MECHANISM OF PHENOBARBITAL NEUROTERATOGENICITY

苯巴比妥神经致畸作用机制

• 批准号: 3213359
• 负责人: JOSEPH YANAI
• 金额: $ 9.36万
• 依托单位: HEBREW UNIVERSITY OF JERUSALEM
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-02-01 至 1994-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3213359
• 关键词: acetylcholine; behavior; brain metabolism; cholinergic receptors; disease /disorder model; dopamine receptor; drug adverse effect; drug metabolism; hippocampus; immunocytochemistry; innervation; inositol phosphates; laboratory mouse; model design /development; neurochemistry; neurotoxins; neurotrophic factors; newborn animals; phenobarbital; second messengers; teratogens; transplantation

The present project was designed to establish an animal model for studying the mechanism of drug neuroteratogenicity. Phenobarbital will be used but the model may apply to other agents as well. Since phenobarbital effect on the brain is rather general the studies will concentrate on behavioral deficits related to the hippocampus. Our preliminary findings in mice after prenatal phenobarbital treatment included the following: (1) deficits in behaviors related to hippocampal function; (2) alterations in hippocampal cholinergic receptors and their second messenger; and (3) reversal of the behavioral deficits by (a) transplantation of cholinergic, but not noradrenergic neurons, into the affected hippocampus and (b) by septal dopaminergic denervation. Our working hypothesis is that septohippocampal cholinergic impairment is one of the causal mechanisms underlying the phenobarbital induced behavioral deficits. Accordingly, we will conduct an extensive study on the relationship between the phenobarbital-induced alterations in the septohippocampal cholinergic innervations and the behavioral deficits using the following experimental approaches: 1. Study of the phenobarbital-induced alterations in the septohippocampal cholinergic innervations and its related eight-arm maze, spontaneous alternations and Morris maze behaviors. Consecutive studies will assess the extent of correction of the behavioral and the biochemical alterations by transplantation of cholinergic neurons into the impaired hippocampus. The transplant will be examined using immunocytochemistry. 2. An attempt will be made to enhance the septohippocampal cholinergic system of the phenobarbital-exposed animals by treatment with Nerve Growth Factor (NGF) during development. The possible behavioral and biochemical consequences of this treatment will be ascertained. 3. The septohippocampal cholinergic system and the behavior of the phenobarbital- exposed animals will be disinhibited by destroying the A10-septal dopaminergic innervations.

本项目旨在建立一个用于研究的动物模型 药物神经染色性的机制。 苯巴比妥将使用，但 该模型也可能适用于其他代理。 由于苯巴比妥对 大脑相当普遍，研究将集中于行为 与海马有关的缺陷。 我们在老鼠中的初步发现 产前苯巴比妥治疗后包括以下内容：（1） 与海马功能有关的行为缺陷； （2）改变 海马胆碱能受体及其第二个使者； （3） 通过（a）移植胆碱能的行为缺陷逆转， 但不是去甲肾上腺素能神经元进入受影响的海马，（b） 间隔多巴胺能神经。 我们工作的假设是 SeptohohAppocampal胆碱能损伤是因果机制之一 苯巴比妥引起的行为缺陷的基础。 因此，我们 将对 苯巴比妥诱导的septohampocampal胆碱能的改变 使用以下实验的神经和行为缺陷 方法：1。研究苯巴比妥诱导的改变 Septohohampocal胆碱能神经及其相关的八臂迷宫， 自发交替和莫里斯迷宫行为。 连续研究 将评估行为和生化的校正程度 通过将胆碱能神经元移植到受损的 海马。 将使用免疫细胞化学检查移植。 2。将尝试增强septohappocampal胆碱能 通过神经生长处理苯巴比妥动物的系统 在开发过程中因素（NGF）。 可能的行为和生化 将确定这种治疗的后果。 3 SeptohohAppocampal胆碱能系统和苯巴比妥的行为 通过销毁A10隔离的动物将被禁用 多巴胺能神经。