Prenatal Cocaine Alters Cortical Dopamine Function

产前可卡因改变皮质多巴胺功能

基本信息

批准号：
6855748
负责人：
ROBERT Henry ROTH
金额：
$ 28.61万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-08-01 至 2007-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Cocaine use among women of childbearing age is alarmingly high and renders a sizable population of children at risk for the long-lasting neurobehavioral abnormalities associated with prenatal cocaine exposure, such as difficulty modulating attention, impulsivity, responsivity, and deficits in short-term memory. While these clinical studies demonstrate harmful effects of prenatal cocaine, controlled studies in laboratory animals are needed to understand more fully the effect that gestational cocaine exposure has on the brain biochemistry of the offspring. Our progress strongly supports our original hypothesis that prenatal cocaine disrupts function in the mesoprefrontal system, namely the medial prefrontal cortex and A10 DA neurons that project there, and that this deficit would be most apparent under mildly stressful conditions. Specifically, in prenatal cocaine rats, we have observed 1) enhanced activation of both the A10 neurons and the intrinsic neurons of the prefrontal cortex, as indicated by expression of the immediate-early gene, Fos, 2) ventromedial prefrontal cortex dopamine turnover and serum corticosterone levels to be hyper-responsive to mild stress, 3) a 25% loss of A10, but not A8 or A9, neurons, likely the result of gestational changes precipitated by cocaine, and 5) poor short-term memory. We now propose to pursue these intriguing results by investigating 3 interrelated aspects of the hyper-reactive mesoprefrontal system, specifically, 1) the mechanism of the altered dopaminergic response to stress in the prefrontal cortex, possibly linked to enhanced excitatory input, 2) the consequences of the 25% loss of A10 neurons including potential changes in innervation and reactivity of prefrontal dopamine neurons, and 3) the hyper-reactive Fos expression in either or both the excitatory pyramidal and inhibitory interneurons of the prefrontal cortex and the relationship to cognitive deficits. These studies will utilize our expertise in catecholamine biochemistry together with recent progress made in our laboratory including development of an intravenous, prenatal cocaine model, use of a predator odor stress (TMT), use of a short-term memory task free of reference memory components, rewards or punishments, and, finally, stereological techniques for microscopy studies. We anticipate that these studies will provide valuable scientific insights into the biochemical underpinnings of the mesoprefrontal system dysfunction induced by prenatal cocaine exposure, advance our understanding of the neurobiology of the deficits, and, ultimately, permit the logical treatment of the deficits induced in exposed children

描述（由申请人提供）：育龄妇女使用可卡因年龄高得惊人，使相当多的儿童面临患病风险与产前可卡因相关的长期神经行为异常暴露，例如难以调节注意力、冲动、反应性，和短期记忆缺陷。虽然这些临床研究表明产前可卡因的有害影响，实验动物对照研究需要更全面地了解妊娠可卡因的影响暴露会对后代的大脑生物化学产生影响。我们的进展有力地支持了我们最初的假设，即产前可卡因破坏中前额叶系统的功能，即内侧前额叶皮层和 A10 DA 神经元投射到那里，这种缺陷将是在轻度压力条件下最为明显。具体来说，在产前可卡因大鼠，我们观察到 1) A10 神经元的激活增强和前额皮质的内在神经元，如表达所示立即早期基因 Fos，2) 腹内侧前额皮质多巴胺周转率和血清皮质酮水平对轻度压力过度反应， 3) A10 神经元损失 25%，但 A8 或 A9 神经元没有损失，可能是由于可卡因引起的妊娠变化，以及 5) 短期记忆力差。我们现在建议通过调查 3 来追求这些有趣的结果过度反应的中前额叶系统的相互关联的方面，具体来说， 1）多巴胺能对应激反应改变的机制前额皮质，可能与增强的兴奋性输入有关，2） A10 神经元损失 25% 的后果包括潜在的变化前额叶多巴胺神经元的神经支配和反应性，以及3）兴奋性锥体和兴奋性锥体或两者中的高反应性 Fos 表达前额皮质的抑制性中间神经元及其关系认知缺陷。这些研究将利用我们在儿茶酚胺方面的专业知识生物化学以及我们实验室最近取得的进展，包括开发静脉注射、产前可卡因模型、使用捕食者气味压力（TMT），使用无参考记忆的短期记忆任务组成部分、奖励或惩罚，以及最后的立体学技术显微镜研究。我们预计这些研究将提供有价值的科学见解中前额叶系统功能障碍的生化基础通过产前接触可卡因，增进我们对神经生物学的理解赤字，并最终允许对赤字进行合乎逻辑的处理暴露儿童中诱发