REGULATION OF BRAIN NORADRENERGIC NEUROTRANSMISSION

本提案的目的是进行基础研究 中枢去甲肾上腺素能神经系统的神经生物学和药理学 系统，一个被认为在中枢神经系统中发挥重要作用的大脑系统。 应激反应与抗抑郁药物的作用机制 行动上 对该系统行为功能的研究， 由于缺乏适当的手段来研究这一活动， 在有意识的自由活动的动物大脑中的受体。 然而，我们实验室最近的研究表明， 植入微透析探针检测技术 第二信使环磷酸腺苷水平的增加 （cAMP），在体内脑中响应于 现在，儿茶酚胺使研究这些受体成为可能， 完整的大脑 拟议研究的目的是 进一步发展这项技术，并利用它来研究体内 调节中枢去甲肾上腺素能受体功能 药理学过程，其涉及的各个方面， 压力和抑郁 该项目的第一个目标是 测定微透析-cAMP法的灵敏度 检测大脑受体功能的实验性改变， 来检测这些受体上正在进行的神经传递。 这 a）通过确定该技术是否可以检测 cAMP反应的慢性脱敏和敏化 由长期服用 抗抑郁药或中枢去甲肾上腺素能病变，和B）通过 确定它是否可以检测到内源性cAMP反应， 包括压力在内的各种过程释放的去甲肾上腺素， 安非他明注入和刺激蓝斑。 的 该项目的第二个目标是利用微透析方法 研究调节输出的生理因素， 体内去甲肾上腺素能受体。 这些研究将集中在 肾上腺皮质系统，一个已知在应激时活跃的系统 并被认为对去甲肾上腺素能受体有调节作用 并将决定皮质酮是否会改变 这些受体上的儿茶酚胺或保护它们免受 在长期暴露于儿茶酚胺的过程中脱敏。 上述 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神经元的作用， 系统在压力和抗抑郁药物的作用，并提供 去甲肾上腺素能神经元的生理调节 感受器在压力和精神病理条件下 其中肾上腺皮质功能水平增加（例如， 内源性抑郁症）。

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).