Maternal Cocaine Use and Neurite Outgrowth

母亲使用可卡因和神经突生长

• 批准号: 6634277
• 负责人: Diane M Snow
• 金额: $ 18.1万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-15 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634277
• 关键词: animal poison; calcium channel blockers; cocaine; dendrites; developmental neurobiology; embryo /fetus; embryo /fetus toxicology; enzyme activity; growth cones; hippocampus; laboratory rat; locus coeruleus; neurogenesis; neuropharmacology; neurotoxicology; neurotoxins; norepinephrine; tyrosine 3 monooxygenase

DESCRIPTION (provided by applicant): Cocaine use during pregnancy is associated with neurobehavioral abnormalities in offspring that include alterations in attentiveness. Understanding the mechanisms by which maternal cocaine abuse adversely affects the developing fetus is critical for the development of appropriate treatments and intervention strategies. The actions of cocaine stem from nonselective inhibition of catecholaminergic neurotransmitter reuptake systems. New evidence shows that norepinephrine (NE) cell bodies within the locus coeruleus (LC), but not dopamine cell bodies with the substantia nigra, are affected following prenatal cocaine exposure using a clinically relevant model. This, combined with previous data showing that cocaine affects LC neuron behavior, give strong reason to pursue this system rigorously to refine previously held hypotheses and to determine new mechanisms for the deleterious effects of prenatal cocaine at the cell biological level. This study focuses on the LC neurons and one target, the hippocampus (limbic system), in rats prenatally exposed to cocaine in vivo and in vitro. Our hypothesis is: maternal cocaine use during a critical period of pregnancy causes selective alterations in the central noradrenergic system evidenced, in part, by effects on neuronal development such as neurite initiation, directed process outgrowth, appropriate neuronal pathfinding, and connectivity. We will test this hypothesis by first, determining effects of maternal cocaine exposure on the noradrenergic cells of the fetal rat LC using a well-established, clinically relevant model for fetal cocaine exposure, followed by analysis during critical outgrowth periods of neurite initiation, the rate of neurite outgrowth, total neurite length, growth cone behaviors (e.g. pathfinding), and characteristics of target (hippocampus) selectivity and connectivity. Second, we will determine effects of physiologically relevant concentrations of cocaine in tissue culture on the noradrenergic cells of the fetal rat LC, by analyzing neurite initiation, the rate of neurite extension, total neurite length, neuronal growth cone behaviors (e.g. pathfinding), and characteristics of target (hippocampus) selectivity and connectivity. The long term goal of this study is to uncover mechanisms of the adverse effects of prenatal cocaine on developing nerve cells that lead to inappropriate connectivity and impaired function. This study represents a novel and innovative approach toward an understanding of the basic cell biology of noradrenergic neurons as they respond to cocaine during development, and may ultimately permit the development of effective pharmacotherapeutic interventions for the treatment of cocaine-exposed offspring.

描述（由申请人提供）：怀孕期间的可卡因使用 后代的神经行为异常包括改变 专心。了解母体可卡因滥用的机制 不利影响发育中的胎儿对发展至关重要 适当的治疗和干预策略。可卡因茎的作用 来自儿茶酚胺能神经递质再摄取的非选择性抑制 系统。新证据表明，去甲肾上腺素（NE）细胞体内 基因座（LC），但没有底虫的多巴胺细胞体， 使用临床相关的产前可卡因暴露后受到影响 模型。这与先前的数据相结合，表明可卡因会影响LC神经元 行为，有充分的理由严格追求该系统以完善 以前持有假设并确定有害的新机制 产前可卡因在细胞生物学水平上的影响。这项研究重点 大鼠的LC神经元和一个靶标Hampocampus（边缘系统） 在体内和体外暴露于可卡因。我们的假设是：母亲 在关键时期，可卡因的使用会导致选择性改变 在中央甲肾上腺素能系统中，部分通过对神经元的影响证明了 开发，例如神经突的启动，定向过程的生长，适当的 神经元探路和连通性。我们将首先通过 确定母体可卡因暴露对去甲肾上腺素能细胞的影响 胎儿大鼠LC使用胎儿的良好临床相关模型 可卡因暴露，然后在关键的出生期间进行分析 神经突的启动，神经突生长的速率，总神经突长度，生长 锥行为（例如探路）和目标特征（海马） 选择性和连通性。其次，我们将确定 可卡因在组织培养的生理相关浓度 胎儿大鼠LC的去肾上腺素能细胞，通过分析神经突的起始， 神经突扩展的速率，总神经突长度，神经元生长锥行为 （例如，探路），以及目标（海马）选择性的特征和 连接性。这项研究的长期目标是发现 产前可卡因对发展导致神经细胞的不利影响 不适当的连通性和功能受损。这项研究代表了一个小说 和创新的方法来理解对基本细胞生物学的理解 去肾上腺素能神经元在发育过程中对可卡因做出反应，并且可能 最终允许开发有效的药物治疗 可卡因暴露后代的干预措施。