Cocaine-Induced Disturbances of Mouse Brain Development

描述(由申请人提供)： 妊娠期接触滥用药物是最大的可预防原因 在今天的美国，婴儿的发育妥协。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子女的影响。啮齿动物模型 特别是关于急性呼吸道感染的发病机制。 以及长期滥用毒品的行为。一系列的动物模型 发育期药物暴露表明可卡因可能作为一种行为 致畸原，一种能够改变胎儿大脑发育和随后 功能。在过去的八年里，我们开发了一个穿透性的模型 在小鼠中接触可卡因，并已经能够识别和确定 结果区分可卡因和可卡因诱导的营养不良在 损害胎儿大脑的生长和发育。宫内可卡因暴露结果 在小鼠幼鼠的特定行为、解剖和生化变化中，许多 它们会一直持续到成年。在我们观察到的可重复的变化中 在暴露于可卡因的小鼠中，具体可归因于：1) 皮质脑中神经元迁移和随后发育的障碍 结构；2)皮层神经元的延迟成熟利用 神经递质GABA；3)类DL偶联持续减少 纹状体和新皮质的受体及其G偶联信号；4)a 5-HT1A自身受体的功能偶联持续增强 中缝背侧的神经元。我们提出了一系列实验来证实和 将这些发现扩展到特定的神经解剖学特征， 胎儿期可卡因引起的药理学和分子后果 青少年和成人特殊的皮质和皮质下脑结构 老鼠。这些包括：具体目标1)对更多的定量神经解剖学研究 准确描述神经病理变化，特别是延迟 GABA能细胞的出生后成熟；特定目标2) 体外受体竞争研究和环化酶检测用于识别受损 前脑Di样信号转导的功能序列和特定目的 3)体外受体竞争研究和[35S]GTPyS分析 5-HT1a自身受体在背侧神经元上的增强功能偶联 拉斐尔。我们希望我们的动物工作可以导致识别相关的， 可在临床环境中使用的选择性治疗干预 以减轻毒性，或改善神经发育结局 子宫内吸食可卡因后大脑发育受损的儿童 曝光。

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.