Cocaine-Induced Disturbances of Mouse Brain Development

描述（由申请人提供）： 滥用药物是全球最大的可预防原因， 在美国婴儿的发展妥协。尽管付出了巨大的努力 在确定特定的神经发育方面，临床进展缓慢， 这些药物对吸毒母亲的子女的影响。啮齿动物模型 已经特别提供了关于急性 以及滥用药物的慢性行为。一些动物模型 发育药物暴露表明可卡因可能作为一种行为， 致畸剂，一种能够改变胎儿大脑发育和随后 功能在过去的八年里，我们开发了一种透明的模型， 可卡因暴露在小鼠中，并且已经能够识别， 结果将可卡因和可卡因引起的营养不良的作用分开， 损害胎儿大脑的生长和发育。子宫内钴暴露结果 在小鼠幼崽的特定行为、解剖学和生化变化中，许多 这些症状会持续到成年。在我们观察到的可重复的变化中， 在接触可卡因的小鼠中，具体归因于可卡因的是：1） 神经元迁移和随后皮质脑发育的中断 结构; 2）延迟成熟的皮质神经元利用 神经递质GABA; 3）Dl样神经递质GABA的偶联持续减少; 纹状体和新皮质中的受体及其G偶联信号;和4）a 5-HT 1A自身受体功能偶联的持续增加， 背中缝的神经元我们提出了一系列的实验来证实和 扩展了这些表征特定神经解剖的发现， 药理学和分子学的后果诱导产前可卡因在 青少年和成年人大脑皮层和皮层下的特殊结构 小鼠这些包括：具体目标1）定量神经解剖学研究， 准确描述神经病理学变化，特别是延迟 GABA能细胞的出生后成熟;特异性目的2） 体外受体竞争研究和环化酶测定， 前脑Di样信号转导的功能性共构和特异性目的 3)体外受体竞争研究和[35 s] GTP γ S测定以鉴定 增强的5-HT 1A自身受体在背侧神经元上的功能偶联 拉斐尔希望我们的动物研究可以导致相关的识别， 可用于临床环境的选择性治疗干预 以改善毒性，或改善神经发育结果， 在子宫内服用可卡因后大脑发育受损的儿童 exposure.

DESCRIPTION(Provided by applicant): Gestational exposure to drugs of abuse is the single largest preventable cause of developmental compromise of infants in America today. Despite intense effort clinical progress has been slow in ascertaining the specific neurodevelopmental effects of these drugs on the children of drug-abusing mothers. Rodent models have been particularly informative regarding mechanisms underlying the acute and chronic actions of drugs of abuse. A number of animal models of developmental drug exposure suggest that cocaine may act as a behavioral teratogen, a drug capable of altering fetal brain development and subsequent function. Over the past eight years we have developed a model of transpiacental cocaine exposure in mice, and have been able to identify, and for certain outcomes separate the role of cocaine and cocaine-induced malnutrition in impairing fetal brain growth and development. Cocaine exposure in utero results in specific behavioral, anatomical and biochemical changes in mouse pups, many of which persist into adulthood. Among the reproducible changes that we observe in exposed mice that are specifically attributable to cocaine are: 1) disruptions in neuronal migration and subsequent development of cortical brain structures; 2) delayed maturation of cortical neurons utilizing the neurotransmitter GABA; 3) a persistent decrease in coupling of Dl -like receptors and their Gscoupled signals in striatum and neocortex; and 4) a persistent increase in the functional coupling of the 5-HT 1 A autoreceptor on neurons in the Dorsal Raphe. We propose a series of experiments to confirm and extend these findings characterizing specific neuroanatomical, pharmnacological, and molecular consequences induced by prenatal cocaine in particular cortical and subcortical brain structures in juvenile and adult mice. These include: Specific Aim 1) quantitative neuroanatomic studies to more accurately characterize neuropathologic changes, and in particular delayed postnatal maturation of GABAergic cells; Specific Aim 2) vitro receptor competition studies and cyclase assays to identify impaired functional coqpling of forebrain Di-like signal transduction; and Specific Aim 3) in vitro receptor competition studies and [35s]GTPyS assays to identify enhanced functional coupling of 5-HT1A autoreceptors on neurons in the Dorsal Raphe. It is hoped that our animal work may lead to identification of relevant, selective therapeutic interventions which can be utilized in clinical settings to ameliorate the toxicity, or to improve the neurodevelopmental outcome of children whose brain development is compromised following in utero cocaine exposure.