PRENATAL COCAINE AND DOPAMINE RECEPTOR SIGNALING

皮质醇穿过胎盘并诱发神经行为异常 在母亲怀孕期间摄入这种兴奋剂的后代中， 表明可卡因的目标是发育中的大脑。 可卡因 竞争性抑制突触多巴胺（DA）和其他 单胺，从而增加突触浓度 已知影响发育的神经递质， CNS的成熟。 因此，有人假设， 中枢神经系统成熟过程中突触递质浓度的变化， 细胞和神经化学的适应性变化， 行为失常 在以前的调查中，我们 表明兔子出生前接触可卡因1）减少了 D1 DA受体与皮质和纹状体中的Galphas蛋白偶联， 2）减少皮层DA的诱发释放。 在出生后10至100天观察。 拟议将 观察到多巴胺能神经传递的持续功能变化 产前可卡因后是脱敏的后果， D1 DA系统，这是由于可卡因诱导的损伤， 妊娠期间的神经递质系统。 拟议的研究旨在 明确了导致 D1 DA受体转导系统的解偶联和功能性 这种影响对DA神经传递的后果。具体地说， 实验的目的是：1）探索翻译后的作用 修饰的Galphas和D1受体在产生解偶联的 D1受体系统，2）确定D1在发育的早期 受体与Gs解偶联，3）测试D1受体是否也 与连接到磷脂酰肌醇的Galphaq解偶联 水解，4）测试D1受体-Gs解偶联是否导致 D1受体介导的功能脱敏，和5）测试 产前可卡因治疗在以下方面影响的特异性： 脑区、神经递质系统和受体亚型。 了解子宫内可卡因损害正常 神经发育并产生其长期的神经行为 异常最终将使我们能够设计特定的策略， 预防或对付可卡因滥用的后果， 怀孕

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.