ADH Genotypes and Alcohol Use and Dependence in Europeans

We have tested for effects of alcohol dehydrogenase ( ADH ) genotypes on self-reported alcohol consumption and symptoms of alcohol dependence, recorded on three occasions up to 15 years apart, in 377 male and female subjects of European descent. ADH2 genotype had significant effects on both consumption and dependence in the men, but not in the women. The effects of ADH3 genotype were considerably less than those of ADH2 , but significant results could be demonstrated when the combined genotypes were considered. The direction of the effects on alcohol consumption and dependence risk were consistent with reports on Asian subjects, and with the in vitro properties of ADH isoenzymes. As with previous studies on the relationship between ADH type and alcohol use, population stratification cannot be excluded as a contributing factor in these results.     

Alcohol Reactions in Subjects of European Descent: Effects on Alcohol Use and on Physical and Psychomotor Responses to Alcohol

Self-reports of reactions to small amounts of alcohol, obtained between 1990 and 1992, were compared with reports of alcohol use, obtained in 1990–1992 and also in 1979–1981, in twin subjects of European descent. Data on subjective, physiological, psychomotor, and metabolic responses to a test dose of alcohol, taken in 1979–1981, were also available. Alcohol reactions were more common in women than in men, and were associated with less alcohol use, both at the time that information about reactions was obtained and as recorded on average 12 years previously, in both sexes. Physiological and psychomotor responses to alcohol were similar across the reaction groups, except that deterioration in standing steadiness was greater in those who subsequently reported adverse reactions to alcohol. Contrary to expectation, skin temperature changes after alcohol were less in the subjects who reported always reacting to alcohol than in the other groups. Subjective reports of intoxication were greatest in subjects who subsequently reported alcohol reactions. The pattern of twin pair concordance for reactions suggests low heritability, so alcohol reactions in subjects of European descent are not caused by a single gene of high penetrance of the type found in the Asian alcohol flush reaction.     

A Small Dose of Morphine Leads Rats to Drink More Alcohol and Achieve Higher Blood Alcohol Concentrations

Male Sprague-Dawley rats were maintained on a daily regimen of 22 hr of fluid deprivation followed by a 2-hr opportunity to take a sweetened alcoholic beverage and water for over 6 months. Durinc the week before the formal procedures of the experiment describee herein, access to the alcoholic beverage was limited to 1.5 hr, but access to water was still for 2 hr. Intakes of ethanol, in terms of g/kg, were tabulated at 30 min for half of the rats and at 90 min for the rest. On the day of formal procedures, half of the rats of the 30- and 90-min measures were given 1 mg/kg of morphine sulfate just before the drinking session, whereas the rest received physiological saline Morphine increased mean g/kg intakes of ethanol, as compared with controls, at 30 and 90 min. Blood alcohol levels were also increased These data suggest that the well-documented ability of small doses of morphine to increase rats' intake of ethanol is probably not related to its ability to produce gastrointestinal effects, but rather due to its ability to modulate central motivational mechanisms associated with ingestion.     

Alcohol consumption is enhanced after naltrexone treatment

BACKGROUND: It is well known that alcohol increases opioid activity, which can contribute to the reinforcing effect of alcohol. Clinical studies have supported reductions in alcohol consumption among alcoholic patients during treatment with opioid antagonists (OAs) and its use is recommended for this purpose. Experimental studies have demonstrated opioid receptor up-regulation after several days of OA treatment, which increases the availability of these receptors. On this basis, the physiological conditions in the period immediately after the OA treatment could increase the reinforcing value of alcohol and in this way enhance alcohol consumption. METHODS: To test this hypothesis, 2 groups of Wistar male rats were used in the present study. After assessing the baseline of voluntary alcohol (10% v/v) consumption, subjects were treated with either the OA naltrexone (Ntx), (2 mg/kg/d/rat) or a saline solution (0.2 mL/d/male) for 7 days. Subsequently, all subjects were given a free choice between ethanol (10%) and water for 5 days. To study a possible cumulative effect, this procedure was sequentially repeated 4 times with each group. Water and food were available ad libitum throughout the experiment. RESULTS: After each period of 7 days of Ntx use, alcohol consumption increased significantly with respect to the baseline and each equivalent period in the control group. When the subjects were exposed to alcohol again 1 week after the last of the 4 sequential periods, alcohol drinking was higher than the baseline in the Ntx group, but not in the control group. Water consumption was decreased during Ntx treatment in the control group in periods 1, 2, and 4. Food intake and body weight did not show differences between groups throughout the study; however, a decrease in food intake was observed over time regardless of treatment. CONCLUSION: These results show that alcohol intake may increase after the Ntx treatment, particularly when alcohol is not available during treatment with the OA, and that this may be due to a higher availability of opioid receptors in that period.     

Laboratory tests for acute alcohol consumption: results of the WHO/ISBRA Study on State and Trait Markers of Alcohol Use and Dependence

BACKGROUND: The WHO/ISBRA Study on State and Trait Markers of Alcohol Use and Dependence aimed partly to evaluate the overall performance and cross-national validity of traditional and new biological markers of alcohol use and abuse. This article focused on the sensitivity and specificity of ethanol and methanol concentrations in plasma, and the 5-hydroxytryptophol (5HTOL) to 5-hydroxyindole-3-acetic acid (5HIAA) ratio in urine, as laboratory tests to identify acute alcohol consumption. Comparison was made with self-reported drinking levels. METHODS: Subjects were recruited in Australia, Brazil, Canada, Finland, and Japan. They were interviewed thoroughly about their alcohol consumption habits, by using the standardized WHO/ISBRA Interview Schedule, and were classified into four categories: nondrinkers, light/moderate drinkers, heavy drinkers (> or =210 g ethanol/week for men, and > or =140 g/week for women), or patients who were receiving treatment for alcohol dependence. Ethanol and methanol determinations in plasma were carried out by headspace gas chromatography. Urinary concentrations of 5HTOL and 5HIAA were determined by using gas chromatography-mass spectrometry and high-performance liquid chromatography, respectively. RESULTS: The baseline levels (in nondrinkers) for methanol and the 5HTOL/5HIAA ratio did not differ markedly between the five populations, except for a considerably higher, but probably artifactual, methanol level in the Finnish plasma samples. Moreover, there were no apparent age or sex differences. The urinary 5HTOL/5HIAA ratio was the most, and ethanol the least, sensitive indicator of recent alcohol consumption, and this was true for the different drinking categories as well as for the five study populations. The highest frequency of elevated test results was observed among those classified as heavy drinkers (e.g., 38% were positive for 5HTOL/5HIAA). However, elevated values also were obtained in nondrinkers and in drinking subjects who denied any intake of alcohol within 2 days before the interview and blood/urine sampling, which suggested a low accuracy of self-reports of alcohol consumption in certain individuals. CONCLUSIONS: The present investigation demonstrated that plasma ethanol and methanol and urinary 5HTOL/5HIAA provide useful exclusion markers for any study of biological parameters that are affected by previous acute ethanol intoxication. The major advantage of methanol and 5HTOL/5HIAA over ethanol is that they can detect recent alcohol consumption even several hours after the ethanol is no longer measurable. The results suggest that the cutoff limits to be used for these markers are not dependent on the country or population to be studied.     

Effect of Recent Alcohol Intake on Parathyroid Hormone and Mineral Metabolism in Men

The mechanisms by which alcohol intake, particularly moderate alcoho1 intake, effects bone metabolism are poorly defined. We have examined the relationship between mineral metabolism and recent self-reported alcohol intake (SRAI) across a wide range of such intakes in a series of 104 men aged 32 to 78 years of age in an outpatient setting. A morning nonfasting urine, serum specimen and recent SRAI were obtained from each subject. SRAI was reported as between 0 and 45 oz/week. SRAI correlated positively with her function tests, including serum bilirubin (r= 0.30, p= 0.002), alkaline phosphatase (r= 0.30, p= 0.004), and aspartate aminotransferase (SGOT) (r= 0.29, p= 0.006). SRAI correlated with serum calcium corrected for albumin (r= -0.39, p < 0.001), estradiol (r= 0.43, p < 0.001), and immunoreactive parathyroid hormone (iPTH) (r= -0.51, p < 0.001), as well as urinary calcium (per 100 mg of creatinine) (r= 0.55, p < 0.001). We have arbitrarily divided the participants into two groups on the basis of their reported alcohol intake. Individuals in the first group had intakes ranging from none to moderate intake (drank 8.4 oz or less of ethanol per week, equivalent to an average of two drinks daily or less). Those in the second group had moderate or heavier intake, with >8.4 oz of ethanol intake/week. Mean serum iPTH was significantly greater in those in the first group (none to moderate), compared with the second group (moderate or heavier) (56.0 ± 3.4 and 39.9 ± 2.0 pM/liter, respectively). Calcium corrected for serum albumin was significantly greater in individuals in the first, compared with the second, group (9.23 ± 0.05 vs. 8.88 ± 0.07 mg/dl, respectively). In addition, urinary calcium (cod per 100 mg of creatinine) was significantly lower in the former, compared with the latter (3.1 ± 0.4 vs. 8.4 ± 1.1 mg/100 mg of creatinine, respectively). Similarly, urinary excretion of collagen crosslinks (corrected per 100 mg of creatinine) was significantly less in men in the second group, compared with the first group (316 ± 38 vs. 530 ± 78 nM/100 mg of creatinine, respectively). Not surprisingly, a series of correlations between iPTH and age, 250-hydroxyvitamin D, and testosterone were significant in individuals with none to moderate SRAI, but not moderate or heavier SRAI. Significant independent predictors of serum iPTH in the entire group of men were age (β= 0.215, p= 0.025), SRAI (β= -0.281, p= 0.003), 250-hydroxyvitamin D (β= -0.309, p= 0.002), and testosterone (β=?184, p= 0.048). We have concluded that, in free-living men, alcohol intake >8.4 oz/week was associated with decreased serum iPTH concentrations.     

Circadian Mechanisms in Alcohol Use Disorder and Tissue Injury

Heavy use of alcohol can lead to addictive behaviors and to eventual alcohol‐related tissue damage. While increased consumption of alcohol has been attributed to various factors including level of alcohol exposure and environmental factors such as stress, data from behavioral scientists and physiological researchers are revealing roles for the circadian rhythm in mediating the development of behaviors associated with alcohol use disorder as well as the tissue damage that drives physiological disease. In this work, we compile recent work on the complex mutually influential relationship that exists between the core circadian rhythm and the pharmacodynamics of alcohol. As we do so, we highlight implications of the relationship between alcohol and common circadian mechanisms of effected organs on alcohol consumption, metabolism, toxicity, and pathology.     

Does Psychomotor Sensitivity to Alcohol Predict Subsequent Alcohol Use?

Data from 42 male and 58 female subjects who participated in the Colorado Alcohol Research on Twins and Adoptees (CARTA) project were subjected to model-fitting analyses. The aim of the present study was to use linear structural equation models to determine whether differences in previously measured psychomotor sensitivity to alcohol predict differences in self-reported alcohol consumption over a 4-year period. LISREL model-fitting results indicate that, for male subjects, only rail walking insensitivity is predictive of alcohol use reported 2 years after their initial CARTA testing. For females, only hand steadiness sensitivity is predictive of alcohol use reported 2 years after their initial CARTA testing. The results for males support a hypothesis that would consider alcohol insensitive individuals at greater risk for alcohol abuse. The female results, however, would argue against such a hypothesis.
With only one measure of sensitivity predicting alcohol use at only one out of four time points, in both men and women, the overall results suggest that our three measures of psychomotor sensitivity to alcohol are, in general, poor predictors of alcohol consumption in this sample.     

ICD-10 and Proposed DSM-IV Harmful Use of Alcohol/ Alcohol Abuse and Dependence, United States 1988: A Nosological Comparison

The purpose of this study was to compare ICD-10 and the proposed DSM-IV (options 1 and 2) diagnostic criteria for harmful use/abuse and dependence in a representative sample of the United States general population. Harmful use/abuse and dependence categories were contrasted in terms of prevalence and overlap. The prevalences of DSM-IV diagnoses of alcohol abuse and dependence combined were much greater than those for the corresponding ICD-10 diagnoses. Disaggregation of the harmful use/abuse and dependence diagnoses showed that the major discrepancy between the classification systems resided between harmful use and abuse categories. The prevalence of the harmful use of alcohol was nearly nonexistent in this general population sample. Reasons for this and other discrepancies are discussed in terms of the hypothesized severity of the harmful use criteria, differences in the number of diagnostic criteria and the content of the ICD-10 and DSM-IV dependence categories, the relationship between the harmful use/abuse and dependence categories, and the impact of the duration criterion.     

Evaluation of the Effect of Alcohol Consumption on Erythrocyte Lipids and Vitamins in a Healthy Population

There is epidemiological evidence that a moderate consumption of alcohol could reduce coronary heart disease. To corroborate this statement and to see how the consumption of red wine affects phospholipid and fatty acid patterns and antioxidant status, a survey was conducted on 58 adult males (20–75 years old). A questionnaire was used to discover their medical history, various constitutional and life-style factors, food habits, and nutrient intake; and the type and amount of alcoholic intake were investigated by means of a questionnaire. Subjects were divided into two groups of nondrinkers and average drinkers (mean 46.5 ± 4.4, range 30.2–63.4 g/day), and the effect of alcohol was made on the following variables: γ-glutamyltranspeptidase, apolipoprotein Al, apolipoprotein B, total and high-density lipoprotein-cholesterol, triglycerides, and antioxidant vitamins were determined in plasma; and phospholipids the fatty acids of phosphatidylcholine (PC) and phosphatidylethanolamine total cholesterol, α-tocopherol, β-carotene, and retinol were determined in red blood cells (RBCs). There were no significant differences between the two groups in protein, fat, carbohydrate, retinol equivalent, a-tocopherol content, and cholesterol/saturated fat index of their diet. Analysis of the plasma levels of biochemical variables–adjusted for age, smoking (number of cigarettes/day), and body mass index– showed a significant increase of γ-glutamyltranspeptidase and apolipoprotein Al concentration in the average drinkers compared with nondrinkers. Plasma α-tocopherol and retinol levels were also significantly higher in average drinkers. In the latter group, ANCOVA demonstrated a lower percentage of sphingomyelin in RBCs, with a lower sphingomyelin/PC ratio. This group also differs from the nondrinkers in RBC monounsaturated fatty acids (increased 18:1n9 and 16:1 n7 in PC) and polyunsaturated fatty acids (increase of 20:4n6 and 22:6n3 in phosphatidylethanolamine). These differences suggest that membrane fluidity may change in relation to alcohol intake.     

Thyrotropin Releasing Hormone Analog TA-0910 Suppresses Alcohol Intake in Alcohol Drinking African Green Monkeys

In previous studies, we found that single injections of the thyrotropin-releasing hormone analog TA-0910 dose-dependently reduced alcohol intake and preference in alcohol-preferring (P) and Fawn-Hooded (FH) rats over a 24-hr period of continuous access to alcohol and water. However, several consecutive daily injections of TA-0910 resulted in the development of tolerance to these effects. In the present study, we found that in a 5-hr limited-access schedule in which monkeys could select an aqueous alcohol solution (7.5% v/v) or tap water, single doses of TA-0910 (0.0625, 0.125, 0.25, 0.5, and 0.75 mg/kg), similar to those found effective in P and FH rats, reduced consumption of alcohol. In this protocol, tolerance to the attenuating effects of TA-0910 on alcohol intake was not evident after five consecutive once-daily doses of 0.5 mg/kg. Furthermore, it was shown that a single dose of 0.75 mg/kg TA-0910 did not significantly influence 24-hr water intake when water was the only available fluid, but did reduce the intake of a preferred solution of saccharin. These findings suggest that activation of brain thyrotropin-releasing hormone systems reduces alcohol intake in primates and that tolerance to this effect is not evident within 5 days under a limited access schedule.