Pharmacologic reversal of behavioral teratogenesis

行为致畸的药物逆转

基本信息

批准号：
6623561
负责人：
JOSEPH YANAI
金额：
$ 7.7万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2004-03-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Prenatal exposure to a wide variety of neuroteratogens can act by different originating mechanisms, nevertheless results in a common pattern of neurobehavioral defect that converge on hippocampal cholinergic function. In previous studies the principal investigator has established a model for the effects of prenatal exposure to phenobarbital on septohippocampal cholinergic innervation; the locus of the defect is at the level of postsynaptic receptor-mediated signaling, with corresponding deficits in hippocampus-related behaviors. Grafting of cholinergic cells reverses both cholinergic and behavioral deficits. While instrumental in tying the biochemical and behavioral events in causal relationship, neural grafting is still not a practical solution for most human neural pathologies, and the current application is designed to provide the initial information about the possibility of pharmacological approaches to the problem. The ability of nicotine to improve cognitive performance has been demonstrated in organic pathologies such as Alzheimer's disease, situations which entail cholinergic dysfunction. Therefore, the investigator proposes to examine whether nicotine treatment in adulthood will reverse the synaptic and functional defects induced by prenatal exposure to phenobarbital, concentrating on cholinergic innervation and its related hippocampal behaviors. In this Small Grant application, the investigator will conduct a pilot study on the deficits in eight-arm maze behavior and alterations in PKC signaling related to muscarinic cholinergic receptor stimulation, with parallel studies of cholinergic presynaptic markers (hemicholinium-3 binding to the choline transporter, and choline acetyltransferase activity). The hippocampus-dependent behavior will be contrasted with control tasks that are not hippocampus-dependent. If this approach is successful, the investigator will then have the initial information necessary to commence intensive studies of whether the same approach works on prenatal exposure to various other neuroteratogens relevant to human drug use or environmental exposures, which produce similar hippocampal defects, but by different originating mechanisms. Accordingly, the specific aim is to ascertain whether the behavioral deficits and alterations in septohippocampal cholinergic synaptic function induced by prenatal phenobarbital administration can be reversed or ameliorated by nicotine administration drug adulthood.

描述（由申请人提供）：产前暴露于各种各样的神经毒素可以通过不同的原始机制作用，但是导致神经行为缺陷的常见模式，该缺陷会收敛海马胆碱能功能。在先前的研究中研究者已经建立了一个模型，以实现产前暴露于 Septohappocampal胆碱能神经支配的苯巴比妥；轨迹缺陷处于突触后受体介导的信号传导的水平，有海马相关行为的相应缺陷。嫁接胆碱能细胞逆转胆碱能和行为缺陷。尽管在因果关系中绑定生化和行为事件的作用关系，神经嫁接仍然不是大多数人的实际解决方案神经病理，当前的应用旨在提供有关药理学方法的初始信息问题。尼古丁提高认知表现的能力已经在诸如阿尔茨海默氏病等有机病理学中证明了这需要胆碱能功能障碍。因此，调查员提议检查成年后的尼古丁治疗是否会逆转突触和产前暴露于苯巴比妥引起的功能缺陷，专注于胆碱能神经及其相关海马行为。在这个小型赠款申请中，调查人员将进行试点研究八臂迷宫行为的缺陷和PKC的改变与毒蕈碱胆碱能受体刺激相关的信号传导，与胆碱能突触前标记的平行研究（Hemicholinium-3结合到胆碱转运蛋白和胆碱乙酰转移酶活性）。这海马依赖性行为将与控制任务形成对比不依赖海马。如果这种方法成功，调查员然后将获得开始强化研究所需的初始信息关于同样的方法是否在产前暴露于其他各种方法方面起作用与人类药物使用或环境暴露有关的神经毒素，这是产生类似的海马缺陷，但通过不同的起源机制产生。因此，具体目的是确定行为不足是否存在以及由septohampocampal胆碱能突触功能的改变产前苯巴比妥给药可以被逆转或改善尼古丁给药成年。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Functional changes after prenatal opiate exposure related to opiate receptors' regulated alterations in cholinergic innervation.

DOI：
10.1017/s1461145703003523
发表时间：
2003-09
期刊：
The international journal of neuropsychopharmacology
影响因子：
0
作者：
J. Yanai;Rabab Huleihel;M. Izrael;Sally Metsuyanim;H. Shahak;O. Vatury;S. Yaniv
通讯作者：
J. Yanai;Rabab Huleihel;M. Izrael;Sally Metsuyanim;H. Shahak;O. Vatury;S. Yaniv

A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity.

芥子气神经行为致畸机制的小鸡模型。