Adrenergic Receptors During Periadolescent Development

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年人中得到广泛研究，但对它们在幼年动物中的调节知之甚少。由于两个原因，了解药物诱导的幼年动物肾上腺素能受体调节的性质尤为重要。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的肾上腺素能系统的影响是定性的不同，他们对成人的影响。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，因此该系统中的扰动比成熟系统更可能产生更大、性质不同和持续时间更长的影响。拟议研究的中心假设是，与成年大鼠相比，青春期前大鼠的CNS α-2和β肾上腺素能受体受到差异调节，这反映在对影响去甲肾上腺素能和5-羟色胺系统的两种药物（选择性再摄取抑制剂地昔帕明和氟伏沙明）的反应上。将使用定量放射自显影术检测第一个特定假设，即中枢肾上腺素能受体在青春期前动物中上调，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，即与成年动物相比，幼年动物中肾上腺素能受体及其G蛋白之间的功能偶联将增加，将使用环AMP蓄积和GTP γ S结合试验进行测试。第三个假设，即激动剂刺激的功能反应将增加在青春期动物的后果，这些变化的监管和耦合，将研究使用即时早期基因表达和激动剂诱导的低温调节。在大鼠中的这些研究将有助于为了解幼龄动物中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.