CHRONIC COCAINE/STIMULANTS--CARDIOVASCULAR CONSEQUENCES

描述：(申请人摘要) 在过去的几年里，滥用药物的数量惊人地增加了 中枢作用的拟交感神经刺激物及其发生率的增加 心血管毒性。由于时间上的密切关系， 药物使用和临床上最显著的毒性反应的发生 关于这些药物对心血管的影响的报道主要集中在 急性毒性反应。几乎没有人注意到 反复使用兴奋剂可能会改变老年人的心血管功能 这样一种方式，可以增加严重贫困的发展潜力 心血管毒性。因此，这项提案旨在测试 假设反复使用拟交感神经刺激剂 在心血管系统中产生结构和/或功能变化 增加了发生严重心血管疾病的可能性 毒性。这些研究将试图确定重复的 服用可卡因、3，4-亚甲基二氧基甲基苯丙胺(MDMA)或 甲基苯丙胺(冰毒)改变动脉压、心率 心电图活动大小和压力感受器或Bezold-Jarisch反射 功能。组织学和形态计量学分析也将用于 确定重复服用兴奋剂是否会造成损害或 心脏中在光或电子处可见的结构变化 微观层面。将采用两种类型的剂量计划。一 将包括每天服用可卡因、冰毒或摇头丸 到2个月。另一种类型的时间表将涉及大的、紧密间隔的 剂量为4-14天。后一种类型的兴奋剂给药时间表为 与通常用于产生单胺类神经毒性的药物类似 系统。拟议的研究代表了一种独特的组合，即 清醒动物心血管记录的ART技术 组织学分析，以检查心脏，心血管和 重复运动引起的心血管反射结构/功能 使用拟交感神经刺激剂。对这些变化的考察 应该为反复使用兴奋剂的潜力提供新的见解 产生心脏和/或心血管毒性。调停机制 这些变化将为今后的研究提供基础。

DESCRIPTION: (Applicant's Abstract) The past several years have seen an alarming increase in the abuse of centrally acting sympathomimetic stimulants and an increase in the incidence of cardiovascular toxicity. Due to the close temporal relationship between drug use and the onset of most clinically significant toxicities, most reports of the cardiovascular effects of these drugs have focused on the acute toxic responses. Very little attention has been paid to the possibility that repeated stimulant use may alter cardiovascular function in such a way as to increase the potential for the development of serious cardiovascular toxicity. Therefore, this proposal was designed to test the hypothesis that the repeated administration of sympathomimetic stimulants produces structural and/or functional changes in the cardiovascular system that increase the potential for the development of serious cardiovascular toxicity. These studies will attempt to determine whether the repeated administration of cocaine, 3,4-methylenedioxymethamphetamine (MDMA) or methamphetamine (METH) alters arterial pressure, heart rate, electrocardiographic activity size and baroreceptor or Bezold-Jarisch reflex function. Histologic and morphometric analysis will also be performed to determine whether repeated stimulant administration produces damage or structural changes in the heart that are visible at the light or electron microscopic level. Two types of dosing schedules will be employed. One will involve administration of cocaine, METH or MDMA on a daily basis for up to 2 months. The other type of schedule will involve large, closely spaced doses given for 4-14 days. The latter types of stimulant dosing schedule is similar to those often used to produce neurotoxicity in monoaminergic systems. The proposed studies represent a unique combination of "state of the art" techniques for cardiovascular recording in conscious animals and histological analysis to examine the changes in cardiac, cardiovascular and cardiovascular reflex structure/function elicited by the repeated administration of sympathomimetic stimulants. Examination of these changes should provide new insight into the potential for repeated stimulant use to produce cardiac and/or cardiovascular toxicity. The mechanisms mediating these changes will provide the basis for future studies.