in our original grant proposal we tested and verified the hypothesis that ethanol administered in ovo early in neuroembryogenesis or given in culture produced severe neuronotoxic effects, affecting differentially the cholinergic, GABAergic and catecholaminergic neuronal phenotypes. Furthermore, we demonstrated that growth factors, NGF, EGF, GHRH and SRIF given concomitantly with ethanol prevent or reverse these early neurotoxic effects. In this competing renewal application we will continue to use the chick embryo and neuron-enriched cultures either each system alone or in an in ovo/in vitro paradigm to further examine and identify more precisely cellular and molecular components involved in ethanol neuronotoxicity and the interaction of ethanol with growth factors. We propose the following studies: a) We will continue our current studies examining the effects of ethanol on growth factor binding sites and also the levels of mRNA encoding NGF, GHRH and SRIF, b) We will identify the survival of specific neuronal populations (cholinergic, GABAergic, catecholaminergic) after ethanol insult using the in ovo/in vitro paradigm and combination of immunocytochemistry and autoradiography. Similarly, we will test the effects of ethanol on cell migration using a combination of immunocytochemistry and autoradiography and we will examine neural cell adhesion by determining the level of NCAM expression during embryonic development. c) To test the hypothesis that ethanol shifts neuronal phenotypic expression we will examine in early embryos the levels of mRNA encoding TH, CHAT, and GAD proteins. d) To test the effects of ethanol on neuronal maturation we will examine in the in vivo/in vitro paradigm the activity df cAMP-dependent protein kinase as one transduction signal important for cell differentiation. With the recent advances in Fetal therapy, we hope that our studies will provide some basic clues of possible therapy and prevention of the Fetal Alcohol Syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA008026-04A1
Application #
2044228
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1989-01-01
Project End
1997-06-30
Budget Start
1992-09-30
Budget End
1993-08-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Psychiatry
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Kentroti, S (1997) Neuronal plasticity in development: lessons from ethanol neurotoxicity during embryogenesis. Adv Exp Med Biol 429:19-37
Grove, J; Gomez, J; Kentroti, S et al. (1996) Plasticity of astrocytes derived from aged mouse cerebral hemispheres: changes with cell passage and immortalization. Brain Res Bull 39:211-7
Kentroti, S; Vernadakis, A (1996) Immunocytochemical and biochemical characterization of glial phenotypes in normal and immortalized cultures derived from 3-day-old chick embryo encephalon. Glia 18:79-91
Spoerri, P E; Srivastava, N; Vernadakis, A (1996) Role of GABAA receptors in the GABA attenuation of ethanol neurotoxicity. J Neurosci Res 44:499-506
Kentroti, S; Vernadakis, A (1996) Ethanol neurotoxicity in culture: selective loss of cholinergic neurons. J Neurosci Res 44:577-85
Srivastava, N; Vernadakis, A (1995) Maturation of cerebellar granule cells is delayed in cultures derived from ethanol-treated chick embryos: survival and proliferation studies. Int J Dev Neurosci 13:529-37
Spoerri, P E; Srivastava, N; Vernadakis, A (1995) GABA attenuates the neurotoxic effects of ethanol in neuron-enriched cultures from 8-day-old chick embryo cerebral hemispheres. Brain Res Dev Brain Res 86:94-100
Kentroti, S; Vernadakis, A (1995) Early neuroblasts are pluripotential: colocalization of neurotransmitters and neuropeptides. J Neurosci Res 41:696-707
Spoerri, P E; Srivastava, N; Vernadakis, A (1995) Ethanol neurotoxicity on neuroblast-enriched cultures from three-day-old chick embryo is attenuated by the neuronotrophic action of GABA. Int J Dev Neurosci 13:539-44
Srivastava, N; Grove, J; Vernadakis, A (1995) Astrocyte differentiation is enhanced in chick embryos treated with ethanol during early neuroembryogenesis. Neurochem Res 20:985-9

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