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PRENATAL COCAINE AND DOPAMINE RECEPTOR SIGNALING

产前可卡因和多巴胺受体信号传导

基本信息

批准号：
6549360
负责人：
EITAN FRIEDMAN
金额：
$ 13.57万
依托单位：
CITY COLLEGE OF NEW YORK
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-04-15 至 2003-03-31
项目状态：
已结题

项目摘要

Cocaine crosses the placenta and induces neurobehavioral abnormalities in offsprings of mothers ingesting this stimulant during pregnancy, thus suggesting that cocaine targets the developing brain. Cocaine competitively inhibits the removal of synaptic dopamine (DA) and other monoamines and thus increases synaptic concentrations of neurotransmitters which are known to influence the development and maturation of the CNS. It was therefore hypothesized that the increase in synaptic transmitter concentrations during CNS maturation results in cellular and neurochemical adaptive changes which lead to long term behavioral aberrations. In previously performed investigations, we demonstrated that prenatal exposure of rabbits to cocaine 1) reduced coupline of D1 DA receptors to Galphas protein in cortex and striatum, and 2) diminished evoked release of cortical DA. These effects were observed on postnatal days 10 to 100. It is proposed that the persistent functional changes in dopaminergic neurotransmission observed after prenatal cocaine are the consequences of desensitization of the D1 DA system that results from cocaine-induced insult to this neurotransmitter system during gestation. The proposed studies aim at defining the molecular mechanisms responsible for the apparent uncoupling of the D1 DA receptor transduction system and the functional consequences of this effect on DA neurotransmission. Specifically, experiments are designed to 1) explore the role of posttranslational modifications of Galphas and of D1 receptors in producing uncoupling of the D1 receptor system, 2) establish how early in development D1 receptors uncouple from Gs, 3) test whether the D1 receptor also uncouples from Galphaq which is linked to phosphatidylinositol hydrolysis, 4) test whether D1 receptor-Gs uncoupling results in desensitization of D1 receptor-mediated functions, and 5) test the specificity of the effects of prenatal cocaine treatment in terms of brain region, neurotransmitter system, and receptor subtype. Understanding the mechanism by which in utero cocaine impairs normal neurodevelopment and produces its long-term neurobehavioral abnormalities will ultimately enable us to design specific strategies to prevent or counter the consequences of cocaine abuse during pregnancy.

可卡因通过胎盘并导致神经行为异常在怀孕期间摄入这种兴奋剂的母亲的后代中，因此这表明可卡因针对的是发育中的大脑。可卡因竞争性地抑制突触多巴胺(DA)和其他单胺类神经递质，从而增加突触已知的影响发育的神经递质和中枢神经系统的成熟。因此，它被假设为增加中枢神经系统成熟过程中突触递质浓度的变化导致长期的细胞和神经化学适应性变化行为异常。在之前进行的调查中，我们证明兔子出生前接触可卡因的次数减少了大脑皮质和纹状体D1DA受体与Galphas蛋白的偶联， (2)皮质DA的诱发性释放减少。这些影响是观察时间为出生后10至100天。现建议本局观察到多巴胺能神经传递的持续性功能变化产后可卡因脱敏的后果是可卡因诱导的对此的侮辱导致的D1DA系统妊娠期间的神经递质系统。拟议的研究旨在明确了导致表观症状的分子机制 D1DA受体转导系统的解偶联及其功能这种效应对多巴胺神经传递的影响。具体来说，实验旨在1)探索翻译后翻译的作用 GALPHA和D1R的修饰在产生去偶联 D1受体系统，2)确定发育早期d1 受体与Gs解偶联，3)检测D1R是否也与磷脂酰肌醇有关的Galphaq解偶联水解，4)检测D_1受体-Gs解偶联是否导致 D1受体介导的功能的脱敏，以及5)测试产前可卡因治疗的特异性在以下方面脑区、神经递质系统和受体亚型。了解宫内可卡因损害正常的机制神经发育并产生其长期的神经行为反常现象最终将使我们能够设计具体的战略预防或对抗可卡因滥用的后果怀孕了。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prenatal exposure to cocaine disrupts D1A dopamine receptor function via selective inhibition of protein phosphatase 1 pathway in rabbit frontal cortex.

产前接触可卡因会通过选择性抑制兔额叶皮质中的蛋白磷酸酶 1 通路来破坏 D1A 多巴胺受体功能。

DOI：
10.1523/jneurosci.21-23-09160.2001
发表时间：
2001
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Zhen,X;Torres,C;Wang,HY;Friedman,E
通讯作者：
Friedman,E

Attenuation of cocaine-induced genomic and functional responses in prenatal cocaine-exposed rabbits.

产前接触可卡因的兔子中可卡因诱导的基因组和功能反应减弱。