Prenatal Cocaine Alters Cortical Dopamine Function

描述(申请人提供)：育龄妇女使用可卡因 年龄高得令人担忧，这使得相当大的儿童群体面临患上 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、响应性、 以及短期记忆的缺陷。虽然这些临床研究表明 对实验动物进行的对照研究：产前可卡因的有害影响 需要更充分地了解怀孕可卡因的影响 暴露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，即产前可卡因 破坏中前额叶系统的功能，即内侧前额叶 大脑皮层和A10个DA神经元投射到那里，这种缺陷将是 在压力较小的情况下最为明显。具体来说，在产前 可卡因大鼠，我们观察到1)两个A10神经元的激活 以及前额叶皮质的内源性神经元，如表达所示 即刻早期基因Fos，2)腹内侧额叶皮质多巴胺 周转率和血清皮质酮水平对轻度压力反应强烈， 3)A10神经元25%的损失，而不是A8或A9神经元的损失，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个人来追求这些有趣的结果 高反应性中前叶系统的相关方面，具体地说， 1)应激引起的多巴胺能反应改变的机制 前额叶皮质，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； 兴奋性锥体细胞和/或兴奋性锥体细胞高反应性Fos的表达 前额叶皮质抑制性中间神经元及其与神经元的关系 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的最新进展，包括 利用捕食者气味建立静脉注射、产前可卡因模型 应激(TMT)，使用没有参考记忆的短期记忆任务 组件、奖励或惩罚，最后是立体技术 显微镜研究。 我们预计这些研究将提供有价值的科学见解 前额叶系膜系统功能障碍的生化基础 通过产前接触可卡因，增进了我们对糖尿病神经生物学的理解 赤字，并最终允许合乎逻辑地处理赤字 在接触过的儿童中诱发

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