COCAINE ABUSE--SYMPATHETIC & CARDIOVASCULAR CONSEQUENCES

可卡因滥用——同情

• 批准号: 2120738
• 负责人: Kurt J. Varner
• 金额: $ 10.32万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-02-15 至 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2120738
• 关键词: amines; blood pressure; brain stem; cardiovascular function; cardiovascular pharmacology; cocaine; dorsal raphe nucleus; drug abuse; drug addiction antagonist; electrophysiology; heart rate; laboratory rat; microinjections; neuropharmacology; nontherapeutic iontophoresis; stimulant /agonist; sympathetic block; sympathetic nervous system

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.

过去几年可卡因的使用量急剧增加 以及美国与可卡因相关的死亡率。临床和 病理报告表明，大部分毒性与 可卡因的使用是由于该药物对心血管的作用所致 系统。心血管作用的机制 可卡因仍然鲜为人知。然而，人们普遍认为，许多 这些反应的结果是可卡因介导的中枢神经系统增加 同情心流出。这种信念最近受到研究的挑战 在麻醉和去脑制剂中，表明可卡因可能 实际上抑制中枢交感神经流出。因此，总体目标 该应用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 涉及。这些研究将使用三种主要策略。第一个 研究将描述动脉压、心率的频谱特征 以及可卡因在有意识和清醒状态下引起的交感神经反应 麻醉的老鼠。其次，特定的单胺能拮抗剂 显微注射到延髓头侧腹外侧 (RVLM) 腹内侧髓质 (RVMM) 和尾中缝核以努力阻断 可卡因引起的交感神经和心血管反应。 第三，将使用电生理单单元记录技术 识别和表征 RVLM、RVMM 和 中缝核具有与交感神经放电相关的活动和/或 心动周期。静脉注射可卡因对人体的影响 将测试这些交感神经元的放电。离子电渗疗法 将特定的拮抗剂应用到这些神经元上将用于 确定机制（单胺能和/或局部麻醉） 负责可卡因对这些神经元的影响。成功的 完成这些研究将提供新的重要信息 关于参与调解的中心地点和机制 可卡因对交感神经和心血管系统的影响 清醒和麻醉的老鼠。这些研究也将提供第一个 RVMM 和中缝尾部交感神经元的特征 原子核。最后，将开发一个新的有用的模型来研究 拟交感神经药的交感神经和心血管作用，例如 安非他明对清醒和麻醉的大鼠的作用。