REGULATION OF BRAIN NORADRENERGIC NEUROTRANSMISSION

本建议的目的是进行基础研究。 中枢去甲肾上腺素能神经生物学和药理学研究 系统，一个被认为在中枢起重要作用的大脑系统 抗抑郁药物的应激反应及其机制研究 行动。对该系统的行为功能进行了研究 由于缺乏适当的手段来研究这项活动而受到阻碍 在有意识、自由活动的动物的大脑中。 然而，我们实验室最近的研究表明，一种新的 植入型微透析探头检测技术 第二信使环磷酸腺苷水平的增加 (CAMP)，在体脑内对输注 儿茶酚胺现在使这些受体的研究成为可能 完整的大脑。拟议研究的目的是 进一步发展这项技术，并将其用于体内研究 中枢性去甲肾上腺素受体功能的调节 与以下各方面有关的药理过程 压力和抑郁。该项目的第一个目标是 微透析法-cAMP法在临床应用中的敏感性测定 检测大脑感受器功能的实验性变化和 在检测这些受体上正在进行的神经传递时。这 将通过确定该技术是否可以检测到 CAMP反应的慢性脱敏和增敏 长期服用安非他明引起的儿茶酚胺 抗抑郁药物或中枢去甲肾上腺素能损害，以及b)通过 确定它是否能检测到内源性cAMP反应 去甲肾上腺素通过包括压力在内的各种程序释放， 安非他明注射和刺激蓝斑。这个 该项目的第二个目标是利用微透析法 研究调节生物产量的生理因素 体内的去甲肾上腺素能受体。这些研究将集中在 肾上腺皮质系统，一种已知在应激期间活跃的系统 被认为对去甲肾上腺素能受体有调节作用 并将确定皮质酮是否会改变 这些受体上的儿茶酚胺或保护它们 儿茶酚胺长期暴露时的脱敏。以上内容 因此，研究有可能提供一种新的工具， 将有助于研究去甲肾上腺素能 应激和抗抑郁药物作用和提供 深入了解去甲肾上腺素的生理调节作用 应激和精神病理状态中的受体 其中增加了肾上腺皮质功能的水平(例如， 内源性抑郁)。

The purpose of the present proposal is to conduct basic research on the neurobiology and pharmacology of the central noradrenergic system, a brain system thought to play an important role in central responses to stress and in mechanisms of antidepressant drug action. Research on the behavioral functions of this system has been hampered by the lack of a suitable means to study the activity of its receptors in the brains of conscious, freely moving animals. Recent studies in our laboratory however have indicated that a new technique involving the detection by implanted microdialysis probes of increases in the level of the second messenger, cyclic AMP (cAMP), in the brain in vivo in response to infusion of catecholamines now makes possible the study of these receptors in the intact brain. The purpose of the proposed research is to further develop this technique and to use it to study the in vivo regulation of central noradrenergic receptor function by pharmacological processes which are related to various aspects of stress and depression. The first aim of the project is to determine the sensitivity of the microdialysis-cAMP method in detecting experimental alterations in brain receptor function and in detecting ongoing neurotransmission at these receptors. This will be accomplished a) by determining if the technique can detect the chronic desensitization and sensitization of cAMP responses to catecholamines caused by chronic administration of an antidepressant drug or a central noradrenergic lesion, and b) by determining if it can detect cAMP responses to endogenous norepinephrine released by various procedures including stress, amphetamine infusion and stimulation of the locus coeruleus. The second aim of the project is to utilize the microdialysis method to investigate physiological factors that modulate the output of noradrenergic receptors in vivo. The studies will focus on the adrenocortical system, a system known to be active during stress and thought to have regulatory effects on noradrenergic receptors and will determine if corticosterone alters the action of catecholamines on these receptors or protects them from desensitization during prolonged catecholamine exposure. The above research therefore has the potential for providing a new tool that will facilitate investigations of the role of the noradrenergic system in stress and antidepressant drug actions and of providing insight into the physiological regulation of noradrenergic receptors during stress and during psychopathological conditions in which the level of adrenocortical function is increased (e.g., endogenous depression).