To support the free and open dissemination of research findings and information on alcoholism and alcohol-related problems. To encourage open access to peer-reviewed articles free for all to view.

For full versions of posted research articles readers are encouraged to email requests for "electronic reprints" (text file, PDF files, FAX copies) to the corresponding or lead author, who is highlighted in the posting.


Saturday, August 20, 2011

Moderate alcohol use may reduce dementia, cognitive damage: study

About to uncork that bottle of merlot? A study finds that moderate drinking may decrease the risk of dementia and cognitive decline in older people.

Researchers analyzed 143 studies that looked at the association between moderate alcohol consumption and mental abilities. The meta-analysis, published this month in the journal
Neuropsychiatric Disease and Treatment,
looked at research dating back to 1977. > > > > Read More

Chronic alcohol ingestion exacerbates skeletal muscle myopathy in HIV-1 transgenic rats

Separately, chronic alcohol ingestion and HIV-1 infection are associated with severe skeletal muscle derangements, including atrophy and wasting, weakness, and fatigue. One prospective cohort study reported that 41% of HIV-infected patients met the criteria for alcoholism, however; few reports exist on the co-morbid effects of these two disease processes on skeletal muscle homeostasis.

Thus, we analyzed the atrophic effects of chronic alcohol ingestion in HIV-1 transgenic rats and identified alterations to several catabolic and anabolic factors.

Relative plantaris mass, total protein content, and fiber cross-sectional area were reduced in each experimental group compared to healthy, control-fed rats. Alcohol abuse further reduced plantaris fiber area in HIV-1 transgenic rats. Consistent with previous reports, gene levels of myostatin and its receptor activin IIB were not increased in HIV-1 transgenic rat muscle.

However, myostatin and activin IIB were induced in healthy and HIV-1 transgenic rats fed alcohol for 12 weeks. Catabolic signaling factors such as TGFbeta1, TNFalpha, and phospho-p38/total-p38 were increased in all groups compared to controls. There was no effect on IL-6, leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), or ciliary neurotrophic factor (CNTF) in control-fed, transgenic rats.

However, the co-morbidity of chronic alcohol abuse and HIV-1-related protein expression decreased expression of the two anabolic factors, CT-1 and CNTF.

Consistent with previous reports, alcohol abuse accentuated skeletal muscle atrophy in an animal model of HIV/AIDS. While some catabolic pathways known to drive alcoholic or HIV-1-associated myopathies were also elevated in this co-morbid model (e.g., TGFbeta1), consistent expression patterns were not apparent.

Thus, specific alterations to signaling mechanisms such as the induction of the myostatin/activin IIB system or reductions in growth factor signaling via CT-1- and CNTF-dependent mechanisms may play larger roles in the regulation of muscle mass in alcoholic, HIV-1 models.

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News Release - Show Me My Buzz Smartphone App Now Available

MoDOT is launching a new smartphone application to help people make smart choices about designating a sober driver.

The "Show Me My Buzz" free smartphone app, available soon in the Apple App Store and the Google Market, allows users to calculate their estimated blood-alcohol concentration (BAC) based on how many drinks they have consumed, how long they have been drinking and their gender.

"Drinking and driving is always a bad decision because even a small amount of alcohol affects your reflexes," said Don Hillis, MoDOT's assistant chief engineer. "This new app is a creative way to get people talking about the subject and then finding a sober driver."

The app indicates designating a driver who has not been drinking is the only safe option, and it will even provide the phone number of a local cab company with just a tap of the screen.

"The added feature of finding a phone number for a taxi in more urban locations, takes away one more excuse for a person who has been drinking," said Hillis. "It is easy to just touch the button to call a cab." > > > > Read More

Racial and Ethnic Differences in All-Cause Mortality Risk According to Alcohol Consumption Patterns in the National Alcohol Surveys

Previous studies have found J-shaped relations between volume of alcohol consumed and mortality risk in white Americans but not in African Americans, suggesting the need for studies in which race/ethnicity-defined subgroups are analyzed in separate comparable models.

In the present study, the authors utilized mortality follow-up data (through 2006) on respondents from the 1984 and 1995 National Alcohol Surveys, including similar numbers of black, white, and Hispanic respondents by oversampling the minority groups. Cox proportional hazards models controlling for demographic, socioeconomic, mental health, and drug- and tobacco-use measures were used to estimate mortality risk from all causes.

Findings indicated a protective effect of moderate alcohol drinking (2–30 drinks/month for women and 2–60 drinks/month for men) with no monthly ≥5-drink days) relative to lifetime abstention for whites only.

Elevated mortality risk relative to moderate drinking was found in former drinkers with lifetime alcohol problems.

Moderate drinkers who consumed ≥5 drinks in 1 day at least monthly were also found to have increased risk, suggesting the importance of identifying heavy-occasion drinking for mortality analyses.

These differential results regarding lifetime abstainers may suggest bias from differential unmeasured confounding or unmeasured aspects of alcohol consumption pattern or may be due to genetic differences in the health impact of alcohol metabolism.

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The TTTAn aromatase (CYP19A1) polymorphism is associated with compulsive craving of male patients during alcohol withdrawal

Alcoholism is associated with alterations of the hypothalamus–pituitary–gonadal hormone axis. We recently reported a leptin-mediated relation between the CAGn polymorphism of the androgen receptor and craving during alcohol withdrawal. This study investigated whether the TTTAn polymorphism of the aromatase (CYP19A1) is equally linked to craving.

An association between TTTAn and compulsive craving (p=0.029) was revealed in our sample of 118 male alcohol addicts at day of hospital admission. Genotype-dependent subgroups showed differences in that the patients with short alleles suffered from lower compulsive craving during withdrawal than those with the longer alleles (p=0.027). The additional inclusion of leptin revealed no further significant association in the present study.

Our finding is a further step on the way to elucidate the genesis of craving for alcohol with its extensive underlying interactions of different genetic and non-genetic factors. Future investigations should enrol women and consider sex hormone levels for further clarification of the observed TTTAn-craving relationship.

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Reinforcement of Smoking and Drinking: Tobacco Marketing Strategies Linked With Alcohol in the United States

We investigated tobacco companies’ knowledge about concurrent use of tobacco and alcohol, their marketing strategies linking cigarettes with alcohol, and the benefits tobacco companies sought from these marketing activities.

We performed systematic searches on previously secret tobacco industry documents, and we summarized the themes and contexts of relevant search results.

Tobacco company research confirmed the association between tobacco use and alcohol use. Tobacco companies explored promotional strategies linking cigarettes and alcohol, such as jointly sponsoring special events with alcohol companies to lower the cost of sponsorships, increase consumer appeal, reinforce brand identity, and generate increased cigarette sales. They also pursued promotions that tied cigarette sales to alcohol purchases, and cigarette promotional events frequently featured alcohol discounts or encouraged alcohol use.

Tobacco companies’ numerous marketing strategies linking cigarettes with alcohol may have reinforced the use of both substances. Because using tobacco and alcohol together makes it harder to quit smoking, policies prohibiting tobacco sales and promotion in establishments where alcohol is served and sold might mitigate this effect. Smoking cessation programs should address the effect that alcohol consumption has on tobacco use.

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Alcohol consumption and body weight: a systematic review

Based on the fact that energy content in 1 gram of alcohol is 29 kJ or 7.1 kcal, alcohol consumption can lead to weight gain. The present review was conducted to analyze the effects of alcohol consumption on body weight.

A search of the Medline database for the period 1984 to March 2010 was conducted to identify cross-sectional, prospective cohort studies and intervention trials investigating the relationship between alcohol consumption and the risk of weight gain. Thirty-one publications were selected on the basis of relevance and quality of design and methods.

The findings from large cross-sectional studies as well as from well-powered, prospective, cohort studies with long periods of follow-up were contradictory. Findings from short-term experimental trials also did not show a clear trend.

The overall results do not conclusively confirm a positive association between alcohol consumption and weight gain; however, positive findings between alcohol intake and weight gain have been reported, mainly from studies with data on higher levels of drinking. It is, therefore, possible that heavy drinkers may experience such an effect more commonly than light drinkers. Moreover, light-to-moderate alcohol intake, especially wine intake, may be more likely to protect against weight gain, whereas consumption of spirits has been positively associated with weight gain.

Further research should be directed towards assessing the specific roles of different types of alcoholic beverages. Studies should also take the effect of consumption patterns into account. In addition, a potential effect modifier that has not been evaluated before but might be important to consider is the subjects' previous tendency to gain weight.

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Friday, August 19, 2011

Relationship between Personality Change and the Onset and Course of Alcohol Dependence in Young Adulthood

Examine the reciprocal effects between the onset and course of alcohol use disorder (AUD) and normative changes in personality traits of behavioral disinhibition and negative emotionality during the transition between adolescence and young adulthood.

Longitudinal-epidemiological study assessing AUD and personality at age 17 and 24.

Participants were recruited from the community and took part in a day-long, in-person assessment.

Male (n = 1161) and female (n = 1022) twins participating in the Minnesota Twin Family Study.

The effects of onset (adolescent versus young adult) and course (persistent versus desistent) of AUD on change in personality traits of behavioral disinhibition and negative emotionality from age 17 to 24.

Onset and course of AUD moderated personality change from age 17 to 24. Adolescent onset AUD was associated with greater decreases in behavioral disinhibition. Those with an adolescent onset and persistent course failed to exhibit normative declines in negative emotionality. Desistence was associated with a “recovery” toward psychological maturity in young adulthood, while persistence was associated with continued personality dysfunction. Personality traits at age 11 predicted onset and course of AUD, indicating personality differences were not due to active substance abuse.

Personality differences present prior to initiation of alcohol use increase risk for alcohol use disorder, but the course of alcohol use disorder affects the rate of personality change during emerging adulthood. Examining the reciprocal effects of personality and alcohol use disorder within a developmental context is necessary to improve understanding of theory and intervention.

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An invariant dimensional liability model of gender differences in mental disorder prevalence: Evidence from a national sample

Epidemiological studies of categorical mental disorders consistently report that gender differences exist in many disorder prevalence rates and that disorders are often comorbid. Can a dimensional multivariate liability model be developed to clarify how gender impacts diverse, comorbid mental disorders?

We pursued this possibility in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; N = 43,093).

Gender differences in prevalence were systematic such that women showed higher rates of mood and anxiety disorders, and men showed higher rates of antisocial personality and substance use disorders.

We next investigated patterns of disorder comorbidity and found that a dimensional internalizing-externalizing liability model fit the data well, where internalizing is characterized by mood and anxiety disorders, and externalizing is characterized by antisocial personality and substance use disorders.

This model was gender invariant, indicating that observed gender differences in prevalence rates originate from women and men's different average standings on latent internalizing and externalizing liability dimensions.

As hypothesized, women showed a higher mean level of internalizing, while men showed a higher mean level of externalizing.

We discuss implications of these findings for understanding gender differences in psychopathology and for classification and intervention.

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Optimal alcohol taxation: Simulation results for Estonia

The aim of this paper is to empirically estimate the optimal level of alcohol taxes for Estonia on externality as well as fiscal grounds.

For this purpose, a static general-equilibrium model
with a representative agent was used.

Simulation results showed that raising alcohol taxes
a certain amount is warranted. However, if one were to use conservative parameter values,this result is undermined.

With an eye towards future research, more reliable estimates for
several parameters are required in order to increase the policy relevance of the model.

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A Framework for the Specificity of Addictions

Research over the last two decades suggests that a wide range of substance and behavioral addictions may serve similar functions. Yet, co-occurrence of addictions has only been reported among a minority of addicts. “Addiction specificity” pertains to a phenomenon in which one pattern of addictive behaviors may be acquired whereas another is not.

This paper presents the PACE model as a framework which might help explain addiction specificity. Pragmatics, attraction, communication, and expectation (PACE) variables are described, which may help give some direction to future research needs in this arena.

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The association between the incidence of emergency department attendances for alcohol problems and assault incidents attended by police in New South W

To assess the short-term temporal relationship between emergency department (ED) attendances for acute alcohol problems and assaults reported to police.

Cross-sectional time series analysis.

Population of New South Wales (NSW), Australia between 2003 and 2008.

All patients who attended any of 56 large NSW public hospital EDs and had a recorded diagnosis of acute alcohol problems, and all persons involved in assault incidents reported to the NSW Police Force.

Weekly count time series were formed for ED attendances, assault incidents and persons of interest in assault incidents. Cross correlation analysis was used to determine any time lag in the relationship between the alcohol and the assault series. Poisson regression was used to assess the magnitude of the relationship. Splines of week controlled for seasonality.

There was no time lag found between the ED and police series. A weekly increase of 100 attendances in persons 15 years and above to EDs for alcohol problems was associated with an 11% (95% confidence interval (CI) 7%-15%) increase in the number of incident assaults attended by police. The relationship was similar and statistically significant for domestic and non-domestic assaults and urban areas. The association was stronger between ED attendances and persons of interest aged 15-24 year-olds (23%, 95% CI 17%-29%), 15-24 year-old males (39%, 95% CI: 16%-66%) and 15-24 year-old females (66%, 95% CI: 20%-129%).

There is a clear, short-term temporal association between independent population level markers of excessive alcohol use and violence.

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Surveillance of Certain Health Behaviors and Conditions Among States and Selected Local Areas — Behavioral Risk Factor Surveillance System, United Sta

Chronic diseases and conditions (e.g., heart disease, cancer, stroke, and diabetes) are the leading causes of death in the United States. Controlling health risk behaviors and conditions (e.g., smoking, physical inactivity, poor diet, excessive drinking, and obesity) and using preventive health-care services (e.g., physical examination, vaccination, screening for high blood pressure and high cholesterol, consumption of fruits and vegetables, and participation in regular leisure-time physical activity) can reduce morbidity and mortality from chronic diseases.

Reporting Period: January 2009–December 2009.

Description of the System: The Behavioral Risk Factor Surveillance System (BRFSS) is an ongoing state-based random-digit–dialed telephone survey of noninstitutionalized adults aged ≥18 years residing in the United States. BRFSS collects data on health risk behaviors and conditions, chronic diseases and conditions, access to health care, and use of preventative health services and practices related to the leading causes of death and disabilities in the United States. This report presents results for 2009 for all 50 states, the District of Columbia, the Commonwealth of Puerto Rico, Guam, the U.S. Virgin Islands, 180 metropolitan and micropolitan statistical areas (MMSAs), and 283 selected counties.

  • Binge Drinking
Binge drinking was defined as adult men having five or more drinks and adult women having four or more drinks on at least one occasion during the last 30 days. In 2009, the estimated overall prevalence of binge drinking among adults aged ≥18 years ranged from 6.8% in Tennessee to 23.9% in Wisconsin (median: 15.5%) (Table 31). Among selected MMSAs, the estimated prevalence of binge drinking ranged from 3.5% in Provo–Orem, Utah, to 23.2% in Butte–Silver Bow, Montana (median: 15.5%) (Table 32). Among selected counties, the estimated prevalence ranged from 3.4% in Utah County Utah, to 26.3% in Macomb County, Michigan (median: 15.5%) (Table 33).

  • Heavy Drinking
Heavy drinking was defined as adult men having more than two drinks and adult women having more than one drink per day during the last 30 days. In 2009, the estimated overall prevalence of heavy drinking among adults aged ≥18 years ranged from 1.9% in Tennessee to 8.1% in Vermont (median: 5.1%) (Table 34). Among selected MMSAs, the estimated prevalence of heavy drinking ranged from 1.0% in Provo–Orem, Utah, to 11.1% in Kapaa, Hawaii (median: 5.1%) (Table 35). Among selected counties, the estimated prevalence ranged from 0.9% in Utah County, Utah, to 11.1% in Kauai County, Hawaii (median: 5.1%) (Table 36).

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Conference - Unlocking Recovery in Prisons

13 October 2011
Chandos House, London

Conference overview

In April 2011 the funding for drug treatment in prisons passed from the MOJ to the DOH and with it the responsibility to commission these services passed to local partnerships. Many of those with the commissioning responsibility are new to the prison setting and are stepping into unfamiliar territory. There are questions like:

  • What works in prison?
  • How does the prison system itself work?
  • What opportunities are there to deliver recovery focused treatment?
  • What are the challenges to working within a prison environment?
The main target group for the conference is those newly responsible for commissioning substance misuse treatment in prisons. The conference will focus on the non-clinical aspects of substance use treatment in prisons. Recovery in prisons is not new. There are many examples of people finding freedom from dependency during their time spent in prison. The conference aims to explore examples of good practice in recovery in prisons in the UK today, explore the risks and opportunities for enhancing recovery through local commissioning and explore what can be done to enhance the recovery journey of those in the prison system. > > > > Read More

Alcohol-related brief intervention in patients treated for opiate or cocaine dependence: A randomized controlled study

Despite the importance of heavy drinking and alcohol dependence among patients with opiate and cocaine dependence, few studies have evaluated specific interventions within this group. The aim of the present study was to evaluate the impact of screening with the Alcohol Use Disorders Identification Test (AUDIT) and of brief intervention (BI) on alcohol use in a sample of patients treated for opioid or cocaine dependence in a specialized outpatient clinic.

Adult outpatients treated for opioid or cocaine dependence in Switzerland were screened for excessive alcohol drinking and dependence with the AUDIT. Patients with AUDIT scores that indicated excessive drinking or dependence were randomized into two groups--treatment as usual or treatment as usual together with BI--and assessed at 3 months and 9 months.

Findings revealed a high rate (44%) of problematic alcohol use (excessive drinking and dependence) among patients with opiate and cocaine dependence. The number of drinks per week decreased significantly between T0 (inclusion) and T3 (month 3). A decrease in average AUDIT scores was observed between T0 and T3 and between T0 and T9 (month 9). No statistically significant difference between treatment groups was observed.

In a substance abuse specialized setting, screening for alcohol use with the AUDIT, followed by feedback on the score, and use of alcohol BI are both possibly useful strategies to induce changes in problematic alcohol use. Definitive conclusions cannot, however, be drawn from the study because of limitations such as lack of a naturalistic group. An important result of the study is the excellent internal consistency of AUDIT in a population treated for opiate or cocaine dependence.

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Recommendations on Dram Shop Liability and Overservice Law Enforcement Initiatives to Prevent Excessive Alcohol Consumption and Related Harms

The Task Force on Community Preventive Services recommends the use of dram shop liability laws, on the basis of strong evidence of effectiveness in preventing and reducing alcohol-related harms. The Task Force found insufficient evidence to determine the effectiveness of overservice law enforcement initiatives as a means to reduce excessive alcohol consumption and related harms, because too few studies were identified and findings were inconsistent.

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Effects of Dram Shop Liability and Enhanced Overservice Law Enforcement Initiatives on Excessive Alcohol Consumption and Related Harms: Two Community

Dram shop liability holds the owner or server(s) at a bar, restaurant, or other location where a patron, adult or underage, consumed his or her last alcoholic beverage responsible for harms subsequently inflicted by the patron on others. Liability in a state can be established by case law or statute. Overservice laws prohibit the sale of alcoholic beverages to intoxicated patrons drinking in on-premises retail alcohol outlets (i.e., premises where the alcohol is consumed where purchased); enhanced enforcement of these laws is intended to ensure compliance by premises personnel. Both of these interventions are ultimately designed to promote responsible beverage service by reducing sales to intoxicated patrons, underage youth, or both. This review assesses the effectiveness of dram shop liability and the enhanced enforcement of overservice laws for preventing excessive alcohol consumption and related harms.

Studies assessing alcohol-related harms in states adopting dram shop laws were evaluated, as were studies assessing alcohol-related harms in regions with enhanced overservice enforcement. Methods previously developed for systematic reviews for the Guide to Community Preventive Services were used.

Eleven studies assessed the association of state dram shop liability with various outcomes, including all-cause motor vehicle crash deaths, alcohol-related motor vehicle crash deaths (the most common outcome assessed in the studies reviewed), alcohol consumption, and other alcohol-related harms. There was a median reduction of 6.4% (range of values 3.7% to 11.3% reduction) in alcohol-related motor vehicle fatalities associated with the presence of dram shop liability in jurisdictions where premises are licensed. Other alcohol-related outcomes also showed a reduction. Only two studies assessed the effects of enhanced enforcement initiatives on alcohol-related outcomes; findings were inconsistent, some indicating benefit and others none.

According to Community Guide rules of evidence, the number and consistency of findings indicate strong evidence of the effectiveness of dram shop laws in reducing alcohol-related harms. It will be important to assess the possible effects of legal modifications to dram shop proceedings, such as the imposition of statutes of limitation, increased evidentiary requirements, and caps on recoverable amounts. According to Community Guide rules of evidence, evidence is insufficient to determine the effectiveness of enhanced enforcement of overservice laws for preventing excessive alcohol consumption and related harms.

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Evaluation of an Internet-Based Alcohol Misuse Prevention Course for College Freshmen: Findings of a Randomized Multi-Campus Trial Purchase

Internet-based alcohol misuse prevention programs are now used by many universities. One popular 2- to 3-hour online course known as AlcoholEdu for College is typically required for all incoming freshmen and thus constitutes a campus-level strategy to reduce student alcohol misuse.

Multi-campus study to evaluate the effectiveness of an Internet-based alcohol misuse prevention course.

RCT with 30 universities: 21 entered the study in Fall 2007, nine in Fall 2008. Fifteen were randomly assigned to receive the online course and the other 15 were assigned to the control condition. The course was implemented by intervention schools during the late summer and/or fall semester. Cross-sectional surveys of freshmen were conducted at each university, beginning prior to the intervention in Spring 2008–2009; post-intervention surveys were administered in Fall 2008–2009 and Spring 2009–2010.

Public and private universities of varying sizes across the U.S. Random samples of 200 freshmen per campus were invited to participate in online surveys for the evaluation. Overall survey response rates ranged from 44% to 48% (M ≈ 90 participants per campus).

The online course includes five modules; the first four (Part I) are typically offered in the late summer before matriculation, and the fifth (Part II) in early fall. Course content includes defining a standard drink, physiologic effects of alcohol, the need to monitor blood alcohol level, social influences on alcohol use, alcohol laws, personalized normative feedback, and alcohol harm-reduction strategies. Students must pass an exam after Part I to advance to Part II.

Past-30-day alcohol use, average number of drinks per occasion, and binge drinking.

Multilevel intent-to-treat analyses indicated significant reductions in the frequency of past-30-day alcohol use (beta = –0.64, p<0.05) and binge drinking (beta = –0.26, p<0.05) during the fall semester immediately after completion of the course. However, these effects did not persist when assessed in the spring semester. Post hoc comparisons suggested stronger course effects on these outcomes at colleges with higher rates of student course completion. No course effects were observed for average number of drinks per occasion or prevalence of binge drinking, regardless of the campus course completion rate.

This study provides initial evidence that the Internet-based alcohol misuse prevention course has beneficial short-term effects on hazardous drinking behavior among first-year college students, which should be reinforced through effective environmental prevention strategies.

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Thursday, August 18, 2011

Debate over warning labels on alcohol heats up

HEALTH warnings linking alcohol with dire outcomes such as brain damage and cancer have been backed by health groups but described as potentially ''alarming'' by an industry-backed group.

The fight over safety labels between the health sector and the multibillion-dollar liquor industry is warming up just as the federal government finally begins formal consultations today on long-awaited warnings, introduced in the United States 22 years ago.

The federally-funded Alcohol Education and Rehabilitation Foundation yesterday released its favoured warnings, including: ''Drinking alcohol increases your risk of developing cancers'' and ''drinking alcohol damages the young developing brain''.

The foundation has dismissed as ''weak'' the voluntary warnings being introduced by most beer, wine and spirit companies.

The foundation's warnings have been developed on advice from health promotion experts and were backed by the Australian Medical Association, which has urged the government to introduce tough mandatory warnings. > > > > Read More

ESBRA 2011, European Society for Biomedical Research on Alcoholism, Vienna, Austria, September 4–7, 2011 - SYMPOSIA ABSTRACTS


ESBRA 2011, European Society for Biomedical Research on Alcoholism, Vienna, Austria, September 4–7, 2011 - SYMPOSIA ABSTRACTS


ESBRA 2011, European Society for Biomedical Research on Alcoholism, Vienna, Austria, September 4–7, 2011 - SYMPOSIA ABSTRACTS


  1. R. Ward1,
  2. P. De Witte2,
  3. F. Lallemand3,
  4. L. Della Corte4 and
  5. D. T. Dexter5

+ Author Affiliations

  1. 1Louvain-la-Neuve, Belgium
  2. 2Universite catholique de Louvain, Louvain-la-Neuve, Belgium
  3. 3Unversite catholique de Louvain, Louvain-la-Neuve, Belgium
  4. 4University of Florence, Florence, Italy
  5. 5Imperial College, London, UK


Chronic and intermittent alcohol consumption leads to cognitive impairment in the brain due to the ethanol's action on specific neurotransmitter systems and intricate signalling pathways. Glial cells actively participate in brain function by nurturing neurons and facilitating neuronal activity as well having an immunological role to protect brain cells from invading pathogens. Dysregulation of this immune function induced by intermittent alcohol abuse may shift the homeostatic balance of inflammatory mediators to a proinflammatory state, activating microglia and inducing neuronal loss thereby inducing behavioural and cognitive impairments. Molecules, which could prevent the microglial activation and cytokine production would downregulate the pro-inflammatory state and help to prevent the decline of cognitive impairment. Studies of a ‘binge drinking’ adolescent female rats identified increased levels of glutamate in the dentate gyrus region of the hippocampus, which were associated with activated microglia. Such microglia will release glutamate when activated as well as a plethora of pro-inflammatory cytokines, e.g. IL-6 and TNFα. Oral administration of a taurine analogue, ethane-β-sultam to such ‘binge drinking’ rats for a 3-week period stabilized IKBα within the microglial cell, thereby preventing NFkappaB translocation to the nucleus and cytokine production. Activated microglia were no longer visible after immunohistochemical staining of the dentate gyrus brain region. The innate immune system, which is activated by intermittent alcohol use, can be suppressed by the use of molecules which target specific activators of this system, i.e. NFkappaB.

ERAB funding is gratefully acknowledged.

  1. G. Bakalkin and
  2. T. Yakovleva

+ Author Affiliations

  1. Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden


Alcohol dependence and associated cognitive impairment appear to result from maladaptive neuroplasticity in response to chronic alcohol consumption, neuroinflammation and neurodegeneration. The inherent stability of behavioral alterations associated with the addicted state suggests that transcriptional and epigenetic mechanisms are operative. NF-kappaB transcription factors are regulators of synaptic plasticity and inflammation, and responsive to a variety of stimuli including alcohol. These factors are abundant in the brain where they have diverse functions that depend on the composition of the NF-kappaB complex and cellular context. In neuron cell bodies, NF-kappaB is constitutively active, and involved in neuronal injury and neuroprotection. However, at the synapse, NF-kappaB is present in a latent form and upon activation is transported to the cell nucleus. In glia, NF-kappaB is inducible and regulates inflammatory processes that exacerbate alcohol-induced neurodegeneration. Animal studies demonstrate that acute alcohol exposure transiently activates NF-kappaB, which induces neuroinflammatory responses and neurodegeneration. Our postmortem studies of brains of human alcoholics suggest that cycles of alcohol consumption/withdrawal cause adaptive changes in the NF-kappaB system that permit the system to better tolerate excessive stimulation. This tolerance, ensuring a low degree of responsiveness to applied stimuli, may represent a compensatory response that protects brain cells against alcohol neurotoxicity. This is supported by findings showing preferential downregulation of pro-apoptotic gene expression in the affected brain areas in human alcoholics. Although further verification is needed, we speculate that NF-kappaB-driven neuroinflammation and disruption to neuroplasticity play a significant role in regulating alcohol dependence and cognitive impairment.

  1. M. Pascual-Mora1,
  2. P. Baliño2,
  3. S. Alfonso-Loeches1,
  4. C. Aragón2 and
  5. C. Guerri1

+ Author Affiliations

  1. 1Principe Felipe Research Centre, Valencia, Spain
  2. 2University of Jaume I, Castellón, Spain


Toll-like receptors (TLRs) play an important role in the innate immune response, and emerging evidence indicates their role in brain injury and neurodegeneration. Our recent results have demonstrated that ethanol is capable of activating glial TLR4 receptors and that the elimination of these receptors in mice protects against ethanol-induced glial activation, induction of inflammatory mediators and apoptosis. However, whether ethanol-induced inflammatory damage causes behavioural and cognitive consequences, and if behavioural alterations are dependent of TLR4 functions are presently unknown. Here we show in mice drinking alcohol for 5 months, followed by a 15-day withdrawal period, that activation of the astroglial and microglial cells in frontal cortex and striatum is maintained and that these events are associated with cognitive and anxiety-related behavioural impairments in wild-type (WT) mice, as demonstrated by testing the animals with object memory recognition, conditioned taste aversion and dark and light box anxiety tasks. Mice lacking TLR4 receptors (TLR4−/−) are protected against ethanol-induced inflammatory damage, and behavioural associated effects. We further assess the possibility of the epigenetic modifications participating in short- or long-term behavioural effects associated with neuroinflammatory damage. We show that chronic alcohol treatment decreases H4 histone acetylation and histone acetyltransferases activity in frontal cortex, striatum and hippocampus of WT mice. Alterations in chromatin structure were not observed in TLR4−/− mice. These results provide the first evidence of the role that TLR4 functions play in the behavioural consequences of alcohol-induced inflammatory damage and suggest that the epigenetic modifications mediated by TLR4 could contribute to short- or long-term alcohol-induced behavioural or cognitive dysfunctions.

This study was supported by SAF-2009-07503, Institute of Heath, Carlos III (RTA-Network).

  1. F. Crews

+ Author Affiliations

  1. University of North Carolina School of Medicine, Chapel Hill, NC, USA


Addiction evolves through progressively reduced behavioral control and cognitive flexibility with increasing negative emotion and craving. Recent discoveries indicating neuroimmune signaling contribute to addiction and co-morbid depression. Low threshold microglia undergoes progressive stages of innate immune activation involving astrocytes and neurons with repeated drug abuse, stress and immune signals. Increased brain NF-κB transcription of proinflammatory chemokines, cytokines, oxidases, proteases, TLR and other genes create loops amplifying NF-κB transcription and neuroimmune gene expression. Human post-mortem alcoholic brain has increased microglial markers, chemokine-MCP1, TLR receptors and endogenous TLR agonists. Ethanol activates persistent neuroimmune signaling through the formation of loops of NF-κB transcription in glia contributing to a hyperglutamate state. Chronic ethanol treatment induces reversal learning deficits coincident with frontal cortical damage mimicking human drug addict deficits in behavioral flexibility. Increasing limbic negative emotion and depression-like behavior are reflected in hippocampal neurogenesis. Chronic ethanol inhibits neurogenesis coincident with depression-like behavior with both reversed by antidepressants. Antidepressants, naltrexone and anti-inflammatory drugs block ethanol neuroimmune activation, inhibition of neurogenesis and neurotoxicity. The hypothesis that neuroimmune gene induction underlies addiction and affective disorders creates new targets for therapy.

This study was supported by NIH and NIAAA.

ESBRA 2011, European Society for Biomedical Research on Alcoholism, Vienna, Austria, September 4–7, 2011 - SYMPOSIA ABSTRACTS



  1. H. Tilg1,2

+ Author Affiliations

  1. 1University of Innsbruck, Innsbruck, Austria
  2. 2Abt. für Innere Medizin, Bezirkskrankenhaus Hall, Hall in Tirol, Austria


Ethanol treatment increases the production of reactive oxygen species (ROS) and lowers antioxidant levels, thereby enhancing oxidative stress in many tissues. ROS are capable of initiating lipid peroxidation and lead to the release of reactive aldehydes with potent pro-inflammatory and pro-fibrotic properties. Various pro-inflammatory cytokines such as TNFα, IL-1, IL-8 and others have been proposed to play a major role in alcoholic steatohepatitis (ASH). Serum concentrations TNF and of various TNF-inducible cytokines such as IL-1 and IL-8 are increased in patients with acute ASH. Several studies in rats, mice and tissue culture focused on the role of cytokines, especially TNF, in experimental models of alcoholic liver disease. Studies neutralizing other pro-inflammatory cytokines such as IL-1 or IL-8 are currently not available. Furthermore, alcohol-associated liver injury is inhibited when the animals are treated with poorly absorbed oral antibiotics or lactobacillus to decrease endotoxaemia, supporting the hypothesis that gut-derived bacterial products such as endotoxin might be important in activation of Kupffer cells and/or other cell types in the liver. This fits with the observation that chronic ethanol feeding causes more severe liver injury in wild-type mice than in CD14 knockouts. These results further support that gut-derived endotoxin acting via its cellular receptor CD14 plays a major role in the development of alcohol-induced liver injury. In experimental models and isolated hepatocytes, alcohol has been shown to induce liver cell apoptosis. Evidence from rat studies indicates that ethanol-induced gut leakiness and endotoxemia precedes liver inflammation, suggesting that indeed ethanol-induced gut damage come firs. Even though cytokine dysregulations in ASH may constitute secondary phenomena, blockade of these highly pro-inflammatory molecules remains a potential treatment concept.

  1. V. Buko,
  2. P. Kirvel,
  3. E. Naruta,
  4. E. Belanovskaya,
  5. P. Voronov and
  6. O. Lukivskaya

+ Author Affiliations

  1. Institute of Pharmacology and Biochemistry, National Academy of Sciences, Grodno, Belarus


The activation of TNFα, the key pro-inflammatory cytokine, plays an important role in alcoholic liver disease. TNFα mediates inflammatory process and accelerates lipid accumulation in the liver under alcoholic steatohepatitis (ASH). Therapy with anti-TNFα antibodies is mainly in use in the clinics for acute alcoholic hepatitis but not for ASH. In the study that we carried out, the monoclonal anti-TNFα antibodies remicade (REM; 1 and 10 mg/kg, i.p) administered during 10 days decreased necrotic foci and lymphocytic infiltration but unaffected steatosis in the liver of rats with ASH induced by feeding of the Lieber-DeCarli ethanol-containing diet (LCD). Only the high dose of REM lowered liver triglyceride content and serum alkaline phosphatase (AP) activity. Both REM doses raised phagocytic index and circulating immune complexes and normalized complement activity. As the treatment of ASH with REM rather benefits inflammatory signs, we used REM in combinations with promising hepatoprotectors to improve steatosis. We administered REM simultaneously with i.g. administration of sesamine (500 mg/kg), pioglytasone (10 mg/kg), betaine (100 mg/kg) or metformine (50 mg/kg). The combinations of REM with betaine and sesamine were more effective than REM alone in decreasing serum AP activity, square of sudanophylic staining and triglyceride content in the liver. All combinations did not disturb immunomodulatory properties of REM. These experimental studies suggest that anti-TNFα antibodies combined with the hepatoprotectors (sesamine, betaine) are effective in necrosis, inflammation and steatosis in the experimental model of ASH induced by LCD feeding.

  1. K. Pantopoulos

+ Author Affiliations

  1. McGill University, Montreal, QC, Canada


Alcoholic liver disease (ALD) is frequently associated with hepatic iron overload that contributes to liver injury and is considered as a risk factor for the development of liver fibrosis. Dietary iron absorption and body iron traffic are controlled by the iron regulatory hormone hepcidin, a liver-derived peptide that binds to the iron exporter ferroportin and promotes its internalization and degradation. This leads to retention of iron within ferroportin-expressing cells, including duodenal enterocytes, reticuloendothelial macrophages and hepatocytes. The expression of hepcidin is regulated transcriptionally in response to iron, inflammation and stress signals. Experiments in cells and mouse models demonstrated that ethanol suppresses hepcidin mRNA transcription by inhibiting the binding of the constitutive transcription factor C/EBPα within its promoter. Ethanol-dependent downregulation of hepcidin is associated with increased expression of the duodenal iron transporters DMT1 and ferroportin at the apical and basolateral membranes of enterocytes, respectively. These findings provide a framework to understand the molecular mechanisms underlying hepatic iron accumulation in ALD patients. To better characterize the role of iron in chemically induced liver fibrogenesis, hemojuvelin knockout (Hjv − /−) mice, a model of hemochromatosis, and wild-type controls were subjected to intoxication with CCl4. Hjv − /− mice developed earlier and more acute liver damage, reflected in dramatic levels of serum transaminases and ferritin and the development of severe coagulative necrosis and fibrosis. These responses were associated with an oxidative burst and early upregulation of mRNAs encoding α1-(I)-collagen, the profibrogenic cytokines TGF-β1, endothelin-1 and PDGF. Thus, hepatic iron overload potentiates the effects of chemical intoxication and triggers precocious profibrogenic gene expression. Although the CCl4 model may simulate pathophysiological responses of ALD, further experiments with ethanol intoxication are required to validate these data


  1. G. Millonig

+ Author Affiliations

  1. University of Heidelberg, Salem Medical Center, Heidelberg, Germany


Hepatitis of any kind is characterized by increased concentrations of reactive oxygen species. H2O2 is the main reactive oxygen intermediate derived from a multitude of cellular metabolic processes as well as from oxidative burst by granulocytes or macrophages. Due to its relatively long half-life time, there is growing evidence that H2O2 also acts as a signaling molecule. Iron metabolism can be influenced by H2O2 by activating the iron regulatory protein 1, which regulates intracellular iron metabolism but also by increasing transferrin receptor 1 that is responsible for cellular iron uptake. Both mechanisms lead to increased cellular iron uptake and decreased levels of circulating serum iron. Hepcidin, the systemic iron regulator, has not been linked to oxidative stress so far. New experiments, however, point out that H2O2 is able to increase hepcidin via STAT3 signaling, thus decreasing iron recycling by macrophages and iron resorption by the duodenum. This is a third mechanism to lower serum iron during increased oxidative stress and preventing toxic reactions between H2O2 and iron.