Although alcoholism and alcohol abuse are recognized as important health problems among the elderly, little is known about the pathophysiological consequences of prolonged ethanol intake in this population. The main objective of this study is to test the hypothesis that both alcohol and aging can cause deterioration of brain membrane and that ethanol accelerates the brain aging process and alters neural membrane integrity, as evident from changes in membrane physical properties, lipid composition, transport enzymes, and neurotransmitter uptake and release systems. Experiments are designed to evaluate the effects of alcohol and aging on structure and functions of brain synaptic membranes. Specifically, the effects of acute and chronic ethanol administration on various biophysical and biochemical parameters will be examined in C57BL/6NNIA mice of different age groups. These parameters will be correlated to the behavioral response to acute ethanol intoxication and development of tolerance and physical dependence among different age groups. We will also compare mice from different age groups with respect to their recovery from chronic ethanol treatment. For acute ethanol studies, mice of different ages will be given ethanol intragastrically or by i.p. injection. For chronic studies, mice will be pair-fed the Bioserv liquid diet containing 5% (w/v) ethanol or the Bioserv control diet. Tolerance developed among different age groups will be assessed by their sleep time and hypothermic response after a challenge dose of ethanol (3.0g/kg). Synaptosomes and synaptic plasma membranes will be isolated for various biophysical and biochemical studies: (1) examination of the membrane physical properties (fluidity by ESR and fluorescence polarization), (2) analysis of membrane lipid composition (the acidic phospholipids and cholesterol), (3) measurement of neurotransmitter uptake and release processes, and (4) assay of membrane-bound enzymes such as (Na+K)-ATPase, acetylcholinesterase and 5'-nucleotidase. In addition, the response of synaptic membranes isolated from control and ethanol-tolerant mice towards in vitro challenge of ethanol and aliphatic alcohols of different carbon chain lengths will be evaluated among mice of different age groups. It is anticipated that the result of this investigation will lead to further understanding of alcohol-membrane interaction in the brain and provide greater insight into the action of alcohol on the aging process. The eventual goal is to provide appropriate and effective treatment for alcohol-induced impairment and related disorders of the central nervous system.
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