DRUGS AND DEVELOPMENT OF ADRENERGIC NERVOUS SYSTEM

药物和肾上腺素能神经系统的发育

• 批准号: 3311152
• 负责人: THEODORE A SLOTKIN
• 金额: $ 16.42万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1976
• 资助国家: 美国
• 起止时间: 1976-06-15 至 1987-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3311152
• 关键词: central nervous system; decarboxylase inhibitor; drug adverse effect; drug metabolism; histamine; hormone regulation /control mechanism; neural information processing; neural transmission; neurochemistry; neuropharmacologic agent; ornithine decarboxylase; pediatric pharmacology; peripheral nervous system; polyamines; postnatal growth disorder; sympathetic nervous system; synapses

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.

本研究探讨了突触前输入在神经元发育中的作用。 突触后细胞和器官的生长，并决定如何药物诱导 神经元发育和/或功能的改变可产生突触后 发育异常 突触前和突触后功能的发展 去甲肾上腺素系统将在大脑皮层、心脏和肾上腺中进行跟踪 通过生物化学、功能和形态学的结合， 程序. 这些将决定正常和药物改变的发展， 突触接触，突触摄取机制，突触囊泡和 突触后反应系统（β受体、腺苷酸环化酶、鸟氨酸 脱羧酶、分泌系统）。 将评估以下因素之间的相关性 突触前水平和突触后水平的改变 涉及神经传递和受神经支配组织的生长（包括 蛋白质和核酸合成的测量）。 选择药物模型 它们通过不同的机制产生加速或减速， 突触前发育的三种组织：乙啶产生长期 周围交感神经的破坏，但毒性要小得多， 新生儿大脑并引起新生儿肾上腺髓质的刺激。 利血平暂时阻断去甲肾上腺素能神经传递 但当给予怀孕的大鼠时， 中枢介导的后代交感-肾上腺紧张性激活。 三碘甲状腺原氨酸加速功能性交感神经系统的发作 心脏和肾上腺髓质的神经传递，并增强中枢 突触发生 尼古丁刺激自主神经节， 刺激肾上腺髓质。 这些不同的模型将阐明 神经元输入在中枢和外周突触后发育中的作用 系统，并将识别突触前和突触后的特定改变， 与药物暴露或药物模型相关的发育 紊乱