Prenatal Cocaine Alters Cortical Dopamine Function

描述（由申请方提供）：育龄妇女中的避孕药使用 年龄高得惊人，使相当多的儿童面临死亡的危险。 与产前可卡因有关的长期神经行为异常 暴露，如难以调节注意力，冲动，反应， 以及短期记忆的缺陷虽然这些临床研究表明 产前可卡因的有害影响，在实验室动物中的对照研究 需要更全面地了解妊娠期可卡因 会对后代的大脑生化产生影响。 我们的进展有力地支持了我们最初的假设， 破坏了中前额叶系统的功能，即内侧前额叶 皮质和A10 DA神经元投射在那里，这种缺陷将是 在轻度压力条件下最明显。特别是在产前 可卡因大鼠，我们已经观察到1）增强激活的A10神经元 和前额叶皮层的内在神经元，如表达 即早基因Fos的表达，2）腹内侧前额叶皮层多巴胺 周转率和血清皮质酮水平对轻度应激反应过度， 3)A10神经元减少25%，但A8或A9神经元没有减少，可能是由于 可卡因引起的妊娠期变化，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。 高反应性中前额系统的相互关联方面，具体来说， 1)多巴胺能神经元对应激反应改变的机制 前额叶皮层，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 前额叶多巴胺神经元的神经支配和反应性，以及3） 兴奋性锥体细胞和/或海马神经元中Fos的过度表达 前额叶皮层的抑制性中间神经元及其与 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，最后，体视学技术， 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 通过产前可卡因暴露，推进我们对神经生物学的理解， 赤字，并最终允许赤字的逻辑处理 在暴露儿童中诱导

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