It is likely that many of the pharmacological actions of ethanol are related to ethanol's ability to disrupt hydrophobic domains of proteins and lipids. This proposal will study the effects of ethanol on a major neurotransmitter and hormonal signal transduction cascade which involves membrane proteins and membranes at each level of the signal cascade. The hydrolysis of a unique class of lipids, the phosphoinositides, appears to be due to the interaction of plasma membrane receptors with intramembrane guanine-nucleotide binding proteins which activate a phosphoinositide phosphodiesterase (e.g. phospholipase C). Calcium flux may also activate a phospholipase. Phosphoinositide hydrolysis results in the formation of at least two second messengers, diacylglycerol and inositol triphosphate. These second messengers may activate a phospholipid dependent protein kinase and release calcium from membrane bound intracellular calcium stores. We have found that ethanol in vitro can inhibit phosphoinositide hydrolysis in both the liver and brain. Radiolabels will be used to follow phosphoinositide hydrolysis stimulated by cholinergic, adrenergic and ionic stimulation in several brain regions. The role of calcium flux and the effects of ethanol on calcium flux will be examined. Parallel studies will be done in the liver which is sensitive to ethanol, but is not responsive to depolarization. The effects of in vitro, acute and chronic ethanol treatment on phosphoinositide hydrolysis will be examined using tissue slices, isolated membrane preparations and receptor binding determinations to establish the sites of action of ethanol on phosphoinositide hydrolysis. Additional studies will follow second messenger release of intracellular calcium and protein kinase changes. The experiments proposed will determine the similarities and differences in the effects of ethanol on the phosphoinositide cascade in liver and brain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA006069-05
Application #
3109309
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1984-03-01
Project End
1992-02-29
Budget Start
1988-03-01
Budget End
1989-02-28
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Crews, Fulton T; Lawrimore, Colleen J; Walter, T Jordan et al. (2017) The role of neuroimmune signaling in alcoholism. Neuropharmacology 122:56-73
Coleman Jr, Leon Garland; Liu, Wen; Oguz, Ipek et al. (2014) Adolescent binge ethanol treatment alters adult brain regional volumes, cortical extracellular matrix protein and behavioral flexibility. Pharmacol Biochem Behav 116:142-51
Coleman Jr, Leon G; Oguz, Ipek; Lee, Joohwi et al. (2012) Postnatal day 7 ethanol treatment causes persistent reductions in adult mouse brain volume and cortical neurons with sex specific effects on neurogenesis. Alcohol 46:603-12
Coleman Jr, Leon G; He, Jun; Lee, Joohwi et al. (2011) Adolescent binge drinking alters adult brain neurotransmitter gene expression, behavior, brain regional volumes, and neurochemistry in mice. Alcohol Clin Exp Res 35:671-88
Zou, Jian; Crews, Fulton (2010) Induction of innate immune gene expression cascades in brain slice cultures by ethanol: key role of NF-ýýB and proinflammatory cytokines. Alcohol Clin Exp Res 34:777-89
Coleman Jr, Leon G; Jarskog, L Fredrik; Moy, Sheryl S et al. (2009) Deficits in adult prefrontal cortex neurons and behavior following early post-natal NMDA antagonist treatment. Pharmacol Biochem Behav 93:322-30
Crews, Fulton Timm; Boettiger, Charlotte Ann (2009) Impulsivity, frontal lobes and risk for addiction. Pharmacol Biochem Behav 93:237-47
Stevenson, Jennie R; Schroeder, Jason P; Nixon, Kimberly et al. (2009) Abstinence following alcohol drinking produces depression-like behavior and reduced hippocampal neurogenesis in mice. Neuropsychopharmacology 34:1209-22
He, Jun; Crews, Fulton T (2008) Increased MCP-1 and microglia in various regions of the human alcoholic brain. Exp Neurol 210:349-58
Monti, Peter M; Miranda Jr, Robert; Nixon, Kimberly et al. (2005) Adolescence: booze, brains, and behavior. Alcohol Clin Exp Res 29:207-20

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