PHARMACOLOGICAL SUBSTRATES IN AGING

该方案项目的基本目标仍然是 肾上腺素能神经元增龄性变化机制的研究 心血管和中枢神经系统的药理学。 虽然有大量的文献介绍了药物之间的差异， 在年轻和年老的生物体的反应，鲜为人知的是， 这些差异背后的机制。 在这个项目中，我们 将研究两名男性中与年龄相关的药物反应性变化， 和实验动物模型中。 的分子机制 对于这种变化，在受体方面，腺苷酸环化酶， 磷酸肌醇周转，以及突触前神经元的调节 将利用人类和生物化学的方法来实现功能， 动物组织 将使用以下方法检查生理相关性 电记录技术，体内计时电流法， 和刺激。 在神经元和 将评价非神经元成分。 组织移植 将被用来确定内在与外在的性质 任何与年龄相关的中枢神经变化 主要假设 要追求的是，突触前和/或突触后的变化， 外周自主神经效应器机制或中枢神经系统 突触回路将成为药物改变的基础， 随着年龄的增长而出现的反应性。

The basic objective of this program project continues to be the study of the mechanism of age-related changes in the adrenergic pharmacology of the cardiovascular and central nervous systems. While there is a rich literature on differences between drug response in young and aged organisms, little is known about the mechanisms which underlie these differences. In this program, we will study age-related changes in drug responsiveness in both man and in experimental animal models. The molecular mechanisms for such changes, in terms of receptors, of adenylate cyclase, of phosphoinositol turnover, and of the regulation of presynaptic function will be pursued biochemically using both human and animal tissues. Physiological correlates will be examined using techniques of electrical recording, in vivo chronoamperometry, and stimulation. Morphological correlates in both neuronal and non-neuronal elements will be evaluated. Tissue transplantation will be utilized to determine the intrinsic versus extrinsic nature of any age-related central nervous changes. The major hypothesis to be pursued is that pre- and/or postsynaptic changes in peripheral autonomic neuroeffector mechanisms or in CNS synaptic circuitry will underlie many of the alterations in drug responsitivity seen with aging.