Polymorphisms of Alcohol Dehydrogenase-1B and Aldehyde Dehydrogenase-2 and the Blood and Salivary Ethanol and Acetaldehyde Concentrations of Japanese

The effects of genetic polymorphism of aldehyde dehydrogenase-2 (ALDH2) on alcohol metabolism are striking in nonalcoholics, and the effects of genetic polymorphism of alcohol dehydrogenase-1B (ADH1B) are modest at most, whereas genetic polymorphisms of both strongly affect the susceptibility to alcoholism and upper aerodigestive tract (UADT) cancer of drinkers.

We evaluated associations between ADH1B/ADH1C/ALDH2 genotypes and the blood and salivary ethanol and acetaldehyde levels of 168 Japanese alcoholic men who came to our hospital for the first time in the morning and had been drinking until the day before.

The ethanol levels in their blood and saliva were similar, but the acetaldehyde levels in their saliva were much higher than in their blood, probably because of acetaldehyde production by oral bacteria. Blood and salivary ethanol and acetaldehyde levels were both significantly higher in the subjects with the less active ADH1B*1/*1 genotype than in the ADH1B*2 carriers, but none of the levels differed according to ALDH2 genotype. Significant linkage disequilibrium was detected between the ADH1B and ADH1C genotypes, but ADH1C genotype did not affect the blood or salivary ethanol or acetaldehyde levels. High blood acetaldehyde levels were found even in the active ALDH2*1/*1 alcoholics, which were comparable with the levels of the inactive heterozygous ALDH2*1/*2 alcoholics with less active ADH1B*1/*1. The slope of the increase in blood acetaldehyde level as the blood ethanol level increased was significantly steeper in alcoholics with inactive heterozygous ALDH2*1/*2 plus ADH1B*2 allele than with any other genotype combinations, but the slopes of the increase in salivary acetaldehyde level as the salivary ethanol level increased did not differ between the groups of subjects with any combinations of ALDH2 and ADH1B genotypes.

The ADH1B/ALDH2 genotype affected the blood and salivary ethanol and acetaldehyde levels of nonabstinent alcoholics in a different manner from nonalcoholics, and clear effects of ADH1B genotype and less clear effects of ALDH2 were observed in the alcoholics. Alterations in alcohol metabolism as a result of alcoholism may modify the gene effects, and these findings provide some clues in regard to associations between the genotypes and the risks of alcoholism and UADT cancer.

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Request Reprint E-Mail: a_yokoyama@kurihama1.hosp.go.jp


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Validity Study of Kessler's Psychological Distress Scales Conducted Among Patients Admitted to French Emergency Department for Alcohol Consumption–Rel

Alcohol-related disorders (ARD) encountered in emergency departments (ED) have a high prevalence and are underestimated. It is necessary to provide professionals with a tool to identify patients in whom there is a risk that alcohol-related and mental health problems may be associated. Kessler's K6/10 psychological distress scales are fast, easy-to-use, and have been shown to achieve a good performance in the identification of psychological distress associated with ARD.

The aim of this study was to evaluate the psychometric properties of the Kessler scales, version 6 and 10, with a sample of patients admitted to EDs for alcohol consumption.

On the day after their admission, with a zero "blood" alcohol concentration, 71 patients were randomly assigned to be assessed using 6 or 10 items version. The internal consistency and factor structure of the K6/10 versions were examined. Convergent validity was measured using the Hospital Anxiety and Depression Scale (HADS) and the Hamilton Depression Rating Scale (HDRS).

The prevalence of psychological distress in our sample was approximately 60%. The selected threshold scores were 10 for K6 (Sensitivity: 0.92; Specificity: 0.62) and 14 for K10 (Sensitivity: 0.95; Specificity: 0.54). The Cronbach coefficients for K6 and K10 were 0.76 and 0.84, respectively. The factor analyses indicated the multidimensional nature of K6/10. The 2 versions, containing 6 and 10 items respectively, correlated better with the HADS (0.83 and 0.70, respectively) than with the HDRS (0.51 and 0.49, respectively). The areas under the ROC Curve indicated a high level of accuracy for both the K6 (0.87) and the K10 (0.77). The difference was not statistically significant.

This study confirms the good psychometric characteristics of Kessler's psychological distress scale. Even though similar performances were observed for K6/10, the brevity of the K6 makes it more suitable for use in EDs.

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Request Reprint E-Mail: gbrousse@chu-clermontferrand.fr

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Chronic Ethanol Disrupts Circadian Photic Entrainment and Daily Locomotor Activity in the Mouse

Chronic ethanol abuse is associated with disrupted circadian rhythms and sleep. Ethanol administration impairs circadian clock phase-resetting, suggesting a mode for the disruptive effect of alcohol abuse on circadian timing.

Here, we extend previous studies to explore the effects of chronic forced ethanol on photic phase-resetting, photic entrainment, and daily locomotor activity patterns in C57BL/6J mice.

First, microdialysis was used to characterize the circadian patterns of ethanol uptake in the suprachiasmatic (SCN) circadian clock and correlate this with systemic ethanol levels and episodic drinking of 10 or 15% ethanol. Second, the effects of chronic forced ethanol drinking and withdrawal on photic phase-delays of the circadian activity rhythm were assessed. Third, the effects of chronic ethanol drinking on entrainment to a weak photic zeitgeber (1 minute of 25 lux intensity light per day) were assessed. This method was used to minimize any masking actions of light that could mask ethanol effects on clock entrainment.

Peak ethanol levels in the SCN and periphery occurred during the dark phase and coincided with the time when light normally induces phase-delays in mice. These delays were dose-dependently inhibited by chronic ethanol and its withdrawal. Chronic ethanol did not impede re-entrainment to a shifted light cycle but affected entrainment under the weak photic zeitgeber and disrupted the daily pattern of locomotor activity.

These results confirm that chronic ethanol consumption and withdrawal markedly impair circadian clock photic phase-resetting. Ethanol also disturbs the temporal structure of nighttime locomotor activity and photic entrainment. Collectively, these results suggest a direct action of ethanol on the SCN clock.

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Request Reprint E-Mail: jglass@kent.edu

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Impact of Chronic Alcohol Ingestion on Cardiac Muscle Protein Expression

Chronic alcohol abuse contributes not only to an increased risk of health-related complications, but also to a premature mortality in adults. Myocardial dysfunction, including the development of a syndrome referred to as alcoholic cardiomyopathy, appears to be a major contributing factor. One mechanism to account for the pathogenesis of alcoholic cardiomyopathy involves alterations in protein expression secondary to an inhibition of protein synthesis. However, the full extent to which myocardial proteins are affected by chronic alcohol consumption remains unresolved.

The purpose of this study was to examine the effect of chronic alcohol consumption on the expression of cardiac proteins. Male rats were maintained for 16 weeks on a 40% ethanol-containing diet in which alcohol was provided both in drinking water and agar blocks. Control animals were pair-fed to consume the same caloric intake. Heart homogenates from control- and ethanol-fed rats were labeled with the cleavable isotope coded affinity tags (ICAT™). Following the reaction with the ICAT™ reagent, we applied one-dimensional gel electrophoresis with in-gel trypsin digestion of proteins and subsequent MALDI-TOF-TOF mass spectrometric techniques for identification of peptides. Differences in the expression of cardiac proteins from control- and ethanol-fed rats were determined by mass spectrometry approaches.

Initial proteomic analysis identified and quantified hundreds of cardiac proteins. Major decreases in the expression of specific myocardial proteins were observed. Proteins were grouped depending on their contribution to multiple activities of cardiac function and metabolism, including mitochondrial-, glycolytic-, myofibrillar-, membrane-associated, and plasma proteins. Another group contained identified proteins that could not be properly categorized under the aforementioned classification system.

Based on the changes in proteins, we speculate modulation of cardiac muscle protein expression represents a fundamental alteration induced by chronic alcohol consumption, consistent with changes in myocardial wall thickness measured under the same conditions.

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Request Reprint E-Mail: tvary@psu.edu

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Inflexible and Indifferent Alcohol Drinking in Male Mice

Alcoholism is characterized by compulsive alcohol intake, but this critical feature of alcoholism is seldom captured in preclinical studies.

Here, we evaluated whether alcohol-preferring C57BL/6J mice develop compulsive alcohol drinking patterns, using adulteration of the alcohol solution with quinine, in a limited access choice paradigm. We assessed 2 independent aspects of compulsive drinking: (i) inflexible alcohol intake by testing whether mice would drink bitter alcohol solutions if this was their only source of alcohol and (ii) indifferent drinking by comparing intake of aversive and nonaversive alcohol solutions.

C57BL/6J mice rapidly developed compulsive alcohol drinking patterns. Adulteration of the alcohol solution with an aversive quinine concentration failed to reduce intake, indicative of inflexible drinking behavior, after only 2 weeks of alcohol experience, although quinine adulteration did suppress the acquisition of alcohol drinking in naïve mice. After 8 weeks of alcohol consumption, the mice also became indifferent to quinine. They consumed an aversive, quinine-containing alcohol solution, despite the simultaneous availability of an unadulterated alcohol solution. Prolonged alcohol ingestion did not alter the sensitivity to the bitter taste of quinine itself.

These findings demonstrate the staged occurrence in mice of 2 distinct behavioral characteristics of alcoholism, i.e., inflexible and indifferent alcohol drinking.

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Request Reprint E-Mail: h.m.b.lesscher@umcutrecht.nl

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Transcallosal White Matter Degradation Detected With Quantitative Fiber Tracking in Alcoholic Men and Women: Selective Relations to Dissociable Functi

Excessive alcohol consumption can adversely affect white matter fibers and disrupt transmission of neuronal signals.

Here, we examined six anatomically defined transcallosal white matter fiber bundles and asked whether any bundle was specifically vulnerable to alcohol, what aspect of white matter integrity was most affected, whether women were more vulnerable than men, and whether evidence of compromise in specific bundles was associated with deficits in balance, sustained attention, associative learning, and psychomotor function, commonly affected in alcoholics.

Diffusion tensor imaging quantitative fiber tracking assessed integrity of six transcallosal white matter bundles in 87 alcoholics (59 men, 28 women) and 88 healthy controls (42 men, 46 women). Measures included orientational diffusion coherence (fractional anisotropy, FA) and magnitude of diffusion, quantified separately for axial (longitudinal; λL) and radial (transverse; λT) diffusivity. The Digit Symbol Test and a test of ataxia were also administered.

Alcoholism negatively affected callosal FA and λT of all but the sensory-motor bundle. Women showed no evidence for greater vulnerability to alcohol than men. Multiple regression analyses confirmed a double dissociation: higher diffusivity in sensory-motor and parietal bundles was associated with poorer balance but not psychomotor speed, whereas higher diffusivity in prefrontal and temporal bundles was associated with slower psychomotor speed but not balance.

This study revealed stronger alcohol effects for FA and radial diffusivity than axial diffusivity, suggesting myelin degradation, but no evidence for greater vulnerability to alcohol in women than men. The presence of brain-behavior relationships provides support for the role of alcoholism-related commissural white matter degradation as a substrate of cognitive and motor impairment. Identification of a double dissociation provides further support for the role of selective white matter integrity in specific domains of performance.

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Request Reprint E-Mail: edie@stanford.edu

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MAOA Interacts With the ALDH2 Gene in Anxiety–Depression Alcohol Dependence

Alcohol dependence is usually comorbid with anxiety disorder, depressive disorder, or both; this comorbidity may increase drinking behavior. We previously hypothesized that anxiety–depressive alcohol dependence (ANX/DEP ALC) was a genetically specific subtype of alcohol dependence. ANX/DEP ALC may be related to dopamine and serotonin, which are catalyzed by monoamine oxidase A (MAOA) and acetaldehyde dehydrogenase 2 (ALDH2).

The aim of this study was to determine whether the interaction between the MAOA and the ALDH2 genes is associated with ANX/DEP ALC.

We recruited 383 Han Chinese men in Taiwan: 143 ANX/DEP ALC and 240 healthy controls. The diagnosis of ANX/DEP ALC (alcohol dependence with a past or current history of anxiety, depressive disorder, or both) was made using DSM-IV criteria. Genotypes of ALDH2 and MAOA-uVNTR (variable number of tandem repeat located upstream) were determined using PCR-RFLP.

The ALDH2, but not the MAOA-uVNTR, polymorphism was associated with ANX/DEP ALC. After stratifying the MAOA-uVNTR polymorphism, we found a stronger association between the ALDH2*1/*2 and *2/*2 genotypes and the controls in the MAOA-uVNTR 4-repeat subgroup. Logistic regression significantly associated the interaction between ALDH2 and MAOA variants with ANX/DEP ALC.

We conclude that the MAOA and ALDH2 genes interact in ANX/DEP ALC. Although the MAOA gene alone is not associated with ANX/DEP ALC, we hypothesize that different variants of MAOA-uVNTR polymorphisms modify the protective effects of the ALDH2*2 allele on ANX/DEP ALC in Han Chinese in Taiwan.

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Request Reprint E-Mail: rblu@mail.ncku.edu.tw

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Paradoxical Effects of Alcohol Information on Alcohol Outcome Expectancies

Cognitive associations with alcohol predict both current and future use in youth and young adults. Much cognitive and social cognitive research suggests that exposure to information may have unconscious influences on thinking and behavior.

The present study assessed the impact of information statements on the accessibility of alcohol outcome expectancies.

The 2 studies reported here investigated the effects of exposure to alcohol statements typical of informational approaches to prevention on the accessibility of alcohol outcome expectancies. High school and university students were presented with information statements about the effects of alcohol and other commercial products. The alcohol statements were taken from expectancy questionnaires. Some of these statements were presented as facts and others as myths. The retention of detailed information about these statements was manipulated by (i) divided attention versus focused attention or (ii) immediate versus delayed testing. Accessibility of personal alcohol outcome expectancies was subsequently measured using an open-ended question about the expected effects of alcohol.

Participants reported more alcohol outcomes seen during the information task as personal expectations about the effects of alcohol use than similar unseen items. Paradoxically, myth statements were also more likely to be reported as expectancies than unseen items in all conditions. Additionally, myth statements were generated less often than fact statements only under the condition of immediate testing with strong content processing instructions.

These observations are consistent with findings from cognitive research where familiarity in the absence of explicit memory can have an unconscious influence on performance. In particular, the exposure to these items in an informational format increases accessibility of the seen items even when the participants were told that they were myths. The findings have implications for the development of effective prevention materials.

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Request Reprint E-Mail: marvin.krank@ubc.ca

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Acute Ethanol Effects on Brain Activation in Low- and High-Level Responders to Alcohol

A low level of response (LR) to alcohol is an important endophenotype associated with an increased risk of alcoholism. However, little is known about how neural functioning may differ between individuals with low and high LRs to alcohol.

This study examined whether LR group effects on neural activity varied as a function of acute alcohol consumption.

A total of 30 matched high- and low-LR pairs (N = 60 healthy young adults) were recruited from the University of California, San Diego, and administered a structured diagnostic interview and laboratory alcohol challenge followed by two functional magnetic resonance imaging (fMRI) sessions under placebo and alcohol conditions, in randomized order. Task performance and blood oxygen level-dependent response contrast to high relative to low working memory load in an event-related visual working memory (VWM) task were examined across 120 fMRI sessions.

Both LR groups performed similarly on the VWM task across conditions. A significant LR group by condition interaction effect was observed in inferior frontal and cingulate regions, such that alcohol attenuated the LR group differences found under placebo (p <>

Alcohol had differential effects on brain activation for low- and high-LR individuals within frontal and cingulate regions. These findings represent an additional step in the search for physiological correlates of a low LR and identify brain regions that may be associated with the low LR response.

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Request Reprint E-Mail: mschuckit@ucsd.edu

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Age-Related Changes in Drinking Patterns From Mid- to Older Age: Results From the Wisconsin Longitudinal Study

Drinking has generally been shown to decline with age in older adults. However, results vary depending on the measure of alcohol consumption used and the study population.

The goals of this study were to (i) describe changes in drinking in a current cohort of older adults using a variety of measures of drinking and (ii) examine a number of different possible predictors of change.

From age 53 to 64, average drinks per drinking day and heavy drinking decreased. Frequency of drinking increased for men and women, and total drinks per month increased for men. The most consistent predictors of drinking changes were gender, health, and education. Other factors predicted drinking change but were not consistent across drinking measures including: adolescent IQ, income, lifetime history of alcohol-related problems, religious service attendance, depression, debt, and changes in employment.

Heavy drinking decreases with age, but we may see more frequent moderate drinking with current and upcoming cohorts of older adults. Components of quantity and frequency of drinking change differently. Composite measures of total alcohol consumption may not be adequate for describing relevant changes in drinking over time. A number of factors predicted patterns of change in drinking and warrant further exploration.

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Request Reprint E-Mail: r.molander@hosp.wisc.edu

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Age of Drinking Onset as a Moderator of the Efficacy of Parent-Based, Brief Motivational, and Combined Intervention Approaches to Reduce Drinking and

The current study tested age of onset as a moderator of intervention efficacy on drinking and consequence outcomes among a high-risk population of college students (i.e., former high school athletes).

Students were randomized to one of four conditions: assessment only control, combined parent-based intervention (PBI) and brief motivational intervention (BMI), PBI alone, and BMI alone. Participants (n = 1,275) completed web-administered measures at baseline (summer before starting college) and 10-month follow-up.

Overall, the combined intervention demonstrated the strongest and most consistent reductions across all outcomes, particularly with the youngest initiators. Participants who initiated drinking at the youngest ages had significantly lower peak drinking, typical weekly drinking, and reported consequences at follow-up when they received the combined intervention when compared to the control group. The BMI and PBI groups, when examined independently, demonstrated significant effects across outcomes but were inconsistent across the different age groups.

Results suggest the combination of a PBI and a peer-delivered BMI is an appropriate and efficacious way to reduce drinking and related consequences among individuals who initiated drinking earlier in adolescence and are at an increased risk of experiencing alcohol problems.

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Request Reprint E-Mail: kmallett@psu.edu

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ERP and RT Delays in Long-Term Abstinent Alcoholics in Processing of Emotional Facial Expressions During Gender and Emotion Categorization Tasks

There is considerable evidence that alcoholics differ from nonalcoholics in the processing of stimuli that have emotional content. The current study examines those differences that are present in multi-year abstinent individuals.

We compared reaction time (RT), accuracy, and Event Related Potentials (ERP) measures in long-term abstinent alcoholics (LTAA, n = 52) with that in age- and gender-comparable nonalcoholic controls (NAC, n = 47). Subjects were presented with male and female faces exhibiting happy, neutral, or sad facial expressions and were instructed to identify the picture gender in 1 task and the emotion being expressed in a subsequent task.

LTAA had slower RTs than NAC when instructed to identify emotion, while RT was comparable when identifying gender. There were no differences between groups on task accuracy. P160 latency was increased in LTAA for both tasks compared to NAC, though P160 amplitude did not differ between groups. The P160 effect was about 5 × as large as the RT effect and was statistically independent of the RT effect, while the RT effect was no longer present after removing variance because of the P160 effect.

Our data demonstrate slower early processing of emotional facial stimuli in alcoholics that is unresolved by long-term abstinence and is most sensitively indexed by delayed P160 latency in LTAA.

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Request Reprint E-Mail: george@nbresearch.com

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Ethanol Acutely Modulates mGluR1-Dependent Long-Term Depression in Cerebellum

Acute and chronic ethanol exposure produces profound impairments in motor functioning. Individuals with lower sensitivity to the acute motor impairing effects of ethanol have an increased risk of developing alcohol dependence and abuse, and infants with subtle delays in motor coordination development may have an increased risk for subsequently developing alcoholism. Thus, understanding the mechanism by which ethanol disrupts motor functioning is very important.

We determined whether ethanol acutely affects parallel fiber LTD using whole-cell patch-clamp recordings from Purkinje cells. Application of ethanol both externally (50 mM) and internally (17 and 10 mM) significantly suppressed mGluR-mediate slow currents. Short-term external ethanol exposure (50 but not 17 mM) during tetanus blocked mGluR-dependent parallel fiber LTD. Furthermore, internal 17 and 10 mM ethanol completely inhibited this LTD.

The results of the current study demonstrate that ethanol acutely suppresses parallel fiber LTD and may influence the mGluR-mediated slow current intracellularly. This study, plus previous evidence by Carta and colleagues (2006) and Belmeguenai and colleagues (2008), suggests significant actions of ethanol on mGluR-mediated currents and its dependent plasticity in brain.

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Request Reprint E-Mail: yshen@zju.edu.cn

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Nearly Four Million California Adults Are Victims of Intimate Partner Violence

Nearly 1 in 6 adults in California, about 3.7 million persons, report experiencing physicalintimate partner violence (IPV) as adults. Over one million Californians were forced to have sex (5%) by an intimate partner during adulthood.

Overall, 17.2% of adults—nearly four million Californians—report being a victim of physical and/or sexual IPV as an adult (Exhibit 1). These acts of violence are not merely a criminal justice problem, but a public health problem with deep and lingering social, psychological and health-related costs.

Beyond the immediate trauma facing adult victims, IPV incidents may have a prolonged impact on the emotional and mental health of the victims, affect their ability to complete school or maintain employment, and result in adverse health behaviors to cope with the trauma, such as engaging in risky alcohol, tobacco or other drug use.

Violence that occurs between intimates or family members is especially damaging when it takes place in the presence of children; previous studies have shown that witnessing violence can lead to intergenerational cycles of violence.


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Alcohol blamed for kick-starting suicide bids

A new study has found that alcohol is to blame for most suicide attempts by overdosing.

Wellington Hospital emergency doctor Paul Quigley says at least 80 per cent of the 127 people who turned up at his emergency department last year after taking an overdose had alcohol as "the initiating agent".

Most (56 per cent) arrived at the weekend, mainly on the "party nights" of Friday and Saturday.

"When you analyse it, where their situation started from is the two bottles of wine they had to start with, or the four bottles of wine," he told the Alcohol Advisory Council's annual conference in Manukau yesterday. . . . . .

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Media Release - AER WELCOMES HENRY RECOMMENDATIONS ON ALCOHOL TAXATION ALCOHOL REFORM MUST BE PUT BACK ON THE FEDERAL GOVT AGENDA

The Alcohol Education and Rehabilitation Foundation (AER), Australia's leading alcohol harm minimisation body, today welcomed the Henry Review recommendations on alcohol taxation reform, but said it is disappointed with the Federal Government’s response. . . . . .

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Energized Alcohol

Vodka and Red Bull has been the choice of concert and club goers almost since it was launched in the U.S. back in 1997. With more than one billion cans sold worldwide every year, and a significant percentage of those mixed with booze, it was only a matter of time before enterprising liquors decided to spare us all the effort of mixing the two - bottling their own premixed energy drinks with varying amounts of alcohol. . . . . . .

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Treatment with Neuropeptides Attenuates c-fos Expression in a Mouse Model of Fetal Alcohol Syndrome

Fetal alcohol syndrome (FAS) is the most common nongenetic cause of mental retardation and is characterized by neurodevelopmental anomalies. C-fos is a cellular marker of transcriptional activity in the stress-signal pathway. Previously, we showed the treatment with NAP (NAPVSIPQ) + SAL (SALLRSIPA) reversed the learning deficit after prenatal alcohol exposure in FAS.

Our objective was to evaluate if the mechanism of actions of NAP + SAL involves the stress-signal pathway differentiating c-fos expression in mouse brains after prenatal alcohol exposure.

Adult treatment with NAP + SAL restored the down-regulation of c-fos in the hippocampus after prenatal alcohol exposure (p < class="ITALIC">c-fos expression in the cortex.

Adult treatment with NAP + SAL restored the down-regulation of c-fos expression in hippocampus attenuating the alcohol-induced alteration of the stress-signal pathway.

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Request Reprint E-Mail: incertim@mail.nih.gov

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Pen portraits: alcohol segmentation series report 4

To further understand population segmentation in alcohol misuse, the North West Public Health Observatory has published a series of four reports utilising segmentation tools to discuss alcohol consumption, attitudes and related admission.

The first three reports in the series discuss attitudes to alcohol consumption, consumption and related hospital admissions respectively.

This report, the fourth in the series, summarises the findings and presents them by classification in order to present an overview of the attitudes, consumption and harms experienced by each segmentation type.

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Alcohol-attributable hospital admission: segmentation series report 3

To further understand population segmentation in alcohol misuse, the North West Public Health Observatory has published a series of four reports utilising segmentation tools to discuss alcohol consumption, attitudes
and related admission.

This is the third report in the series and focuses on different types of alcohol-related hospital admissions.

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