FETAL ALCOHOL SYNDROME--THIRD TRIMESTER MODEL

胎儿酒精综合症——妊娠晚期模型

• 批准号: 2043290
• 负责人: JAMES R WEST
• 金额: $ 23.14万
• 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/2043290
• 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.

智力低下是对后代最具破坏性的影响 在子宫内承受大量酒精暴露的人。 尽管有 大量的临床和实验文献，一些重要的 关于重度酒精暴露的影响仍然存在疑问 对中枢神经系统（CNS）的影响。 本提案使用 在此期间暴露于酒精的动物模型系统 大脑发育最快的时期，称为大脑生长突增期 CNS，发生在人类的妊娠晚期。 在老鼠身上， 该时期发生在产后前十天内，并出现 当中枢神经系统容易受到酒精暴露时。 在此期间 在此期间，可以对大鼠进行人工饲养，使其暴露在空气中 严格控制酒精剂量，同时确保 他们获得足够的营养。 使用第三个模型 妊娠期暴露，我们建议确定血峰是否 酒精浓度 (BAC) 或 BAC-时间曲线下面积 （AUC）是使用多种方法更好地预测中枢神经系统损伤的指标 酒精剂量和给药方式的组合。 使用 根据第一项研究的数据选择合适的剂量、效果 关于锥体神经元的树突域和密度 GABA、苯二氮卓类和阿片受体的定位 将检查 10、25 和 90 日龄大鼠的海马体。 这些研究将确定哪些措施是永久性的 扰乱，哪些措施显示发育迟缓，哪些 措施不受影响。 永久性影响尤其明显 重要的是，因为被诊断出有胎儿的孩子 酒精综合症现在才进入成熟期，因此 关于人类永久性影响的信息非常少。 该提案将特别关注 隔海马毒蕈碱胆碱能系统，正弦此系统 可能与多动和认知能力密切相关 胎儿酒精综合症儿童中发现的缺陷。 胆碱 乙酰转移酶、毒蕈碱胆碱能受体密度，以及 将检查循环 GMP 反应性。 最后，我们打算 对其药理机制进行初步研究 酒精对中枢神经系统的致畸作用 前列腺素合成酶抑制剂，前列腺素前体，和 一种酒精拮抗剂，采用人工饲养程序。 这 多学科方法来检查永久性影响和 第三阶段酒精暴露对中枢神经系统的影响机制 三个月等效应提供有关的重要发现 胎儿酒精综合症。