELOPMENT OF THE ADRENERGIC NERVOUS SYSTEM

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The ultimate goals are to identify the cellular mechanisms underlying neurotransmitter control of cell development and corresponding drug- induced functional teratology. We have identified two potential beta- adrenergic mechanisms for control of cell development: effects on the timing of cell replication and differentiation, and "programming" of intracellular messenger systems. The specific aims are: (l) Identify the requirement for neuronal input in the development of beta-adrenergic receptor mediated responses that influence differentiation of noradrenergic target cells. This will be evaluated by neonatal chemical denervation with 6-hydroxydopamine. (2) Identify the role of beta-receptor desensitization in the developmental process; several aspects of receptor desensitization cannot be elicited by agonist administration in the neonate, and appear only with the onset of presynaptic neuronal function and a maturational surge in neuronal impulse activity. This will be evaluated by challenging animals with repeated injections of isoproterenol, begun at different stages of development. (3) Evaluate the permissive role of perinatal thyroid hormones in establishing beta-receptor-mediated responses in the developmental period preceding the maturational surge of neuronal activity. For each specific aim, we will assess the development of beta-receptor binding sites (numbers, affinity state, and affinity shift linked to G- protein function), as well as the receptor link to adenylate cyclase via G-S. Comparisons will be made with alpha2-receptors, which are transiently overexpressed in developing tissues, and with the alpha2-link to inhibition of adenylate cyclase via G-i. Endpoints of receptor stimulation that are relevant to neurotransmitter control of cell differentiation will be evaluated with each model: receptor-mediated termination of DNA synthesis; stimulation of the developmentally-expressed protooncogene, c-fos; and its functional endpoint of formation of AP- l binding complexes; and the timing of postsynaptic differentiation, evaluated by switchovers of adrenergic receptor subtypes, myosin isoform transitions and RNA/DNA ratios. Two tissues, heart and liver, will be studied because of their different developmental patterns: in the heart beta-receptors and their linkage to adenylate cyclase are present early in development and increase with development; in the liver, there is a developmental decline in beta- receptors and their ability to stimulate adenylate cyclase. These studies should thus identify the role of neuronal and hormonal input in the development of the major components of the beta-adrenergic signaling cascade, and in the control of target cell differentiation by adrenergic neuronal input; contrasting two tissues that have disparate patterns of receptor ontogeny should enable us to determine if these roles are universal or rather are specified to selective target tissues.