Adrenergic Receptors During Periadolescent Development

描述(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。药物诱导的中枢儿茶酚胺受体的调节在成年动物中得到了广泛的研究，但对其在幼年动物中的调节知之甚少。了解药物诱导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，肾上腺素能药物用于儿童和青少年的临床。我们的初步数据显示，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，且在青春期前发育过程中仍在变化，因此这一系统中的干扰比成熟系统更有可能产生更大的、质的不同的、持续时间更长的影响。这项研究的中心假设是，与成年大鼠相比，青春期前大鼠的中枢神经系统α-2和β肾上腺素能受体受到不同的调节，这反映在两种影响去甲肾上腺素和5-羟色胺系统的药物(选择性再摄取抑制剂地昔帕明和氟伏沙明)的反应上。第一个特定的假设是，中央肾上腺素能受体在青春期前的动物中上调，而不是像在成年动物中观察到的那样下调，将使用定量放射自显影来测试，以确定α-2和β肾上腺素能受体密度。第二个假设是，幼年动物的肾上腺素能受体及其G蛋白之间的功能偶联将比成年动物增加，这将通过循环AMP积累和GTPyS结合分析来检验。第三个假设是，青春期动物对激动剂刺激的功能反应将会增加，这是这些调节和偶联变化的结果，将使用即刻早期基因表达的调节和激动剂诱导的低温来研究。这些在大鼠身上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。

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.