MECHANISMS OF PRENATAL COCAINE AND ETHANOL TOXICITY

产前可卡因和乙醇毒性的机制

• 批准号: 6298544
• 负责人: ELLEN S MITCHELL
• 金额: $ 2.54万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6298544
• 关键词: cocaine; cytotoxicity; embryo /fetus hypoxia; embryo /fetus toxicology; ethanol; fetal alcohol syndrome; immunocytochemistry; laboratory rat; neurotoxicology; physiology; predoctoral investigator; pregnancy; prenatal stress; vasoconstriction

This project will examine the contributing mechanisms in prenatal cocaine and ethanol exposure. Both drugs have been shown to cause vasoconstriction of uterine vasculature as well as direct effects within the CNS. It is essential to evaluate the significance of hypoxia in fetuses exposed to drugs as a major inducer of toxicity to neurons. Pregnant rats will be exposed to a combination of cocaine and ethanol and the offspring's brains will be analyzed by immunocytochemical studies using antibodies against known indicators of cell toxicity and activity. The results will be compared to data collected from pups' brains that have been exposed to hypoxia only. The model used to separate the effects of hypoxia from other direct drug effects in fetal pups will take advantage of the differential vasoconstriction at each end of the rat uterine horn during cocaine exposure. This study proposes that intrauterine position has significance in not only the amount of drug reaching a fetus but also alters the severity of physiological changes (i.e. hypoxia) brought on by the drug. After gestational cocaine and ethanol exposure, a C-section will be performed to identify the intrauterine position of each pup. Separation of pups by amount of drug exposure and hypoxia will enable determine of whether specific drug effects of hypoxia is the more significant mechanism. We will compare the distal, more hypoxic brains with hypoxia-only brains to assess differences caused by the added drug exposure. In addition, we will assess exposed pups for susceptibility to further hypoxia at birth and monitor physiological differences after they reach adulthood.

该项目将研究产前可卡因和乙醇暴露的影响机制。这两种药物均已被证明会引起子宫脉管系统的血管收缩以及对中枢神经系统的直接影响。有必要评估暴露于药物的胎儿缺氧作为神经元毒性主要诱因的重要性。怀孕的大鼠将接触可卡因和乙醇的组合，并且将使用针对已知细胞毒性和活性指标的抗体通过免疫细胞化学研究来分析后代的大脑。结果将与从仅暴露于缺氧的幼崽大脑中收集的数据进行比较。用于将胎儿幼崽中缺氧的影响与其他直接药物影响分开的模型将利用可卡因暴露期间大鼠子宫角两端的差异血管收缩。这项研究提出，宫内位置不仅对到达胎儿的药物量具有重要意义，而且还能改变药物引起的生理变化（即缺氧）的严重程度。妊娠期接触可卡因和乙醇后，将进行剖腹产以确定每只幼犬在子宫内的位置。通过药物暴露量和缺氧量来区分幼仔将能够确定缺氧的特定药物作用是否是更重要的机制。我们将比较远端缺氧程度较高的大脑与仅缺氧的大脑，以评估因药物暴露增加而引起的差异。此外，我们将评估暴露的幼犬出生时对进一步缺氧的敏感性，并监测成年后的生理差异。