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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Request Reprint E-Mail: lindells@mail.nih.gov

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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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Request Reprint E-Mail: u.beijer@telia.com
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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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Request Reprint E-Mail: boekeloo@umd.edu
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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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Request Reprint E-Mail: jst@niph.dk

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AKT REGULATES A DIAMETRIC RESPONSE TO ALCOHOL BY NEURONS AND GLIA

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 problem.

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).

Smoking 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.

Finally, 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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Request Reprint E-Mail: stefan.gazdzinski@uj.edu.pl
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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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Request Reprint E-Mail: sabrina.agnihotri@gmail.com

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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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Request Reprint E-Mail: manfred.laucht@zi-mannheim.de

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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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Request Reprint E-Mail: cadlugos@buffalo.edu

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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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Request Reprint E-Mail: olmstead@queensu.ca

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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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Request Reprint E-Mail: thakkarmm@health.missouri.edu

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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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Request Reprint E-Mail: bernice.porjesz@downstate.edu

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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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Request Reprint E-Mail: rpautassi@gmail.com
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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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Request Reprint E-Mail: peter.jatlow@yale.edu
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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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Request Reprint E-Mail: rlitten@mail.nih.gov
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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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Request Reprint E-Mail: wfreeman@psu.edu
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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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Request Reprint E-Mail: Jan.Hoek@jefferson.edu
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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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Request Reprint E-Mail: jbond@arg.org

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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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Request Reprint E-Mail: choids@mayo.edu

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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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Request Reprint E-Mail: peter.martin@vanderbilt.edu

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Effects of Naltrexone Treatment for Alcohol-Related Disorders on Healthcare Costs in an Insured Population

To determine the impact of treatment with oral naltrexone on healthcare costs in patients with alcohol-related disorders.

Naltrexone patients (n = 1,138; 62% men; mean age 45 ± 11 years) had significantly higher total healthcare expenditures in the pre-index period than either of the control groups. In the postindex period, naltrexone patients had a significantly smaller increase than alcohol controls in total alcohol-related expenditures. Total nonalcohol-related expenditures also increased significantly less for the naltrexone group than for the alcohol control group.

Multivariate analyses showed that naltrexone treatment significantly reduced alcohol-related, nonalcohol-related, and total healthcare costs relative to alcohol controls.

Although prior to treatment patients with alcohol-related disorders had higher healthcare costs, treatment with oral naltrexone was associated with reductions both in alcohol-related and nonalcohol-related healthcare costs.

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Request Reprint E-Mail: kranzler@psychiatry.uchc.edu

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The Remarkably High Prevalence of Epilepsy and Seizure History in Fetal Alcohol Spectrum Disorders

Fetal alcohol spectrum disorder (FASD) is the umbrella term that describes the range of adverse developmental outcomes that may occur in the offspring of mothers who drink alcohol during pregnancy. FASD is associated with several comorbidities including epilepsy.

The objective of the study was to evaluate the prevalence of epilepsy or a history of seizures in subjects with FASD and the contribution of relevant risk factors.

Twenty-five (5.9%) individuals in the study population had a confirmed diagnosis of epilepsy, and 50 (11.8%) had at least one documented seizure episode, yielding an overall prevalence of 17.7% in this population. Importantly, a history of epilepsy or seizures was not different across the three diagnostic subgroups.

In those subjects with available maternal drinking histories, first trimester exposure or drinking throughout all three trimesters were the predominant forms of fetal exposure. None of the other risk factors were associated with a greater prevalence of epilepsy or seizures.

There is a remarkably high prevalence of epilepsy/seizures in the FASD population.

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Request Rerprint E-Mail: carlen@uhnresearch.ca

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Prospective Follow-Up of Empirically Derived Alcohol Dependence Subtypes in Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditi

We have previously reported on an empirical classification of Alcohol Dependence (AD) individuals into subtypes using nationally representative general population data from the 2001 to 2002 Wave 1 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and latent class analysis.

Our results suggested a typology of 5 separate clusters based upon age of onset of AD, multigenerational familial AD, rates of antisocial personality disorder (ASPD), endorsement of specific AD and Alcohol Abuse (AA) criteria, and the presence of comorbid mood, anxiety, and substance use disorders (SUD). In this report, we focus on the clinical follow-up of these cluster members in Wave 2 of the NESARC (2004 to 2005).

The mean interval between NESARC Wave 1 and NESARC Wave 2 interviews was 36.6 (SD = 2.6) months. For these analyses, we utilized a Wave 2 NESARC sample that was comprised of a total of 1,172 individuals who were initially ascertained as having past-year AD at NESARC Wave 1 and initially subtyped into one of 5 groupings using latent class analysis.

We identified these subtypes as:

(i) Young Adult, characterized by very early age of onset, minimal family history, and low rates of psychiatric and SUD comorbidity;

(ii) Functional, characterized by older age of onset, higher psychosocial functioning, minimal family history, and low rates of psychiatric and SUD comorbidity;

(iii) Intermediate Familial, characterized by older age of onset, significant familial AD, and elevated comorbid rates of mood disorders SUD;

(iv) Young Antisocial, characterized by early age of onset and elevated rates of ASPD, significant familial AD, and elevated rates of comorbid mood disorders and SUD;

(v) Chronic Severe, characterized by later onset, elevated rates of ASPD, significant familial AD, and elevated rates of comorbid mood disorders and SUD.

In this report, we examine Wave 2 recovery status, health status, alcohol consumption behavior, and treatment episodes based upon these subtypes.

Significantly fewer of the Young Adult and Functional subtypes continued to meet full DSM-IV AD criteria in Wave 2 than did the Intermediate Familial, the Young Antisocial, and the Chronic Severe subtypes. However, we did not find that treatment seeking for alcohol problems increased over Wave 1 reports. In Wave 2, Young Antisocial and Chronic Severe subtypes had highest rates of past-year treatment seeking.

In terms of health status, the Intermediate Familial, the Young Antisocial, and the Chronic Severe subtypes had significantly worse mental health scores than the Young Adult and Functional subtypes.

For physical health status, the Functional, Intermediate Familial, Young Antisocial, and the Chronic Severe subtypes had significantly worse scores than the Young Adult subtype.

In terms of alcohol consumption behavior, the Young Adult, Functional, and Young Antisocial subtypes significantly reduced their risk drinking days between Wave 1 and Wave 2, whereas the Intermediate Familial and the Chronic Severe subtypes did not.

The results suggest that the empirical AD typology predicts differential clinical outcomes 3 years later. Persistence of full AD, treatment seeking, and worse mental health status were associated most strongly with those subtypes manifesting the greatest degree of psychiatric comorbidity. Reductions in alcohol consumption behavior and good physical health status were seen among the 2 younger subtypes.

Overall, the least prevalent subtype, the Chronic Severe, showed the greatest stability in the manifestations of AD, despite having the highest rate of treatment seeking.

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The Relationship Between Genetic Influences on Alcohol Dependence and on Patterns of Alcohol Consumption

Genetic factors impact substantially both on alcohol consumption (AC) and on the risk for alcohol dependence (AD). However, we know little about the degree to which measures of AC index the genetic risk for AD.

We found evidence for different genetic structure in the sexes. In women, genetic risk for AD and for the four measures of AC was entirely shared. In men, the AC measures captured 85% of the genetic risk for AD. In women, the genetic relationship with AD was strongest for drunk frequency and in men for both drunk frequency and regular quantity.

In a population-based sample of twins, four relatively simple measures of AC obtained for the time of lifetime heaviest drinking were able to capture all (in women) or a very large proportion (in men) of the genetic risk for the complex multi-dimensional construct of AD.

If replicated, these results have practical implications for studies aiming to assess genetic risk for AD.

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Request Reprint E-Mail: kendler@vcu.edu

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Sensation Seeking in Long-Term Abstinent Alcoholics, Treatment-Naïve Active Alcoholics, and Nonalcoholic Controls

Elevated sensation seeking is associated with the development of alcohol dependence; however, it has not been studied in long-term abstinent alcoholics.

In the current study, we examine sensation seeking in middle-aged long-term abstinent alcoholics (LTAA) and in younger actively drinking treatment-naïve alcoholics (TxN).

The 2 NAC samples did not differ on the SSS, allowing the 2 NAC samples to be combined into a single control group (NAC = 118), and the LTAA and TxN samples to be directly compared without concern for cohort effects. LTAA did not differ from NAC on the SSS; however, the TxN group had higher SSS scores compared with NAC on all subscales except Boredom Susceptibility. Sensation seeking was comparably associated with lower socialization in each group.

The results suggest that either sensation seeking normalizes with long-term abstinence or that relatively normal levels of sensation seeking predict the ability to achieve long-term abstinence.

In either case, the results have important implications for our understanding of long-term abstinence.

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Request Reprint E-Mail: george@nbresearch.com

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Childhood Sleep Problems, Response Inhibition, and Alcohol and Drug Outcomes in Adolescence and Young Adulthood

To our knowledge, no prospective studies examine the relationships among childhood sleep problems, adolescent executive functioning, and substance outcomes (i.e., substance use and substance-related problems).

In this study, we examined whether childhood sleep problems predicted adolescent sleep problems and response inhibition. We also tested whether adolescent sleep problems and poor response inhibition mediated the relationship between childhood sleep problems and substance (alcohol and drug) outcomes in young adulthood.

When compared to their counterparts, those with trouble sleeping in childhood were twice as likely to have the same problem in adolescence. Childhood overtiredness predicted poor response inhibition in adolescence. Persistent trouble sleeping from childhood to adolescence and response inhibition in adolescence mediated the relationship between childhood sleep problems and drug outcomes in young adulthood, whereas overtiredness in childhood directly predicted alcohol use outcomes and alcohol-related problems in young adulthood.

This is the first study showing a long-term relationship between childhood sleep measures and subsequent alcohol and drug outcomes. The developmental and clinical implications of these findings were discussed.

Prevention and intervention programs may want to consider the role of sleep problems and response inhibition on substance use and abuse.

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Request Reprint E-Mail: zuckerra@umich.edu.

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Women's experiences of caring when in treatment for alcohol dependency

Despite the fact of increased levels of alcohol dependency in women and gender differences in how the disease affects men and women, the research on alcohol dependency continues to have a dominating perspective on men. The meaning of the phenomenon of caring in formal care for women with alcohol dependency is not well known. Thus, formal caregivers may find it problematic to know what is caring for women with alcohol dependency.

The aim of the study was to illuminate the meaning of caring in formal care for women with alcohol dependency, as narrated by the women.

The study was performed using a phenomenological-hermeneutic method. Data were collected in ten in-depth interviews with alcohol-dependent women. The themes presented are availability, being a patient and being a learner.

The findings reveal that the women with alcohol dependency receiving a mandate from formal care, experience the relation between them and their caregiver as a mutual transformation. Within the mutual transformation, the participants experienced being respected as a responsible human being which renders possibilities for the women with alcohol dependency to continue in formal care even when the struggle against the disease became hard.

Continual meetings with the caregiver allowed the women to gain structure in their daily life as well as allowing the women and their caregivers to develop mutual transformation, which both relieved the women's suffering and increased their experience of being involved in the care process.

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Request Reprint E-Mail: anna.thurang@sll.se
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The Future of AA, NA and Other Recovery Mutual Aid Organizations

Addiction recovery mutual aid societies have played a significant role in the resolution of severe alcohol and other drug problems throughout the world and have exerted a particularly profound influence on the professional treatment of addiction (Humphreys, 2004; White, 2004).

The purpose of this article is to discuss five current contextual influences that will influence the future of Alcoholics Anonymous (AA), Narcotics Anonymous (NA), and other addiction recovery mutual aid groups.

First, we will place that future within its historical context. . . . . . .

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Education, Alcohol Use and Abuse among Young Adults in Britain

In this article we explore the relationship between education and alcohol consumption.

We examine whether the probability of abusing alcohol differs across educational groups.

We use data from the British Cohort Study, a longitudinal study of one week's birth in Britain in 1970. We analysed data collected at age 34 (in 2004) and complement it with information gathered at previous sweeps. Measures of alcohol abuse include alcohol consumption above NHS guidelines, daily alcohol consumption and problem drinking.

We found that higher educational attainment is associated with increased odds of daily alcohol consumption and problem drinking. The relationship is stronger for females than males. Individuals who achieved high educational test scores in childhood are at a significantly higher risk of abusing alcohol across all dimensions.

Our results also suggest that educational qualifications and academic performance are associated with the probability of belonging to different typologies of alcohol consumers among women while this association is not present in the case of educational qualifications and is very weak in the case of academic performance among males.

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Request Reprint E-Mail: f.borgonovi@lse.ac.uk

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Ethanol and Cognition: Indirect Effects, Neurotoxicity and Neuroprotection: A Review

Ethanol affects cognition in a number of ways. Indirect effects include intoxication, withdrawal, brain trauma, central nervous system infection, hypoglycemia, hepatic failure, and Marchiafava-Bignami disease. Nutritional deficiency can cause pellagra and Wernicke-Korsakoff disorder.

Additionally, ethanol is a direct neurotoxin and in sufficient dosage can cause lasting dementia. However, ethanol also has neuroprotectant properties and in low-to-moderate dosage reduces the risk of dementia, including Alzheimer type.

In fetuses ethanol is teratogenic, and whether there exists a safe dose during pregnancy is uncertain and controversial.

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Alcohol Levels Do Not Accurately Predict Physical or Mental Impairment in Ethanol-Tolerant Subjects: Relevance to Emergency Medicine and Dram Shop

The human body and the central nervous system can develop tremendous tolerance to ethanol. Mental and physical dysfunctions from ethanol, in an alcohol-tolerant individual, do not consistently correlate with ethanol levels traditionally used to define intoxication, or even lethality, in a nontolerant subject.

Attempting to relate observed signs of alcohol intoxication or impairment, or to evaluate sobriety, by quantifying blood alcohol levels can be misleading, if not impossible.

We report a case demonstrating the disconnect between alcohol levels and generally assigned parameters of intoxication and impairment. In this case, an alcohol-tolerant man, with a serum ethanol level of 515 mg/dl, appeared neurologically intact and cognitively normal. This individual was without objective signs of impairment or intoxication by repeated evaluations by experienced emergency physicians.

In alcohol-tolerant individuals, blood alcohol levels cannot always be predicted by and do not necessarily correlate with outward appearance, overt signs of intoxication, or physical examination.

This phenomenon must be acknowledged when analyzing medical decision making in the emergency department or when evaluating the ability of bartenders and party hosts to identify intoxication in dram shop cases.

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Request Reprint E-Mail: JRoberts@mercyhealth.org
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Unnatural deaths in reindeer-herding Sami families in Sweden, 1961–2001

Unnatural deaths among Indigenous populations, including the Swedish Sami, occur more often than among the general population.

To find prevention strategies, we explored the circumstances of the unnatural deaths of members of reindeer-herding Sami families.

Transport-related deaths and suicides were the most common unnatural deaths among Swedish reindeer-herding Sami family members. Suicides contributed to 23% of all deaths, road traffic accidents to 16%, and snowmobile fatalities to 11%. The accidents generally reflected an “outdoor lifestyle” and the working conditions were characterized by the use of off-road vehicles such as snowmobiles.

Half of the number of victims tested positive for alcohol and alcohol abuse was documented in 15% of all victims. The results indicate that alcohol is an important factor in preventing unnatural deaths among reindeer-herding Sami, together with increased safety of both on-road and off-road transportation.

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Alcohol Intake and Risk of Coronary Heart Disease in Younger, Middle-Aged, and Older Adults

Light to moderate alcohol consumption is associated with a reduced risk of coronary heart disease. This protective effect of alcohol, however, may be confined to middle-aged or older individuals.

This study examined whether the beneficial effect of alcohol on coronary heart disease depends on age

In this pooled analysis of 8 prospective studies from North America and Europe including 192 067 women and 74 919 men free of cardiovascular diseases, diabetes, and cancers at baseline, average daily alcohol intake was assessed at baseline with a food frequency or diet history questionnaire.

An inverse association between alcohol and risk of coronary heart disease was observed in all age groups; hazard ratios among moderately drinking men (5.0 to 29.9 g/d) 39 to 50, 50 to 59, and 60 years of age were 0.58 (95% confidence interval [CI], 0.36 to 0.93), 0.72 (95% CI, 0.60 to 0.86), and 0.85 (95% CI, 0.75 to 0.97) compared with abstainers.

However, the analyses indicated a smaller incidence rate difference between abstainers and moderate consumers in younger adults (incidence rate difference, 45 per 100 000; 90% CI, 8 to 84) than in middle-aged (incidence rate difference, 64 per 100 000; 90% CI, 24 to 102) and older (incidence rate difference, 89 per 100 000; 90% CI, 44 to 140) adults. Similar results were observed in women.

Alcohol is also associated with a decreased risk of coronary heart disease in younger adults; however, the absolute risk was small compared with middle-aged and older adults.

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Request Reprint E-Mail: jst@niph.dk

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Possible new ways in the pharmacological treatment of bipolar disorder and comorbid alcoholism

About half of all bipolar patients have an alcohol abuse problem at some point of their lifetime. However, only one randomized, controlled trial of pharmacotherapy (valproate) in this patient population was published as of 2006.

Therefore, we reviewed clinical trials in this indication of the last four years (using mood stabilizers, atypical antipsychotics, and other drugs). Priority was given to randomized trials, comparing drugs with placebo or active comparator. Published studies were found through systematic database search (PubMed, Scirus, EMBASE, Cochrane Library, Science Direct).

In these last four years, the only randomized, clinically relevant study in bipolar patients with comorbid alcoholism is that of Brown and colleagues (2008) showing that quetiapine therapy decreased depressive symptoms in the early weeks of use, without modifying alcohol use.

Several other open-label trials have been generally positive and support the efficacy and tolerability of agents from different classes in this patient population.

Valproate efficacy to reduce excessive alcohol consumption in bipolar patients was confirmed and new controlled studies revealed its therapeutic benefit to prevent relapse in newly abstinent alcoholics and to improve alcohol hallucinosis.

Topiramate deserves to be investigated in bipolar patients with comorbid alcoholism since this compound effectively improves physical health and quality of life of alcohol-dependent individuals.

In conclusion, randomized, controlled research is still needed to provide guidelines for possible use of valproate and other agents in patients with a dual diagnosis of bipolar disorder and substance abuse or dependence.

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Request Reprint E-Mail: Jazorin@Ap-Hm.Fr
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