MECHANISMS OF ONSET & OFFSET OF RAPID STIMULANT EFFECTS

描述：(申请人摘要) 这个临床医生科学家发展奖的长期目标是 了解药物使用后的早期事件会如何影响 药物滥用的后果。在这些研究中，调查人员将 研究药代动力学、神经化学和神经化学之间的相互关系 两种典型兴奋剂滥用的行为反应 (甲基苯丙胺和苯环利定)。对共性和多样性的研究 人体真实用药动物模型中的刺激效应机制 应导致在急性护理环境中制定更合理的治疗计划，并 更好地了解兴奋剂滥用的长期后果。至 为了实现这些目标，调查人员将执行一系列单独的 每种药物的研究都是相同的。第一，系统性的 将进行血浆和组织浓度的药代动力学研究 确定中枢神经系统(CNS)用药的速度和程度 穿透力。第二，神经化学和药物的剂量-反应关系 行为反应将被确定。在这些研究中，体内快速 自由活动动物中枢多巴胺水平的电化学变化 被测量。然后，这些数据将被用来开发一个组合的 每种药物药物反应的药代动力学-药效学模型。 第三，途径(静脉注射与腹膜内注射)的影响和 将测量给药对神经化学和行为反应的影响。 这些研究应该为为什么吸毒者提供神经化学基础 通常更喜欢快速给药(静脉注射和吸烟)而不是其他 给药方式(例如，口服)。第四，综合虐待模式 将使用新发明的治疗剂进行测试和推广。高 亲和力药物特异性抗体将被用来迅速减少大脑 浓度。该疗法对神经化学和行为学的影响 对每一种原型药物的反应将进行分析。科学 成长将通过与一位知名导师的合作来实现， 顾问和其他科学家。具体的培训将在 分析和行为药理学、统计学、计算机领域 建模和神经科学。

DESCRIPTION: (Applicant's Abstract) The long term goal of this clinician scientist development award is to understand how early events, immediately after drug use, can affect the outcome of substance abuse. In these studies, the investigators will examine the interrelationships among pharmacokinetic, neurochemical and behavioral responses for two prototypic stimulant drugs of abuse (methamphetamine and phencyclidine). The study of the common and diverse mechanisms of stimulant effects in animal models of real-life human drug use should lead to more rational treatment plans in acute care settings and to a better understanding of the long-term consequences of stimulant abuse. To accomplish these goals, the investigators will perform a separate series of identical studies for each of the drugs. First, a systematic pharmacokinetic study of plasma and tissue concentrations will be conducted to determine the rate and extent of central nervous system (CNS) drug penetration. Second, dose-response relationships for neurochemical and behavioral responses will be determined. In these studies, rapid in vivo electrochemical changes in CNS dopamine levels in freely moving animals will be measured. These data will then be used to develop a combined pharmacokinetic- pharmacodynamic model of drug response for each drug. Third, the effects of route (iv vs. intraperitoneal) and rate of administration on neurochemical and behavioral responses will be measured. These studies should provide a neurochemical basis for why drug abusers usually prefer rapid routes of administration (iv and smoking) over other modes of administration (e.g, oral). Fourth, the combined models of abuse will be tested and extended using newly invented therapeutic agents. High affinity drug- specific antibodies will be used to rapidly reduce brain concentrations. The effects of this therapy on neurochemical and behavioral responses to each of the prototypic drugs will be analyzed. Scientific growth will be aided through collaboration with a well established mentor, consultant, and other scientists. Specific training will be obtained in the areas of analytical and behavioral pharmacology, statistics, computer modeling, and neuroscience.