Adrenergic Receptors During Periadolescent Development

青春期发育期间的肾上腺素能受体

• 批准号: 6544586
• 负责人: DAVID B BYLUND
• 金额: $ 33.08万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-20 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6544586
• 关键词: G protein; adrenergic receptor; age difference; animal puberty; autoradiography; cyclic AMP; hypothermia; immature animal; laboratory rat; mature animal; neuropharmacology; neurotransmitter agonist; pharmacokinetics; protein localization; receptor coupling; receptor expression; regulatory gene

DESCRIPTION (provided by applicant): The up-regulation or down-regulation of neurotransmitter receptors has become one of the major, proposed mechanisms for a variety of therapeutic drugs. Drug-induced regulation of central catecholamine receptors has been extensively studied in adults, but little is known about their regulation in young animals. It is particularly important to understand the nature of drug-induced regulation of adrenergic receptors in young animals for two reasons. First, adrenergic agents are used clinically in children and adolescents. Our preliminary data show that the effects of adrenergic agents on the young adrenergic system are qualitatively different from their effects on the adult. Second, because the adrenergic system is late developing, and is still changing during periadolescent development, perturbations in this system are more likely to have greater, qualitatively different, and longer-lasting effects than on a mature system. The central hypothesis of the proposed studies is that CNS alpha-2 and beta adrenergic receptors are differentially regulated in periadolescent as compared to adult rats, as reflected by responses to two drugs that effect the noradrenergic and serotonin systems (the selective re-uptake inhibitors desipramine and fluvoxamine). The first specific hypothesis, that central adrenergic receptors will be up-regulated in periadolescent animals rather than down-regulated as observed in adult animals, will be tested using quantitative autoradiography to determine alpha-2 and beta adrenergic receptor density. The second hypothesis, that the functional coupling between the adrenergic receptors and their G proteins will be increased in the young animals as compared to adults, will be tested using cyclic AMP accumulation and GTPyS binding assays. The third hypothesis, that the functional responses to agonist stimulation will be increased in periadolescent animals as consequences of these alterations in regulation and coupling, will be studied using regulation of immediate early gene expression and agonist induced-hypothermia. These studies in rats will help provide the necessary foundation for understanding the regulation of the adrenergic receptor systems in young animals leading to an eventual understanding of the effects of chronic drug treatment in children.

描述（由申请人提供）：神经递质受体的上调或下调已成为各种治疗药物的主要机制之一。药物诱导的中央儿茶酚胺受体调节已在成年人中进行了广泛的研究，但对它们在年轻动物中的调节知之甚少。了解药物诱导的幼年动物肾上腺素受体调节的性质尤其重要，原因有两个。首先，肾上腺素能在儿童和青少年临床上使用。我们的初步数据表明，肾上腺素能对年轻肾上腺素能系统的影响与对成年人的影响在质上不同。其次，由于肾上腺素能系统正在迟到，并且在周围的发育过程中仍在变化，因此该系统中的扰动更有可能具有更大，质量不同且持久的效果，而不是对成熟系统的扰动。拟议研究的中心假设是，与成年大鼠相比，CNSα-2和β肾上腺素能受体在周围的周围有差异调节，这反映了对两种影响去甲肾上腺素能和5-羟色胺系统的反应（选择性重新激发抑制剂脱发子甲状腺素和氟乙胺和氟乙胺）。第一个特定的假设是，将使用定量自显影术测试中央肾上腺素能受体在周围动物中上调，而不是在成年动物中观察到的下调，以确定α-2和β肾上腺素能受体密度。第二个假设是，与成年人相比，年轻动物中肾上腺素能受体及其G蛋白之间的功能耦合将增加，将使用环状AMP积累和GTPYS结合测定进行测试。第三个假设将通过调节直接的早期基因表达和激动剂诱导的热疗法来研究，将在周围动物中增加对激动剂刺激的功能反应，这是这些调节和偶联的结果。在大鼠中的这些研究将有助于为了解年轻动物的肾上腺素能受体系统的调节提供必要的基础，从而最终了解慢性药物治疗对儿童的影响。