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FETAL ALCOHOL SYNDROME--THIRD TRIMESTER MODEL

胎儿酒精综合症——妊娠晚期模型

基本信息

批准号：
2413232
负责人：
JAMES R WEST
金额：
$ 25.17万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
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

项目摘要

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.

智力迟钝是对后代最具破坏性的影响在子宫内大量酒精暴露下存活下来尽管有大量的临床和实验文献，一些重要的关于大量饮酒的影响，中枢神经系统（CNS）。本提案使用一个动物模型系统暴露于酒精中，所谓的大脑生长突增期，是大脑发育最快的时期。中枢神经系统，发生在人类妊娠晚期。在老鼠体内，这一时期发生在出生后的前十天，当中枢神经系统易受酒精影响时。在此在此期间，大鼠可以人工饲养，在严格控制酒精剂量的同时，他们得到足够的营养。使用第三个模型三个月的暴露，我们建议确定是否峰值血液酒精浓度（BAC）或BAC-时间曲线下面积 (AUC)是更好的预测中枢神经系统损伤，酒精剂量和给药方式的组合。使用第一项研究的数据来选择适当的剂量、效果对锥体神经元树突区和密度的影响， GABA、苯二氮卓类和阿片受体的定位对10、25和90日龄大鼠的海马体进行检查。这些研究将确定哪些措施是永久性的中断，哪些措施显示发育迟缓，措施不受影响。特别是永久性影响这一点很重要，因为被诊断为胎儿酒精综合征现在才进入成熟期，关于对人类的永久性影响的信息非常少。本建议将特别注意隔-海马毒蕈碱胆碱能系统可能与多动症和认知功能有关胎儿酒精综合征患儿中发现的缺陷胆碱乙酰转移酶，毒蕈碱胆碱能受体密度，和将检查环GMP反应性。最后，我们打算初步研究了其药理作用机制，酒精在中枢神经系统中的致畸性，前列腺素合成酶抑制剂，前列腺素前体，和酒精拮抗剂，使用人工饲养程序。这采用多学科方法审查长期影响，酒精暴露对中枢神经系统的作用机制三个月当量应提供重要的调查结果，胎儿酒精综合症