Prenatal Cocaine Alters Cortical Dopamine Function

产前可卡因改变皮质多巴胺功能

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/6855748
• 关键词: animal developmental psychology; behavior test; behavioral /social science research tag; cell population study; cocaine; cognition disorders; developmental genetics; developmental neurobiology; dopamine; drug abuse; embryo /fetus toxicology; fos protein; gene environment interaction; gene expression; high performance liquid chromatography; immunocytochemistry; laboratory rat; neurochemistry; neurogenesis; neurogenetics; neurotransmitter transport; prefrontal lobe /cortex; pregnancy; prenatal growth disorder; prenatal stress; protein structure function

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）：可卡因在生育妇女中使用 年龄令人震惊，并使大量的儿童有危险 与产前可卡因有关的持久神经行为异常 暴露，例如难以调节注意力，冲动，反应性， 和短期内存中的缺陷。这些临床研究表明 产前可卡因的有害作用，实验动物对照研究 需要更充分地了解妊娠可卡因的影响 暴露于后代的大脑生物化学。 我们的进步强烈支持我们原始可卡因的原始假设 中间额叶系统中的干扰功能，即内侧前额叶 皮质和A10 DA神经元在那里投射，这种赤字将是 在轻度压力条件下最明显。具体来说，在产前 可卡因大鼠，我们观察到1）增强了两个A10神经元的激活 以及前额叶皮质的固有神经元，如表达所示 直接至上的基因，fos，2）腹侧前额叶皮层多巴胺 营业额和血清皮质酮水平超应为轻度压力， 3）A10的25％损失，而不是A8或A9，神经元，这可能是 可卡因沉淀和5）短期记忆不佳的妊娠变化。 我们现在建议通过研究3来追求这些有趣的结果 特别是介质系统的相互关联的方面，特别是 1）多巴胺能反应对应激的改变的机制 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，包括潜在变化 前额叶多巴胺神经元的神经和反应性，3） 兴奋性金字塔和两者中的过度反应性FOS表达和 前额叶皮层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），免费使用短期内存任务 组成部分，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为您提供宝贵的科学见解 介孔系统功能障碍的生化基础引起的 通过产前可卡因暴露，提高了我们对神经生物学的理解 缺陷，最终允许对缺陷的逻辑治疗 在暴露的孩子中诱导