Dopaminergic Influences on Brain Formation and Function

多巴胺能对大脑形成和功能的影响

• 批准号: 7022952
• 负责人: GREGG D STANWOOD
• 金额: $ 7.45万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7022952
• 关键词: biological signal transduction; brain metabolism; brain morphology; cerebral cortex; cocaine; confocal scanning microscopy; dendrites; developmental disease /disorder; developmental neurobiology; disease /disorder model; dopamine receptor; dosage; drug delivery systems; drug metabolism; embryo /fetus toxicology; immunocytochemistry; intravenous drug abuse; laboratory mouse; model design /development; neuropharmacology; neurophysiology; pharmacokinetics; phosphorylation; pregnancy circulation; receptor coupling

Biogenic amines such as dopamine regulate the formation and function of neural circuits within the developing forebrain. The pharmacological and genetic alterations of these systems during pre- and postnatal development are linked to both neurological and neuropsychiatric abnormalities. Using a rabbit model of low dose fetal cocaine exposure, we previously described specific neuroanatomical, biochemical,and behavioral deficits following permanent inhibition of dopamine D1 receptor signaling. The biobehavioral changes observed in this model reproduce some of the alterations that have been observed in the children of human mothers who have abused cocaine during a sensitive period of fetal development. The current availability of sophisticated transgenic and genetic targeting technologies affords a unique opportunity to gain additional insight into the molecular mechanisms that influence the effects of cocaine on brain development and circuit function. However, these studies require the generation of a novel model of low dose intravenous prenatal cocaine exposure in the mouse strain typically used in genetic studies of brain development and function. The experiments proposed in this application are therefore designed to develop such a murine model. In Aim 1 we will establish the successful delivery of drugs to pregnant C57BL/6J mice via chronic jugular catheters and deliver low dose, intravenous cocaine to dams during the period of peak cortical development. Plasma and brain cocaine and metabolite concentrations will be monitored to determine the extent to which specific doses mimic the pharmacokinetic responses that have been documented in rat models and in humans abusing cocaine. In Aim 2, the effects of this treatment on the physiological and neurological development of offspring will be assessed by histological, neuroanatomical, and biochemical approaches. Permanent alterations in dendritic structure of neurons and impairment of D1 receptor signaling in DA-rich cortical regions are central hallmarks of the rabbit model and we will initially survey the mouse model for similar deficits. The successful establishment of the intravenous murine model will provide the requisite preliminary data to propose a more complete series of genetic, pharmacological and behavioral studies. The mouse model will thus facilitate sophisticated molecular and cellular analyses of altered neurotransmitter signaling, and may lead to novel intervention strategies to normalize the resultant developmental disabilities.

生物胺如多巴胺调节发育中的前脑内神经回路的形成和功能。这些系统在产前和产后发育过程中的药理学和遗传学改变与神经和神经精神异常有关。使用低剂量胎儿可卡因暴露的兔模型，我们以前描述了特定的神经解剖学，生化和行为缺陷后永久抑制多巴胺D1受体信号。在这个模型中观察到的生物行为变化再现了在胎儿发育的敏感时期滥用可卡因的人类母亲的孩子中观察到的一些变化。当前 先进的转基因和遗传靶向技术的出现为进一步深入了解影响可卡因对大脑发育和回路功能的作用的分子机制提供了独特的机会。然而，这些研究需要在通常用于脑发育和功能的遗传研究的小鼠品系中产生低剂量静脉内产前可卡因暴露的新模型。因此，本申请中提出的实验被设计用于开发这样的鼠模型。在目标1中，我们将建立通过慢性颈静脉导管向妊娠C57 BL/6 J小鼠成功递送药物，并在皮质发育高峰期向母鼠递送低剂量静脉内可卡因。将监测血浆和脑可卡因和代谢物浓度，以确定特定剂量在多大程度上模拟在大鼠模型和滥用可卡因的人类中记录的药代动力学反应。在目标2中，将通过组织学、神经解剖学和生物化学方法评估该处理对后代生理和神经发育的影响。神经元树突结构的永久性改变和DA丰富的皮质区域中D1受体信号传导的损伤是兔模型的中心标志，我们将首先调查小鼠模型的类似缺陷。小鼠静脉注射模型的成功建立将为更完整的遗传学、药理学和行为学研究提供必要的初步数据。因此，小鼠模型将有助于对改变的神经递质信号进行复杂的分子和细胞分析，并可能导致新的干预策略，使由此产生的发育障碍正常化。