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, April 10, 2010

A high-performing NHS? A review of progress 1997–2010

With a general election imminent, the NHS has once again emerged as a priority among voters in England, and political parties are competing to be seen as the best qualified to improve the service. Opposition parties paint a picture of an NHS with major deficiencies while the Labour government believes that the NHS is ‘good’ but needs further transformation to become ‘great’. These calls for further reform follow an unprecedented increase in funding for the NHS since 2000.

This review assesses how far the investment and accompanying reforms since 1997 have transformed the NHS in England into a high-performing health system. The review focuses on England because health policy has now diverged from that in the devolved administrations of Scotland, Wales and Northern Ireland. It has drawn on official data, government and other official reports and academic research to assess how much progress the NHS has made in eight domains since 1997. The review asks whether the NHS is: accessible; safe; promoting health and managing long-term conditions; clinically effective; delivering a positive patient experience; equitable; efficient and accountable.

Alcohol pp. 37-40
Overall, there is no sign that the government’s aims to reduce harmful alcohol consumption have been achieved. However, as the government has recently acknowledged, much of the potential improvement lies outside the NHS, including greater control of advertising, pricing strategies, and initiatives to limit the physical availability of alcohol.

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β-Endorphin Mediates Behavioral Despair and the Effect of Ethanol on the Tail Suspension Test in Mice

The opioid peptide β-endorphin (β-E) is synthesized and released in response to stressful stimuli as well as acute alcohol administration. The release of β-E following exposure to an inescapable aversive situation may mediate behaviors that contribute to allostasis of the stress response.

The present study examines the effects of β-E on immobility in assays involving inescapable stress, both under basal conditions and after acute administration of EtOH.

Female and male transgenic mice with varying capacities to translate β-E were subjected to either the forced swim (FST, Experiment 1) or the tail suspension test (TST, Experiment 2). In Experiment 3, mice were divided into three groups based on hormonal status (male, female-estrous, and female-nonestrous) and injected with either 1 g/kg EtOH or equivolume saline 14 minutes prior to behavioral assessment on the TST.

Experiments 1 and 2 demonstrated a direct relationship between β-E levels and immobility. There were also sex differences in behavior in these tests, with males displaying more immobility than females. A main effect of genotype in Experiment 3 replicated findings in Experiments 1 and 2. There was also an effect of EtOH (increasing immobility) and a significant interaction reflecting a particularly robust effect of the drug in mice with low β-E. In addition, there were interactions between β-E, EtOH effects, and hormonal status.

These findings support the contention that β-E moderates behavioral responses to stressful stimuli and suggest a role for this peptide in coping behavior. Furthermore, the effects of EtOH on the response to stress may be mediated by β-E. Sex differences in this influence may contribute to sex differences in disease susceptibility and expression.

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Friday, April 9, 2010

Perceived Social Support from Counselors and Client Sobriety During Aftercare: A Pilot Study of Emotional and Functional Support

In an empirical study, we asked whether client perceptions of the degree of emotional support and functional support provided by counselors during treatment are related to client sobriety during the aftercare phase of clients' recovery.

Functional support was assessed using a scale that tapped the degree to which clients felt encouraged to become actively involved in six key components of Alcoholics Anonymous.

Results derived from 76 former inpatients showed associations linking abstinence at the point of 2-year follow-up to counselor provision of both kinds of social support in early-stage recovery.

Mental health service providers may be able to strengthen their client's long-term ability to maintain sobriety by providing them, in the short term, with high levels of esteem support and abstinence-focused “instrumental” support.

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Maternal alcohol use and medically indicated vs. spontaneous preterm birth outcomes: a population-based study

The aetiology of preterm birth remains poorly understood.

The purpose of this study is to investigate if an association exists between prenatal alcohol consumption and preterm birth and to determine if such an association differs by subcategories of preterm birth.

Prenatal alcohol use was associated with
elevated risk for preterm birth. The strength of association was more prominent for spontaneous preterm delivery {adjusted odds ratio (AOR) [95% confidence interval (CI)] = 1.34 (1.28–1.41)} than for medically indicated preterm birth [AOR (95% CI) = 1.16 (1.05–1.28)].

The overall risk for drinking-related spontaneous
preterm birth increased with incremental rise in the number of drinks consumed per week.

Prenatal alcohol use is a risk factor for preterm delivery, and especially for spontaneous preterm birth.

These findings
enhance our understanding of the aetiology of preterm birth and could be utilized in the development of appropriate prevention strategies that will assist in decreasing perinatal mortality and morbidity associated with preterm delivery.

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A Pair of Dopamine Neurons Target the D1-Like Dopamine Receptor DopR in the Central Complex to Promote Ethanol-Stimulated Locomotion in Drosophila Dop

Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known.

We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure.

A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR.

Elimination of
DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body.

These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol.

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Long-Term Effects of the Strong African American Families Program on Youths' Alcohol Use

This report extends earlier accounts by addressing the effects of the Strong African American Families (SAAF) program across 65 months.

Two hypotheses were tested: (a) Rural African American youths randomly assigned to participate in SAAF would demonstrate lower rates of alcohol use than would control youths more than 5 years later, and (b) SAAF's effects on deterring the onset of alcohol use in early adolescence would carry forward to mediate the program's long-term effects.

SAAF participants increased their alcohol use at a slower rate than did adolescents in the control condition across the follow-up assessments. At the 65-month assessment, SAAF participants reported having drunk alcohol half as often as did youths in the control group. Consistent with the second hypothesis, SAAF's effects on deterring initiation carried forward to account for its effects on alcohol use across time.

Training in protective parenting processes and self-regulatory skills during preadolescence may contribute to a self-sustaining trajectory of disinterest in and avoidance of alcohol use during adolescence when peers begin to model and sanction it.

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Thursday, April 8, 2010

Service to Others in Sobriety (SOS)

Alcoholics Anonymous participation has been measured in addiction research, but few validated tools distinguish components of this multidimensional construct.

This study provides psychometric findings for the scale Service to Others in Sobriety, a brief assessment of AA-related helping.

Data are derived from a sample of treatment-seeking alcoholics, and Service to Others in Sobriety validity and response stability is reported by using a test-retest sample.

Findings demonstrated adequate psychometric properties of the Service to Others in Sobriety, including convergent validity, internal consistency (alpha = 0.92) and test-rest reliability (r = 0.94).

The Service to Others in Sobriety is a valid measure of AA-related helping activities pertinent to the daily lives of recovering alcoholics.

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Behavioral Differences Between C57BL/6J × FVB/NJ and C57BL/6J × NZB/B1NJ F1 Hybrid Mice: Relation to Control of Ethanol Intake

C57BL/6J × FVB/NJ F1 (B6 × FVB) mice consume more alcohol than C57BL/6J × NZB/B1NJ F1 (B6 × NZB) mice and this high alcohol consumption is stable after abstinence whereas B6 × NZB show reduced consumption, thus providing models of Sustained Alcohol Preference (SAP) and Reduced Alcohol Preference (RAP).

In female hybrids, we assessed several behavioral responses to define behaviors which might predict SAP and RAP.

B6 × FVB exhibited less severe ethanol-induced conditioned taste aversion and were less sensitive to ethanol-induced loss of righting reflex than B6 × NZB.

Both hybrids demonstrated ethanol-induced place preference and a low ethanol withdrawal severity.

We found that these hybrids differ in their sensitivity to the aversive and sedative, but not rewarding, effects of ethanol.

Results of elevated plus maze, mirror chamber, and locomotor tests reveal B6 × FVB mice are less anxious and more active than B6 × NZB mice.

Results obtained offer insights about factors that determine SAP and RAP in these new genetic models of alcohol consumption.

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High ethanol dose during early adolescence induces locomotor activation and increases subsequent ethanol intake during late adolescence

Adolescent initiation of ethanol consumption is associated with subsequent heightened probability of ethanol use disorders.

The present study examined the relationship between motivational sensitivity to ethanol initiation in adolescent rats and later ethanol intake.

Experiment 1 determined that ethanol induces locomotor activation shortly after administration but not if tested at a later post-administration interval. In Experiment 2, adolescent rats were assessed for ethanol-induced locomotor activation on postnatal Day 28.

These animals were then evaluated for ethanol-mediated conditioned taste aversion and underwent a 16-day-long ethanol intake protocol.

Ethanol-mediated aversive effects were unrelated to ethanol locomotor stimulation or subsequent ethanol consumption patterns. Ethanol intake during late adolescence was greatest in animals initiated to ethanol earliest at postnatal Day 28. Females that were more sensitive to ethanol's locomotor-activating effects showed a transient increase in ethanol self-administration. Blood ethanol concentrations during initiation were not related to ethanol-induced locomotor activation.

Adolescent rats appeared sensitive to the locomotor-stimulatory effects of ethanol. Even brief ethanol exposure during adolescence may promote later ethanol intake.

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The effects of cannabis and alcohol on simulated arterial driving: Influences of driving experience and task demand

This study compared the effects of three doses of cannabis and alcohol (placebo, low and high doses), both alone and in combination, on the driving performance of young, novice drivers and more experienced drivers.

Alcohol was administered as ethanol (95%) mixed with orange juice in doses of approximately 0, 0.4 and 0.6 g/kg. Cannabis was administered by inhalation of smoke from pre-rolled cannabis cigarettes (supplied by the National Institute of Drug Abuse, USA). Active cigarettes contained 19 mg delta-9-THC.

Using a counterbalanced design, the simulated driving performance of 25 experienced and 22 inexperienced drivers was tested under the nine different drug conditions in an arterial driving environment during which workload was varied through the drive characteristics as well as through the inclusion of a secondary task.

High levels of cannabis generally induced greater impairment than lower levels, while alcohol at the doses used had few effects and did not produce synergistic effects when combined with cannabis.

Both cannabis and alcohol were associated with increases in speed and lateral position variability, high dose cannabis was associated with decreased mean speed, increased mean and variability in headways, and longer reaction time, while in contrast alcohol was associated with a slight increase in mean speed.

Given the limitations of the study, it is of great interest to further explore the qualitative impairments in driving performance associated with cannabis and alcohol separately and how these impairments may manifest in terms of crash characteristics.

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Does alcohol consumption reinforce mental problems in adolescence?

The main goal of this article is to provide empirical evidence that alcohol consumption reinforces the occurrence of mental illnesses even at early stages of life.

We control probit estimations for unobserved heterogeneity and endogeneity. We have drawn a sample of 73,024 individuals from the Spanish National Survey on Drug Use in the School Population (2000, 2002, 2004).

Our results confirm our theoretical hypothesis that alcohol consumption has a negative influence on youth state of health, but the magnitude of this influence is lower once we controlled for unobserved heterogeneity and endogeneity.

Gender differences reveal that females are more likely to have been prescribed tranquilizers, and they are also more vulnerable to alcohol consumption than males are.

As effective instruments to improve young people well-being, we suggest increasing the price of liquors and a greater parental control in how their children spend their available budget, and more important, in how they feel.

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Fruit and Vegetable Intake and Overall Cancer Risk in the European Prospective Investigation Into Cancer and Nutrition (EPIC)

It is widely believed that cancer can be prevented by high intake of fruits and vegetables. However, inconsistent results from many studies have not been able to conclusively establish an inverse association between fruit and vegetable intake and overall cancer risk.

We conducted a prospective analysis of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to assess relationships between intake of total fruits, total vegetables, and total fruits and vegetables combined and cancer risk during 1992–2000. Detailed information on the dietary habit and lifestyle variables of the cohort was obtained. Cancer incidence and mortality data were ascertained, and hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox regression models. Analyses were also conducted for cancers associated with tobacco and alcohol after stratification for tobacco smoking and alcohol drinking.

Of the initial 142 605 men and 335 873 women included in the study, 9604 men and 21 000 women were identified with cancer after a median follow-up of 8.7 years. The crude cancer incidence rates were 7.9 per 1000 person-years in men and 7.1 per 1000 person-years in women.

Associations between reduced cancer risk and increased intake of total fruits and vegetables combined and total vegetables for the entire cohort were similar (200 g/d increased intake of fruits and vegetables combined, HR = 0.97, 95% CI = 0.96 to 0.99; 100 g/d increased intake of total vegetables, HR = 0.98, 95% CI = 0.97 to 0.99); intake of fruits showed a weaker inverse association (100 g/d increased intake of total fruits, HR = 0.99, 95% CI = 0.98 to 1.00).

The reduced risk of cancer associated with high vegetable intake was restricted to women (HR = 0.98, 95% CI = 0.97 to 0.99).

Stratification by alcohol intake suggested a stronger reduction in risk in heavy drinkers and was confined to cancers caused by smoking and alcohol.

A very small inverse association between intake of total fruits and vegetables and cancer risk was observed in this study. Given the small magnitude of the observed associations, caution should be applied in their interpretation.

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Identification of a FOXA-dependent enhancer of human alcohol dehydrogenase 4 (ADH4)

Human alcohol dehydrogenase 4 (ADH4
) is one of the key enzymes involved in the metabolism of alcohol. ADH4 is highly expressed in the liver, and previous studies have revealed several cis-acting elements in the proximal promoter region.

In this study we have identified a distal upstream enhancer, 4E, of

In HepG2 human hepatoma cells, 4E increased the activity of an
ADH4 basal promoter by 50-fold. 4E was cell-specific, as no enhancer activity was detected in a human lung cell line, H1299.

We have narrowed the enhancer activity to a 565 bp region and have identified multiple liver-enriched transcription factor binding sites in the region. By electrophoretic mobility shift assays, we confirmed binding of FOXA proteins to these sites.

Site-directed mutagenesis studies demonstrated that sites 1 and 4 have the biggest effect on enhancer function, and mutations in multiple sites have multiplicative effects.

We also studied the effects of three variations in the minimal enhancer region. Two variations had a significant effect on enhancer activity, decreasing the activity to 0.6-fold, while one had small but significant effect.

The differences in the functional activity in different haplotypes suggest that this region could play an important role in the risk for alcoholism

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The Spread of Alcohol Consumption Behavior in a Large Social Network - Video News Release

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The Spread of Alcohol Consumption Behavior in a Large Social Network

Alcohol consumption has important health-related consequences and numerous biological and social determinants.

To explore quantitatively whether alcohol consumption behavior spreads from person to person in a large social network of friends, coworkers, siblings, spouses, and neighbors, followed for 32 years.

Clusters of drinkers and abstainers were present in the network at all time points, and the clusters extended to 3 degrees of separation. These clusters were not only due to selective formation of social ties among drinkers but also seem to reflect interpersonal influence.

Changes in the alcohol consumption behavior of a person's social network had a statistically significant effect on that person's subsequent alcohol consumption behavior. The behaviors of immediate neighbors and coworkers were not significantly associated with a person's drinking behavior, but the behavior of relatives and friends was.

Network phenomena seem to influence alcohol consumption behavior. This has implications for clinical and public health interventions and further supports group-level interventions to reduce problematic drinking.

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Wednesday, April 7, 2010

Functional NPY Variation as a Factor in Stress Resilience and Alcohol Consumption in Rhesus Macaques

Neuropeptide Y (NPY) counters stress and is involved in neuroadaptations that drive escalated alcohol drinking in rodents. In humans, low NPY expression predicts amygdala response and emotional reactivity. Genetic variation that affects the NPY system could moderate stress resilience and susceptibility to alcohol dependence.

To determine whether functional NPY variation influences behavioral adaptation to stress and alcohol consumption in a nonhuman primate model of early adversity (peer rearing).

The G allele altered binding of regulatory proteins in all nuclear extracts tested, and –1002 T > G resulted in lower levels of NPY expression in the amygdala. Macaques exposed to adversity had lower cerebrospinal fluid NPY levels and exhibited higher levels of arousal during stress, but only as a function of the G allele. We also found that stress-exposed G allele carriers consumed more alcohol and exhibited an escalation in intake over cycles of alcohol availability and deprivation.

Our results suggest a role for NPY promoter variation in the susceptibility to alcohol use disorders and point to NPY as a candidate for examining gene x environment interactions in humans.

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Gender, hospitalization and mental disorders among homeless people compared with the general population in Stockholm

The aim was to study the prevalence of mental disorders among homeless men and women admitted for inpatient treatment in hospitals.

Hospital care utilization of homeless people, 1364 en and 340 women, was compared with a control group consisting of 3750 men and 1250 women from the general population, 1996–2002.

Homeless women ran a higher risk for mental disorders than women in the population [risk ratio (RR) 20.88]; their risk was also higher than the risk for homeless men (RR 1.20). Younger homeless women had the highest risk (RR 2.17). Alcohol use disorders were equally common among homeless men and women, but women had more drug use disorders (RR 1.32). Women had higher risk of schizophrenia (RR 2.79), and personality disorders (RR 2.73). When adjustment was made for substance use disorders, no increased risk for mental disorder was found in the homeless group.

The elevated risk for mental disorders among the homeless was mainly related to substance use problems. Younger homeless women had the highest risk of mental disorder.

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Impact of the "Peers as Family" Dormitory Wing-Based Intervention on College Student Alcohol Use and Its Secondhand Effects

An intervention to reduce college alcohol use and secondhand effects was tested. Freshmen dormitory wings at a large Mid-Atlantic public university were assigned to single-gender (SG) or mixed-gender (MG) Information-Motivation-Behavior (IMB) workshops implemented during the first weeks of school, or a control condition. Students were surveyed before school began and at 2- and 6-month follow-up.

Analyses indicated that, among males, the adjusted mean weekly alcohol use was lower in the SG than the control condition (1.89 vs. 2.72,
p = .041).

Among females, the adjusted mean weekly alcohol use was lower in the MG than the SG (1.60 vs. 2.44,
p = .021) and control condition (1.60 vs. 2.27, p = .056).

Further research should identify underlying mechanisms for effective alcohol behavior change among male and female wing-mates.

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Prenatal alcohol exposure and autistic spectrum disorders—a population-based prospective study of 80 552 children and their mothers

To examine whether maternal alcohol intake, including binge drinking (intake ≥5 drinks, equivalent to 60 g pure ethanol on a single occasion), is associated with autistic spectrum disorders (ASD) and infantile autism.

Participants were 80 552 children and their mothers enrolled in the Danish National Birth Cohort from 1996 to 2002. Alcohol consumption was obtained by self-report during pregnancy. Information on ASD was obtained from the Danish Central Psychiatry Register. Follow-up ended on February 2008. Data were analysed by means of Cox regression.

In total, 401 children were diagnosed with ASD and 157 with infantile autism. No association was found between average alcohol consumption and ASD or infantile autism, respectively. For binge drinking, the adjusted hazard ratio (HR) for ASD was 0.72 [95% confidence interval (CI): 0.53–0.97] among women who binge drank once during pregnancy compared with women who did not binge drink. The corresponding HR for infantile autism was 0.61 (95% CI: 0.36–1.02). However, the HR for ASD was 0.84 (95% CI: 0.51–1.36) when restricting the analysis to first-time pregnancies conceived within 6 months of trying. No estimate was made for infantile autism due to low number of cases. No association was seen for more than one binge episode and for the timing of binge drinking.

Our findings do not support that a low prenatal alcohol exposure increases the risk of ASD or infantile autism. The lower risk for women who binge drank once during pregnancy is most likely non-causal.

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51st Annual Drosophila Research Conference

Abstract #146 PLATFORMS: Neural Physiology and Behavior

Our understanding of the genetic aetiology of alcoholism continues to be overshadowed by what is a debilitating individual and familial

A low level of response to alcohol is a characteristic trait associated with heavy drinking and alcohol problems. Therefore, to discover
novel genes that regulate the level of response to ethanol we conducted an unbiased genetic screen for ethanol sensitivity mutants in Drosophila.

We identify the arouser (aru) gene and demonstrate its opposing function in neurons and a subpopulation of glia in the regulation of ethanol
sensitivity. Whereas aru functions in neurons to promote ethanol resistance, in glia it functions to inhibit ethanol resistance.

We show that aru acts
upstream of, and in opposition to, the function of Akt in regulating ethanol sensitivity in both neurons and glia. Simultaneous manipulations of aru or Akt in neurons and glia show neurons suppress glial mediated effects on ethanol sensitivity. Within neurons aru also mediates Erk/rolled induced increases in ethanol resistance, suggesting Akt and Erk act antagonistically in regulating ethanol sensitivity.

Taken together, this data
reveals that ethanol sensitivity in the fly is regulated by both neurons and glia, and by the integration of two major growth factor signaling pathways.

Mark Eddison1, Douglas Guarnieri2, Che Hsiung Liu3, Kevin Moffat3, Ulrike Heberlein1. 1) UCSF, Dept of Anatomy, Box2822, San Francisco, CA 94158; 2) Dept. of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT 06510; 3) Dept of Biological Sciences, University of Warwick, Coventry CV4 7AL, U. K.

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Cerebral white matter recovery in abstinent alcoholics—a multimodality magnetic resonance study

Most previous neuroimaging studies of alcohol-induced brain injury and recovery thereof during abstinence from alcohol used a single imaging modality. They have demonstrated widespread microstructural, macrostructural or metabolite abnormalities that were partially reversible with abstinence, with the cigarette smoking potentially modulating these processes.

The goals of
this study were to evaluate white matter injury and recovery thereof, simultaneously with diffusion tensor imaging, magnetic resonance imaging and spectroscopy in the same cohort; and to evaluate the relationships between outcome measures of similar regions.

We scanned 16 non-smoking and 20 smoking alcohol-dependent
individuals at 1 week of abstinence from alcohol and 22 non-smoking light drinkers using a 1.5 T magnetic resonance scanner. Ten non-smoking alcohol-dependent individuals and 11 smoking alcohol-dependent individuals were re-scanned at 1 month of abstinence. All regional diffusion tensor imaging, magnetic resonance imaging and spectroscopic outcome measures were calculated over comparable volumes of frontal, temporal, parietal and occipital white matter.

At 1
week of abstinence and relative to non-smoking light drinkers, non-smoking alcohol-dependent individuals had higher mean diffusivity in frontal, temporal and parietal white matter (all P <> whereas smoking alcohol-dependent individuals had elevated mean diffusivity only in frontal white matter (P = 0.03).

alcohol-dependent individuals demonstrated lower concentrations of N-acetyl-aspartate (a marker of neuronal viability) in frontal white matter (P = 0.03), whereas non-smoking alcohol-dependent individuals had lower N-acetyl-aspartate in parietal white matter (P = 0.05).

These abnormalities were not accompanied by detectable white matter atrophy. However, the patterns of white matter recovery were different between non-smoking alcohol-dependent individuals and smoking alcohol-dependent individuals. In non-smoking alcohol-dependent individuals, the increase in fractional anisotropy of temporal white matter (P = 0.003) was accompanied by a pattern of decreases mean diffusivity in all regions over 1 month of abstinence; no corresponding changes were observed in smoking alcohol-dependent individuals. In contrast, a pattern of white matter volume increase in frontal and temporal lobes was apparent in smoking alcohol-dependent individuals but not in non-smoking alcohol-dependent individuals. These results were not accompanied by significant changes in metabolite concentrations.

there were no consistent patterns of association between measures obtained with different imaging modalities, either cross-sectionally or longitudinally.

These data demonstrate significant white
matter improvements with abstinence from alcohol, reflected either as microstructural recovery or volumetric increases that depend on the smoking status of the participants.

We believe
our results to be important, as they demonstrate that use of a single imaging modality provides an incomplete picture of neurobiological processes associated with alcohol-induced brain injury and recovery thereof that may even lead to improper interpretation of results.

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ACMD calls for further action on alcohol

The Advisory Council for the Misuse of Drugs (ACMD) has called for further attention on alcohol harm in a recently published report. Pathways to Problems 2009 reviews progress on its previous recommendations report in 2006, commending government action in many areas but also calling for further progress, particularly in relation to young people's exposure to alcohol. . . . . .

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Sensory Processing and Adaptive Behavior Deficits of Children Across the Fetal Alcohol Spectrum Disorder Continuum

Prenatal alcohol exposure can have detrimental effects on a child's development of adaptive behaviors necessary for success in the areas of academic achievement, socialization, and self-care. Sensory processing abilities have been found to affect a child's ability to successfully perform adaptive behaviors.

The current study explored whether significant differences in sensory processing abilities, adaptive behavior, and neurocognitive functioning are observed between children diagnosed with partial Fetal Alcohol Syndrome (pFAS), Alcohol-Related Neurodevelopmental Disorder (ARND), or children who were prenatally exposed to alcohol (PEA), but did not meet criteria for an FASD diagnosis. The influence of IQ on adaptive behavior as well as further exploration of the relationship between sensory processing and adaptive behavior deficits among these children was also examined.

A secondary analysis was conducted on some of the Short Sensory Profile (SSP) scores, Adaptive Behavior Assessment System—Second Edition (ABAS-II) scores, and Wechsler Intelligence Scale—Fourth Edition/Wechsler Preschool and Primary Scale of Intelligence—Third Edition (WISC- IV/WPPSI—III) scores of 46 children between 3 and 14 years of age with pFAS, ARND, or who were PEA.

Greater sensory processing deficits were found in children with a diagnosis of pFAS and ARND compared to those in the PEA group. Children with an ARND diagnosis scored significantly worse on measures of adaptive behavior than the PEA group. Children with pFAS scored significantly lower than children with ARND or PEA on perceptual/performance IQ. No correlation was found between IQ scores and adaptive behaviors across the FASD diagnostic categories. A significant positive correlation was found between SSP and ABAS-II scores.

Regardless of the diagnosis received under the FASD umbrella, functional difficulties that could not be observed using traditional measures of intelligence were found, supporting guidelines that a broad range of standardized assessments be included when screening children for FASD.

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Drinking Against Unpleasant Emotions: Possible Outcome of Early Onset of Alcohol Use?

Recent animal and human studies indicate that the exposure to alcohol during early adolescence increases the risk for heavy alcohol use in response to stress. The purpose of this study was to examine whether this effect may be the consequence of a higher susceptibility to develop "drinking to cope" motives among early initiators.

Data from 320 participants were collected as part of the Mannheim Study of Children at Risk, an ongoing epidemiological cohort study. Structured interviews at age 15 and 19 were used to assess age at first alcohol experience and drunkenness. The young adults completed questionnaires to obtain information about the occurrence of stressful life events during the past 4 years and current drinking habits. In addition, alcohol use under conditions of negative states was assessed with the Inventory of Drinking Situations.

The probability of young adults' alcohol use in situations characterized by unpleasant emotions was significantly increased the earlier they had initiated the use of alcohol, even when controlling for current drinking habits and stressful life events. Similar results were obtained for the age at first drunkenness.

The findings strengthen the hypothesis that alcohol experiences during early adolescence facilitate drinking to regulate negative affect as an adverse coping strategy which may represent the starting point of a vicious circle comprising drinking to relieve stress and increased stress as a consequence of drinking.

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Structural and Functional Effects of Developmental Exposure to Ethanol on the Zebrafish Heart

Fetal alcohol exposure during development results in a host of cardiac abnormalities including atrial and ventricular septal defects, teratology of Fallot, d-transposition of the great arteries, truncus arteriosus communis, and aortico-pulmonary window. The mechanisms behind these ethanol-induced deficits are unknown.

The purpose of this study was to determine whether the zebrafish, a simple model in which heart development and the sequence of gene expression is well elucidated and comparable to that in higher vertebrates, is sensitive to developmental exposure of pharmacologically relevant concentrations of ethanol.

Zebrafish eggs of the AB strain were raised in egg water or in 0.5% (v/v) ethanol solution for either 54 hpf (hours postfertilization) or 72 hpf. Heart pathology and volumes were evaluated on the latter group at 5 dpf (days postfertilization) on tissue sections from fixed larvae embedded in glycolmethacrylate. Heart rates were determined in embryos of 54 hpf and larvae of 5 dpf. The functional maturity of the heart's conducting system was measured by determining the response of ethanol-treated and control embryos and larvae to the adrenergic agonist, isoproterenol, and the cholinergic agonist, carbachol.

Ethanol-induced alterations occurred in heart morphology and heart volume. A developmental lag in the isoproterenol response and the absence of carbachol-mediated bradycardia were also observed following ethanol treatment.

These results show that exposure of the zebrafish to ethanol during development results in structural and functional changes in the heart that mimic malformations that occur in patients with fetal alcohol syndrome (FAS).

These findings promote the zebrafish heart as a future model for investigating the mechanisms responsible for ethanol's adverse effects on vertebrate heart development.

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Preference Conditioning in Healthy Individuals: Correlates With Hazardous Drinking

Conditioned reward is a classic measure of drug-induced brain changes in animal models of addiction. The process can be examined in humans using the Conditioned Pattern Preference (CPP) task, in which participants associate nonverbal cues with reward but demonstrate low awareness of this conditioning. Previously, we reported that alcohol intoxication does not affect CPP acquisition in humans, but our data indicated that prior drug use may impact conditioning scores.

To test this possibility, the current study examined the relationship between self-reported alcohol use and preference conditioning in the CPP task. Working memory was assessed during conditioning by asking participants to count the cues that appeared at each location on a computer screen. Participants (69 female and 23 male undergraduate students) completed the Alcohol Use Disorders Identification Test (AUDIT) and the Rutgers Alcohol Problem Index (RAPI) as measures of hazardous drinking.

Self-reported hazardous drinking was significantly correlated with preference conditioning in that individuals who scored higher on these scales exhibited an increased preference for the reward-paired cues. In contrast, hazardous drinking did not affect working memory errors on the CPP task.

These findings support evidence that repeated drug use sensitizes neural pathways mediating conditioned reward and point to a neurocognitive disposition linking substance misuse and responses to reward-paired stimuli. The relationship between hazardous drinking and conditioned reward is independent of changes in cognitive function, such as working memory.

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Role of Wake-Promoting Basal Forebrain and Adenosinergic Mechanisms in Sleep-Promoting Effects of Ethanol

Ethanol intake has significant impact on sleep. However, the cellular substrates responsible for sleep promotion following ethanol intake are unknown. The purine nucleoside, adenosine, is responsible for mediating many neuronal and behavioral responses to ethanol. Studies performed in cell cultures suggest that ethanol inhibits equilibrative nucleoside transporter 1 to block the reuptake of adenosine resulting in increased extracellular adenosine. Adenosine also has a pivotal role in sleep regulation. Adenosine acts via A1 receptor to inhibit the wake-promoting neurons of the basal forebrain (BF) resulting in the promotion of sleep. Is ethanol-induced sleep associated with the inhibition of the BF wake-promoting neurons? Do adenosinergic mechanisms in the BF have a role in sleep-promoting effects of ethanol?

To address these questions, we performed 3 experiments in Sprague–Dawley rats. First, we verified the effect of ethanol on sleep promotion. Second, we evaluated the effect of ethanol on c-Fos expression (a marker of neuronal activation) in the BF wake-promoting neurons and third we monitored the effects of A1 receptor blockade in the BF on ethanol-induced sleep.

Significant increase in non-rapid eye movement (NREM) sleep with a concomitant decrease in wakefulness was observed during the first 12 hours postethanol. REM sleep remained unaffected. Ethanol administration caused a significant decrease in the number of BF wake-promoting neurons with c-Fos immunoreactivity. Bilateral microinjections of a selective A1R receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine into the BF significantly attenuated sleep-promoting effects of ethanol.

These results suggest that the inhibition of BF wake-promoting neurons by adenosinergic mechanism may be responsible for the sleep promoting effects of ethanol. We believe our study is the first to investigate the cellular mechanisms responsible for the somnogenic effects of ethanol.

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Single-Nucleotide Polymorphisms in Corticotropin Releasing Hormone Receptor 1 Gene (CRHR1) Are Associated With Quantitative Trait of Event-Related Pot

Endophenotypes reflect more proximal effects of genes than diagnostic categories, hence providing a more powerful strategy in searching for genes involved in complex psychiatric disorders.

There is strong evidence suggesting the P3 amplitude of the event-related potential (ERP) as an endophenotype for the risk of alcoholism and other disinhibitory disorders.

Recent studies demonstrated a crucial role of corticotropin releasing hormone receptor 1 (CRHR1) in the environmental stress response and ethanol self-administration in animal models.

The aim of the present study was to test the potential associations between single-nucleotide polymorphisms (SNPs) in the CRHR1 gene and the quantitative trait, P3 amplitude during the processing of visual target signals in an oddball paradigm, as well as alcohol dependence diagnosis.

We analyzed a sample from the Collaborative Study on the Genetics of Alcoholism (COGA) comprising 1049 Caucasian subjects from 209 families (including 472 alcohol-dependent individuals). Quantitative transmission disequilibrium test (QTDT) and family-based association test (FBAT) were used to test the association, and false discovery rate (FDR) was applied to correct for multiple comparisons.

Significant associations were found between the P3 amplitude and alcohol dependence with multiple SNPs in the CRHR1 gene.

Our results suggest that CRHR1 may be involved in modulating the P3 component of the ERP during information processing and in vulnerability to alcoholism.

These findings underscore the utility of electrophysiology and the endophenotype approach in the genetic study of psychiatric disorders.

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Genetic and Environmental Influences on Ethanol Consumption: Perspectives From Preclinical Research

Alcohol use disorders (abuse and dependence, AUD) are multifactorial phenomena, depending on the interplay of environmental and genetic variables.

This review describes current developments in animal research that may help (a) develop gene therapies for the treatment of alcoholism, (b) understand the permissive role of stress on ethanol intake, and (c) elucidate why exposure to ethanol early in life is associated with a greater risk of AUD.

The polymorphisms found in liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) affect the elimination of ethanol and the susceptibility to ethanol intake. A highly active ADH protects against alcoholism, an effect related to a presteady state burst in arterial acetaldehyde. Social stressors, such as repeated early maternal separation or social defeat, exert a permissive effect on ethanol intake, perhaps by altering the normal development of the hypothalamic-pituitary-adrenal axis. Ethanol exposure during gestation, infancy, or adolescence increases the likelihood of AUD later in life. Early perception of ethanol's positive and negative (anti-anxiety) reinforcing effects may play a role in this phenomenon.

The review underscores the advantages of using preclinical animal models of AUD and highlights points of intersection between the topics to help design a more integrated approach for the study of alcohol-related problems.

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Clinical (Nonforensic) Application of Ethyl Glucuronide Measurement: Are We Ready?

Ethyl glucuronide (EtG) and ethyl sulfate (EtS) are minor metabolites of ethanol. Multiple studies have documented that, depending upon the amount of alcohol consumed, they can be measured in biological fluids for hours to days after the parent compound can no longer be detected.

Testing for the presence of EtG, in a manner analogous to urinary drug abuse screening, has largely been restricted to forensic and law enforcement situations.

Despite a real need for an objective and possibly quantitative marker of ethanol exposure for use in conjunction with outpatient clinical trials and treatment programs, measurement of these metabolites has seen only limited clinical application.

The barriers to more extensive clinical use of EtG/EtS testing, particularly misleading assay results that can occur as a consequence of inadvertent exposure to nonbeverage ethanol-containing substances, are reviewed and put into perspective.

Additional information needed to develop guidelines for optimal clinical utilization of EtG/EtS measurements is discussed.

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Alcohol Biomarkers in Applied Settings: Recent Advances and Future Research Opportunities

During the past decade, advances have been made in the identification, development, and application of alcohol biomarkers. This is important because of the unique functions that alcohol biomarkers can serve in various applied settings. To carry out these functions, biomarkers must display several features including validity, reliability, adequacy of temporal window of assessment, reasonable cost, and transportability.

During the past two decades, several traditional alcohol biomarkers have been studied in multiple human studies. Meanwhile, several new, promising biomarkers, including various alcohol metabolites and alcohol biosensors, are being explored in human studies.

In addition, researchers have explored using biomarkers in combination and using biomarkers in combination with self-reports, resulting in increased sensitivity with little sacrifice in specificity.

Despite these advances, more research is needed to validate biomarkers, especially the new ones, in humans. Moreover, recent advances in high-throughput technologies for genomics, proteomics, and metabolomics offer unique opportunities to discover novel biomarkers, while additional research is needed to perfect newly developed alcohol sensors.

Development of more accurate biomarkers will help practicing clinicians to more effectively screen and monitor individuals who suffer from alcohol use disorders.

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Future Prospects for Biomarkers of Alcohol Consumption and Alcohol-Induced Disorders

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis, treatment, and research of alcohol abuse and alcoholism.

Successful development of a biomarker that allows for accurate assessment of alcohol intake and drinking patterns would not only be a major advance in clinical care but also a valuable research tool.

A number of advances have been made in testing the validity of proposed biomarkers as well as in identifying potential new biomarkers through systems biology approaches.

This commentary will examine the definition of a biomarker of heavy drinking, the types of potential biomarkers, the steps in biomarker development, the current state of biomarker development, and critical obstacles for the field.

The challenges in developing biomarkers for alcohol treatment and research are similar to those found in other fields. However, the alcohol research field must reach a competitive level of rigor and organization.

We recommend that NIAAA consider taking a leadership role in organizing investigators in the field and providing a common set of clinical specimens for biomarker validation studies.

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Advancing Alcohol Biomarkers Research

Biomarkers to detect past alcohol use and identify alcohol-related diseases have long been pursued as important tools for research into alcohol use disorders as well as for clinical and treatment applications and other settings.

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) sponsored a workshop titled "Workshop on Biomarkers for Alcohol-Induced Disorders" in June 2008. The intent of this workshop was to review and discuss recent progress in the development and implementation of biomarkers for alcohol use and alcohol-related disorders with a goal to formulate a set of recommendations to use to stimulate and advance research progress in this critical area of alcoholism research.

Presentations at this workshop reviewed the current status of alcohol biomarkers, providing a summary of the history of biomarkers and the major goals of alcohol biomarker research. Moreover, presentations provided a comprehensive overview of the current status of several well-recognized biomarkers of alcohol use, a summary of recent studies to characterize novel biomarkers and their validation, along with perspectives and experiences from other NIH institutes and from other federal agencies and industry, related to regulatory issues.

Following these presentations, a panel discussion focused on a set of issues presented by the organizers of this workshop. These discussion points addressed: (i) issues related to strategies to be adopted to stimulate biomarker discovery and application, (ii) the relevance of animal studies in biomarker development and the status of biomarkers in basic science studies, and (iii) issues related to the opportunities for clinical and commercial applications.

This article summarizes these perspectives and highlights topics that constituted the basis for recommendations to enhance alcohol biomarker research.

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The Relationship Between Self-Reported Drinking and BAC Level in Emergency Room Injury Cases: Is it a Straight Line?

While the validity of self-reported consumption based on blood alcohol concentration (BAC) has been found to be high in emergency room (ER) samples, little research exists on the estimated number of drinks consumed given a BAC level. Such data would be useful in establishing a dose–response relationship between drinking and risk (e.g., of injury) in those studies for which the number of drinks consumed is not available but BAC is.

Several methods were used to estimate the number of drinks consumed in the 6 hours prior to injury based on BAC obtained at the time of ER admission of n = 1,953 patients who self-reported any drinking 6 hours prior to their injury and who arrived to the ER within 6 hours of the event, from the merged Emergency Room Collaborative Alcohol Analysis Project (ERCAAP) and the World Health Organization Collaborative Study on Alcohol and Injury across 16 countries.

The relationship between self-reported consumption and averaged BAC within each consumption level appeared to be fairly linear up to about 7 drinks and a BAC of approximately 100 mg/dl. Above about 7 reported drinks, BAC appeared to have no relationship with drinking, possibly representing longer consumption periods than only the 6 hours before injury for those reporting higher quantities consumed. Both the volume estimate from the bivariate BAC to self-report relationship as well as from a Widmark calculation using BAC and time from last drink to arrival to the ER indicated a somewhat weak relationship to actual number of self-reported drinks.

Future studies may benefit from investigating the factors suspected to be driving the weak relationships between these measures, including the actual time over which the reported alcohol was consumed and pattern of drinking over the consumption period.

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ENT1 Regulates Ethanol-Sensitive EAAT2 Expression and Function in Astrocytes

Equilibrative nucleoside transporter 1 (ENT1) and excitatory amino acid transporter 2 (EAAT2) are predominantly expressed in astrocytes where they are thought to regulate synaptic adenosine and glutamate levels. Because mice lacking ENT1 display increased glutamate levels in the ventral striatum, we investigated whether ENT1 regulates the expression and function of EAAT2 in astrocytes, which could contribute to altered glutamate levels in the striatum.

We examined the effect of ENT1 inhibition and overexpression on the expression of EAAT2 using quantitative real-time PCR and measured glutamate uptake activity in cultured astrocytes. We also examined the effect of 0 to 200 mM ethanol doses for 0 to 24 hours of ethanol exposure on EAAT2 expression and glutamate uptake activity. We further examined the effect of ENT1 knockdown by a specific siRNA on ethanol-induced EAAT2 expression.

An ENT1-specific antagonist and siRNA treatments significantly reduced both EAAT2 expression and glutamate uptake activity while ENT1 overexpression up-regulated EAAT2 mRNA expression. Interestingly, 100 or 200 mM ethanol exposure increased EAAT2 mRNA expression as well as glutamate uptake activity. Moreover, we found that ENT1 knockdown inhibited the ethanol-induced EAAT2 up-regulation.

Our results suggest that ENT1 regulates glutamate uptake activity by altering EAAT2 expression and function, which might be implicated in ethanol intoxication and preference.

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Monday, April 5, 2010

Recruitment of Additional Brain Regions to Accomplish Simple Motor Tasks in Chronic Alcohol-Dependent Patients

Chronic alcohol-dependent patients (ALC) exhibit neurocognitive impairments attributed to alcohol-induced fronto-cerebellar damage. Deficits are typically found in complex task performance, whereas simple tasks may not be significantly compromised, perhaps because of little understood compensatory changes.

We compared finger tapping with either hand at externally paced (EP) or maximal self-paced (SP) rates and concomitant brain activation in ten pairs of right-hand dominant, age-, and gender-matched, severe, uncomplicated ALC and normal controls (NC)

Mean tapping rates were not significantly different in ALC and NC for either task, but SP tapping variances were greater in ALC for both hands. SP tapping was more rapid with dominant hand (DH) than non-dominant hand (NDH) for both groups. EP and SP tapping with the non-dominant hand demonstrated significantly more activation in ALC than NC in the pre and postcentral gyri, inferior frontal gyrus, inferior parietal lobule, and the middle temporal gyrus. Areas activated only by ALC (not at all by NC) during NDH tapping included the inferior frontal gyrus, middle temporal gyrus, and postcentral gyrus. There were no significant group activation differences with DH tapping. No brain regions activated more in NC than ALC. SP tapping in contrast to EP activated fronto-cerebellar networks in NC, including postcentral gyrus, anterior cingulate, and the anterior lobe and vermis of the cerebellum, but only parietal precuneus in ALC.

These findings with NDH finger tapping support previous reports of neurocognitive inefficiencies in ALC. Inferior frontal activation with EP in ALC, but not in NC, suggests engagement of regions needed for planning, organization, and impulse regulation; greater contralateral parietal lobe activation with SP in ALC may reflect right hemispheric impairments in visuospatial performance.

Contrasting brain activation during SP and EP suggests that ALC may not have enlisted a fronto-cerebellar network as did NC but rather employed a higher order planning mode by recruiting parietal lobe functions to attain normal mean finger tapping rates.

Elucidation of the compensatory neural mechanisms that allow near normal performance by ALC on simple tasks can inform functional rehabilitation of patients in recovery.

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