Cocaine-Induced Disturbances of Mouse Brain Development

可卡因引起的小鼠大脑发育障碍

• 批准号: 6515513
• 负责人: BARRY E KOSOFSKY
• 金额: $ 32.39万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6515513
• 关键词: biological signal transduction; brain mapping; cocaine; developmental neurobiology; disease /disorder model; dorsal raphe nucleus; embryo /fetus toxicology; gamma aminobutyrate; histopathology; laboratory mouse; neuroanatomy; neuropharmacology; prenatal growth disorder; receptor coupling

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.

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 当今美国婴儿发育受损的问题。尽管付出了巨大的努力 确定特定神经发育的临床进展缓慢 这些药物对吸毒母亲的孩子的影响。啮齿动物模型 关于急性发作机制的信息特别丰富 和滥用药物的长期行为。多种动物模型 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的药物 功能。在过去的八年里，我们开发了一种跨皮中心模型 小鼠中的可卡因暴露，并且已经能够识别，并且对于某些 结果区分了可卡因和可卡因引起的营养不良在 损害胎儿大脑的生长发育。子宫内可卡因暴露结果 在小鼠幼崽的特定行为、解剖和生化变化中，许多 其中持续到成年。在我们观察到的可重现的变化中 在暴露于可卡因的小鼠中，具体可归因于：1) 神经元迁移和皮质脑随后发育的破坏 结构； 2）利用延迟皮质神经元的成熟 神经递质 GABA； 3) Dl-like耦合持续减少 纹状体和新皮质中的受体及其 Gs 耦合信号；和 4) 5-HT 1 A 自身受体的功能耦合持续增加 中缝背侧的神经元。我们提出了一系列实验来确认和 扩展这些具有特定神经解剖学特征的发现， 产前可卡因引起的药理学和分子后果 青少年和成人的特殊皮质和皮质下大脑结构 老鼠。其中包括： 具体目标 1) 定量神经解剖学研究 准确地表征神经病理变化，特别是延迟的 GABA能细胞出生后成熟；具体目标 2) 体外受体竞争研究和环化酶测定以识别受损的 前脑Di样信号转导的功能性调节；和具体目标 3) 体外受体竞争研究和 [35s]GTPyS 测定来鉴定 增强背侧神经元上 5-HT1A 自身受体的功能耦合 拉斐。希望我们的动物工作能够识别出相关的、 可用于临床环境的选择性治疗干预措施 改善毒性，或改善神经发育结果 子宫内吸食可卡因后大脑发育受到损害的儿童 接触。