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Adrenergic Receptors During Periadolescent Development

青春期发育期间的肾上腺素能受体

基本信息

批准号：
6920626
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
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-20 至 2007-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6920626
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

项目摘要

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多种治疗药物的主要拟议机制之一。药物诱导的中枢儿茶酚胺受体调节已在成人中进行了广泛研究，但对其在幼年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能受体调节的本质尤为重要，原因有两个。首先，肾上腺素能药物在临床上用于儿童和青少年。我们的初步数据表明，肾上腺素能药物对年轻肾上腺素能系统的影响与对成人的影响有本质上的不同。其次，由于肾上腺素能系统发育较晚，并且在青春期发育期间仍在变化，因此与成熟系统相比，该系统中的扰动更有可能产生更大、性质不同和更持久的影响。拟议研究的中心假设是，与成年大鼠相比，青春期大鼠的 CNS α-2 和 β 肾上腺素受体受到不同的调节，这反映在对影响去甲肾上腺素能和血清素系统的两种药物（选择性再摄取抑制剂地昔帕明和氟伏沙明）的反应上。第一个具体假设是，中枢肾上腺素受体在青春期动物中会上调，而不是像在成年动物中观察到的那样下调，该假设将使用定量放射自显影术进行测试，以确定 α2 和 β 肾上腺素能受体密度。第二个假设是，与成年动物相比，幼年动物的肾上腺素受体与其 G 蛋白之间的功能耦合会增强，将使用环 AMP 积累和 GTPγS 结合测定来测试。第三个假设是，由于这些调节和耦合的改变，青春期动物对激动剂刺激的功能反应将会增强，将利用立即早期基因表达的调节和激动剂诱导的低温来研究。这些对大鼠的研究将有助于为了解幼年动物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。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Differential effects of inescapable stress on locus coeruleus GRK3, alpha2-adrenoceptor and CRF1 receptor levels in learned helpless and non-helpless rats: a potential link to stress resilience.

DOI：
10.1016/j.bbr.2011.02.018
发表时间：
2011-08-01
期刊：
BEHAVIOURAL BRAIN RESEARCH
影响因子：
2.7
作者：
Taneja, Manish;Salim, Samina;Saha, Kaustuv;Happe, H. Kevin;Qutna, Nidal;Petty, Frederick;Bylund, David B.;Eikenburg, Douglas C.
通讯作者：
Eikenburg, Douglas C.

Development of the norepinephrine transporter in the rat CNS.

大鼠中枢神经系统去甲肾上腺素转运蛋白的发育。