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, July 3, 2010

Australia's health 2010

Australia's health 2010 is the 12th biennial health report of the Australian Institute of Health and Welfare. It's the nation's premier source of statistics and informed commentary on: determinants of health and keys to prevention; diseases and injury; how health varies across population groups; health across the life stages; health services, expenditure and workforce; the health sector's performance.

pg. 90 Alcohol use, risk of harm and health status

This section reports against the 2001 NHMRC alcohol consumption guidelines as these were the guidelines in place when the data were collected. The guidelines were expressed in terms of short-term and long-term risk of harm (injury, ill health and death).

In 2007, an
estimated 17.1% of Australians aged 14 years and older had not consumed alcohol in the previous 12 months (AIHW 2008b), and so are not assessed for risk here. The majority of Australians (60.8%) had drunk at levels considered low risk for harm in the short and long term, and 8.6% had drunk at levels considered risky or high risk for both short- and long-term harm.

Perhaps unsurprisingly, people who drank at high-risk levels in 2007, both in the short and long term, were more likely than other drinkers to assess their own health as fair or poor (AIHW 2008b).

People who abstained from alcohol consumption were more
likely to report their health as fair or poor compared with risky or low-risk drinkers. It is important to note that other factors such as age and socioeconomic status may also affect self-assessment of health status.

Risky drinkers also appeared to have poorer mental health: a higher proportion of those
who drank at levels considered to be high risk in the short term reported that they had a mental health illness (13.2%) compared with low-risk drinkers (10.2%) or the whole population aged 14 years and over (10.8%) (AIHW 2008b). The survey also showed that high-risk (15.3%) and risky (11.0%) drinkers were more likely than low-risk drinkers (8.5%) to experience high or very high levels of psychological distress.

The relationship
between mental health and alcohol consumption is not in one direction. In some cases, mental health issues may have preceded or prompted alcohol use, while for others the alcohol use may have occurred first.

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Why Do Adolescents Drink? Motivational Patterns Related to Alcohol Consumption and Alcohol-Related Problems

The present study was designed to investigate motivational patterns for drinking alcohol and their relation about alcohol consumption and problems related to alcohol consumption.

Data were collected by semistructured interviews and questionnaires, containing questions about reasons for drinking, alcohol consumption, and problems related to alcohol consumption during the years 2001, 2004, and 2005. Three independent population samples from two different counties of central Sweden were included. A total of 11,167 adolescents participated. Data on reasons for drinking were analyzed by factor analysis to extract components explaining drinking motives. Relationships between motivational patterns and alcohol use were examined with correlation analysis.

Three drinking motives emerged (social-enhancement, coping, and dominance motives) and related to alcohol consumption and problems related to alcohol consumption.

Limitations of the study are noted and discussed.

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What Aspects of Human Alcohol Use Disorders Can Be Modeled Using Selectively Bred Rat Lines?

The use of selective breeding to produce animal models for the study of alcohol abuse and alcoholism represents one of the major advances in the field of alcohol research.

Rats selectively bred for alcohol preference and alcohol nonpreference have been useful to both preclinical and clinical investigators in the alcohol research community for studying the behavioral, neurobiological, and molecular basis of alcohol drinking, for identifying the genes that may contribute to the development of alcohol abuse and alcoholism, and for evaluating the utility of drugs aimed at reducing alcohol intake and preventing alcohol relapse.

Rats selectively bred for alcohol preference (alcohol preferring or “P” line) have enhanced responsiveness to the low dose reinforcing effects of alcohol, less aversion to moderate/high doses of alcohol, and are able to develop tolerance to the aversive effects of alcohol more rapidly and to maintain tolerance longer than rats selectively bred for alcohol nonpreference (alcohol nonpreferring or “NP” line).

The increased potency of low-dose alcohol as a reinforcer for P rats might be expected to foster and maintain alcohol drinking. Weaker aversion to the pharmacological effects of moderate/high doses of alcohol in the P line would allow P rats to drink more alcohol than NP rats before the postingestional effects become aversive.

Rapid induction of tolerance to the aversive effects of alcohol with repeated bouts of voluntary alcohol drinking, as well as persistence of alcohol tolerance in rats of the P line might serve to maintain alcohol drinking.

These are powerful mechanisms that may serve to promote and maintain a high alcohol drinking behavior. Although these rat lines have been used to address several characteristics of excessive alcohol consumption in humans, they have not yet been used to model several aspects of human alcohol use disorders.

New applications of these selectively bred rat lines are discussed which may further our understanding of the factors contributing to alcohol abuse and alcoholism.

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The Fast Alcohol Screening Test (FAST) is as Good as the AUDIT to Screen Alcohol Use Disorders

This study was aimed at assessing the psychometric qualities of the fast alcohol screening test (FAST), and at comparing these qualities to those of the alcohol use disorders identification test (AUDIT) in three samples of Brazilian adults: (i) subjects attended at an emergency department (530); (ii) patients from a psychosocial care center (40); and (iii) university students (429).

The structured clinical interview for diagnosis (SCID)-IV was used as gold standard.

The FAST demonstrated high test–retest and interrater reliability coefficients, as well as high predictive and concurrent validity values.

The results attest the validity and reliability of the Brazilian version of the FAST for the screening of indicators of alcohol abuse and dependence.

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Neuromodulation of Decision-Making in the Addictive Brain

Noninvasive brain stimulation of the dorsolateral prefrontal cortex with repetitive transcranial magnetic stimulation and transcranial direct current stimulation can modify decision-making behaviors in healthy subjects.

The same type of noninvasive brain stimulation can suppress drug craving in substance user patients, who often display impaired decision-making behaviors.

We discuss the implications of these studies for the cognitive neurosciences and their translational applications to the treatment of addictions.

We propose a neurocognitive model that can account for our findings and suggests a promising therapeutic role of brain stimulation in the treatment of substance abuse and addictive behavior disorders.

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Subjective Responses to Alcohol Consumption as Endophenotypes: Advancing Behavioral Genetics in Etiological and Treatment Models of Alcoholism

Individual differences in subjective responses to alcohol consumption represent genetically mediated biobehavioral mechanisms of alcoholism risk (i.e., endophenotype).

The objective of this review is three-fold:

(1) to provide a critical review the literature on subjective response to alcohol and to discuss the rationale for its conceptualization as an endophenotype for alcoholism;

(2) to examine the literature on the neurobiological substrates and associated genetic factors subserving individual differences in subjective response to alcohol; and

(3) to discuss the treatment implications of this approach and to propose a framework for conceptualizing, and systematically integrating, endophenotypes into alcoholism treatment.

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Impact of prenatal alcohol consumption on placenta-associated syndromes

The biology of placental and fetal development suggests that alcohol may play a significant role in increasing the risk of feto-infant morbidity and mortality, but study results are inconsistent and the mechanism remains poorly defined. Previous studies have not examined the risk of placenta-associated syndromes (PASs: defined as the occurrence of either placental abruption, placenta previa, preeclampsia, small for gestational age, preterm, or stillbirth) as a unique entity.

Therefore, we sought to examine the relationship between prenatal alcohol use and the risk of PAS among singleton births in the Missouri maternally linked data files covering the period 1989–2005. Logistic regression with adjustment for intracluster correlation was used to generate adjusted odds ratios (ORs) and 95% confidence intervals (CIs).

Compared with nondrinkers, drinkers were more likely to be smokers, 35 years of age or older, black, and multiparous. Drinkers had an increased risk of PAS (OR=1.26, 95% CI=1.22,1.31) when compared with their nondrinking counterparts. The risk of PAS was progressively amplified with increasing prenatal alcohol consumption (P for trend <.01). Women who reported consuming five or more alcoholic drinks per week had more than twofold increased risk of PASs, whereas women in the lowest drinking category (one to two drinks per week) had only a slight increased risk of PAS (OR=1.09, 95% CI=1.05, 1.14).

Enhanced understanding of the mechanism by which prenatal alcohol consumption leads to PAS may aid in the development of more targeted interventions designed to prevent adverse pregnancy outcomes.

Screening women for alcohol use may assist providers in protecting developing fetuses from the potential dangers of prenatal alcohol use.

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Distribution of ADH1B, ALDH2, CYP2E1*6, and CYP2E1*7B genotypes in Turkish population

The most well-known metabolic pathways from ethanol to acetaldehyde include alcohol dehydrogenase (ADH) and the microsomal ethanol oxidizing system that involves cytochrome P450 2E1 (CYP2E1). Acetaldehyde is further oxidized to acetate by aldehyde dehydrogenase (ALDH). The genetic variation of ADH1B, ALDH2, and CYP2E1 is different among racial populations and cause difference in elimination rates of alcohol.

The aim of this study was to determine the polymorphisms of
ADH1B (rs1229984; Arg47His), ALDH2 (rs671; Glu487Lys), CYP2E1*6 (rs6413432; T7632A), and CYP2E1*7B (rs6413420; G-71T) in unrelated healthy Turkish population and compare it with other populations.

ADH1B and ALDH2 polymorphisms were analyzed with an allele-specific polymerase chain reaction (PCR) assay, and CYP2E1*6 and CYP2E1*7B polymorphisms were genotyped by PCR-restriction fragment length polymorphism method.

ADH1B polymorphism analysis yielded the genotype distribution as 83.9% ADH1B*1/1 and 16.1% ADH1B*1/2, and no individuals with ALDH2*1/2 and ALDH2*2/2 genotypes were found in Turkish population.

The genotype frequencies for
CYP2E1*6 polymorphism were found as 85.3% for homozygote common, 14.1% for heterozygote, and 0.6% for homozygote uncommon. For CYP2E1*7B polymorphism, the genotype frequencies were determined to be 86.5% G/G, 13.5% for G/T; however, no individuals with homozygote uncommon genotype were detected.

According to our study results, the genotype distributions of
ADH1B, ALDH2, CYP2E1*6, and CYP2E1*7B in Turkish population were similar compared with Caucasian and some European populations, whereas differed significantly from East Asian populations.

This study may be useful in epidemiological studies of the influence of
ADH1B, ALDH2, CYP2E1*6, and CYP2E1*7B polymorphisms on diseases, including several types of cancer related to alcohol consumption and alcohol dependence.

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Friday, July 2, 2010

New 'self-help' website for alcohol and cocaine users

A new OASIS website for alcohol and cocaine users offers 'self-help' approaches to reducing harmful use. Visitors however need to choose between the substance they are most concerned about, though both can be taken separately.

For alcohol, the site uses the AUDIT screening tool, an effective approach for identifying levels of alcohol risk for the delivery of brief interventions and treatment responses. The cocaine screening tool is not known but asks about levels of alcohol use. > > > > Read More


Acetyl-L-Carnitine for Alcohol Craving and Relapse Prevention in Anhedonic Alcoholics: A Randomized, Double-Blind, Placebo-Controlled Pilot Trial

The study aimed to evaluate the efficacy of acetyl-L-carnitine (ALC), at different doses, in relapse prevention and craving in anhedonic detoxified alcohol-dependent subjects.

Randomized, double-blind, placebo-controlled, pilot study in 64 alcohol-dependent anhedonic patients: 23 received ALC at a dose of 3 g/day, 21 received ALC at a dosage of 1 g/day and 20 were given placebo. Intensity of alcohol craving was evaluated by Visual Analogue Scale. Subjects were evaluated at the beginning of treatment and after 10, 30, 60 and 90 days.

Survival analysis showed that patients treated with ALC remained completely abstinent for longer than those treated with placebo (Z = –2.27; P <> onwards, a greater reduction of craving was observed in the ALC 1 g group than with placebo (P = 0.035).

The two groups
did not differ in the percentage of subjects remaining abstinent for the entire study period or the number of subjects who relapsed (defined as five or more standard drinks (four for women) on a single occasion or drinking on five or more days in 1 week).

The results of this study suggest that ALC can reduce craving and the time to first drink. ALC use was safe. Further studies are needed to clarify to confirm, over longer periods, these short-term outcome benefits.

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Thursday, July 1, 2010

AA Isn't the Best Solution: Alternatives for Alcoholics

Building on an essay in Wired magazine by Brendan Koerner, New York Times conservative columnist David Brooks lauds to the sky AA and its founder, Bill Wilson. Both Brooks and Koerner point out the worldwide spread of AA (although it is limited mainly to the U.S. and like-minded countries), and the spread of the 12 steps to nearly all areas of behavior change, indeed, to how we approach social problems of all sorts.

Along the way, Brooks makes the good points that there is no scientific way to program behavior change -- that it is indefinite and rooted in individual choice. He points out the benefits of the social networks AA provides its members, and the decentralization of the AA movement, so that individual chapters are able to organize as its own members see fit. These are strong organization and psychological pluses.

But, unfortunately for a rational conservative, Brooks misses a few downsides to the AA movement.

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Alcohol Treatment in Cheshire and Merseyside 2008/09

A report analysing recorded alcohol treatment in Cheshire and Merseyside has been produced by the Liverpool John Moores University (JMU). The report used data recorded by treatment providers through the National Treatment Agency's drug (NDTMS) and alcohol (NATMS) monitoring systems.
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Alcohol increases circulatory disease mortality in Russia: acute and chronic effects or misattribution of cause?

There is a consensus that the large fluctuations in mortality seen in Russia in the past two decades can be attributed to trends in alcohol consumption. However, the precise mechanisms linking alcohol to mortality from circulatory disease remain unclear. It has recently been argued that a substantial number of such deaths currently ascribed to cardiovascular disorders are misclassified cases of acute alcohol poisoning.

Analysis of routine mortality data and of a case–control study of mortality among working-age (25–54 years) men occurring in the Russian city of Izhevsk, west of the Ural mountains, 2003–05. Interviews were carried out with proxy informants for both the dead cases (N = 1750) and the controls (N = 1750) selected at random from a population register. Mortality was analysed according to indicators of alcohol problems.

Hazardous drinking was associated with an increased risk of death from circulatory diseases as a whole [odds ratio (OR) = 4.14, 95% confidence interval (CI) 3.23, 5.31] adjusted for age, smoking and education. The association with alcoholic cardiomyopathy was particularly strong (OR = 15.7, 95% CI 9.5, 25.9). Although there was no association with deaths from myocardial infarction (MI; OR = 1.17, 95% CI 0.59, 2.32), there was a strong association with the aggregate of all other ischaemic heart disease (IHD; OR = 4.04, 95% CI 2.79, 5.84). Stronger associations for each of these causes (other than MI) were seen with whether or not the man had drunk very heavily in the previous week. However, associations also remained when analyses were restricted to subjects with no evidence of recent heavy drinking, suggesting that misclassification of acute alcohol poisonings is unlikely to explain these overall associations.

Taken as a whole, the available evidence suggests that the positive association of alcohol with increased cardiovascular disease mortality may be best explained as being the result of a combination of chronic and acute alcohol consumption resulting in alcohol-related cardiac disorders, especially cardiomyopathy, rather than being due to misclassification of acute alcohol poisoning.

Further work is required to understand the mechanisms underlying the link between heavy alcohol consumption and deaths classified as being due to IHD (other than MI).

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Wednesday, June 30, 2010

Involvement of AMPK in Alcohol Dehydrogenase Accentuated Myocardial Dysfunction Following Acute Ethanol Challenge in Mice Binge alcohol drinking often

Binge alcohol drinking often triggers myocardial contractile dysfunction although the underlying mechanism is not fully clear. This study was designed to examine the impact of cardiac-specific overexpression of alcohol dehydrogenase (ADH) on ethanol-induced change in cardiac contractile function, intracellular Ca2+ homeostasis, insulin and AMP-dependent kinase (AMPK) signaling.

ADH transgenic and wild-type FVB mice were acutely challenged with ethanol (3 g/kg/d, i.p.) for 3 days. Oral glucose tolerance test, cardiac AMP/ATP levels, cardiac contractile function, intracellular Ca2+ handling and AMPK signaling (including ACC and LKB1) were examined.

Ethanol exposure led to glucose intolerance, elevated plasma insulin, compromised cardiac contractile and intracellular Ca2+ properties, downregulated protein phosphatase PP2A subunit and PPAR-γ, as well as phosphorylation of AMPK, ACC and LKB1, all of which except plasma insulin were overtly accentuated by ADH transgene. Interestingly, myocardium from ethanol-treated FVB mice displayed enhanced expression of PP2Cα and PGC-1α, decreased insulin receptor expression as well as unchanged expression of Glut4, the response of which was unaffected by ADH. Cardiac AMP-to-ATP ratio was significantly enhanced by ethanol exposure with a more pronounced increase in ADH mice. In addition, the AMPK inhibitor compound C (10 µM) abrogated acute ethanol exposure-elicited cardiomyocyte mechanical dysfunction.

In summary, these data suggest that the ADH transgene exacerbated acute ethanol toxicity-induced myocardial contractile dysfunction, intracellular Ca2+ mishandling and glucose intolerance, indicating a role of ADH in acute ethanol toxicity-induced cardiac dysfunction possibly related to altered cellular fuel AMPK signaling cascade.

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Involvement of the atrial natriuretic peptide transcription factor GATA4 in alcohol dependence, relapse risk and treatment response to acamprosate

In alcoholism, both relapse to alcohol drinking and treatment response are suggested to be genetically modulated.

This study set out to determine whether the top 15 single nucleotide polymorphisms (SNPs) of a recent genome-wide association (GWA) and follow-up study of alcohol dependence are associated with relapse behavior and pharmacological treatment response in 374 alcohol-dependent subjects who underwent a randomized, double-blind, placebo-controlled trial with acamprosate, naltrexone or placebo.

The single nucleotide polymorphism, rs13273672, an intronic SNP in the gene for GATA-binding protein 4 (GATA4), was associated with relapse within the 90-day medical treatment period.

Subsequent pharmacogenetic analyses showed that this association was mainly based on patients treated with acamprosate >In line with the observation that natriuretic peptide promoters are modulated by GATA4, a significant gene dose effect on the variance of atrial natriuretic peptide (ANP) plasma concentration in the different GATA4 genotypes.

Hence, genetic variations in GATA4 might influence relapse and treatment response to acamprosate in alcohol-dependent patients via modulation of ANP plasma levels.

These results could help to identify those alcohol-dependent patients who may be at an increased risk of relapse and who may better respond to treatment with acamprosate.

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Tuesday, June 29, 2010

Genome-wide association study of conduct disorder symptomatology

Conduct disorder (CD) is one of the most prevalent childhood psychiatric conditions, and is associated with a number of serious concomitant and future problems. CD symptomatology is known to have a considerable genetic component, with heritability estimates in the range of 50%. Despite this, there is a relative paucity of studies aimed at identifying genes involved in the susceptibility to CD.

In this study, we report results from a genome-wide association study of CD symptoms. CD symptoms were retrospectively reported by a psychiatric interview among a sample of cases and controls, in which cases met the criteria for alcohol dependence.

Our primary phenotype was the natural log transformation of the number of CD symptoms that were endorsed, with data available for 3963 individuals who were genotyped on the Illumina Human 1M beadchip array. Secondary analyses are presented for case versus control status, in which caseness was established as endorsing three or more CD symptoms (N=872 with CD and N=3091 without CD).

We find four markers that meet the criteria for genome-wide significance with the CD symptom count, two of which are located in the gene C1QTNF7 (C1q and tumor necrosis factor-related protein 7). There were six additional SNPs in the gene that yielded converging evidence of association.

These data provide the first evidence of a specific gene that is associated with CD symptomatology. None of the top signals resided in traditional candidate genes, underscoring the importance of a genome-wide approach for identifying novel variants involved in this serious childhood disorder.

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Brief interventions should be integrated within diabetes care

A study has recommended that brief interventions for alcohol (or 'IBA') should be incorporated into routine diabetes care. The abstract of the report 'Alcohol use of diabetes patients: the need for assessment and intervention' identifies: > > > Read More


Maternal alcohol consumption during pregnancy and semen quality in the male offspring: two decades of follow-up

Concurrent alcohol exposure has been associated with reduced fecundity, but no studies have estimated the effect of prenatal alcohol exposure on male fecundity.

The aim of this study was to investigate the association between maternal alcohol consumption during pregnancy, semen quality and levels of reproductive hormones in young, adult men.

From a Danish pregnancy cohort established in 1984–1987, 347 sons were selected for a follow-up study conducted in 2005–2006. Semen and blood samples were analyzed for conventional semen characteristics and reproductive hormones, respectively, and results were related to prospectively self-reported information on maternal alcohol consumption during pregnancy.

The sperm concentration decreased with increasing prenatal alcohol exposure. The adjusted mean sperm concentration among sons of mothers drinking ≥4.5 drinks per week during pregnancy was 40 (95% CI: 25–60) millions/ml. This concentration was ~32% lower compared with men exposed to > had a sperm concentration of 59 (95% CI: 44–77) millions/ml. The semen volume and the total sperm count were also associated with prenatal alcohol exposure; sons prenatally exposed to 1.0–1.5 drinks per week had the highest values. No associations were found for sperm motility, sperm morphology or any of the reproductive hormones, including testosterone.

These results indicate that prenatal exposure to alcohol may have a persisting adverse effect on Sertoli cells, and thereby sperm concentration. If these associations are causal they could explain some of the reported differences between populations and long-term changes in semen quality.

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Press Release - Drinking alcohol during pregnancy may damage semen quality in sons

Mothers who drink alcohol while they are pregnant may be damaging the fertility of their future sons, according to new research to be presented at the 26th annual meeting of the European Society of Human Reproduction and Embryology in Rome today (Tuesday 29 June).

Doctors in Denmark found that if mothers had drunk 4.5 or more drinks a week while pregnant, then the sperm concentration of their sons, measured about 20 years later, was a third lower in comparison to men who were not exposed to alcohol while in the womb. A drink was measured as 12 grams of alcohol, which is the equivalent to one 330 ml beer, one small (120 ml) glass of wine or one glass of spirits (40 ml). > > > Read More


Pregnant Teen Admissions to Substance Abuse Treatment: 1992 and 2007

A nationwide report issued by the Substance Abuse and Mental Health Services Administration (SAMHSA) reveals that from 1992 to 2007 there were significant changes in the patterns of substance abuse treatment admissions among pregnant teens both in terms of the kinds of substances involved and among different ethnic and racial groups.

According to the report, the proportion of pregnant teen admissions for marijuana abuse more than doubled from 19.3 percent in 1992 to 45.9 percent in 2007. Marijuana has surpassed alcohol as the primary substance of abuse cited in admissions for pregnant teens—alcohol represented 44.1 percent of all pregnant teen admissions in 1992 -- but dropped to 20.3 percent by 2007. In addition, the proportion of pregnant teen admissions for methamphetamine use has more than quadrupled, from 4.3 percent in 1992 to18.8 percent in 2007.

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News Release - National Study: New Data Show Teen Girls More Likely to See Benefits in Drug and Alcohol Use

Survey data released today by the Partnership for a Drug-Free America® and MetLife Foundation found that teenage girls are more likely than teenage boys to perceive potential benefits from drug use and drinking, making teen girls more vulnerable to drug and alcohol abuse.

According to a new research analysis of the 2009 Partnership Attitude Tracking Study (PATS), sponsored by MetLife Foundation, teen girls are more likely to associate "self-medicating" benefits with drinking and getting high. More than two-thirds of teen girls responded positively to the question "using drugs helps kids deal with problems at home" (an 11 percent increase, up from 61 percent in 2008 to 68 percent in 2009) and more than half reported that drugs help teens forget their troubles (a 10 percent increase, up from 48 percent in 2008 to 53 percent in 2009). Stress has been identified as a key factor leading to drinking, smoking and drug use among girls and more than three times as many young girls as boys reported having symptoms of depression in 2008 (1). > > > > Read More


Secret of AA: After 75 Years, We Don’t Know How It Works

The church will be closed tomorrow, and the drunks are freaking out. An elderly lady in a prim white blouse has just delivered the bad news, with deep apologies: A major blizzard is scheduled to wallop Manhattan tonight, and up to a foot of snow will cover the ground by dawn. The church, located on the Upper West Side, can’t ask its staff to risk a dangerous commute. Unfortunately, that means it must cancel the Alcoholics Anonymous meeting held daily in the basement.
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Monday, June 28, 2010

Quercetin and Ethanol Attenuate the Progression of Atherosclerotic Plaques With Concomitant Up Regulation of Paraoxonase1 (PON1) Gene Expression and P

As moderate wine drinking is atheroprotective, it is clinically relevant to elucidate its possible mechanism/s of action/s.

Our objective is to demonstrate the potential benefits of the wine components, quercetin and ethanol, on the development of aortic plaques with parallel changes in antiatherogenic factors.

The effects of quercetin and ethanol on the development of aortic atherosclerotic lesions, liver PON1 gene expression, and serum PON1 activity were measured in LDLR−/− mice on an atherogenic diet for 4 and 8 weeks.

Depending on the duration and dosage of these modulators, 12.5 to 25 mg/dl quercetin (12.5Q to 25Q) and 18 to 25% ethanol, the magnitude of decreases in aortic lesions caused by moderate ethanol and quercetin ranged from 20 to 70% , Pearson r = 0.79 for 4-week treatment; p = 0.000004, Pearson r = 0.84 for 8-week treatment).

Concomitantly, 4-week treatments with 12.5Q and 18% ethanol up regulated liver PON1 mRNA by 41%.

Based on these findings, we conclude that quercetin and moderate ethanol significantly inhibit the progression of atherosclerosis by up regulating the hepatic expression of the antiatherogenic gene, PON1, with concomitant increased serum PON1 activity.

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Differential Changes in MAP Kinases, Histone Modifications, and Liver Injury in Rats Acutely Treated With Ethanol

Acute ethanol is known to affect cells and organs but the underlying molecular mechanisms are poorly explored. Recent developments highlight the potential importance of mitogen-activated protein kinases, MAPKs (i.e., ERK1/2, p38, and JNK1/2) signaling, and histone modifications (i.e., acetylation, methylation, and phosphorylation) in the actions of ethanol in hepatocytes.

We have therefore investigated significance of these molecular steps in vivo using a model in which rats were acutely administered ethanol intraperitoneally (IP).

Ethanol was administered IP (3.5 gm/kg body weight) to 12-week-old male Sprague–Dawley rats. Liver was subsequently removed at 1 and 4 hours. Serum was used for alcohol and ALT assays. At the time of the removal of liver, small portions of each liver were formalin-fixed and stained with hematoxylin and eosin (H&E) and used for light microscopy. Western blot analysis was carried out with specific primary antibodies for various parameters.

There were clear differences at 1 and 4 hours in blood ethanol, ALT, steatosis, and cleaved caspase 3. Apoptosis at 1 hour was followed by necrosis at 4 hours. Acute alcohol elicited a marked increase in the phosphorylation of ERK1/2 and moderate increases in the phosphorylation of p38 MAPK and JNK. Temporally different phosphorylation of histone H3 at ser-10 and ser-28 occurred and acetylation of histone H3 at lys 9 increased progressively.

There were distinct differences in the behavior of the activation of the 3 MAP kinases and histone modifications after acute short exposure of liver to ethanol in vivo. Although all 3 MAPKs were rapidly activated at 1 hour, the necrosis, occurring at 4 hours, correlated to sustained activation of ERK1/2. Transient activation of p38 is associated with rapid phosphorylation of histone H3, whereas prolonged activation of ERK1/2 is correlated to persistent histone H3 acetylation.

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Withdrawal Severity After Chronic Intermittent Ethanol in Inbred Mouse Strains

To study withdrawal, ethanol is usually administered chronically without interruption. However, interest has recurred in models of episodic exposure. Increasing evidence suggests that chronic intermittent exposure to ethanol leads to a sensitization effect in both withdrawal severity and ethanol consumption.

The goal of the present study was to examine mouse inbred strain differences in withdrawal severity following chronic intermittent exposure using the handling-induced convulsion as the behavioral endpoint. We also sought to compare the withdrawal responses of inbred strains across acute, chronic continuous, and chronic intermittent exposure regimens.

Male mice from 15 standard inbred strains were exposed to ethanol vapor for 16 hours each day for 3 days and removed to an air chamber during the intervening 8 hours. Mice in the control groups were handled the same, except that they were exposed only to air. Daily blood ethanol concentrations were averaged for each mouse to estimate total dose of ethanol experienced.

Across strains, mice had an average daily blood ethanol concentration (BEC) of 1.45 ± 0.02 mg/ml and we restricted the range of this value to 1.00–2.00 mg/ml. To evaluate strain differences, we divided data into two dose groups based on BEC, low dose (1.29 ± 0.1 mg/ml) and high dose (1.71 ± 0.02 mg/ml). After the third inhalation exposure, ethanol-exposed and air-exposed groups were tested hourly for handling-induced convulsions for 10 hour and at hour 24 and 25. Strains differed markedly in the severity of withdrawal (after subtraction of air control values) in both dose groups.

The chronic intermittent exposure paradigm is sufficient to elicit differential withdrawal responses across nearly all strains. Data from the high-dose groups correlated well with withdrawal data derived from prior acute (single high dose) and chronic continuous (for 72 hours) ethanol withdrawal studies, supporting the influence of common genes on all three responses.

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Motivation for Alcohol Becomes Resistant to Quinine Adulteration After 3 to 4 Months of Intermittent Alcohol Self-Administration

Continued consumption of alcohol despite deleterious consequences is a hallmark of alcoholism and represents a critical challenge to therapeutic intervention. Previous rat studies showed that enduring alcohol self-administration despite pairing alcohol with normally aversive stimuli was only observed after very long-term intake (>8 months). Aversion-resistant alcohol intake has been previously interpreted to indicate pathological or compulsive motivation to consume alcohol. However, given the time required to model compulsive alcohol seeking in previous studies, there is considerable interest in developing more efficient and quantitative rodent models of aversion-resistant alcohol self-administration.

Outbred Wistar rats underwent 3 to 4 months or approximately 1.5 months of intermittent, home-cage, two-bottle access (IAA) to 20% alcohol (v/v) or water. Then, after brief operant training, the effect of the bitter-tasting quinine (0.1 g/l) on the motivation to seek alcohol was quantified via progressive ratio (PR). Motivation for quinine-adulterated 2% sucrose under PR was assayed in a separate cohort of 3 to 4 months IAA rats. The effects of quinine on home-cage alcohol consumption in IAA rats and rats with continuous access to alcohol were also examined. Finally, a dose–response for quinine taste preference in IAA and continuous-access animals was determined.

Motivation for alcohol after 3 to 4 months IAA, measured using an operant PR procedure, was not altered by adulteration of alcohol with 0.1 g/l quinine. In contrast, after 3 to 4 months of IAA, motivation for sucrose under PR was significantly reduced by adulteration of sucrose with 0.1 g/l quinine. In addition, motivation for alcohol after only approximately 1.5 months IAA was significantly reduced by adulteration of alcohol with 0.1 g/l quinine. Furthermore, home-cage alcohol intake by IAA rats was insensitive to quinine at concentrations (0.01, 0.03 g/l) that significantly reduced alcohol drinking in animals with continuous access to alcohol. Finally, no changes in quinine taste preference after 3 to 4 months IAA or continuous access to alcohol were observed.

We have developed a novel and technically simple hybrid operant/IAA model in which quinine-resistant motivation for alcohol is evident after an experimentally tractable period of time (3 to 4 months vs. 8 months). Quinine dramatically reduced sucrose and water intake by IAA rats, indicating that continued responding for alcohol in IAA rats despite adulteration with the normally aversive quinine might reflect maladaptive or compulsive motivation for alcohol. This model could facilitate identification of novel therapeutic interventions for pathological alcohol seeking in humans.

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Effects of Alcohol Cue Exposure on Response Inhibition in Detoxified Alcohol-Dependent Patients

There is evidence that exerting self-control during alcohol craving can diminish performance on subsequent tasks that require self-control.

Based on the resource depletion model (Muraven and Baumeister, 2000), we examined the influence of alcohol cue exposure on detoxified alcohol-dependent patients' ability to inhibit ongoing responses.

Twenty alcohol-dependent patients were randomly assigned to an alcohol-cue exposure and a control-cue exposure condition and thereafter had to perform an inhibition task (i.e., stop-signal task).

Participants who sniffed alcohol before performing the inhibition task reported a stronger urge to drink alcohol than the control group that sniffed water. Participants who sniffed alcohol were also impaired in their inhibitory performance but not in their noninhibitory performance on the stop-signal task.

The urge to drink presumably reduced participants' self-control, and this interfered with their ability to inhibit responding.

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Ethanol Alters Cell Fate of Fetal Human Brain-Derived Stem and Progenitor Cells

Prenatal ethanol (ETOH) exposure can lead to fetal alcohol spectrum disorder (FASD). We previously showed that ETOH alters cell adhesion molecule gene expression and increases neurosphere size in fetal brain-derived neural stem cells (NSC).

Here, our aim was to determine the effect of ETOH on the cell fate of NSC, premature glial-committed precursor cells (GCP), and premature neuron-committed progenitor cells (NCP).

NSC, GCP, and NCP were isolated from normal second-trimester fetal human brains (n = 3) by positive selection using magnetic microbeads labeled with antibodies to CD133 (NSC), A2B5 (GCP), or PSA-NCAM (NCP). As a result of the small percentage in each brain, NSC were cultured in mitogenic media for 72 hours to produce neurospheres. The neurospheres from NSC and primary isolates of GCP and NCP were used for all experiments. Equal numbers of the 3 cell types were treated either with mitogenic media or with differentiating media, each containing 0 or 100 mM ETOH, for 120 hours. Expression of Map2a, GFAP, and O4 was determined by immunoflourescence microscopy and western blot analysis. Fluorescence intensities were quantified using Metamorph software by Molecular Devices, and the bands of western blots were quantified using densitometry.

ETOH in mitogenic media promoted formation of neurospheres by NSC, GCP, and NCP. Under control conditions, GCP attached and differentiated, NSC and NCP formed neurospheres that were significantly smaller in size than those in ETOH. Under differentiating conditions, Map2a expression increased significantly in NSC and GCP and reduced significantly in NCP, and GFAP expression reduced significantly in GCP and NCP, and Gal-C expression reduced significantly in all 3 cell types in the presence of ETOH compared to controls.

This study shows that ETOH alters the cell fate of neuronal stem and progenitor cells. These alterations could contribute to the mechanism for the abnormal brain development in FASD.

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Delay Discounting Behavior and White Matter Microstructure Abnormalities in Youth With a Family History of Alcoholism

Youth with family history of alcohol abuse have a greater risk of developing an alcohol use disorder (AUD). Brain and behavior differences may underlie this increased vulnerability.

The current study examined delay discounting behavior and white matter microstructure in youth at high risk for alcohol abuse, as determined by a family history of alcoholism (FH+), and youth without such family history (FH−).

Thirty-three healthy youth (FH+ = 15, FH− = 18), ages 11 to 15 years, completed a delay discounting task and underwent diffusion tensor imaging. Tract-based spatial statistics (Smith et al., 2006), as well as follow-up region-of-interest analyses, were performed to compare fractional anisotropy (FA) between FH+ and FH− youth.

FH+ youth showed a trend toward increased discounting behavior and had significantly slower reaction times (RTs) on the delay discounting paradigm compared to FH− youth. Group differences in FA were seen in several white matter tracts. Furthermore, lower FA in the left inferior longitudinal fasciculus and the right optic radiation statistically mediated the relationship between FH status and slower RTs on the delay discounting task.

Youth with a family history of substance abuse have disrupted white matter microstructure, which likely contributes to less efficient cortical processing and may act as an intrinsic risk factor contributing to an increased susceptibility of developing AUD.

In addition, FHP youth showed a trend toward greater impulsive decision making, possibly representing an inherent personal characteristic that may facilitate substance use onset and abuse in high-risk youth.

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Interactions of Stress and CRF in Ethanol-Withdrawal Induced Anxiety in Adolescent and Adult Rats

Repeated stress or administration of corticotropin-releasing factor (CRF) prior to ethanol exposure sensitizes anxiety-like behavior in adult rats.

Current experiments determined whether adolescent rats were more sensitive to these challenges in sensitizing ethanol withdrawal-induced anxiety and altering CRF levels in brain during withdrawal.

Male adult and adolescent Sprague–Dawley rats were restraint stressed (1 hour) twice 1 week apart prior to a single 5-day cycle of ethanol diet (ED; stress/withdrawal paradigm). Other rats received control diet (CD) and three 1-hour restraint stress sessions. Rats were then tested 5, 24, or 48 hours after the final withdrawal for anxiety-like behavior in the social interaction (SI) test. In other experiments, adolescent rats were given two microinjections of CRF icv 1 week apart followed by 5 days of either CD or ED and tested in social interaction 5 hours into withdrawal. Finally, CRF immunoreactivity was measured in the central nucleus of the amygdala (CeA) and paraventricular nucleus (PVN) after rats experienced control diet, repeated ethanol withdrawals, or stress/withdrawal.

Rats of both ages had reduced SI following the stress/withdrawal paradigm, and this effect recovered within 24 hours. Higher CRF doses were required to reduce SI in adolescents than previously reported in adults. CRF immunohistochemical levels were higher in the PVN and CeA of CD-exposed adolescents. In adolescent rats, repeated ethanol withdrawals decreased CRF in the CeA but was not associated with decreased CRF cell number. There was no change in CRF from adult treatments.

In the production of anxiety-like behavior, adolescent rats have equal sensitivity with stress and lower sensitivity with CRF compared to adults. Further, adolescents had higher basal levels of CRF within the PVN and CeA and reduced CRF levels following repeated ethanol withdrawals. This reduced CRF within the CeA could indicate increased release of CRF, and future work will determine how this change relates to behavior

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Period 2 Gene Deletion Abolishes β-Endorphin Neuronal Response to Ethanol

Ethanol exposure during early life has been shown to permanently alter the circadian expression of clock regulatory genes and the β-endorphin precursor proopiomelanocortin (POMC) gene in the hypothalamus. Ethanol also alters the stress- and immune-regulatory functions of β-endorphin neurons in laboratory rodents.

Our aim was to determine whether the circadian clock regulatory Per2 gene modulates the action of ethanol on β-endorphin neurons in mice.

Per2 mutant (mPer2Brdml) and wild type (C57BL/6J) mice were used to determine the effect of Per2 mutation on ethanol-regulated β-endorphin neuronal activity during neonatal period using an in vitro mediobasal hypothalamic (MBH) cell culture model and an in vivo milk formula feeding animal model. The β-endorphin neuronal activity following acute and chronic ethanol treatments was evaluated by measuring the peptide released from cultured cells or peptide levels in the MBH tissues, using enzyme-linked immunosorbent assay (ELISA).

Per2 mutant mice showed a higher basal level of β-endorphin release from cultured MBH cells and a moderate increase in the peptide content in the MBH in comparison with control mice. However, unlike wild type mice, Per2 mutant mice showed no stimulatory or inhibitory β-endorphin-secretory responses to acute and chronic ethanol challenges in vitro. Furthermore, Per2 mutant mice, but not wild type mice, failed to show the stimulatory and inhibitory responses of MBH β-endorphin levels to acute and chronic ethanol challenges in vivo.

These results suggest for the first time that the Per2 gene may be critically involved in regulating β-endorphin neuronal function. Furthermore, the data revealed an involvement of the Per2 gene in regulating β-endorphin neuronal responses to ethanol.

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Milk Fat Globule EGF Factor 8 Attenuates Sepsis-Induced Apoptosis and Organ Injury in Alcohol-Intoxicated Rats

Despite advances in our understanding of excessive alcohol-intake-related tissue injury and modernization of the management of septic patients, high morbidity and mortality caused by infectious diseases in alcohol abusers remain a prominent challenge. Our previous studies have shown that milk fat globule epidermal growth factor-factor VIII (MFG-E8), a protein required to opsonize apoptotic cells for phagocytosis, is protective in inflammation. However, it remains unknown whether MFG-E8 ameliorates sepsis-induced apoptosis and organ injury in alcohol-intoxicated rats.

The purpose of this study was to determine whether recombinant murine MFG-E8 (rmMFG-E8) attenuates organ injury after acute alcohol exposure and subsequent sepsis.

Acute alcohol intoxication was induced in male adult rats by a bolus injection of intravenous alcohol at 1.75 g/kg BW, followed by an intravenous infusion of 300 mg/kg BW/h of alcohol for 10 hours. Sepsis was induced at the end of 10-hour alcohol infusion by cecal ligation and puncture (CLP). rmMFG-E8 or vehicle (normal saline) was administered intravenously 3 times (i.e., at the beginning of alcohol injection, the beginning of CLP, and 10 hours post-CLP) at a dose of 20 μg/kg BW each. Blood and tissue samples were collected 20 hours after CLP in alcoholic animals for various measurements.

Acute alcohol exposure per se did not affect the production of MFG-E8; however, it primed the animal and enhanced sepsis-induced MFG-E8 downregulation in the spleen. Administration of rmMFG-E8 reduces alcohol/sepsis-induced apoptosis in the spleen, lungs, and liver. In addition, administration of rmMFG-E8 after alcohol exposure and subsequent sepsis decreases circulating levels of TNF-α and interleukin-6 and attenuates organ injury.

rmMFG-E8 attenuates sepsis-induced apoptosis and organ injury in alcohol-intoxicated rats.

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Results of a Type 2 Translational Research Trial to Prevent Adolescent Drug Use and Delinquency - A Test of Communities That Care

To test whether the Communities That Care (CTC) prevention system reduces adolescent alcohol, tobacco, and other drug use and delinquent behavior communitywide.

The Community Youth Development Study is the first randomized trial of CTC.

In 2003, 24 small towns in 7 states, matched within state, were randomly assigned to control or CTC conditions.

A panel of 4407 fifth-grade students was surveyed annually through eighth grade.

A coalition of community stakeholders received training and technical assistance to install the CTC prevention system. They used epidemiological data to identify elevated risk factors and depressed protective factors in the community, and chose and implemented tested programs to address their community's specific profile from a menu of effective programs for families, schools, and youths aged 10 to 14 years.

Incidence and prevalence of alcohol, tobacco, and other drug use and delinquent behavior by spring of grade 8.

The incidences of alcohol, cigarette and smokeless tobacco initiation, and delinquent behavior were significantly lower in CTC than in control communities for students in grades 5 through 8. In grade 8, the prevalences of alcohol and smokeless tobacco use in the last 30 days, binge drinking in the last 2 weeks, and the number of different delinquent behaviors committed in the last year were significantly lower for students in CTC communities.

Using the CTC system to reduce health-risking behaviors in adolescents can significantly reduce these behaviors communitywide.

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