Aims

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.

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Tuesday, June 7, 2011

Local and Regional Network Function in Behaviorally Relevant Cortical Circuits of Adult Mice Following Postnatal Alcohol Exposure



Ethanol consumption during pregnancy can lead to fetal alcohol spectrum disorder (FASD), which consists of the complete spectrum of developmental deficits including neurological dysfunction. FASD is associated with a variety of neurobehavioral disturbances dependent on the age and duration of exposure. Ethanol exposure in neonatal rodents can also induce widespread apoptotic neurodegeneration and long-lasting behavioral abnormalities similar to FASD. The developmental stage of neonatal rodent brains that are at the peak of synaptogenesis is equivalent to the third trimester of human gestation.

Male and female C57BL/6By mice were injected with ethanol (20%, 2.5 g/kg, 2 s.c. injections) or an equal volume of saline (controls) on postnatal day 7 (P7). Animals were allowed to mature and at 3 months were tested on an olfactory habituation task known to be dependent on piriform cortex function, a hippocampal-dependent object place memory task, and used for electrophysiological testing of spontaneous and odor-evoked local field potential (LFP) activity in the olfactory bulb, piriform cortex, and dorsal hippocampus.

P7 ethanol induced widespread cell death within 1 day of exposure, with highest levels in the neocortex, intermediate levels in the dorsal hippocampus, and relatively low levels in the primary olfactory system. No impairment of odor investigation or odor habituation was detected in P7 ethanol-exposed 3-month-old mice compared to saline controls. However, hippocampal-dependent object place memory was significantly impaired in the P7 ethanol-treated adult mice. Odor-evoked LFP activity was enhanced throughout the olfacto-hippocampal pathway, primarily within the theta frequency band, although the hippocampus also showed elevated evoked delta frequency activity. In addition, functional coherence between the piriform cortex and olfactory bulb and between the piriform cortex and dorsal hippocampus was enhanced in the beta frequency range in P7 ethanol-treated adult mice compared to controls.

P7 ethanol induces an immediate wave of regionally selective cell death followed by long-lasting changes in local circuit and regional network function that are accompanied by changes in neurobehavioral performance. The results suggest that both the activity of local neural circuits within a brain region and the flow of information between brain regions can be modified by early alcohol exposure, which may contribute to long-lasting behavioral abnormalities known to rely on those circuits.


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Alteration of Ethanol Drinking in Mice via Modulation of the GABAA Receptor with Ganaxolone, Finasteride, and Gaboxadol



Neurosteroids and other γ-aminobutyric acidA (GABAA) receptor–modulating compounds have been shown to affect ethanol intake, although their mechanism remains unclear. 

This study examined how patterns of 24-hour ethanol drinking in mice were altered with the synthetic GABAergic neurosteroid ganaxolone (GAN), with an inhibitor of neurosteroid synthesis (finasteride [FIN]), or a GABAA receptor agonist with some selectivity at extrasynaptic receptors (gaboxadol HCL [THIP]).

Male C57BL/6J mice had continuous access to a 10% v/v ethanol solution (10E) or water. Using lickometer chambers, drinking patterns were analyzed among mice treated in succession to GAN (0, 5, and 10 mg/kg), FIN (0 or 100 mg/kg), and THIP (0, 2, 4, 8, and 16 mg/kg).

GAN shifted drinking in a similar but extended manner to previous reports using low doses of the neurosteroid allopregnanolone (ALLO); drinking was increased in hour 1, decreased in hours 2 and 3, and increased in hours 4 and 5 postinjection. THIP (8 mg/kg) and FIN both decreased 10E drinking during the first 5 hours postinjection by 30 and 53%, respectively, while having no effect on or increasing water drinking, respectively. All 3 drugs altered the initiation of drinking sessions in a dose-dependent fashion. FIN increased and GAN decreased time to first lick and first bout. THIP (8 mg/kg) decreased time to first lick but increased time to first bout and attenuated first bout size.

The present findings support a role for the modulation of ethanol intake by neurosteroids and GABAA receptor–acting compounds and provide hints as to how drinking patterns are shifted. The ability of THIP to alter 10E drinking suggests that extrasynaptic GABAA receptors may be involved in the modulation of ethanol intake. Further, the consistent results with THIP to that seen previously with high doses of ALLO suggest that future studies should further examine the relationship between neurosteroids and extrasynaptic GABAA receptors, which could provide a better understanding of the mechanism by which neurosteroids influence ethanol intake.


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Recovery High Schools: Giving Students a Second Chance



Students who return to their high school after leaving to deal with substance abuse issues often find that getting thrown back in with old friends quickly leads to relapse. 

Around the country, a small number of recovery high schools offer a safe and sober alternative for students struggling to avoid falling back into old harmful routines.
“It’s just too easy for these students to go back to using drugs and drinking at their old school,” says Andrew J. Finch, PhD, a co-founder and former Executive Director of the Association of Recovery Schools, who is currently Assistant Clinical Professor of Human and Organizational Development at Vanderbilt University in Nashville, TN. “We want to create a safe place for them so they’re not confronted by drugs and alcohol during the school day.”

The first recovery high school was established in 1987 in Minnesota. Currently, the Association of Recovery Schools has 22 member high schools in nine states.
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Alcohol News - 23/2011




PR Newswire (USA) - Public Health Experts Advise Against Further Privatization of Alcohol Sales
National public health experts are recommending against further privatization of retail alcohol sales based on evidence that privatization would increase excessive alcohol consumption and associated health and social problems, the Keystone Research Center reports in a new policy brief.
BBC News (Scotland) - Willie Rennie in minimum pricing u-turn
The new leader of the Scottish Liberal Democrats has signalled a policy u-turn on the introduction of a minimum unit price for alcohol.
Telegraph.co.uk - Young people 'should avoid alcohol until 24
People should avoid drinking until their mid-20s because alcohol consumption can hinder brain development, according to a leading scientist.
IcelandReview (Iceland) - Call for Stricter Laws on Alcohol and Tobacco
Minister of the Interior Ögmundur Jónasson submitted a bill in parliament yesterday evening on amendments to the law on alcohol with the purpose of making the ban on advertising alcoholic beverages clearer and more efficient.
The Telegraph (India) - Mumbai votes to increase alcohol age limit
Mumbai has voted to raise the age limit for buying spirits from 21 to 25 and beer 18 to 21, sparking concern from the drinks industry and fury among young people.
Medscape - Alcohol Dependence More Likely Among Mentally Ill
Adults with mental illness are 4 times more likely to develop a dependence on alcohol than adults without mental illness, according to a new report based on data from the 2009 National Survey on Drug Use and Health (NSDUH).
News and Views from Norway (Norway) - Alcohol often involved in rape cases
Norwegian police released a new statistical report on rape cases in the capital, and could tie many of them to both consumption of alcohol and a new, more liberal “sexual culture” that has confused the limits of what’s allowed and what’s not.
BBC News (UK) - Alcohol-related problems: Survey checks nurse training
Nottingham researchers have launched a national survey to find out if nurses need extra training to deal with patients who have drink problems.
BBC News (UK) - Stafford bishop accuses government over alcohol abuse
The Bishop of Stafford has criticised the government for "doing little" to prevent alcohol abuse. The Rt Rev Geoff Annas has described alcohol misuse as "one of the major sins of our time".
ERR News (Estonia) - Ministers Debate Alcohol Ads Ban
Coalition parties are at odds over a proposed all-out ban on the advertising of alcoholic beverages on television, radio and in outdoor media.
Morning Advertiser (Scotland) - Scottish Government clarifies under-21 law
The Scottish Government has dismissed reports that local authorities have been given the “green light” to prevent under- 21s from buying alcohol in the off-trade.
CanadaEast.com (Canada) - Playing blood-alcohol roulette risky for any driver who drinks
Trying to determine how many drinks a person can consume and still get behind the wheel after New Brunswick passes a new law to toughen its stance against drunk drivers later this month is risky business because there are so many variables that can affect a blood alcohol reading, says a forensic toxicologist.
Chambersburg Public Opinion - Study shifts outlook on liquor consumption after privatization
A new report challenges earlier studies that claimed that privatizing liquor sales would not affect alcohol consumption. As Pennsylvania debates liquor privatization, a task force of national health experts recommended against further privatization of retail alcohol sales.
Stuff.co.nz (New Zealand) - Police stunned by drink driving results
Police are astounded a Bay of Plenty man, caught more than three and a half times the legal limit, was able to co-ordinate himself to drive.
ABC Online (Australia) - Aussies drinking less beer, more wine
Official statistics show the volume of beer consumed by Australians per capita has slipped to a 62-year low.
Business Wire (China) - Research and Markets: China Alcohol Market Report 2011
This report presents a clear picture about the overall development of alcohol market in China and the trend in recent years based on detailed data analysis. This report includes the analysis on the alcohol market size and market share in China, the study on major hot areas in this market, introduction of key data and the comparison of top 10 enterprises in terms of sales revenue and market share, the detailed description of the import and export.
Hurriyet Daily News (Turkey) - Turkish regulatory agency chief defends alcohol ordinance
A regulation partly overruled by the Council of State would have helped prevent the recent deaths of several Russian tour guides from consuming unlicensed alcohol, the president of Turkey’s alcohol regulatory agency has said.
Fleet News Online (EU) - Police begin week-long alcohol and drug operation on Europe’s roads
Police officers across more than 25 European countries, including the UK, today begin a seven-day crackdown on drink driving and drugged driving. The operation is co-ordinated by TISPOL, the European Traffic Police Network.
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The economic burden of ill health due to diet, physical inactivity, smoking, alcohol and obesity in the UK: an update to 2006–07 NHS costs


Estimates of the economic cost of risk factors for chronic disease to the NHS provide evidence for prioritization of resources for prevention and public health. Previous comparable estimates of the economic costs of poor diet, physical inactivity, smoking, alcohol and overweight/obesity were based on economic data from 1992–93. 

Diseases associated with poor diet, physical inactivity, smoking, alcohol and overweight/obesity were identified. Risk factor-specific population attributable fractions for these diseases were applied to disease-specific estimates of the economic cost to the NHS in the UK in 2006–07. 

In 2006–07, poor diet-related ill health cost the NHS in the UK £5.8 billion. The cost of physical inactivity was £0.9 billion. Smoking cost was £3.3 billion, alcohol cost £3.3 billion, overweight and obesity cost £5.1 billion. 

The estimates of the economic cost of risk factors for chronic disease presented here are based on recent financial data and are directly comparable. They suggest that poor diet is a behavioural risk factor that has the highest impact on the budget of the NHS, followed by alcohol consumption, smoking and physical inactivity. 



  
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Maternal effects on ethanol teratogenesis in a cross between A/J and C57BL/6J mice



Genetic factors influence adverse pregnancy outcome in both humans and animal models. Animal research reveals that both the maternal and fetal genetic profiles are important for determining the risk of physical birth defects and prenatal mortality. 

Using a reciprocal-cross breeding design, we investigated whether the mother’s genes may be more important than fetal genes in determining risk for ethanol teratogenesis. 

Examination of possible synergistic genetic effects on ethanol teratogenesis was made possible by using two mouse strains known to be susceptible to specific malformations. Inbred A/J (A) and C57BL/6J (B6) mice were mated to produce four fetal genotype groups: the true-bred AċA and B6ċB6 genotypes and the genetically identical AċB6 and B6ċA genotypes (the F1 genotype). Dams were administered either 5.8g/kg ethanol or an isocaloric amount of maltose–dextrin on day 9 of pregnancy. Fetuses were removed by laparotomy on gestation day 18, weighed, and assessed for digit, vertebral, and kidney malformations. 

Digit malformations in the genetically identical F1 ethanol-exposed litters showed a pattern consistent with a maternal genetic effect (AċB6 [2%] and B6ċA [30%]).   In contrast, vertebral malformations were similar in all ethanol-exposed litters (AċA [26%], AċB6 [18%], B6ċA [22%], and B6ċB6 [33%]). 

The percentage of malformations did not differ between male and female fetuses, indicating sex-linked factors are not responsible for the maternal effect.  Ethanol exposure decreased litter weights but did not affect litter mortality compared with maltose-exposed controls. 

This study supports the idea that genes influence malformation risk following in utero alcohol exposure. Specifically, maternal genes influence risk more than fetal genes for some teratogenic outcomes.  No evidence supported synergistic genetic effects on ethanol teratogenesis. 

This research supports the conclusion that uterine environment contributes to determining risk of Fetal Alcohol Spectrum Disorder.



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Hidden harm? Alcohol and older people in Wales



Alcohol Concern Cymru have released a briefing paper on alcohol and older people:
An Alcohol Concern page states:
'To make sure older people in Wales receive the support they need to enjoy alcohol healthily, Alcohol Concern is recommending that professionals working with older people need to be aware of alcohol misuse; better joint working is needed between local older people's services and alcohol treatment services; and research is needed into whether current unit guidance and screening methods for alcohol misuse are relevant to older people.'   > > > >   Read More
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Morbidity and Mortality Weekly Report (MMWR) - Sexual Identity, Sex of Sexual Contacts, and Health-Risk Behaviors Among Students in Grades 9--12 --- Youth Risk Behavior Surveillance, Selected Sites, United States, 2001--2009



Sexual minority youths are youths who identify themselves as gay or lesbian, bisexual, or unsure of their sexual identity or youths who have only had sexual contact with persons of the same sex or with both sexes. 

Population-based data on the health-risk behaviors practiced by sexual minority youths are needed at the state and local levels to most effectively monitor and ensure the effectiveness of public health interventions designed to address the needs of this population.

The Youth Risk Behavior Surveillance System (YRBSS) monitors priority health-risk behaviors (behaviors that contribute to unintentional injuries, behaviors that contribute to violence, behaviors related to attempted suicide, tobacco use, alcohol use, other drug use, sexual behaviors, dietary behaviors, physical activity and sedentary behaviors, and weight management) and the prevalence of obesity and asthma among youths and young adults. YRBSS includes state and local school-based Youth Risk Behavior Surveys (YRBSs) conducted by state and local education and health agencies. 

This report summarizes results from YRBSs conducted during 2001--2009 in seven states and six large urban school districts that included questions on sexual identity (i.e., heterosexual, gay or lesbian, bisexual, or unsure), sex of sexual contacts (i.e., same sex only, opposite sex only, or both sexes), or both of these variables. The surveys were conducted among large population-based samples of public school students in grades 9--12.

Across the nine sites that assessed sexual identity, the prevalence among gay or lesbian students was higher than the prevalence among heterosexual students for a median of 63.8% of all the risk behaviors measured, and the prevalence among bisexual students was higher than the prevalence among heterosexual students for a median of 76.0% of all the risk behaviors measured. In addition, the prevalence among gay or lesbian students was more likely to be higher than (rather than equal to or lower than) the prevalence among heterosexual students for behaviors in seven of the 10 risk behavior categories (behaviors that contribute to violence, behaviors related to attempted suicide, tobacco use, alcohol use, other drug use, sexual behaviors, and weight management). Similarly, the prevalence among bisexual students was more likely to be higher than (rather than equal to or lower than) the prevalence among heterosexual students for behaviors in eight of the 10 risk behavior categories (behaviors that contribute to unintentional injuries, behaviors that contribute to violence, behaviors related to attempted suicide, tobacco use, alcohol use, other drug use, sexual behaviors, and weight management).

Across the 12 sites that assessed sex of sexual contacts, the prevalence among students who had sexual contact with both sexes was higher than the prevalence among students who only had sexual contact with the opposite sex for a median of 71.1% of all the risk behaviors measured, and the prevalence among students who only had sexual contact with the same sex was higher than the prevalence among students who only had sexual contact with the opposite sex for a median of 29.7% of all the risk behaviors measured. Furthermore, the prevalence among students who had sexual contact with both sexes was more likely to be higher than (rather than equal to or lower than) the prevalence among students who only had sexual contact with the opposite sex for behaviors in six of the 10 risk behavior categories (behaviors that contribute to violence, behaviors related to attempted suicide, tobacco use, alcohol use, other drug use, and weight management). The prevalence among students who only had sexual contact with the same sex was more likely to be higher than (rather than equal to or lower than) the prevalence among students who only had sexual contact with the opposite sex for behaviors in two risk behavior categories (behaviors related to attempted suicide and weight management).

Sexual minority students, particularly gay, lesbian, and bisexual students and students who had sexual contact with both sexes, are more likely to engage in health-risk behaviors than other students.


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Monday, June 6, 2011

An Effectiveness Trial of Group Cognitive Behavioral Therapy for Patients With Persistent Depressive Symptoms in Substance Abuse Treatment



Although depression frequently co-occurs with substance abuse, few individuals entering substance abuse treatment have access to effective depression treatment.
 
The Building Recovery by Improving Goals, Habits, and Thoughts (BRIGHT) study is a community-based effectiveness trial that compared residential substance abuse treatment with residential treatment plus group cognitive behavioral therapy for depression delivered by substance abuse treatment counselors. We hypothesized that intervention clients would have improved depression and substance use outcomes compared with those of clients receiving usual care.

A nonrandomized controlled trial using a quasi-experimental intent-to-treat design in which 4 sites were assigned to alternate between the intervention and usual care conditions every 4 months for 2 years.

Four treatment programs in Los Angeles County.

We screened 1262 clients for persistent depressive symptoms (Beck Depression Inventory-II score >17). We assigned 299 clients to receive either usual care (n = 159) or usual care plus the intervention (n = 140). Follow-up rates at 3 and 6 months after the baseline interview were 88.1% and 86.2%, respectively, for usual care and 85.7% and 85.0%, respectively, for the intervention group.

Sixteen 2-hour group sessions of cognitive behavioral therapy for depression.

Change in depression symptoms, mental health functioning, and days of alcohol and problem substance use.

Intervention clients reported significantly fewer depressive symptoms (P < .001 at 3 and 6 months) and had improved mental health functioning (P < .001 at 3 months and P < .01 at 6 months). At 6 months, intervention clients reported fewer drinking days (P < .05) and fewer days of problem substance use (P < .05) on days available.

Providing group cognitive behavioral therapy for depression to clients with persistent depressive symptoms receiving residential substance abuse treatment is associated with improved depression and substance use outcomes. These results provide support for a new model of integrated care.




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Eighth plenary meeting of the European Alcohol and health Forum, Brussels, 8 April 2011 - Summary report available


European Alcohol and health Forum

Eighth plenary meeting,
Brussels, 08 April 2011

Presentations

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    Press Release - Are frontline nurses prepared for alcohol-related cases?



    Nurses are often on the frontline when patients are brought into hospital with alcohol-related illnesses or injuries but how prepared are they for dealing with cases of this kind?

    A researcher at The University of Nottingham is launching a national survey to establish whether student nurses are receiving the alcohol training and education which is so vital to their job.

    The survey follows news that alcohol-related admissions to hospital have topped one million for the first time. A recent NHS Information Centre report said that admissions had increased by 12 per cent, reaching 1,057,000 in 2009-10 compared to 945,500 for the previous year. In 2002-03, alcohol-related hospital admissions stood at just 510,800.         > > > >   Read More
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    Video - Genes, Environment, and Development: An Interdisciplinary Approach to Understanding Alcohol Misuse

     




    NIH Behavioral and Social Sciences Seminar Series 


    Dick, Danielle M.
    National Institutes of Health (U.S.). Office of Behavioral and Social Sciences Research. 


    Alcohol dependence is a complex behavioral disorder, known to be influenced by both genetic and environmental factors, with trajectories of risk behavior that manifest long before the eventual development of problems. 

    This talk will present findings across a variety of complementary research areas, including twin studies, gene identification projects, and longitudinal, community-based samples, all of which have the goal of contributing to our understanding of how genetic and environmental influences impact the development of alcohol use disorders. Twin studies allow us to characterize the nature of (latent) genetic and environmental influences on behavior. 

    Data from the Finnish twin studies, population-based epidemiological samples with assessments spanning ages 12 to 26, will be presented that demonstrate the changing influence of genetic effects on alcohol use and related phenotypes as a function of the environment, and across adolescence into young adulthood. 

    A second line of investigation focuses on identifying specific genes involved in alcohol use and related phenotypes. 

    Data will be presented from two of the largest on-going gene identification projects for alcohol dependence: the Collaborative Study of the Genetics of Alcoholism, and the Irish Affected Sib-Pair Study of Alcohol Dependence. 

    Thirdly, in order to understand how genetic influences result in the eventual alteration of risk for psychiatric and substance use outcomes, it will be necessary to characterize the risk associated with identified genes using community-based samples of individuals studied longitudinally. To this end, data will be presented from the Child Development Project, a community-based study of ~500 children followed annually from age 5-25; the Mobile Youth Study, an on-going community-based sample of children ages 10-18 from high-risk, impoverished neighborhoods in Mobile, Alabama; and the Avon Longitudinal Study of Parents and Children, an epidemiological cohort of ~10,000 children enrolled when their mothers were pregnant and assessed yearly -- prenatally through young adulthood. 

    Highlights from these projects will be presented to illustrate how, through interdisciplinary research, we are gaining a greater understanding of how genetic and environmental influences contribute to the risk for alcohol related problems, and how that risk manifests across development. 


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    Sunday, June 5, 2011

    Age-Dependent Inverse Association Between Alcohol Consumption and Obesity in Japanese Men



    The aim of this study was to determine whether age influences the relationship between alcohol drinking and obesity. 

    Japanese men receiving periodic health checkups (20–70 years old, n = 36,121) were divided into non-, light (<22 g ethanol/day), moderate (≥22 and <44 g ethanol/day), and heavy (≥44 g ethanol/day) drinkers. Relationships between alcohol intake and obesity-related indices were compared among the quartiles of age.

    BMI was lower in light and moderate drinkers than in nondrinkers, and these differences were more prominent in the 1st and 2nd quartiles of age than in the higher quartiles. 

    In the 1st and 2nd quartiles of age, waist circumference and waist-to-height ratio were significantly smaller and lower, respectively, in light and moderate drinkers than in nondrinkers, and these differences were less prominent in the 3rd quartile and were not found in the 4th quartile. 

    In the 1st and 2nd quartiles of age, odds ratios vs. nondrinkers for large waist circumference were significantly low (P < 0.01) in light drinkers (1st quartile: 0.64 (0.54–0.75); 2nd quartile: 0.69 (0.60–0.80)) and moderate drinkers (1st quartile: 0.69 (0.61–0.78); 2nd quartile: 0.84 (0.76–0.93)), whereas the odds ratio was significantly low (P < 0.05) only in light drinkers in the 3rd quartile (0.84 (0.73–0.97)) and was not significant in any drinker groups of the 4th quartile. 

    The results suggest that alcohol consumption is associated with lower risk of obesity in Japanese men and this association is more prominent in younger men than in older men.



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    E.M. Jellinek at Worcester: A Bare Beginning



    Had Bill W. or Dr. Bob been employed in some capacity at Worcester State Hospital for almost a decade in the 1930s, it’s a pretty safe bet there’d be more than a little written material on that patch of their lives in the recovery movement’s literature. E.M. Jellinek worked at Worcester for almost a decade, yet that phase of his research career is virtually a blank in his biographical treatments. As it happens, Jellinek wasn’t sitting on his hands at Worcester either; near the end of his tenure there he’d earned an appointment to the New York Academy of Arts and Sciences.

    Worcester State Hospital was the first public asylum for the insane in New England; its doors opened on January 12, 1833. Almost a hundred years later, in 1927, a Schizophrenia Research Service (SRS) was launched at Worcester, under the direction of Roy G. Hoskins. The service had an unlikely initial chief external funding source in Katherine Dexter McCormick (1875-1967), wife of Stanley Robert McCormick (1874-1947), youngest son of McCormick harvester developer, Cyrus Hall McCormick (1809-1884).

    There are two convenient ciphers available in the literature for approaching Worcester’s Schizophrenia Research Service and Jellinek’s experience there. The first, on the McCormicks, is an article by Miriam Kleiman, titled “Rich, Famous, and Questionably Sane: When a Wealthy Heir’s Family Sought Help from a Hospital for the Insane,” published in 2007 in Prologue Magazine.(1) The second, published in 1972, is an organizational history of the SRS by David Shakow, its Chief Psychologist and Director of Psychological Research from 1927 to 1946.    > > > >   Read More
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    The role of connexin-36 gap junctions in alcohol intoxication and consumption



    Ventral tegmental area (VTA) GABA neurons appear to be critical substrates underlying the acute and chronic effects of ethanol on dopamine (DA) neurotransmission in the mesocorticolimbic system implicated in alcohol reward. 

    The aim of this study was to examine the role of midbrain connexin-36 (Cx36) gap junctions (GJs) in ethanol intoxication and consumption. 

    Using behavioral, molecular, and electrophysiological methods, we compared the effects of ethanol in mature Cx36 knockout (KO) mice and age-matched wild-type (WT) controls. 

    Compared to WT mice, Cx36 KO mice exhibited significantly more ethanol-induced motor impairment in the open field test, but less disruption in motor coordination in the rotarod paradigm. Cx36 KO mice, and WT mice treated with the Cx36 antagonist mefloquine (MFQ), consumed significantly less ethanol than their WT controls in the drink-in-the-dark procedure. The firing rate of VTA GABA neurons in WT mice was inhibited by ethanol with an IC50 of 0.25 g/kg, while VTA GABA neurons in KO mice were significantly less sensitive to ethanol. Dopamine neuron GABA-mediated sIPSC frequency was reduced by ethanol (30 mM) in WT mice, but not affected in KO mice. Cx36 KO mice evinced a significant up-regulation in DAT and D2 receptors in the VTA, as assessed by quantitative RT-PCR. 

    These findings demonstrate the behavioral relevance of Cx36 GJ-mediated electrical coupling between GABA neurons in mature animals, and suggest that loss of coupling between VTA GABA neurons results in disinhibition of DA neurons, a hyper-DAergic state and lowered hedonic valence for ethanol consumption.



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    Saturday, June 4, 2011

    Strategies for characterizing complex phenotypes and environments: General and specific family environmental predictors of young adult tobacco dependence, alcohol use disorder, and co-occurring problems



    Defining phenotypes in studies of tobacco and alcohol misuse is difficult because of the complexity of these behaviors and their strong association with each other and with other problem behaviors. The present paper suggests a strategy for addressing this issue by conceptualizing and partitioning variance in phenotypes into either general or substance/behavior-specific. The paper also applies the general or substance/behavior-specific conceptualization to environmental predictors of tobacco and alcohol misuse and other problem behaviors.

    Data were drawn from the Seattle Social Development Project, a contemporary, ethnically diverse and gender-balanced longitudinal panel including 808 participants. Latent variable modeling was used to partition variance in young adult (age 24) nicotine dependence, alcohol abuse and dependence, illicit drug abuse and dependence, involvement in crime, and engagement in HIV sexual risk behavior into general problem behavior and behavior-specific variance. Similarly, measures of general, drinking-specific, and smoking-specific adolescent family environment were constructed.

    Consistent with expectations, more positive general family environment during adolescence was associated with lower levels of shared variance in problem behaviors at age 24, but not with unique variance in tobacco or alcohol use disorder. Higher levels of family smoking and drinking environments during adolescence, however, were positively associated with unique variance in tobacco and alcohol use disorder, respectively, but did not predict shared variance in problem behaviors.

    Results support the utility of the proposed approach. Ways in which this approach might contribute to future molecular genetic studies are discussed.



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    Friday, June 3, 2011

    Effects of high-profile collisions on drink-driving penalties and alcohol-related crashes in Japan



    Japanese road traffic law was amended in 2002 and 2007 to increase the penalties for drink-driving in response to media coverage, publicity campaigns, and debates following high-profile alcohol-related motor-vehicle crashes in 1999 and 2006. 

    To test the hypothesis that the proportion of crashes involving drink-driving started to decline before the law amendments, because of changes in social norms and driver behaviour after the high-profile crashes.

    In order to assess the impact of the cases in 1999 and 2006, time-series analyses were used to examine the trends in the proportion of crashes involving drink-driving, and whether there were abrupt changes in the level or slope at the expected time points, using monthly police data for the period between January 1995 and December 2008.

    In 1999, the proportion of alcohol-related fatal crashes in which the driver had a blood alcohol concentration (BAC) ≥0.5 mg/ml started to decline with a slope change of −0.09 percentage points per month (95% CI −0.15 to −0.03) but no level change, whereas there were no changes for drivers with a BAC <0.5. In 2006, the trends for drivers with a BAC ≥0.5 or <0.5 showed significant level declines of −3.1 (−5.0 to −1.2) and −1.7 (−2.5 to −0.9) percentage points, respectively, but no slope changes.

    Media coverage of high-profile crashes, and subsequent publicity campaigns and debates might have altered social norms and driver behaviour, reducing the proportion of alcohol-related crashes before the introduction of more severe penalties for drink-driving. 



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    Persistent Escalation of Alcohol Drinking in C57BL/6J Mice With Intermittent Access to 20% Ethanol



    Intermittent access (IA) to drugs of abuse, as opposed to continuous access, is hypothesized to induce a kindling-type transition from moderate to escalated use, leading to dependence. Intermittent 24-hour cycles of ethanol access and deprivation can generate high levels of voluntary ethanol drinking in rats.

    The current study uses C57BL/6J mice (B6) in an IA to 20% ethanol protocol to escalate ethanol drinking levels. Adult male and female B6 mice were given IA to 20% ethanol on alternating days of the week with water available ad libitum. Ethanol consumption during the initial 2 hours of access was compared with a short-term, limited access “binge” drinking procedure, similar to drinking-in-the-dark (DID). B6 mice were also assessed for ethanol dependence with handling-induced convulsion, a reliable measure of withdrawal severity.

    After 3 weeks, male mice given IA to ethanol achieved high stable levels of ethanol drinking in excess of 20 g/kg/24 h, reaching above 100 mg/dl blood ethanol concentrations, and showed a significantly higher ethanol preference than mice given continuous access to ethanol. Also, mice given IA drank about twice as much as DID mice in the initial 2-hour access period. B6 mice that underwent the IA protocol for longer periods of time displayed more severe signs of alcohol withdrawal. Additionally, female B6 mice were given IA to ethanol and drank significantly more than males (ca. 30 g/kg/24 h).

    The IA method in B6 mice is advantageous because it induces escalated, voluntary, and preferential per os ethanol intake, behavior that may mimic a cardinal feature of human alcohol dependence, though the exact nature and site of ethanol acting in the brain and blood as a result of IA has yet to be determined.



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    Neurocognitive Performance, Alcohol Withdrawal, and Effects of a Combination of Flumazenil and Gabapentin in Alcohol Dependence



      Among some alcohol-dependent individuals, early alcohol abstinence is marked by alcohol withdrawal (AW), a phenomenon mediated by GABA and glutamate signaling. We previously reported that a combination of 2 medications that affect GABA and glutamate tone, gabapentin and flumazenil, more effectively reduced drinking among individuals with higher pretreatment AW (Anton et al., 2009). 

    This study evaluated whether this finding is related to changes in neurocognitive performance, which is also affected by cortical GABA and glutamate tone.

    Neurocognitive performance was assessed at baseline and twice during the first week of treatment among 60 alcohol-dependent participants in the previously published clinical trial.

    AW was associated with poorer baseline performance on 4 of 8 measures, and individuals with higher baseline AW who received the gabapentin and flumazenil combination demonstrated greater improvement on a measure of response inhibition than those with lower AW or those who received a combination of placebos. Improvement in response inhibition during the first week and medication group interacted in their effect on subsequent drinking, such that improvement predicted greater abstinence only among individuals who received gabapentin and flumazenil. Improvement on other neurocognitive measures was neither differentially impacted by medication or baseline AW nor related to subsequent drinking.

    Taken together, these data suggest that acute AW accounts for a small proportion of variance in neurocognitive performance, that gabapentin and flumazenil slightly improve response inhibition during early abstinence, and that such improvement may somewhat reduce later drinking. However, these medications may not affect other neurocognitive domains.


     
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    Request Reprint E-Mail: schacht@musc.edu       
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    Ethanol consumption and pineal melatonin daily profile in rats


    It is well known that melatonin participates in the regulation of many important physiological functions such as sleep–wakefulness cycle, motor coordination and neural plasticity, and cognition. 

    However, as there are contradictory results regarding the melatonin production diurnal profile under alcohol consumption, the aim of this paper was to study the phenomenology and mechanisms of the putative modifications on the daily profile of melatonin production in rats submitted to chronic alcohol intake. 

    The present results show that rats receiving 10% ethanol in drinking water for 35 days display an altered daily profile of melatonin production, with a phase delay and a reduction in the nocturnal peak.

    This can be partially explained by a loss of the daily rhythm and the 25% reduction in tryptophan hydroxylase activity and, mainly, by a phase delay in arylalkylamine N-acetyltransferase gene expression and a 70% reduction in its peak activity. 

    Upstream in the melatonin synthesis pathway, the results showed that noradrenergic signaling is impaired as well, with a decrease in β1 and α1 adrenergic receptors' mRNA contents and in vitro sustained loss of noradrenergic-stimulated melatonin production by glands from alcohol-treated rats. 

    Together, these results confirm the alterations in the daily melatonin profile of alcoholic rats and suggest the possible mechanisms for the observed melatonin synthesis modification.




    Request Reprint E-Mail:    cipolla@icb.usp.br 
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    Interleukin-15 and Other Myokines in Chronic Alcoholics



    Interleukin (IL)-15 is highly expressed in skeletal muscle, where it exerts anabolic effects, increasing protein content in muscle fibres and promoting muscle growth. Alcoholics frequently suffer myopathy. Therefore, we analyse the behaviour of IL-15 (and other myokines, such as IL-6, IL-8 and tumour necrosis factor α (TNF-α)) in alcoholics.
     
    These myokines and also malondialdehyde (MDA)—a lipid peroxidation product—were determined by radioimmunoanalytic techniques in blood samples of 35 chronic alcoholics and 13 age- and sex-matched controls, and compared with body composition, nutritional status, liver function, amount of ethanol and routine biochemical variables. 

    IL-15, IL-6, TNF-α, IL-8 and MDA were all higher in alcoholics than in controls; MDA and IL-6 were clearly related with liver function impairment and short-term prognosis, whereas IL-15 was higher among those who died and was related to serum bilirubin. No relation was found between IL-15 and lean mass.
     
    IL-15 levels were higher in alcoholics than in controls, especially among those who died within 18 months after admission. They are not related with muscle mass, intensity of alcoholism or nutritional status, but only with serum bilirubin. IL-6 showed inverse correlations with liver function, intensity of alcoholism, nutritional status, left arm muscle mass and short-term mortality.




    Request Reprint E-Mail:  egonrey@ull.es     
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    Thursday, June 2, 2011

    Cellular DNA methylation program during neurulation and its alteration by alcohol exposure



    Epigenetic changes are believed to be among the earliest key regulators for cell fate and embryonic development. To support this premise, it is important to understand whether or not systemic epigenetic changes coordinate with the progression of development. We have demonstrated that DNA methylation is programmed when neural stem cells differentiate (Zhou et al.,2011). Here, we analyzed the DNA methylation events that occur during early neural tube development. 

    Using immunocytochemistry, we demonstrated that the DNA methylation marks – 5-methylcytosine (5-MeC), DNA methylation binding domain 1 (MBD1), and DNA methytransferases 1 (DNMT1) were highly coordinated in temporal and spatial patterns that paralleled the progress of embryonic development. The above ontogenic program of DNA methylation was, however, subjected to environmental modification. Alcohol exposure during fetal development, which is known to cause fetal alcohol spectrum disorder, altered the density and distribution of the DNA methylation marks. The alcohol exposure (88 mM) over 6 or 44 hours at gestation day 8 (GD-8) to GD-10 altered timely DNA methylation and retarded embryonic growth. We further demonstrated that the direct inhibiting of DNA methylation with 5-aza-cytidine (5-AZA) resulted in similar growth retardation. 

    We identified a temporal and spatial cellular DNA methylation program after initial erasure, which parallels embryonic maturation. Alcohol delayed the cellular DNA methylation program and also retarded embryonic growth. Since direct inhibiting of DNA methylation resulted in similar retardation, alcohol thus can affect embryonic development through a epigenetic pathway. 




    Request Reprint E-Mail:  imce100@iupui.edu  
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    Associations between periconceptional alcohol consumption and craniosynostosis, omphalocele, and gastroschisis



    Alcohol consumption during pregnancy is known to be associated with certain birth defects, but the risk of other birth defects is less certain. The authors examined associations between maternal alcohol consumption during pregnancy and craniosynostosis, omphalocele, and gastroschisis among participants in the National Birth Defects Prevention Study, a large, multicenter case–control study.  

    A total of 6622 control infants and 1768 infants with birth defects delivered from 1997–2005 were included in the present analysis. Maternal alcohol consumption was assessed as any periconceptional consumption (1 month prepregnancy through the third pregnancy month), and by quantity-frequency, duration, and beverage type. Alcohol consumption throughout pregnancy was explored for craniosynostosis since the period of development may extend beyond the first trimester. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression analysis. OR were adjusted for age, race/ethnicity, and state of residence at time of infant's birth. Gastroschisis OR were also adjusted for periconceptional smoking. 

    Periconceptional alcohol consumption and craniosynostosis showed little evidence of an association (OR = 0.92; CI: 0.78–1.08), but alcohol consumption in the second (OR = 0.65; CI: 0.47–0.92) and third trimesters (OR = 0.68; CI: 0.49–0.95) was inversely associated with craniosynostosis. Periconceptional alcohol consumption was associated with omphalocele (OR = 1.50; CI: 1.15–1.96) and gastroschisis (OR = 1.40; CI: 1.17–1.67).
    Results suggest that maternal periconceptional alcohol consumption is associated with omphalocele and gastroschisis, and second and third trimester alcohol consumption are inversely associated with craniosynostosis.




    Request Reprint E-Mail:   sdr06@health.state.ny.us      
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