ALCOHOL REPORTS

Monday, April 9, 2012

Intakes of Alcohol and Folate During Adolescence and Risk of Proliferative Benign Breast Disease

To examine the combined effect of alcohol and folate intake during adolescence on the risk of proliferative benign breast disease (BBD).

We used data from 29 117 women in the Nurses’ Health Study II who completed both adolescent alcohol consumption questions in 1989 and an adolescent diet questionnaire in 1998. A total of 659 women with proliferative BBD diagnosed between 1991 and 2001 were confirmed by central pathology review. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals (CIs), adjusted for established risk factors of breast cancer.

Adolescent alcohol consumption was dose-dependently associated with an increased risk of proliferative BBD (hazard ratio = 1.15 per 10 g/day consumption; 95% CI, 1.03–1.28). There was no significant association between adolescent folate intake and the risk of proliferative BBD. Stratified analyses showed that each 10-g/day alcohol intake during adolescence was associated with a 21% (95% CI, 1.01–1.45) increase in the risk of proliferative BBD among women with low folate intake during adolescence, which was not significantly different from the alcohol-associated risk among women with moderate and high folate intake during adolescence (P for interaction = 0.18).

Adolescent alcohol consumption is associated with increased risk of proliferative BBD, which may not be reduced by increased folate intake during adolescence.

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Request Reprint E-Mail: pp6yliu@gmail.com

Mindfulness-Based Relapse Prevention for Substance Craving

Craving, defined as the subjective experience of an urge or desire to use substances, has been identified in clinical, laboratory, and preclinical studies as a significant predictor of substance use, substance use disorder, and relapse following treatment for a substance use disorder.

Various models of craving have been proposed from biological, cognitive, and/or affective perspectives, and, collectively, these models of craving have informed the research and treatment of addictive behaviors.

In this article we discuss craving from a mindfulness perspective, and specifically how mindfulness-based relapse prevention (MBRP) may be effective in reducing substance craving. We present secondary analyses of data from a randomized controlled trial that examined MBRP as an aftercare treatment for substance use disorders.

In the primary analyses of the data from this trial, Bowen and colleagues (2009) found that individuals who received MBRP reported significantly lower levels of craving following treatment, in comparison to a treatment-as-usual control group, which mediated subsequent substance use outcomes.

In the current study, we extend these findings to examine potential mechanisms by which MBRP might be associated with lower levels of craving.

Results indicated that a latent factor representing scores on measures of acceptance, awareness, and nonjudgment significantly mediated the relation between receiving MBRP and self-reported levels of craving immediately following treatment. The mediation findings are consistent with the goals of MBRP and highlight the importance of interventions that increase acceptance and awareness, and help clients foster a nonjudgmental attitude toward their experience.

Attending to these processes may target both the experience of and response to craving.

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Request Reprint E-Mail: katie.witkiewitz@wsu.edu

Alcohol Use and Social Adjustment in Adolescence: A Longitudinal, Multilevehttp://www.blogger.com/l Study

The study examined to what extent alcohol use among Dutch adolescents (1,421 adolescents, aged 12–16) was related to sociability and whether the social context affects this association. Data were based on self-reports and peer reports during 2005 and 2006.

The results indicated that in contrast to previous assumptions, alcohol use did not predict changes in subsequent sociability.

The findings also did not support the idea of curvilinear effects of alcohol use. In addition, the proportion of peers in class who drank had no effect on this association.

Limitations and directions for future research are given.

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Request Reprint E-Mail: r.scholte@bsi.ru.nl

Religiosity and Tobacco and Alcohol Use in a Brazilian Shantytown

This article analyzes the role of religious involvement and religious beliefs in the prevalence and frequency of smoking and alcohol consumption.

This was a cross-sectional, population-based study. In 2005, we conducted door-to-door interviews with 383 people, aged 18 years or more, randomly selected from the “Paraisopolis” shantytown in São Paulo, Brazil. Four regression models were created to explain the relationships among religious involvement, tobacco and alcohol use, controlling for demographic, social, and psychobehavioral factors.

High religious attendance was associated with less alcohol use, alcohol abuse, tobacco use, and combined alcohol/tobacco use, as well as less days consuming alcoholic beverages per week, controlling for confounding factors.

Additionally, high nonorganizational religious behavior was associated with less tobacco and combined alcohol/tobacco use.

Religiosity plays an important role in the control of alcohol and tobacco use in a shantytown setting; further management initiatives in the area should consider this issue. The study's limitations are noted.

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Request Reprint E-Mail: g.lucchetti@yahoo.com.br

ASTN1 and alcohol dependence: Family-based association analysis in multiplex alcohol dependence families

A previous genome-wide linkage study of alcohol dependence (AD) in multiplex families found a suggestive linkage result for a region on Chromosome 1 near microsatellite markers D1S196 and D1S2878. The ASTN1 gene is in this region, a gene previously reported to be associated with substance abuse, bipolar disorder and schizophrenia.

Using the same family data consisting of 330 individuals with phenotypic data and DNA, finer mapping of a 26 cM region centered on D1S196 was undertaken using SNPs with minor allele frequency (MAF) ≥ 0.15 and pair-wise linkage disequilibrium (LD) of r² < 0.8 using the HapMap CEU population.

Significant FBAT P-values for SNPs within the ASTN1 gene were observed for four SNPs (rs465066, rs228008, rs6668092, and rs172917), the most significant, rs228008, within intron 8 had a P-value of 0.001.

Using MQLS, which allows for inclusion of all families, we find three of these SNPs with MQLS P-values < 0.003. In addition, two additional neighboring SNPs (rs10798496 and rs6667588) showed significance at P = 0.002 and 0.03, respectively.

Haplotype analysis was performed using the haplotype-based test function of FBAT for a block that included rs228008, rs6668092, and rs172917.

This analysis found one block (GCG) over-transmitted and another (ATA) under-transmitted to affected offspring.

Linkage analysis identified a region consistent with the association results. Family-based association analysis shows the ASTN1 gene significantly associated with alcohol dependence.

The potential importance of the ASTN1 gene for AD risk may be related its role in glial-guided neuronal migration.

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Request Reprint E-Mail: syh50@imap.pitt.edu

The 5-HTTLPR polymorphism moderates the effect of stressful life events on drinking behavior in college students of African descent

Covault et al. [Covault et al. (2007); Biol Psychiatry 61(5): 609–616] reported that the common functional polymorphism, 5-HTTLPR, in the serotonin transporter gene moderated the association between past-year stressful events and daily reports of drinking in a sample of European-American (EA) college students.

We examined this effect in college students of African descent. Students recruited at a Historically Black University (n = 564) completed web-based measures of past-year stressful life experiences and daily reports of drinking and heavy drinking over a 30-day period. Participants were genotyped for the tri-allelic 5-HTTLPR polymorphism and dichotomized as low-activity S′ allele carriers or high-activity L′ homozygotes. Generalized linear models were used to examine the effects of life stress, genotype, and their interaction on the two drinking measures.

In students who completed 15 or more daily surveys (n = 393), there was a significant interaction of past-year stressful events, 5-HTTLPR genotype, and gender on the number of drinking days (P = 0.002).

Similar findings were obtained in relation to heavy drinking days (P = 0.007).

Men showed a main effect of past-year stressful events on both drinking outcomes (P's < 0.001), but no main or moderator effects of genotype.

In women, the S′ allele moderated the impact of past-year life stressors on the frequency of drinking and heavy drinking days (P's < 0.001).

In college students of African descent, past-year stressful events were associated with more frequent drinking and heavy drinking, an effect that was moderated by the 5-HTTLPR polymorphism.

However, in contrast to the findings in EA students, in the current sample, 5-HTTLPR moderated the association only among women.

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Request Reprint E-Mail: jocovault@uchc.edu

Alcohol News - 15/2012

YLE News (Finland) - 80 years since end of prohibition — happy birthday ALKO

Thursday marks 80 years since the first state-operated liquor stores opened their doors in Finland. The first 48 ALKO shops welcomed thirsty customers on April 5, 1932, following a government decision to end prohibition.

The Foreigner (Norway) - Norwegians descend on Swedish town

True to tradition, Norwegians are in Sweden this year to celebrate Maundy Thursday and the Easter weekend joined by alcohol.

The Nordic Page (Norway) - Six out of Ten Norwegians Think Wine is Healthy

In the Norwegian Health Directorate's recent population survey, nearly 1300 men and women were interviewed. According tothe results of the survey, 58 percent of the respondents believe drinking wine regularly is healthy. Also, 63 percent of the participants believe that red wine is healthier than other alcohols.

The Local (Sweden) - Carers can help alcoholic buy booze: agency

Swedish home-help service workers have recently been instructed to assist a disabled man who suffers from alcohol addiction to purchase drink.

Reuters - Most alcohol, drug abuse starts in teen years-study

A survey of U.S. teenagers found that most have used alcohol and drugs by the time they reach adulthood, and researchers said this could be setting many of those kids up for a lifetime of substance abuse.

Boston.com (Turkmenistan) - Turkmenistan bans alcohol during 'Happiness Week'

Authorities in Turkmenistan have put a dampener on so-called "Happiness Week" by quietly banning the sale of alcohol.

U.S. News & World Report (USA) - Drug, Alcohol Abuse Common Among U.S. Teens, Study Finds

Alcohol and drug use is common among American teens and more than 15 percent of them meet the criteria for substance abuse, a new study finds.

U.S. News & World Report - Teen Drinking May Boost Odds of Precancerous Breast Changes

Teenage girls and young adult women who drink even moderate amounts of alcohol appear to increase their risk of developing breast changes that can lead to cancer, according to a large new study.

CBS News - Study proves "beer goggles" phenomenon does exist

We often joke that alcohol can make a person look more attractive. But do these rumored "beer goggles" exist? According to a new study published on April 4 in Addiction, alcohol can make the heart grow fonder - or at least make people look more attractive.

MSN Health & Fitness - ER Docs Can Help Curb Patient Alcohol Abuse, Drunk Driving

Problem drinkers are more likely to reduce their alcohol consumption after receiving counseling from an emergency room physician, according to a new study. ER doctors can also deter heavy drinkers from driving while under the influence, the study found.

Prague Post (Chech Republic) - ČR tops alcohol rankings

Europeans drink the most of any region in the world, and Czechs drink the most of any Europeans, according to a recent World Health Organization (WHO) study - and there are health problems that follow.

Telegraph.co.uk - Dentists 'should screen patients for alcohol abuse'

Dentists should screen patients for unhealthy drinking habits during routine appointments to help promote general health, experts have claimed.

Irish Times (Ireland) - Independent off-licences blame closure rate on below-cost alcohol sales by supermarkets

THE SPECIALIST off-licence sector will “die a death within five years” unless the Government “urgently” implements key Department of Health recommendations to address alcohol abuse, its representative group has claimed.

National Business Review (New Zealand) - EXECUTIVE HEALTH: Alcohol lifts breast cancer risk

Alcohol is known to increase the risk of several cancers, in both sexes, including bowel cancer. But breast tissue is thought to be particularly sensitive to its carcinogenic effects, according to a review of research by Helmut Seiz, of the University of Heidelberg and colleagues.

BBC News (UK) - Illegal sales of alcohol in Suffolk reach record low

Illegal sales of alcohol to underage teenagers in Suffolk have reached a record low as "traders are becoming more vigilant."

Herald Sun (Australia) - Professor warns of dangers of cheap alcohol

CHEAP booze and disposable income have contributed to a quarter of Australians drinking at dangerous levels, an addiction expert claims.

SunHerald.com - Research and Markets: Analyzing the Global Premium Alcohol Market 2012

Alcohol consumption is declining in most of the developed countries, and rising in many of the developing countries and the countries of Central and Eastern Europe.

This is Bristol (UK) - Health chief calls for higher alcohol prices in South Gloucestershire

A HEALTH expert is calling for alcohol-free venues in South Gloucestershire to help combat soaring alcohol consumption. They would help to change the drinking culture by providing an alternative place for people to socialise, according to Dr Chris Payne, director of public health for NHS South Gloucestershire, in his annual report.

Selenium or Selenium Plus Folic Acid–Supplemented Diets Ameliorate Renal Oxidation in Ethanol-Exposed Pups

Ethanol (EtOH) exposure during gestation and lactation induces an oxidative stress in offspring. In kidney, the oxidative damage is the primary pathway to alcohol-induced injury. In this study, we have demonstrated that a diet supplemented with selenium (Se) (0.5 ppm) or with Se (0.5 ppm) + folic acid (8 ppm) administered to EtOH-exposed (20% v/v) dams during gestation and lactation prevents the oxidative EtOH-provoked effects in their offspring's kidneys.

All the studies were performed on 21-day-old pups. Serum, urine, and kidney Se levels were assessed by graphite-furnace atomic absorption spectrometry. Se and creatinine clearance, antioxidant enzyme activities, and lipid and protein peroxidation were determined by a spectrophotometric method in kidney.

Dietary supplementation treatments used could not improve the glomerular filtration function altered by EtOH exposure during gestation and lactation; however, they did improve renal Se deposits, renal development, and renal protein content while decreasing lipid and protein oxidation and modifying antioxidant enzymes' activity.

Se or Se + folic acid supplementations improve renal development and protein content and modify antioxidant enzymes' activity, decreasing lipid and protein oxidation after EtOH exposure. In this context, a double-supplemented diet appears to reduce protein peroxidation more efficiently than the Se-only-supplemented one, probably via superoxide dismutase and catalase.

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Request Reprint E-Mail: olimpia@us.es

Ethanol Metabolism and Osmolarity Modify Behavioral Responses to Ethanol in C. elegans

Ethanol (EtOH) is metabolized by a 2-step process in which alcohol dehydrogenase (ADH) oxidizes EtOH to acetaldehyde, which is further oxidized to acetate by aldehyde dehydrogenase (ALDH). Although variation in EtOH metabolism in humans strongly influences the propensity to chronically abuse alcohol, few data exist on the behavioral effects of altered EtOH metabolism. Here, we used the nematode Caenorhabditis elegans to directly examine how changes in EtOH metabolism alter behavioral responses to alcohol during an acute exposure. Additionally, we investigated EtOH solution osmolarity as a potential explanation for contrasting published data on C. elegans EtOH sensitivity.

We developed a gas chromatography assay and validated a spectrophotometric method to measure internal EtOH in EtOH-exposed worms. Further, we tested the effects of mutations in ADH and ALDH genes on EtOH tissue accumulation and behavioral sensitivity to the drug. Finally, we tested the effects of EtOH solution osmolarity on behavioral responses and tissue EtOH accumulation.

Only a small amount of exogenously applied EtOH accumulated in the tissues of C. elegans and consequently their tissue concentrations were similar to those that intoxicate humans. Independent inactivation of an ADH-encoding gene (sodh-1) or an ALDH-encoding gene (alh-6 or alh-13) increased the EtOH concentration in worms and caused hypersensitivity to the acute sedative effects of EtOH on locomotion. We also found that the sensitivity to the depressive effects of EtOH on locomotion is strongly influenced by the osmolarity of the exogenous EtOH solution.

Our results indicate that EtOH metabolism via ADH and ALDH has a statistically discernable but surprisingly minor influence on EtOH sedation and internal EtOH accumulation in worms. In contrast, the osmolarity of the medium in which EtOH is delivered to the animals has a more substantial effect on the observed sensitivity to EtOH.

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Request Reprint E-Mail: jcbettinger@vcu.edu

Oxidative Stress Modulates KLF6Full and Its Splice Variants

Induction of reactive oxygen species (ROS) is a central mechanism in alcohol hepatotoxicity. Krüppel-like factor 6 (KLF6), a transcription factor and a tumor-suppressor gene, is an early-responsive gene to injury; however, the effect of ROS and alcohol on KLF6 induction is unknown. The aim of this study is to investigate the contribution of 2 sources of ROS, cytochrome P450 2E1 (CYP2E1), NAD(P)H quinone oxidoreductase (NQO1), and alcohol on the modulation of KLF6_Full expression, splicing to KLF6_V1 and KLF6_V2, and the effect on TNFα, a downstream target.

Endogenous ROS production in CYP2E1-expressing HepG2 cells induced mRNA and protein expression of KLF6_Full and its splice variants compared to control cells. Incubation with pro-oxidants such as arachidonic acid (AA), β-naphtoflavone, and H₂O₂ further enhanced KLF6_Full and its splice variants. The AA effects on KLF6_Full and its splice forms were blocked by vitamin E—which prevents lipid peroxidation—and by diallylsulfide—a CYP2E1 inhibitor. Menadione and paraquat, 2 pro-oxidants metabolized via NQO1, induced KLF6_Full mRNA in a thiol-dependent manner. Antioxidants and an NQO1 inhibitor suppressed the menadione-dependent increase in KLF6_Full and its splice variants mRNA. Furthermore, primary hepatocytes and livers from chronic alcohol-fed rats, with elevated lipid peroxidation, H₂O₂ and CYP2E1 but with low GSH, showed a ~2-fold increase in KLF6_Full mRNA compared to controls. Inhibition of p38 phosphorylation further up-regulated the CYP2E1 and the AA effects on KLF6_Full mRNA, whereas inhibition JNK and ERK1/2 phosphorylation decreased both. KLF6_V1 but not KLF6_Full ablation markedly increased TNFα levels in macrophages; thus, TNFα emerges as a downstream target of KLF6_V1.

The novel effect of ROS on modulating KLF6_Full expression and its splice variants could play a relevant role in liver injury and in TNFα regulation.

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Request Reprint E-Mail: natalia.nieto@mssm.edu

Development of an Oral Operant Nicotine/Ethanol Co-Use Model in Alcohol-Preferring (P) Rats

Alcohol abuse is frequently associated with nicotine (Nic) use. The current experiments were conducted to establish an oral operant ethanol + Nic (EtOH + Nic) co-use model and to characterize some aspects of EtOH + Nic co-use.

Rats were allowed to choose between EtOH alone or EtOH + Nic solutions. Additionally, alcohol-preferring (P) rats were allowed to concurrently self-administer 3 distinct EtOH solutions (10, 20, and 30%) with varying amounts of Nic (0.07, 0.14, or 0.21 mg/ml) under operant conditions. P rats were also allowed to concurrently self-administer 2 distinct amounts of Nic (0.07 and 0.14 mg/ml) added to saccharin (Sacc; 0.025%) solutions.

During acquisition, P rats responded for the EtOH + Nic solutions at the same level as for EtOH alone, and responding for EtOH + Nic solutions was present throughout all drinking conditions. P rats also readily maintained stable self-administration behaviors for Nic + Sacc solutions. The results demonstrated that P rats readily acquired and maintained stable self-administration behaviors for EtOH + 0.07 and EtOH + 0.14 mg/ml Nic solutions. Self-administration of EtOH + 0.21 mg/ml Nic was established in only 50% of the subjects. P rats readily expressed seeking behaviors for the EtOH + Nic solutions and reacquired EtOH + Nic self-administration during relapse testing. In addition, tail blood samples indicated that EtOH + Nic co-use resulted in pharmacologically relevant levels of both EtOH and Nic in the blood.

Overall, the results indicate that P rats readily consume EtOH + Nic solutions concurrently in the presence of EtOH alone, express drug-seeking behaviors, and will concurrently consume physiologically relevant levels of both drugs. These results support the idea that this oral operant EtOH + Nic co-use model would be suitable for studying the development of co-abuse and the consequences of long-term chronic co-abuse.

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Request Reprint E-Mail: shhauser@iupui.edu

Pilot Study of iPS-Derived Neural Cells to Examine Biologic Effects of Alcohol on Human Neurons In Vitro

Studies of the effects of alcohol on N-methyl-d-aspartate (NMDA) receptor function and gene expression have depended on rodent or postmortem human brain models. Ideally, the effects of alcohol might better be examined in living neural tissue derived from human subjects. In this study, we used new technologies to reprogram human subject-specific tissue into pluripotent cell colonies and generate human neural cultures as a model system to examine the molecular actions of alcohol.

Induced pluripotent stem (iPS) cells were generated from skin biopsies taken from 7 individuals, 4 alcohol-dependent subjects, and 3 social drinkers. We differentiated the iPS cells into neural cultures and characterized them by immunocytochemistry using antibodies for the neuronal marker beta-III tubulin, glial marker s100β, and synaptic marker synpasin-1. Electrophysiology was performed to characterize the iPS-derived neurons and to measure the effects of acute alcohol exposure on the NMDA receptor response in chronically alcohol exposed and nonexposed neural cultures from 1 nonalcoholic. Finally, we examined changes in mRNA expression of the NMDA receptor subunit genes GRIN1,GRIN2A,GRIN2B, and GRIN2D after 7 days of alcohol exposure and after 24-hour withdrawal from chronic alcohol exposure.

Immunocytochemistry revealed positive staining for neuronal, glial, and synaptic markers. iPS-derived neurons displayed spontaneous electrical properties and functional ionotropic receptors. Acute alcohol exposure significantly attenuated the NMDA response, an effect that was not observed after 7 days of chronic alcohol exposure. After 7 days of chronic alcohol exposure, there were significant increases in mRNA expression of GRIN1, GRIN2A, and GRIN2D in cultures derived from alcoholic subjects but not in cultures derived from nonalcoholics.

These findings support the potential utility of human iPS-derived neural cultures as in vitro models to examine the molecular actions of alcohol on human neural cells.

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Request Reprint E-Mail: jocovault@uchc.edu

Rapid Temporal Changes in the Expression of a Set of Neuromodulatory Genes During Alcohol Withdrawal in the Dorsal Vagal Complex: Molecular Evidence o

Chronic alcohol exposure produces neuroadaptation, which increases the risk of cellular excitotoxicity and autonomic dysfunction during withdrawal. The temporal progression and regulation of the gene expression that contributes to this physiologic and behavioral phenotype is poorly understood early in the withdrawal period. Further, it is unexplored in the dorsal vagal complex (DVC), a brainstem autonomic regulatory structure.

We use a quantitative polymerase chain reaction platform to precisely and simultaneously measure the expression of 145 neuromodulatory genes in more than 100 rat DVC samples from control, chronically alcohol-exposed, and withdrawn rats. To gain insight into the dynamic progression and regulation of withdrawal, we focus on the expression of a subset of functionally relevant genes during the first 48 hours, when behavioral symptoms are most severe.

In the DVC, expression of this gene subset is essentially normal in chronically alcohol-exposed rats. However, withdrawal results in rapid, large-magnitude expression changes in this group. We observed differential regulation in 86 of the 145 genes measured (59%), some as early as 4 hours into withdrawal. Time series measurements (4, 8, 18, 32, and 48 hours after alcohol removal) revealed dynamic expression responses in immediate early genes, γ-aminobutyric acid type A, ionotropic glutamate, and G-protein coupled receptors and the Ras/Raf signaling pathway. Together, these changes elucidate a complex, temporally coordinated response that involves correlated expression of many functionally related groups. In particular, the expression patterns of Gabra1, Grin2a, Grin3a, and Grik3 were tightly correlated. These receptor subunits share overrepresented transcription factor binding sites for Pax-8 and other transcription factors, suggesting a common regulatory mechanism and a role for these transcription factors in the regulation of neurotransmission within the first 48 hours of alcohol withdrawal.

Expression in this gene set is essentially normal in the alcohol-adapted DVC, but withdrawal results in immediate, large-magnitude, and dynamic changes. These data support both increased research focus on the biological ramifications of alcohol withdrawal and enable novel insights into the dynamic withdrawal expression response in this understudied homeostatic control center.

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Request Reprint E-Mail: schwaber@mail.dbi.tju.edu

Acute Ethanol Administration and Reinforcer Magnitude Reduction Both Reduce Responding and Increase Response Latency in a Go/No-Go Task

Ethanol (EtOH) administration decreases behavioral inhibition in human subjects, assessed using cued Go/No-Go tasks, in which an unreliable cue suggests whether participants will be required to respond or not when a signal occurs. Few studies have examined EtOH's effects on behavioral inhibition in animals, and those that have done so have used Go/No-Go tasks in which no warning cue was provided.

Two cohorts of male Long-Evans rats were trained and tested on 2 different Go/No-Go procedures with differing ratios of Go to No-Go trials (25 to 75 and 50 to 50). Using a within-subjects design, each rat was administered 0.0, 0.63, 0.95, and 1.27 g/kg of EtOH (i.p.) on 3 separate occasions according to an incomplete Latin square. An additional experiment examined the effects of reducing the amount of sucrose given for correct responses to either the Go or the No-Go signal in the absence of EtOH administration.

Acute intraperitoneal EtOH administration dose-dependently decreased responding during the No-Go signal (false alarms), the Go signal (hits), and responding prior to the occurrence of either signal (precue response rate). These effects were more pronounced in rats with the 50 to 50 ratio. Reducing the amount of sucrose presented generally led to a decrease in responding, although this effect was also moderated by the Go to No-Go ratio employed and the contingency relationship (reduced sucrose for correct Go trial responding or for correct No-Go trial response withholding).

Acute EtOH administration does not decrease behavioral inhibition in rats in this task. Rather EtOH appears to dose-dependently decrease behavior in general, possibly by reducing the efficacy of the sucrose reinforcer, as both EtOH administration and sucrose reduction for Go trials yielded similar patterns of behavioral responding in this task in rats.

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Request Reprint E-Mail: moschakt@ohsu.edu

Regulation of the Activity and Expression of Aryl Hydrocarbon Receptor by Ethanol in Mouse Hepatic Stellate Cells

During the course of alcohol-induced liver damage, hepatic stellate cells are transformed into proliferative, fibrogenic, and contractile myofibroblasts. Aryl hydrocarbon receptor (AhR) is a transcription factor that controls the expression of genes involved in the metabolism of xenobiotics, inflammation, cell proliferation, and death.

Immortal mouse hepatic stellate cells (MHSCs) were isolated from transgenic mice that expressed a thermolabile SV40 tumor antigen. Quantitative real-time reverse transcription polymerase chain reaction assays, Western blot analysis, promoter activity assays, and chromatin immunoprecipitation analyses were performed for studying the effect of ethanol (EtOH) on AhR expression and transcriptional activity.

Treatment of MHSCs with 50 to 200 mM EtOH for 6 hours induced AhR nuclear translocation, enhanced the promoter activity of cytochrome P450 (CYP) 1A1, increased the amount of AhR bound to the promoter of CYP1A1 and 1B1, and up-regulated the mRNA expression of these AhR target genes in a dose-dependent manner. In contrast, EtOH exposure down-regulated AhR mRNA and protein expression. Similarly, benzo(a)pyrene (BaP) at 10 nM reduced AhR and increased CYP1A1 and 1B1 mRNAs. Pretreatment of MHSCs with 50 mM EtOH for 7 days diminished the capacity of MHSCs to express CYP1A1 and 1B1 induced by a 200 mM EtOH challenge, or by 10 nM BaP. However, the up-regulatory effect of EtOH on solute carrier family 16, member 6 (SLC16a6) was unaffected by EtOH pretreatment. Similar to EtOH, dimethyl sulfoxide (DMSO) at concentrations of 50 to 100 mM down-regulated AhR and up-regulated CYP1A1 mRNA expression in a dose-dependent manner.

These data, for the first time, demonstrate that EtOH activates MHSC AhR and down-regulates its expression. Chronic EtOH pretreatment lowers the availability of AhR, and specifically diminishes the inducibility of CYP genes. The effect on AhR appears to not be an EtOH-specific response, as DMSO alone (and possibly other organic solvents) was also able to activate AhR.

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Request Reprint E-Mail: zguo@mmc.edu

Alcohol Consumption Among Pregnant Women in a Swedish Sample and Its Effects on the Newborn Outcomes

The sample comprised 2,264 women from a Swedish antenatal clinic. Retrospective self-report data were collected on alcohol consumption before and during pregnancy, using the Alcohol Use Disorders Identification Test (AUDIT), and on nicotine use. Specific alcohol biomarkers for excessive drinking, carbohydrate-deficient transferrin (CDT) in serum and phosphatidylethanol (PEth) in whole blood, were determined during mid-pregnancy in a subsample of the women. Data on labor and early characteristics of the child were also assessed.

Before pregnancy, 89% of the women regularly consumed alcohol and 49% reported occasional or frequent binge drinking. Nicotine was used by 15% before and by 5% during pregnancy. During pregnancy, 12% continued using alcohol and 5% also admitted binge drinking. However, all alcohol biomarker values were below the reporting limits (CDT ≤ 1.7% disialotransferrin; total PEth < 0.1 μmol/L). Self-reported drinking during pregnancy was associated with a higher AUDIT score before pregnancy, nicotine use at the time of the first prenatal visit, older age, and previous legal abortions.

The AUDIT questionnaire and 2 specific alcohol biomarkers were used in routine maternity care to collect information about drinking during pregnancy and thereby to identify children at risk for alcohol-related complications. While the AUDIT results suggested that a significant number of women continued using alcohol during pregnancy, implying a risk for fetal disorders, the biomarkers showed negative test values thus indicating only modest drinking levels.

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Request Reprint E-Mail: anders.%20helander@ki.se

Comparison of the Effect of the GABAB Receptor Agonist, Baclofen, and the Positive Allosteric Modulator of the GABAB Receptor, GS39783, on Alcohol Sel

Administration of the GABA_B receptor agonist, baclofen, and positive allosteric modulator, GS39783, has been repeatedly reported to suppress multiple alcohol-related behaviors, including operant oral alcohol self-administration, in rats. This study was designed to compare the effect of baclofen and GS39783 on alcohol self-administration in 3 lines of selectively bred, alcohol-preferring rats: Indiana alcohol-preferring (P), Sardinian alcohol-preferring (sP), and Alko Alcohol (AA).

Rats of each line were initially trained to respond on a lever, on a fixed ratio (FR) 4 (FR4) schedule of reinforcement, to orally self-administer alcohol (15%, v/v) in daily 30-minute sessions. Once responding reached stable levels, rats were exposed to a sequence of experiments testing baclofen (0, 1, 1.7, and 3 mg/kg; i.p.) and GS39783 (0, 25, 50, and 100 mg/kg; i.g.) on FR4 and progressive ratio (PR) schedules of reinforcement. Finally, to assess the specificity of baclofen and GS39783 action, rats were slightly food-deprived and trained to lever-respond for food pellets.

The rank of order of the reinforcing and motivational properties of alcohol was P>sP>AA rats. Under both FR and PR schedules of reinforcement, the rank of order of potency and efficacy of baclofen and GS39783 in suppressing alcohol self-administration was P>sP>AA rats. Only the highest dose of baclofen reduced lever-responding for food pellets; this effect was common to all 3 rat lines. Conversely, no dose of GS39783 altered lever-responding for food in any rat line.

These results suggest that: (i) the strength of the reinforcing and motivational properties of alcohol differ among P, sP, and AA rats; (ii) the reinforcing and motivational properties of alcohol in P, sP, and AA rats are differentially sensitive to treatment with baclofen and GS39783; (iii) the heterogeneity in sensitivity to baclofen and GS39783 of alcohol self-administration in P, sP, and AA rats may resemble the differential effectiveness of pharmacotherapies among the different typologies of human alcoholics; and (iv) the GABA_B receptor is part of the neural substrate mediating the reinforcing and motivational properties of alcohol.

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Request Reprint E-Mail: colomb@unica.it

Adolescence and Parental History of Alcoholism: Insights from the Sleep EEG

Disrupted sleep is a common complaint of individuals with alcohol use disorder and in abstinent alcoholics. Furthermore, among recovering alcoholics, poor sleep predicts relapse to drinking. Whether disrupted sleep in these populations results from prolonged alcohol use or precedes the onset of drinking is not known. The aim of this study was to examine the sleep electroencephalogram (EEG) in alcohol-naïve, parental history positive (PH+), and negative (PH−) boys and girls.

All-night sleep EEG recordings in 2 longitudinal cohorts (child and teen) followed at 1.5 to 3 year intervals were analyzed. The child and teen participants were 9/10 and 15/16 years old at the initial assessment, respectively. Parental history status was classified by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria applied to structured interviews (DIS-IV) resulting in 14 PH− and 10 PH+ children and 14 PH− and 10 PH+ teens. Sleep data were visually scored in 30-second epochs using standard criteria. Power spectra were calculated for EEG derivations C3/A2, C4/A1, O2/A1, O1/A2 for nonrapid eye movement (NREM) and rapid eye movement (REM) sleep.

We found no difference between PH+ and PH− individuals in either cohort for any visually scored sleep stage variable. Spectral power declined in both cohorts across assessments for NREM and REM sleep in all derivations and across frequencies independent of parental history status. With regard to parental history, NREM sleep EEG power was lower for the delta band in PH+ teens at both assessments for the central derivations. Furthermore, power in the sigma band for the right occipital derivation in both NREM and REM sleep was lower in PH+ children only at the initial assessment.

We found no gross signs of sleep disruption as a function of parental history. Modest differences in spectral EEG power between PH+ and PH− children and teens indicate that a marker of parental alcohol history may be detectable in teens at risk for problem drinking.

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Request Reprint E-Mail: Leila_Tarokh@brown.edu

Hazardous Drinking and Dimensions of Impulsivity, Behavioral Approach, and Inhibition in Adult Men and Women

Hazardous drinking is characterized by decisions to engage in excessive or risky patterns of alcohol consumption. Levels of impulsivity and behavioral approach and inhibition may differ in hazardous drinkers and nonhazardous drinkers. A comparison of the relative levels of dimensions of impulsivity and behavioral inhibition and approach in adult men and women hazardous and nonhazardous drinkers may inform treatment and prevention efforts.

In the present research, 466 men and women from a community sample were administered the Alcohol Use Disorders Identification Test (AUDIT), the Behavioral Inhibition System/Behavioral Approach System (BIS/BAS) scale, and the Barratt Impulsiveness Scale, version 11 (BIS-11). Relations among the dimensions of these constructs were examined using multivariate analysis of covariance (MANCOVA), with age and race as covariates.

There were main effects of hazardous drinking on all 3 dimensions of impulsivity, the behavioral inhibition system, and the behavioral activation system Reward Responsiveness, and Fun-Seeking components, with hazardous drinkers scoring higher than nonhazardous drinkers.

This research provides a better understanding of the manner in which impulsivity and behavioral inhibition and approach tendencies relate to hazardous alcohol use in men and women. The present results have implications for alcohol-related prevention and treatment strategies for adult men and women.

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Request Reprint E-Mail: kristen.hamilton@yale.edu

Alcohol Exposure Rate Control Through Physiologically Based Pharmacokinetic Modeling

The instantaneous rate of change of alcohol exposure (slope) may contribute to changes in measures of brain function following administration of alcohol that are usually attributed to breath alcohol concentration (BrAC) acting alone. To test this proposition, a 2-session experiment was designed in which carefully prescribed, constant-slope trajectories of BrAC intersected at the same exposure level and time since the exposure began. This paper presents the methods and limitations of the experimental design.

Individualized intravenous infusion rate profiles of 6% ethanol (EtOH) that achieved the constant-slope trajectories for an individual were precomputed using a physiologically based pharmacokinetic model. Adjusting the parameters of the model allowed each infusion profile to account for the subject's EtOH distribution and elimination kinetics. Sessions were conducted in randomized order and made no use of feedback of BrAC measurements obtained during the session to modify the precalculated infusion profiles. In one session, an individual's time course of exposure, BrAC(t), was prescribed to rise at a constant rate of 6.0 mg% per minute until it reached 68 mg% and then descend at −1.0 mg% per minute; in the other, to rise at a rate of 3.0 mg% per minute. The 2 exposure trajectories were designed to intersect at a BrAC (t = 20 minutes) = 60 mg% at an experimental time of 20 minutes.

Intersection points for 54 of 61 subjects were within prescribed deviations (range of ±3 mg% and ±4 minutes from the nominal intersection point).

Results confirmed the feasibility of applying the novel methods for achieving the intended time courses of the BrAC, with technical problems limiting success to 90% of the individuals tested.

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Request Reprint E-Mail: oconnor1@iupui.edu

Aims

Monday, April 9, 2012