Abstract

This proposal examines how presynaptic input plays a role in the development of growth of postsynaptic cells and organs, and determines how drug-induced alterations of neuronal development and/or function can produce post synaptic developmental abnormalities. Development of pre-and post-synaptic function of norepinephrine systems will be followed in cerebral cortex, heart and adrenal medulla by a combination of biochemical, functional and morphological procedures. These will determine normal and drug-altered development of synaptic contacts, synaptic uptake mechanisms, synaptic vesicles and post-synaptic response systems (beta-receptors, adenylate cyclase, ornithine decarboxylase, secretory systems). Correlations will be evaluated between alterations at the presynaptic level and those at the postsynaptic level involving neurotransmission and growth of the innervated tissue (including measurements of protein and nucleic acid synthesis). Drug models are chosen which produce, by different mechanisms, acceleration or retardation of presynaptic development in the three tissues: Guanethidine produces long-term destruction of peripheral sympathetic nerves, but is far less toxic to the neonatal brain and causes stimulation of the neonatal adrenal medulla. Reserpine interrupts on a temporary basis noradrenergic neurotransmission development in heart and brain but when given to pregnant rats produces centrally-mediated activation of sympatho-adrenal tone in the offspring. Triiodothyronine accelerates the onset of functional sympathetic neurotransmission of heart and adrenal medulla and enhances central synaptogenesis. Nicotine causes stimulation of autonomic ganglia and direct stimulation of the adrenal medulla. These different models will elucidate the role of neuronal input in development of central and peripheral postsynaptic systems and will identify specific alterations in presynaptic and postsynaptic development associated with drug exposure or drug models of developmental disorders.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD009713-11
Application #
3311153
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1976-06-15
Project End
1987-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
11
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Kreider, Marisa L; Tate, Charlotte A; Cousins, Mandy M et al. (2006) Lasting effects of developmental dexamethasone treatment on neural cell number and size, synaptic activity, and cell signaling: critical periods of vulnerability, dose-effect relationships, regional targets, and sex selectivity. Neuropsychopharmacology 31:12-35
Aldridge, Justin E; Meyer, Armando; Seidler, Frederic J et al. (2005) Developmental exposure to terbutaline and chlorpyrifos: pharmacotherapy of preterm labor and an environmental neurotoxicant converge on serotonergic systems in neonatal rat brain regions. Toxicol Appl Pharmacol 203:132-44
Meyer, Armando; Seidler, Frederic J; Aldridge, Justin E et al. (2005) Developmental exposure to terbutaline alters cell signaling in mature rat brain regions and augments the effects of subsequent neonatal exposure to the organophosphorus insecticide chlorpyrifos. Toxicol Appl Pharmacol 203:154-66
Kreider, Marisa L; Aldridge, Justin E; Cousins, Mandy M et al. (2005) Disruption of rat forebrain development by glucocorticoids: critical perinatal periods for effects on neural cell acquisition and on cell signaling cascades mediating noradrenergic and cholinergic neurotransmitter/neurotrophic responses. Neuropsychopharmacology 30:1841-55
Slotkin, Theodore A; Oliver, Colleen A; Seidler, Frederic J (2005) Critical periods for the role of oxidative stress in the developmental neurotoxicity of chlorpyrifos and terbutaline, alone or in combination. Brain Res Dev Brain Res 157:172-80
Kreider, Marisa L; Levin, Edward D; Seidler, Frederic J et al. (2005) Gestational dexamethasone treatment elicits sex-dependent alterations in locomotor activity, reward-based memory and hippocampal cholinergic function in adolescent and adult rats. Neuropsychopharmacology 30:1617-23
Rhodes, Melissa C; Seidler, Frederic J; Abdel-Rahman, Ali et al. (2004) Terbutaline is a developmental neurotoxicant: effects on neuroproteins and morphology in cerebellum, hippocampus, and somatosensory cortex. J Pharmacol Exp Ther 308:529-37
Kreider, Marisa L; Seidler, Frederic J; Slotkin, Theodore A (2004) Beta-adrenoceptor modulation of transiently overexpressed alpha 2-adrenoceptors in brain and peripheral tissues: cellular mechanisms underlying the developmental toxicity of terbutaline. Brain Res Bull 62:305-14
Rhodes, Melissa C; Seidler, Frederic J; Qiao, Dan et al. (2004) Does pharmacotherapy for preterm labor sensitize the developing brain to environmental neurotoxicants? Cellular and synaptic effects of sequential exposure to terbutaline and chlorpyrifos in neonatal rats. Toxicol Appl Pharmacol 195:203-17
Kreider, Marisa L; Seidler, Frederic J; Cousins, Mandy M et al. (2004) Transiently overexpressed alpha2-adrenoceptors and their control of DNA synthesis in the developing brain. Brain Res Dev Brain Res 152:233-9

Showing the most recent 10 out of 125 publications