DEVELOPMENTAL NEUROTOXICITY OF COCAINE--AN IV MODEL

可卡因的发育神经毒性——静脉注射模型

• 批准号: 2122210
• 负责人: Charles F. Mactutus
• 金额: $ 11.88万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2122210
• 关键词: animal developmental psychology; behavior disorders; behavior prediction; biological models; cocaine; cognition disorders; developmental neurobiology; dosage; drug metabolism; embryo /fetus toxicology; intravenous drug abuse; laboratory rat; neuropsychology; norepinephrine; prenatal stress; teratogens

The recent establishment of a technically simple, economical, and practical techniques for chronic IV studies in which a vascular port is implanted prior to mating, offers a model for pregnant rats which reasonably mimics the rapidly peaking pharmacokinetics profile of cocaine abused via inhalation or IV administration. The proposed program specifically addresses the major question: Is maternal cocaine abuse during pregnancy a neurobehavioral teratogen when administered via a clinically-relevant route? The specific aims of the program are: 1) To determine the biodistribution of cocaine in the pregnant dam/fetus following intravenous administration. Using an IV vascular access port in unanesthetized pregnant rats we will determine both plasma and brain levels in dam and fetus of cocaine and its major metabolite, benzoylecgonine. Both time-response and dose-response functions will be determined. These studies are of fundamental importance in establishing the magnitude and duration of fetal cocaine exposure following maternal IV administration. 2) To establish the nature and extent of neurobehavioral alterations which occur in the offspring consequent to intravenous maternal cocaine exposure during pregnancy. Using unanesthetized IV-catheterized pregnant rats we will conduct ontogenetic and longitudinal analyses of the neurobehavioral effects of maternal cocaine exposure on the offspring with the inclusion of nutritional controls and surrogate fostering. These studies will identify dose-response functions and critical exposure periods. The dissociation of specific cognitive deficits from sensory or motor impairments will also be provided by the use of both multiple tasks and multiple dependent measures within each task. 3) To establish the nature and extent of the structural and functional alterations in the central noradrenergic system which occur following intravenous maternal cocaine exposure during pregnancy. Quantitative neuroanatomical measurements, quantitative protein analysis (Western blotting), synthetic enzyme activity, and in situ hybridization will be utilized to assess the structural and functional integrity of the central noradrenergic system. As a putative target of maternally administered cocaine, we hypothesize that alterations in the central noradrenergic system may be the neurobiological mechanism underlying the persistent and selective alterations observed in behavior, as particularly evident in "attentionally sensitive" neurobehavioral paradigms. The goals of the proposed program are to program are to provide a characterization of the neurobehavioral effects of maternal cocaine abuse during pregnancy, in an animal model based upon the clinically-relevant IV route of administration, and to characterize a neurobiological mechanism potentially underlying the persistent and selective neurobehavioral alterations.

最近建立了一个技术上简单，经济的和 慢性IV研究的实用技术，其中血管端口为 在交配之前植入，为怀孕大鼠提供模型 合理地模仿可卡因的快速峰值药代动力学概况 通过吸入或IV施用滥用。 拟议的计划 专门解决了主要问题：是母体可卡因滥用 怀孕期间通过 临床上与临床相关的路线？ 该计划的具体目的是： 1）确定可卡因在怀孕的大坝/胎儿中的生物分布 静脉给药后。 使用静脉血管访问端口 在未经麻醉的怀孕大鼠中，我们将确定血浆和大脑 可卡因及其主要代谢产物的大坝和胎儿的水平， 苯甲酸苯胺。 时间响应和剂量响应功能都将是 决定。 这些研究在建立 母体后胎儿可卡因暴露的大小和持续时间 IV给药。 2）建立神经行为改变的性质和程度 发生在静脉内母体可卡因的后代中发生的 怀孕期间的暴露。 使用未经动心的IV插入式怀孕 大鼠我们将进行对纵向和纵向分析 母体可卡因暴露对后代的神经行为影响 随着营养控制和替代培养的包括。 这些研究将确定剂量反应功能和关键暴露 时期。 特定认知缺陷与感觉的解离 或者也将通过两者使用多个来提供运动障碍 每个任务中的任务和多个因措施。 3）建立结构和功能的性质和程度 发生以下情况下发生的中央脱甲肾上腺素能系统的改变 怀孕期间静脉孕妇可卡因暴露。 定量 神经解剖测量，定量蛋白分析（西方 印迹），合成酶活性和原位杂交将是 用于评估中央的结构和功能完整性 去甲肾上腺素能系统。 作为母体管理的推定目标 可卡因，我们假设中央去甲肾上腺素能的改变 系统可能是持续性和的神经生物学机制 在行为中观察到的选择性改变，在 “注意敏感”神经行为范式。 拟议程序的目标是计划 母体可卡因滥用的神经行为影响的表征 在怀孕期间，在基于临床与临床相关的动物模型中 IV给药途径，并表征神经生物学 机制可能是持续和选择性的基础 神经行为改变。