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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH064772-01A1
Application #
6544586
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Brady, Linda S
Project Start
2002-09-20
Project End
2006-06-30
Budget Start
2002-09-20
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$330,750
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Sanders, Jeff (2016) Data on Arc and Zif268 expression in the brain of the ?-2A adrenergic receptor knockout mouse. Data Brief 7:8-11
Sanders, Jeff (2016) Developmental DSP4 effects on cortical Arc expression. Neurosci Lett 618:89-93
Essali, Norah; Sanders, Jeff (2016) Interdependent adrenergic receptor regulation of Arc and Zif268 mRNA in cerebral cortex. Neurosci Lett 612:38-42
Taneja, Manish; Salim, Samina; Saha, Kaustuv et al. (2011) 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. Behav Brain Res 221:25-33
Sanders, J D; Happe, H K; Bylund, D B et al. (2011) Changes in postnatal norepinephrine alter alpha-2 adrenergic receptor development. Neuroscience 192:761-72
Sanders, J D; Happe, H K; Bylund, D B et al. (2008) Differential effects of neonatal norepinephrine lesions on immediate early gene expression in developing and adult rat brain. Neuroscience 157:821-32
Kozisek, Megan E; Middlemas, David; Bylund, David B (2008) The differential regulation of BDNF and TrkB levels in juvenile rats after four days of escitalopram and desipramine treatment. Neuropharmacology 54:251-7
Kozisek, Megan E; Middlemas, David; Bylund, David B (2008) Brain-derived neurotrophic factor and its receptor tropomyosin-related kinase B in the mechanism of action of antidepressant therapies. Pharmacol Ther 117:30-51
Deupree, Jean D; Burke, William J; Bylund, David B (2008) Alpha-2 adrenergic-induced changes in rectal temperature in adult and 13-day old rats following acute and repeated desipramine administration. BMC Pharmacol 8:17
Deupree, Jean D; Montgomery, Megan D; Bylund, David B (2007) Pharmacological properties of the active metabolites of the antidepressants desipramine and citalopram. Eur J Pharmacol 576:55-60

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