Neither chronic exposure to ethanol nor aging affects type I or type II corticosteroid receptors in rat hippocampus.

Both chronic exposure to ethanol and aging are reported to result in a loss of hippocampal pyramidal neurons and an elevation in plasma corticosteroid concentration. Aging has also been reported to result in a reduction in corticosterone receptors and corticosterone-concentrating cells in the hippocampus. Since these aging-associated effects have been hypothesized to be due to the cumulative exposure to corticosteroids over the life span, in the present studies, we investigated the hypothesis that corticosteroids play a similar role in the loss of hippocampal neurons during chronic ethanol ingestion. In contrast to our expectations, when a liquid diet containing either ethanol or sucrose was administered to male Long-Evans rats for 20-24 weeks, a period of treatment found previously to result in hippocampal neuronal loss, there were no ethanol-associated effects on the specific binding of [3H]-aldosterone to Type I or of [3H]dexamethasone to Type II receptors in cytosol derived from either whole hippocampus or dorsal versus ventral hippocampus. Allowing the rats to withdraw from the chronic ethanol exposure for 12 weeks also failed to reveal any ethanol-associated effects on corticosteroid receptor concentrations in the hippocampus. The basal morning concentrations of corticosterone in blood plasma were not affected by any of these treatments. In view of these null findings we next investigated the effects of aging on hippocampal corticosteroid receptors in male Long-Evans and Fischer 344 rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibitory effect of propylthiouracil on the development of metabolic tolerance to ethanol.

Chronic ethanol administration (4-5 weeks) to female spontaneously hypertensive (SH) rats led to a marked increase in the rate of ethanol metabolism. This was accompanied by an increase in hepatic alcohol dehydrogenase (ADH) and by an increase in the rate of oxygen consumption in perfused livers of these animals. Treatment with the antithyroid drug 6-n-propyl-2-thiouracil (PTU) during the last 9 days (40 mg/kg/day) of the chronic administration of ethanol reduced hepatic oxygen consumption, resulting in a net diminution of the metabolic tolerance to ethanol, despite a further elevation in ADH activity. In these animals, microsomal ethanol-oxidizing system (MEOS) activity was not affected by chronic ethanol administration or by treatment with PTU. Data strongly suggest that in the female SH rat all the metabolic tolerance to ethanol proceeds via the ADH pathway, and that the increase in hepatic oxygen consumption is more important in the development of metabolic tolerance to ethanol than the increased ADH levels.

Effect of age on metabolic tolerance and hepatomegaly following chronic ethanol administration.

Chronic consumption of ethanol often results in an increased rate of ethanol metabolism (metabolic tolerance) and in hepatomegaly. However, the extent of these changes is highly variable. We have found that these two phenomena are greatly influenced by age. We studied the effect of age on the development of metabolic tolerance and hepatomegaly and on the increase in hepatic oxygen consumption produced by chronic ethanol administration. The latter has been proposed to contribute to metabolic tolerance to ethanol. Ethanol was administered to female Sprague-Dawley rats with different initial ages (4, 6, 8, 11, and 17 weeks) for a 4-week period in a high-fat liquid diet. Control animals were pair-fed an isocaloric liquid diet in which ethanol was replaced with carbohydrate. Metabolic tolerance and hepatomegaly following chronic ethanol consumption were markedly dependent on the initial age of the animal, with young animals showing the largest increases. Although showing a similar general trend with age, the degree of metabolic tolerance was not linked proportionally with the degree of hepatomegaly. Perfused livers from young rats fed chronically with ethanol showed increases in ethanol metabolism and oxygen consumption, whereas no increase were observed in those from older animals. These findings support the hypothesis that an elevated rate of hepatic oxygen consumption contributes to metabolic tolerance. Total hepatic alcohol dehydrogenase activity was not increased by chronic ethanol consumption in any age group, demonstrating that an increase in the levels of this enzyme is not obligatory for metabolic tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

The inhibitory effect of testosterone on the development of metabolic tolerance to ethanol.

We have investigated the mechanism(s) of metabolic tolerance to ethanol in a rat strain (spontaneously hypertensive or SH) in which liver alcohol dehydrogenase (ADH) levels are very low due to a marked inhibitory effect of testosterone on ADH. Chronic ethanol administration resulted in marked increases in the rate of ethanol metabolism and in ADH activity (+65 to 90%). Oxygen consumption measured in the perfused livers of the ethanol-fed rats was also elevated (+40%). The administration of 6-n-propyl-2-thiouracil (PTU), which was previously found to reduce hepatic oxygen consumption and to increase ADH activity, resulted in no change in the rate of ethanol metabolism in the ethanol-fed rats and an increase in the sucrose-fed controls, suggesting that increased ADH activity is more important for the development of metabolic tolerance to ethanol, in the male SH rat, than increased oxygen consumption. The activity of the microsomal ethanol-oxidizing system (MEOS) in vitro was induced by chronic ethanol treatment (+95%), but it may only account for a small part (32%) of the increase in ethanol metabolism in vivo. Serum testosterone concentrations were lower in the ethanol-fed rats at peak blood ethanol levels, relative to those found in controls. Concurrent chronic administration of ethanol and testosterone abolished about one-third of the absolute increases in ethanol metabolism and in ADH activity in the ethanol-fed rats. In conclusion, most of the metabolic tolerance to ethanol, in the male SH rat, appears to occur mainly due to a testosterone-independent increase in ADH activity and to a lesser degree to an increase in ADH activity produced by a reduction in testosterone levels in the ethanol-fed rats.

Modulation of alcohol dehydrogenase and ethanol metabolism by sex hormones in the spontaneously hypertensive rat. Effect of chronic ethanol administration.

In young (4-week-old) male and female spontaneously hypertensive (SH) rats, ethanol metabolic rate in vivo and hepatic alcohol dehydrogenase activity in vitro are high and not different in the two sexes. In males, ethanol metabolic rate falls markedly between 4 and 10 weeks of age, which coincides with the time of development of sexual maturity in the rat. Alcohol dehydrogenase activity is also markedly diminished in the male SH rat and correlates well with the changes in ethanol metabolism. There is virtually no influence of age on ethanol metabolic rate and alcohol dehydrogenase activity in the female SH rat. Castration of male SH rats prevents the marked decrease in ethanol metabolic rate and alcohol dehydrogenase activity, whereas ovariectomy has no effect on these parameters in female SH rats. Chronic administration of testosterone to castrated male SH rats and to female SH rats decreases ethanol metabolic rate and alcohol dehydrogenase activity to values similar to those found in mature males. Chronic administration of oestradiol-17beta to male SH rats results in marked stimulation of ethanol metabolic rate and alcohol dehydrogenase activity to values similar to those found in female SH rats. Chronic administration of ethanol to male SH rats from 4 to 11 weeks of age prevents the marked age-dependent decreases in ethanol metabolic rate and alcohol dehydrogenase activity, but has virtually no effect in castrated rats. In the intoxicated chronically ethanol-fed male SH rats, serum testosterone concentrations are significantly depressed. In vitro, testosterone has no effect on hepatic alcohol dehydrogenase activity of young male and female SH rats. In conclusion, in the male SH rat, ethanol metabolic rate appears to be limited by alcohol dehydrogenase activity and is modulated by testosterone. Testosterone has an inhibitory effect and oestradiol has a testosterone-dependent stimulatory effect on alcohol dehydrogenase activity and ethanol metabolic rate in these animals.