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.
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