COCAINE ABUSE--SYMPATHETIC & CARDIOVASCULAR CONSEQUENCES

在过去几年中，可卡因的使用大幅增加， 和可卡因相关的死亡率。临床和 病理学报告表明，许多毒性与 可卡因的使用是由于这种药物对心血管系统的作用， 系统心血管效应的机制 可卡因在很大程度上仍不为人所知。然而，人们普遍认为，许多 这些反应的原因是可卡因介导的中枢神经系统的增加。 交感神经流出这一信念最近受到了研究的挑战 在麻醉和去大脑制剂中，可卡因可以 抑制中枢交感神经流出因此，总体目标 本申请的目的是表征可卡因对 清醒和麻醉大鼠的中枢交感神经系统， 特别关注脑干部位和机制 涉案在这些研究中将使用三种主要策略。第一 研究将描述动脉压、心率 和交感神经反应引起的可卡因在有意识的， 麻醉大鼠。第二，特异性单胺能拮抗剂将是 显微注射到延髓头端腹外侧（RVLM），头端 延髓腹内侧核（RVMM）和中缝尾侧核，以阻断 可卡因引起的交感神经和心血管反应。 第三，将使用电生理单单位记录技术 识别和表征RVLM、RVMM和RVLM中的单个神经元， 具有与交感神经放电相关的活动的中缝核和/或 心动周期。静脉注射可卡因对 将测试这些交感神经元的放电。离子电渗 将特异性拮抗剂应用于这些神经元上， 确定机制（单胺能和/或局部麻醉剂） 负责可卡因对这些神经元的影响。成功 这些研究的完成将提供新的重要信息， 关于参与调解冲突的中心地点和机制， 可卡因对交感神经和心血管系统的影响 清醒和麻醉的大鼠。这些研究还将提供第一个 RVMM和中缝尾侧交感神经元的特征 原子核。最后，将开发一个新的和有用的模型来研究 拟交感神经药如 安非他明在清醒和麻醉大鼠。

The last several years has seen a profound increase in the use of cocaine and cocaine-related mortality in the Unites States. Clinical and pathological reports indicate that much of the toxicity associated with cocaine use results from the actions of this drug on the cardiovascular system. The mechanism(s) responsible for the cardiovascular effects of cocaine remain largely unknown. However, it is widely accepted that many of these responses result from a cocaine-mediated increase in central sympathetic outflow. This belief has recently been challenged by studies in anesthetized and decerebrate preparations which show that cocaine may actually inhibit central sympathetic outflow. Therefore, the overall goal of this application is to characterize the effects of cocaine on the central sympathetic nervous system in conscious and anesthetized rats, with special attention being paid to the brain stem sites and mechanisms involved. Three main strategies will be used in these studies. The first studies will characterize the spectrum of arterial pressure, heart rate and sympathetic nerve responses elicited by cocaine in conscious and anesthetized rats. Second, specific monoaminergic antagonists will be microinjected into the rostral ventrolateral medulla (RVLM), rostral ventromedial medulla (RVMM) and caudal raphe nuclei in an effort to block the sympathetic nerve and cardiovascular responses elicited by cocaine. Third, electrophysiological single unit recording techniques will be used to identify and characterize individual neurons in RVLM, RVMM and the raphe nuclei with activity related to sympathetic nerve discharge and/or the cardiac cycle. The effect of intravenously administered cocaine on the discharges of these sympathetic neurons will be tested. Iontophoretic application of specific antagonists onto these neurons will be used to identify the mechanism(s) (monoaminergic and/or local anesthetic) responsible for the effects of cocaine on these neurons. Successful completion of these studies will provide new and important information regarding the central sites and mechanisms involved in mediating the effects of cocaine on the sympathetic and cardiovascular systems in conscious and anesthetized rats. These studies will also provide the first characterization of sympathetic neurons in RVMM and the caudal raphe nuclei. Finally, a new and useful model will be developed to study the sympathetic and cardiovascular effects of sympathomimetic agent such as amphetamine in conscious and anesthetized rats.