Neuroendocrine Evidence for Reduced Dopamine Receptor Sensitivity in Alcoholism

Postsynaptic dopamine (DA) receptor sensitivity was assessed during abstinence in 15 male patients with alcohol dependence. The DA receptor sensitivity was evaluated using growth hormone (GH) responses to the DA receptor agonist apomorphine (0.18-0.24 mg intravenously). The patients were cared for in an alcoholism treatment unit for the 2 months prior to the investigation. They were carefully controlled for sobriety during this period. Thirteen healthy men were used as controls. The maximum GH responses to apomorphine were significantly reduced in patients compared with those in the control group. The patients had a significantly higher proportion of blunted GH responses. The findings suggest reduced postsynaptic DA, possibly D2, receptor sensitivity in abstinent alcoholics. The question whether this abnormal DA receptor status is genetically determined or acquired after long-term alcohol consumption remains to be addressed.     

Five-Shot Questionnaire on Heavy Drinking

To develop an effective, but short, questionnaire to detect heavy drinking, we combined two questions from AUDIT and three from CAGE. We have tested earlier this new Five-Shot questionnaire among male alcoholics who all had a total score of at least 4/7. The purpose of the present study was to find out the effectiveness of the Five-Shot questionnaire among middle-aged men. In the present study, the Five-Shot questionnaire was distributed to all ( n = 853) 40-year-old men attending health screening in a Finnish town. The participation percentage in the screening was 70.3%. Self-reported alcohol consumption was used as a gold standard; 557 of these men gave a self-report that they consumed less absolute alcohol than 140 g/week (moderate drinkers), and 70 reported consuming ≥280 g/week (heavy drinkers). None of the individual Five-Shot questions was superior to any other in detecting heavy drinkers. The cut-off point ≥3 for Five-Shot gave a 77% sensitivity in detecting heavy drinkers, with a specificity of 83% and an overall accuracy of 83%. The corresponding figures with ≥2.5 cut-off were 96%, 76%, and 78%. The commonly used cut-off for CAGE, ≥2, gave a result of 47%, 87%, and 83%, respectively. The area under the receiver operating characteristic curve for the CAGE was clearly worse, compared with that of the Five-Shot. The new Five-Shot questionnaire seems to be efficient in differentiating between moderate and heavy drinkers. It is also easy and fast for physicians to use in different health-care settings. Thus, it can serve as a good aid in early detection of heavy drinking.     

Blood Glucose Level, Alcohol Heavy Drinking, and Alcohol Craving During Treatment for Alcohol Dependence: Results From the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) Study

Background: Heavy drinking may increase blood glucose levels. Moreover, in alcohol‐dependent subjects, glucose may play a putative role in alcohol preference. Methods: This study investigated the relationship between blood glucose levels and both alcohol heavy drinking and craving in alcohol‐dependent subjects participating in the COMBINE Study. The primary objective was to evaluate the relationship between baseline (pretreatment) glucose levels and percentage of heavy drinking day (PHDD) during treatment. The secondary objective was to evaluate the relationship between glucose levels, baseline PHDD, and craving measured by the Obsessive Compulsive Drinking Scale (OCDS). Results: This analysis consisted of 1,324 participants. Baseline glucose levels were significantly and positively associated with PHDD during treatment [F(1, 1225) = 5.21, p = 0.023], after controlling for baseline PHDD [F(1, 1225) = 36.25, p < 0.0001], gender [F (1, 1225) = 3.33, p = 0.07], and body mass index (BMI) [F(1, 1225) = 0.31, p = 0.58]. Higher glucose levels at baseline were associated with a higher percentage of PHDD at pretreatment [F(1, 1304) = 5.96, p = 0.015], after controlling for gender [F(1, 1304) = 0.29, p = 0.59] and BMI [F(1, 1304) = 0.90, p = 0.34]. Glucose was not significantly associated with the OCDS total score [F(1, 1304) = 0.12, p = 0.73], the OCDS Obsessive subscale [F(1, 1304) = 0.35, p = 0.56], or the OCDS Compulsive subscale [F(1, 1304) = 1.19, p = 0.28] scores, after controlling for gender and BMI. Discussion: A link between pretreatment glucose levels and heavy drinking during treatment was found, suggesting a role of glucose in predicting heavy alcohol consumption. Although caution is needed in the interpretation of these results, elevated glucose and heavy drinking may be affected by a common mechanism and manipulations affecting glucose regulation may influence alcohol consumption.     

In heavy drinkers, fatty acid ethyl esters remain elevated for up to 99 hours

BACKGROUND: Both medical and forensic needs require reliable detection of earlier ethanol intake after the disappearance of ethanol from blood. The esters of ethanol with free fatty acids (FAEEs) are candidate markers of this kind. However, it is unknown whether FAEEs can serve as a marker for a single prior ethanol intake. In addition, the period for which FAEEs are elevated is unknown. Therefore, we measured FAEEs in heavy drinkers admitted to detoxification, and in healthy subjects after a drinking experiment. METHODS: Blood from 30 heavy drinkers was obtained for up to 5 days during a detoxification period in a psychiatric hospital. In addition, 17 healthy subjects who participated in a drinking experiment and who were abstinent thereafter gave blood during a similar time period for analysis of FAEEs. Fatty acid ethyl esters were measured by gas chromatography-mass spectroscopy. RESULTS: Heavy drinkers had much higher ethanol and FAEEs concentrations than healthy subjects; however, in both groups, FAEEs decreased rapidly during the first day. Only in heavy drinkers, elevated concentrations of FAEEs were observed at days 2 to 4. Concentrations of FAEEs were not associated with serum triglycerides or patients' body mass index. CONCLUSIONS: It is concluded that kinetics of FAEEs are different in heavy drinkers compared with healthy subjects and that FAEEs are of limited value for the detection of prior single ethanol intake.     

Effect of Citalopram on Alcohol Intake in Heavy Drinkers

The effect of the selective serotonin reuptake inhibitor citalopram (40 mg daily dose) on alcohol intake was investigated in a doubleblind, placebo-controlled cross-over study. Thirty men with heavy alcohol consumption (mean daily alcohol intake 111 ± 51 g pure alcohol) completed the study. After a 2-week baseline period, subjects were randomly allocated to treatment with either citalopram or placebo for 5 weeks. In the total sample of heavy drinkers, no difference was found between citalopram and placebo treatment in alcohol consumption or days of abstinence. However, the response to citalopram was negatively correlated ( r _a=–0.67, p < 0.01) with baseline levels of mean daily alcohol intake. Therefore, we divided the total sample into two subgroups with baseline mean daily alcohol intake above and below median (107 g pure alcohol), respectively. In the group with the higher baseline values (138 ± 25 g pure alcohol), citalopram was not different from placebo in reducing the daily alcohol intake, but in subjects with the lower baseline values (85 ± 15 g pure alcohol), citalopram was significantly ( p < 0.01) superior to placebo. Consequently, citalopram at the present dose appears capable of reducing alcohol intake only in a subgroup of heavy drinkers with a mean daily consumption of between 60 and 100 g pure alcohol.     

Increased Activation of the ACC During a Spatial Working Memory Task in Alcohol‐Dependence Versus Heavy Social Drinking

Background: Activation of the anterior cingulate cortex (ACC) in a spatial working memory task has been associated with risk factors for alcohol use disorders such as low alcohol effects and positive alcohol expectations in adolescents. To transfer these results into adults, we used the same task in adults. Methods: During functional magnetic resonance imaging, 12 light social, 7 heavy social, and 11 non‐abstinent‐dependent alcohol drinkers performed a spatial working memory task and completed measures of automatic alcohol‐related thoughts and behavior (Obsessive–Compulsive Drinking Scale—OCDS), alcohol use of the last 90 days, and general intelligence. Results: Behavioral performance in the spatial working memory task was not significantly different in all 3 groups. Controlling for differences in general intelligence alcohol‐dependent participants showed a higher task‐related activation of the dorsal ACC (dACC) in comparison with light and heavy social drinkers. Measures of the OCDS were positively correlated with the activation in the left hippocampus and right thalamus in all participants. Conclusions: Our results support the findings of increased dACC activation during a spatial working memory task as a risk factor for alcohol dependence. Increased task‐related activation in the dACC was only observed in alcohol‐dependent participants and not in heavy social drinkers with comparable alcohol consumption. Furthermore, the absence of behavioral performance differences between groups as well as an association between dACC activation and working memory performance indicates subtle working memory deficits. Low capacity of working memory has been linked to more automatic and less self‐regulated behavior in studies on natural reward processing. Therefore, additional neural activation during performance of the non‐alcohol‐related working memory task in participants with higher OCDS values in the left hippocampus and the right thalamus may be a consequence of decreased neural capacity because of distracting alcohol‐related thoughts.     

CDT by Anion-Exchange Chromatography Followed by RIA as a Marker of Heavy Drinking Among Men

Carbohydrate-deficient transferrin, CDT, had previously been reported to be an excellent marker for alcoholism. The present population-based study examined the diagnostic value of CDT among consecutive middle-aged males including 122 social drinkers (mean alcohol consumption 88 ± 79 g per week) and 77 non-alcoholic heavy drinkers (301 ± 195 g/wk). Ninety-six men with a well-documented history of chronic alcoholism (≥1000 g/wk) were used as a reference group. The CDT (containing mainly isotransferrin with pl = 5.8 and 5.9) was separated by anion exchange chromatography and assayed by RIA. The CDT values of social drinkers (mean ± SD = 14 ± 5 U/I) were significantly lower than those of heavy drinkers (19 ± 13 U/I, p < 0.01) and alcoholics (34 ± 18 U/I, p < 0.001). In the whole material CDT correlated positively with alcohol consumption ( r = 0.53, p < 0.001). At a specificity of 91.8%, CDT found 28.6% of the heavy drinkers and 79.2% of the alcoholics; the best traditional marker, GGT, with a specificity of 86.9%, found 35.1% and 64.6%, respectively. In conclusion, CDT is a specific marker, which is superior to traditional markers for identifying alcoholics. Unfortunately, it does not seem to provide additional power for identifying the important group, non-alcoholic heavy drinkers.     

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.