FETAL ALCOHOL SYNDROME--THIRD TRIMESTER MODEL

胎儿酒精综合症——妊娠晚期模型

• 批准号: 2043289
• 负责人: JAMES R WEST
• 金额: $ 22.25万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2043289
• 关键词: alcoholic beverage consumption; attention deficit disorder; autoradiography; biological models; cellular pathology; central nervous system disorders; cerebellum; choline acetyltransferase; chronic brain damage; cytotoxicity; developmental neurobiology; dosage; ethanol; fetal alcohol syndrome; gamma aminobutyrate; gender difference; gestational age; hippocampus; histopathology; infant animal; laboratory rat; morphology; muscarinic receptor; neuroanatomy; neurons; radioimmunoassay; teratogens

Mental retardation is the most devastating effect in off spring that survive heavy alcohol exposure in utero. In spite of a substantial clinical and experimental literature, several important questions remain concerning the effect of heavy alcohol exposure on the central nervous system (CNS). The present proposal uses an animal model system of exposure to alcohol during the so- called brain growth spurt, the period of most rapid growth of the CNS, which occurs in the third trimester in humans. In the rat, this period occurs during the first ten postnatal days and appears to be when the CNS is vulnerable to alcohol exposure. During this period, the rats can be artificially reared, which allows exposure to be used in carefully controlled doses of alcohol, while ensuring that they receive adequate nutrition. Using this model of third trimester exposure, we propose to determine whether peak blood alcohol concentration (BAC) or area under the BAC-time curve (AUC) is the better predictor of CNS damage using multiple combinations of alcohol dose and pattern of administration. Using the data from the first study to choose appropriate doses, effects on dendritic fields of pyramidal neurons and density and localization of GABA, benzodiazepine and opiate receptors in the hippocampus will be examined on 10, 25 and 90 day-old rats. These studies will determine which measures are permanently disrupted, which measures show a developmental delay, and which measures are not affected. Permanent effects are particularly important since children who were diagnosed as having fetal alcohol syndrome are only now entering maturity and thus information about permanent effects in humans is very scanty. Particular attention in this proposal will be on the septohippocampal muscarinic cholinergic system, sine this system may be critically involved in the hyperactivity and cognitive deficits found in children with fetal alcohol syndrome. Choline acetyltransferase, muscarinic cholinergic receptor density, and cyclic GMP responsiveness will be examined. Finally, we intend to make initial studies on the pharmacological mechanisms of the teratogenicity of alcohol in the CNS by administering a prostaglandin synthetase inhibitor, a prostaglandin precursor, and an alcohol antagonist, using an artificial rearing procedure. This multidisciplinary approach to examining permanent effects and mechanisms of alcohol exposure on the CNS during the third trimester equivalent should provide important findings pertaining to fetal alcohol syndrome.

智力低下是春季最具破坏性的效果 在子宫内暴露于大量酒精饮料。 尽管有一个 大量的临床和实验文献，有几个重要 关于大量酒精暴露的影响仍然存在问题 在中枢神经系统（CNS）上。 目前的建议使用 在So- 称为大脑生长突变，是最快增长的时期 中枢神经系统发生在人类的三个月中。 在大鼠中， 此期间发生在前十几天，出现 当中枢神经系统容易暴露酒精时。 在此期间 时期，可以人为地饲养大鼠，这允许暴露 在精心控制的酒精中使用，同时确保 他们得到足够的营养。 使用这个第三型 妊娠期暴露，我们建议确定是否峰值血液 酒精浓度（BAC）或BAC时间曲线下的面积 （AUC）是使用多个CNS损伤的更好预测指标 酒精剂量和给药方式的组合。 使用 第一个研究选择适当剂量的数据，效果 在锥体神经元和密度和密度的树突状场上 GABA，苯二氮卓和阿片受体的定位 海马将在10、25和90天大的大鼠上检查。 这些研究将确定哪些措施是永久的 干扰，衡量的措施显示出发育延迟，哪些 措施不受影响。 永久效果尤其是 很重要，因为被诊断为胎儿的孩子 酒精综合征现在才进入成熟，因此 关于人类永久影响的信息非常少。 在此提案中特别关注 SEPTOHOHAPPOCAMPAL毒蕈碱胆碱能系统，正弦该系统 可能参与多动症和认知能力 患有胎儿酒精综合征的儿童缺陷。 胆碱 乙酰基转移酶，毒蕈碱胆碱能受体密度和 将检查环状GMP响应能力。 最后，我们打算 对有关药理机制的初步研究 中枢神经系统中酒精的致化性通过给药 前列腺素合成酶抑制剂，前列腺素前体和 酒精对手，使用人工饲养程序。 这 多学科的方法来检查永久效果和 第三次中枢神经系统酒精暴露的机制 孕期等效物应提供有关的重要发现 胎儿酒精综合征。