Although it is generally conceded that ethanol can be toxic to neurons, it is not known by what mechanisms this toxicity is mediated. The sensitive, reciprocal interactions between calcium and neurotrophic factors, and the importance of each of these with respect to neuronal survival, led the applicants to investigate whether ethanol might produce toxicity through effects on these molecules. Based on a wealth of biochemical studies of ethanol effects on calcium, on preliminary results that ethanol can alter both resting and potassium depolarization-stimulated intracellular calcium, and on more established effects on brain neurotrophic activity, a more detailed investigation is proposed of ethanol effects on intracellular calcium regulation. It is hypothesized that: (1) ethanol may act to disrupt normal calcium homeostasis (resting and/or stimulated); (2) this disruption may (like other treatments that alter [Ca+2]i) affect the expression of neurotrophic factor or receptor genes; (3) ethanol may interfere with the ability of neurotrophic factors to modulate Ca+2i regulation; and (4) neurotrophic factors may be able to offset the effects of ethanol on Ca+2i regulation. These ideas will be tested by measuring Ca+2i in living alcohol- treated neurons, and in situ hybridized neurotrophic factor and receptor mRNAs. Assessment will follow both acute and chronic ethanol treatments, before and after depolarization challenge, in the presence or absence of neurotrophic factors, with a range of ethanol doses, in 3 distinct in vitro systems. The use of 3 culture models offers comparison of different neuronal types which demonstrate different neurotrophic response characteristics, as well as a sequential approximation of in vivo organization. If ethanol is found to disrupt normal Ca+2i metabolism in a manner that is ameliorated by neurotrophic factors, the investigators will test the ability of prolonged neurotrophic factor treatment to reduce the neuropathological consequences of chronic ethanol treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA010480-03
Application #
2442164
Study Section
Special Emphasis Panel (SRCA (44))
Project Start
1995-07-01
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Florida
Department
Neurosciences
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Webb, Barbara; Walker, Don W; Heaton, Marieta B (2003) Nerve growth factor and chronic ethanol treatment alter calcium homeostasis in developing rat septal neurons. Brain Res Dev Brain Res 143:57-71
Webb, Barbara; Burnett, Patricia W; Walker, Don W (2002) Sex differences in ethanol-induced hypnosis and hypothermia in young Long-Evans rats. Alcohol Clin Exp Res 26:695-704
Heaton, M B; Mitchell, J J; Paiva, M et al. (2000) Ethanol-induced alterations in the expression of neurotrophic factors in the developing rat central nervous system. Brain Res Dev Brain Res 121:97-107
Thinschmidt, J S; Webb, B; Martin, D E et al. (1999) The development and pharmacological characterization of calcium channel currents in cultured embryonic rat septal cells. Brain Res Dev Brain Res 118:13-21
Barrow Heaton, M B; Kidd, K; Bradley, D et al. (1999) Prenatal ethanol exposure reduces spinal cord motoneuron number in the fetal rat but does not affect GDNF target tissue protein. Dev Neurosci 21:444-52
Moore, D B; Quintero, M A; Ruygrok, A C et al. (1998) Prenatal ethanol exposure reduces parvalbumin-immunoreactive GABAergic neuronal number in the adult rat cingulate cortex. Neurosci Lett 249:25-8
Webb, B; Heaton, M B; Walker, D W (1997) Ethanol effects on cultured embryonic hippocampal neuronal calcium homeostasis are altered by nerve growth factor. Alcohol Clin Exp Res 21:1643-52
Webb, B; Suarez, S S; Heaton, M B et al. (1997) Cultured postnatal rat septohippocampal neurons change intracellular calcium in response to ethanol and nerve growth factor. Brain Res 778:354-66
Baek, J K; Heaton, M B; Walker, D W (1996) Up-regulation of high-affinity neurotrophin receptor, trk B-like protein on western blots of rat cortex after chronic ethanol treatment. Brain Res Mol Brain Res 40:161-4
Webb, B; Suarez, S S; Heaton, M B et al. (1996) Calcium homeostasis in cultured embryonic rat septohippocampal neurons is altered by ethanol and nerve growth factor before and during depolarization. Brain Res 729:176-89

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