CHRONIC COCAINE/STIMULANTS--CARDIOVASCULAR CONSEQUENCES

描述：（申请人摘要） 在过去几年中，滥用麻醉品的现象令人震惊地增加， 中枢作用拟交感神经兴奋剂和发病率增加 心血管毒性。 由于时间关系密切， 药物使用和大多数临床显著毒性的发作， 这些药物对心血管作用的报道集中在 急性毒性反应。 很少有人注意到 重复使用兴奋剂可能会改变心血管功能， 这样一种方式，以增加发展的潜力， 心血管毒性 因此，本提案旨在测试 假设重复给予拟交感神经兴奋剂 在心血管系统中产生结构和/或功能变化 增加了严重心血管疾病的发展潜力， 毒性 这些研究将试图确定是否重复 可卡因、3，4-亚甲二氧基甲基苯丙胺（MDMA）或 甲基苯丙胺（METH）改变动脉压，心率， 心电图活动大小与压力感受器或Bezold-Jorch反射 功能 还将进行组织学和形态学分析， 确定重复的兴奋剂给药是否会产生损害， 心脏的结构变化，在光或电子可见 微观水平。 将采用两种类型的给药方案。 一 将涉及可卡因，METH或MDMA的日常管理， 到2个月。 另一种类型的时间表将涉及大，紧密间隔 给药4-14天。 后一种类型的兴奋剂给药方案是 类似于通常用于产生单胺能神经毒性的那些 系统. 拟议的研究代表了一个独特的组合“国家的 在清醒动物中进行心血管记录的现有技术， 组织学分析以检查心脏、心血管和 心血管反射结构/功能引起的重复 拟交感神经兴奋剂的施用。 审查这些变化 应该为重复使用兴奋剂的可能性提供新的见解， 产生心脏和/或心血管毒性。 调解机制 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.