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.

最近建立了一种技术简单、经济、 慢性静脉注射研究的实用技术，其中血管端口是 在交配前植入，为怀孕老鼠提供了一个模型 合理地模拟可卡因快速达到峰值的药代动力学特征 通过吸入或静脉注射滥用。 拟议的计划 具体解决了主要问题：母亲是否滥用可卡因 怀孕期间通过药物施用时会产生神经行为致畸作用 临床相关途径？ 该计划的具体目标是： 1) 确定怀孕母鼠/胎儿中可卡因的生物分布 静脉给药后。 使用 IV 血管接入端口 在未麻醉的怀孕大鼠中，我们将测定血浆和大脑 母鼠和胎儿中可卡因及其主要代谢物的水平， 苯甲酰爱康宁。 时间反应和剂量反应函数都将是 决定。 这些研究对于建立 产后胎儿接触可卡因的程度和持续时间 四、给药。 2）确定神经行为改变的性质和程度 因母体静脉注射可卡因而发生在后代中 怀孕期间的暴露。 使用未麻醉的静脉导管孕妇 我们将对大鼠进行个体发育和纵向分析 母亲接触可卡因对后代神经行为的影响 包括营养控制和代孕培育。 这些研究将确定剂量反应函数和关键暴露 期间。 特定认知缺陷与感觉的分离 或运动障碍也将通过使用多种 任务以及每个任务中的多个相关度量。 3) 确定结构和功能的性质和范围 中枢去甲肾上腺素能系统的改变发生在 怀孕期间母亲静脉注射可卡因。 定量 神经解剖学测量、定量蛋白质分析（Western 印迹）、合成酶活性和原位杂交将 用于评估中央的结构和功能完整性 去甲肾上腺素能系统。 作为母体给药的假定目标 可卡因，我们假设中枢去甲肾上腺素能的改变 系统可能是持久和潜在的神经生物学机制 在行为中观察到的选择性改变，尤其明显 “注意敏感”神经行为范式。 拟议计划的目标是提供一个 母亲滥用可卡因的神经行为影响的特征 怀孕期间，在基于临床相关的动物模型中 IV 给药途径，并表征神经生物学 持久性和选择性的潜在机制 神经行为改变。