DRUGS AND DEVELOPMENT OF ADRENERGIC NERVOUS SYSTEM

本研究探讨了突触前输入在神经发育中的作用

This proposal examines how presynaptic input plays a role in the development of growth of postsynaptic cells and organs, and determines how drug-induced alterations of neuronal development and/or function can produce post synaptic developmental abnormalities. Development of pre-and post-synaptic function of norepinephrine systems will be followed in cerebral cortex, heart and adrenal medulla by a combination of biochemical, functional and morphological procedures. These will determine normal and drug-altered development of synaptic contacts, synaptic uptake mechanisms, synaptic vesicles and post-synaptic response systems (beta-receptors, adenylate cyclase, ornithine decarboxylase, secretory systems). Correlations will be evaluated between alterations at the presynaptic level and those at the postsynaptic level involving neurotransmission and growth of the innervated tissue (including measurements of protein and nucleic acid synthesis). Drug models are chosen which produce, by different mechanisms, acceleration or retardation of presynaptic development in the three tissues: Guanethidine produces long-term destruction of peripheral sympathetic nerves, but is far less toxic to the neonatal brain and causes stimulation of the neonatal adrenal medulla. Reserpine interrupts on a temporary basis noradrenergic neurotransmission development in heart and brain but when given to pregnant rats produces centrally-mediated activation of sympatho-adrenal tone in the offspring. Triiodothyronine accelerates the onset of functional sympathetic neurotransmission of heart and adrenal medulla and enhances central synaptogenesis. Nicotine causes stimulation of autonomic ganglia and direct stimulation of the adrenal medulla. These different models will elucidate the role of neuronal input in development of central and peripheral postsynaptic systems and will identify specific alterations in presynaptic and postsynaptic development associated with drug exposure or drug models of developmental disorders.