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.

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