Several studies have demonstrated that alcoholics, as well as problem drinkers, have higher than normal serum levels of Gamma-glutamyl transpeptidase (Gamma-GTP). Animal models of chronic drinkers have been shown to have elevated levels of Gamma-glutamyl transpeptidase in several brain areas. Rats born to mothers which received 35% of their caloric intake in the form of alcohol, both during gestation and lactation were found to have higher levels of Gamma-glutamyl transpeptidase in brain and liver than their controls. Additionally, the offspring of the alcohol treated mothers exhibited many of the dysmorphic characteristics seen in Fetal Alcohol Syndrome. Although the role of Gamma-GTP in brain has not been clarified, evidence suggests that the enzyme may involved in determining an individual's sensitivity to alcohol and in some forms of mental retardation. The membrane-bound enzyme is a vital part of the Gamma-glutamyl cycle, which accounts for the turnover of glutathione (GSH). The Gamma-glutamyl cycle is involved in the synthesis and degradation of GSH and involves transport of GSH out of cells and Gamma-glutamyl amino acids into cells. An increase in Gamma-GTP activity, such as is seen following alcohol treatment, may be a mechanism by which concentrations of GABA, an inhibitory neurotransmitter, may be increased. It may also produce an increased turnover of GSH. An increase in Gamma-GTP activity may be a reflection of the animal's attempt to increase glutathione synthesis to protect itself against the toxic effects of drugs, free radicals and reactive oxygen intermediates. The present study is undertaken to determine the effects of the maternal administration of alcohol on brain, liver and serum Gamma-GTP in neonatal rats. Glutathione and GABA levels in brain will also be measured. We will examine the effects of the maternal administration of alcohol on the ontogenesis of the enzyme and will determine whether the biochemical properties of Gamma-GTP have been altered. We will measure Gamma-GTP activity in brains of pups from gestational age 16 days, to 120 days of age. Female Wistar rats will be bred to adult males and placed on a liquid diet containing alcohol or an isocaloris equivalent amount of carbohydrate in the form of dextrin, starting on day one of gestation. Although there have been many studies involved with determining the effects of the in utero administration of alcohol, most have not given alcohol to the pregnant mothers until after the first 8 days of gestation. We intend to administer alcohol during this critical period of development.
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