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: 6924139
• 负责人: GREGG D STANWOOD
• 金额: $ 7.58万
• 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/6924139
• 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。这些系统在出生前和出生后发育过程中的药理和遗传变化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，我们先前描述了永久性抑制多巴胺D1受体信号后特定的神经解剖学、生化和行为缺陷。在这个模型中观察到的生物行为变化重现了在胎儿发育敏感期滥用可卡因的人类母亲的孩子所观察到的一些变化。海流 先进的转基因和基因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电路功能影响的分子机制提供了独特的机会。然而，这些研究需要在小鼠品系中产生一种新的低剂量产前静脉注射可卡因的模型，该模型通常用于大脑发育和功能的遗传学研究。因此，本申请中提出的实验就是为了开发这样的小鼠模型。在目标1中，我们将通过慢性颈静脉导管成功地将药物输送到怀孕的C57BL/6J小鼠，并在皮质发育高峰期将低剂量的静脉注射可卡因输送到母鼠。将监测血浆、脑内可卡因和代谢物的浓度，以确定特定剂量在多大程度上模拟已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、神经解剖学和生化方法来评估这种治疗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富含DA的皮质区域的D1受体信号受损是兔模型的主要特征，我们将首先调查类似缺陷的小鼠模型。静脉注射小鼠模型的成功建立将为提出一系列更完整的遗传学、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。