Chronic ethanol exposure leads to divergent control of dopaminergic synapses in distinct target regions
Alcohol Article in Press, Corrected Proof 20 March 2008


Neuroadaptations following chronic exposure to alcohol are hypothesized to play important roles in alcohol-induced alterations in behavior, in particular increased alcohol drinking and anxiety like behavior.

Dopaminergic signaling plays a key role in reward-related behavior, with evidence suggesting it undergoes modification following exposure to drugs of abuse. A large literature indicates an involvement of dopaminergic signaling in response to alcohol.

Using a chronic inhalation model of ethanol exposure in mice, we have begun to investigate the effects of alcohol intake on dopaminergic signaling by examining protein levels of tyrosine hydroxylase and the dopamine transporter, as well as monoamine metabolites in three different target fields of three different dopaminergic nuclei.

We have focused on the dorsal lateral bed nucleus of the stria terminalis because of the reported involvement of dorsal lateral bed nucleus of the stria terminalis dopamine in ethanol intake, and the nucleus accumbens and dorsal striatum because of their dense dopaminergic innervation.

After either a chronic intermittent exposure or continuous exposure regimen, mice were killed, and tissue punches collected from the dorsal lateral bed nucleus of the stria terminalis, nucleus accumbens, and striatum for Western analysis.

Strikingly, we found divergent regulation of tyrosine hydroxylase and dopamine transporter protein levels across these three regions that was dependent upon the means of exposure.

These data thus suggest that distinct populations of catecholamine neurons may be differentially regulated by ethanol, and that ethanol and withdrawal interact to produce differential adaptations in these systems.

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Request Reprint E-Mail: thomas.kash@vanderbilt.edu
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Dissociable effects of ethanol consumption during the light and dark phase in adolescent and adult Wistar rats
Alcohol Volume 42, Issue 2, March 2008, Pages 83-89

In adolescence, high levels of drinking over short episodes (binge drinking) is commonly seen in a proportion of the population. Because adolescence is an important neurodevelopmental period, the effects of binge drinking on brain and behavior has become a significant health concern.

However, robust animal models of binge drinking in rats are still being developed and therefore further efforts are needed to optimize paradigms for inducing maximal self-administration of alcohol.

In the present experiment, 1-h limited-access self-administration sessions were instituted to model excessive drinking behavior in adolescent and adult Wistar rats. In addition to age, the involvement of sex and phase within the light/dark cycle (i.e., drinking in the light or dark) on sweetened 5% ethanol intake were also evaluated over 14 limited-access sessions using a between-groups design.

The results of the experiment showed that over 14 limited-access sessions, sweetened ethanol intake (g/kg) was significantly higher for adolescents compared to adults. Females were also found to drink more sweetened ethanol as compared to males.

Additionally, drinking in the light produced a robust increase in sweetened ethanol intake (g/kg) in adolescents, as compared to adults during the light phase and as compared to both adolescent and adult rats drinking in the dark. Furthermore, the increase in ethanol consumption observed in adolescents drinking during the light phase was dissociable from sweetened solution intake patterns.

These results identify that age, sex, and time of day all significantly influence consumption of sweetened ethanol in Wistar rats.

Knowledge of these parameters should be useful for future experiments attempting to evaluate the effects of self-administered ethanol exposure in adult and adolescent rats.

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Request Reprint E-Mail: bwalker@scripps.edu
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Association study of dopamine D2, D4 receptor gene, GABAA receptor β subunit gene, serotonin transporter gene polymorphism with children of alcoholics in Korea: A preliminary study
Alcohol Volume 42, Issue 2, March 2008, Pages 77-81

The studies on the genetic risk factors of the children of alcoholics (COAs) are still in an early stage. The A1 allele of the dopamine receptor 2 gene (DRD2) may be associated with positive alcohol expectancy of the COAs. In addition, several researchers reported that the COAs might be associated with the GABA_A receptor β3 subunit gene (GABRB3) and serotonin transporter gene (5-HTTLPR).

In this study, we investigated the association of the polymorphism of the DRD2, Dopamine D4 receptor gene (DRD4), GABRB3, 5-HTTLPR with the COAs.

Twenty-two COAs and 23 age and sex-matched control children were included for the genetic study (children of nonAlcoholics; nonCOAs). All COAs aged 6–18 were recruited and selected from family of alcoholic patients in Alcohol Clinic of the University hospital.

The genotyping of the DRD2, DRD4, GABRB3, 5-HTTLPR was carried out. We used the Chi-square method for evaluating the association of genetic polymorphic allelic status with the COAs.

The frequency of the A1+ allele at DRD2 in the COAs was significantly higher than nonCOAs. Significant association between the genotype at DRD4 and the COAs was found.

The G1− alleles of the GABRB3 in COAs were significantly higher than nonCOAs.

However, no association of the polymorphic alleles of the 5-HTTLPR with the COAs was found.

We found that the children of alcoholics had a significantly increased number of risk alleles of candidate genes of alcohol drinking expectancy. Despite of several limitations, this study provides some preliminary information on the risk and protective factors associated with the COAs, which can be used as a foundation for prevention and intervention of future psychopathology.

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Request Reprint E-Mail: kacheon@dreamwiz.com or

kacheon@kd.ac.kr
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Are treated alcoholics representative of the entire population with alcohol use disorders? A magnetic resonance study of brain injury
Alcohol Volume 42, Issue 2, March 2008, Pages 67-76

Almost all we know about neurobiological brain injury in alcohol use disorders has been derived from convenience samples of treated alcoholics. Recent research has demonstrated more comorbid conditions, poorer psychosocial functioning, and higher dependence levels in treated alcoholics than in their treatment-naive counterparts.

Thus, it is not clear whether neuroimaging results from convenience samples of treated alcoholics can be generalized to the entire population with alcohol use disorders.

We compared 35 treated alcoholics at 1 week of abstinence (ALC) and 32 treatment-naive heavy drinkers (HD) on regional brain volumes and metabolite concentrations obtained by in vivo magnetic resonance at 1.5 Tesla to evaluate for potential group differences. Then, we evaluated whether comorbid cigarette smoking and common demographic and clinical variables mediated any existing neurobiological group differences.

ALC demonstrated smaller lobar gray matter volumes and thalami than HD, exacerbated by chronic smoking. Furthermore, concentrations of N-acetyl-aspartate (an accepted marker of neuronal viability), choline-containing metabolites (involved in membrane turnover), and myo-inositol (a putative marker of glial cells and osmolyte) were lower in multiple brain regions of ALC compared to HD. The lower N-acetyl-aspartate concentrations in white matter of ALC versus HD were explained by average number of drinks per month over the year preceding study. However, the other group differences were not explained by common drinking, demographic, and clinical variables (used as covariates at the same time) or by excluding participants with comorbid mood disorders.

Taken together, this suggests that the degree of brain atrophy, as well as neuronal and membrane injury in clinical samples of alcoholics cannot be generalized to the much larger population with alcohol use disorders that does not seek treatment.

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Request Reprint E-Mail: stefan.gazdzinski@ucsf.edu
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Advertisers and alcohol industry prepare for inquiry showdown



Julian Lee
March 20, 2008

THE marketing industry's peak bodies have unveiled how they plan to meet the biggest threat to the industry since the fast food advertising debate of recent years.

As a senate inquiry into alcohol advertising begins, the industry will mount a two-pronged approach, with the advertising agency peak body concentrating its efforts on talking up self-regulation for the $12 billion a year alcohol industry.

In its submission to a senate inquiry, its counterpart for advertisers will seek to attack claims that there is a link between advertising and excessive consumption of alcohol.
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Editorial - Pushing 'Alcopops'
A bad bill in Annapolis would promote teen drinking.
March 21, 2008 pg. A16

LIKE THE fruity-flavored, alcohol-laced beverages that appeal so much to the under-21 set, a bill making its way through the Maryland legislature this week may seem non-threatening but could lure more illegal novice drinkers to dangerous habits. As it is, teens are getting their hands on "alcopops" -- also called "flavored malt beverages" and "malternatives" -- thanks in large part to a current practice, which treats these drinks for sales distribution and tax purposes as beer rather than distilled spirits. The result is lower prices and easier access for underage drinkers.

That's the way the industry likes it, but Maryland Attorney General Douglas F. Gansler has issued an opinion that, under state law, these drinks are distilled spirits and should be taxed and distributed as such. The action has prompted an end-around by state lawmakers cozy with the beer and liquor industry, including Democratic Senate President Thomas V. Mike Miller Jr. (D-Calvert). Their bill, passed by the Senate yesterday and now before the House, would formally define the drinks as beer, which would keep the drinks teen-friendly.

The proposed definition is blatantly dishonest. Findings by the U.S. Alcohol and Tobacco Tax and Trade Bureau show that most of the alcohol in these flavored drinks is derived from distilled spirits. As for taxes, which generally get passed along to the buyers, the Maryland tax rate for beer is 9 cents a gallon; for distilled spirits it's $1.50 a gallon. For a six-pack, the beer tax is a nickel, but the distilled spirits tax would be 84 cents. It's well established that entry-level drinkers are sensitive to such price differences. Then there's the loss of tax revenue in a bad year for the state budget.

Ease of access to these sweet but loaded beverages -- which are cutely disguised as cola, lemonade, iced tea or fruit punch -- also depends on how they are classified. Distilled spirits can be sold only by holders of retail liquor licenses. When classified as beer, the alcohol-flavored beverages can be sold by any location holding a beer license -- convenience stores and other spots more likely to be frequented by young people. True, underage consumption of any alcohol is already against the law, and, yes, kids can find older buyers to get any drink. But why increase the ease of access? Maryland lawmakers should reflect on that question before the final vote on this bad bill.

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By Now, "Harm Reduction" Harms Both Science and the Public Health
Clinical Pharmacology & Therapeutics (2008); 83, 4, 513–514

There are few terms used in both the science and the public policy of drug abuse and addiction that are fuzzier or more controversial than "harm reduction." The most straightforward use of the term refers to public health or social policy strategies designed to reduce the negative consequences of drug abuse and addiction to an individual, his or her family, or the broader community in which addicted individuals live. For other people, however, "harm reduction" has over time become distorted into a euphemism for policies and programs that could increase drug use, such as legalization or decriminalization of drug activities. This ambiguity, coupled with the paucity of clear data on the effectiveness of most harm-reduction strategies, has led many people to hold—often with almost religious fervor—very strong positions for or against "harm reduction," however it is conceptualized. That ideology has prevented important science from being done and prevented the implementation of potentially successful social and public health strategies. This suggests that the term should be expunged from the jargon of our fields. It has taken on ideological meanings that get in the way of dealing successfully with serious drug problems around the world.
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Addiction: Damping down alcohol dependence
Nature Reviews Neuroscience 9, 251 (April 2008)

Stress is a well-known trigger of alcoholism relapse in susceptible individuals, and it has been suggested that neural systems that mediate behavioural stress responses could be targets for pharmacotherapy of alcoholism. Now, Heilig and colleagues demonstrate that antagonism of neurokinin 1 receptor (NK1R; also known as TACR1) — a receptor that is highly expressed in brain areas involved in stress responses and brain reward — effectively reduces alcohol cravings.

Previous studies have shown that genetic deletion or pharmacological blockade of NK1R dampens behavioural responses to psychological stressors. So, the authors proposed that modulation of NK1R signalling may also influence stress- and reward-related processes that are important for excessive alcohol use and relapse.
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WINE in MODERATION
A Pan-European Programme Promoting Responsibility
and Moderation in Wine Consumption




The WINE in MODERATION Programme is an initiative of the European wine sector aimed at promoting moderation and responsibility in wine consumption and contributing towards preventing excessive consumption and misuse of alcoholic beverages in Europe.

Download Background Document (PDF)
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Disordered eating and substance use in high-school students: Results from the Youth Risk Behavior Surveillance System
International Journal of Eating Disorders Early View 17 Mar 2008

To examine the association between disordered eating (fasting, diet product use, and vomiting or laxative use) and use of 10 substances (cigarettes, alcohol, marijuana, cocaine, inhalants, heroin, methamphetamines, ecstasy, steroids, and hallucinogens) in a nationally representative adolescent sample.

Disordered eating was significantly associated with the use of each substance. Using effect size estimates that take base rates into consideration, for female students, associations between substance use and disordered eating were weak for all but three forms of substance use: current smoking, binge drinking, and inhalants. Among male students, strong (marijuana, steroids, and inhalants) or moderate effects (all other substances) were observed. Future research needs to focus on inhalant use and methamphetamine use in males. Increased medical attention should be directed toward adolescents who practice disordered eating behaviors because they are also at elevated risk for using cigarettes, alcohol, inhalants, methamphetamines, and steroids Read Full Abstract Request Reprint E-Mail: rstriegel@wesleyan.edu ________________________________________________________________

Men’s and Women’s Patterns of Substance Use Around Pregnancy
Birth Issues in Perinatal Care Volume 35 Issue 1 Page 50-59, March 2008

Little is known about men’s patterns of substance use around their partner’s pregnancy, despite evidence from studies of pregnant women that men’s substance use may reduce women’s ability to desist from substance use during pregnancy, increase the probability that women will return to use postpartum, and increase the risk of adverse child outcomes.

The purpose of this study was to describe the association between pregnancy or partner’s pregnancy and month-by-month patterns of binge drinking, daily smoking, and marijuana use among young men and women.

Births during the calendar period were reported by 131 women and 77 men. Hierarchical generalized linear modeling analyses showed that men’s rates of binge drinking and marijuana use were unaffected by their partner’s pregnancy. Pregnancy decreased the probability of substance use among women, but use returned to prepregnancy levels within 2 years postpartum.

Men’s substance use was not affected by their partner’s pregnancy. Pregnancy decreased the probability of substance use among women, but substantial proportions of women users of cigarettes and marijuana used these substances during pregnancy. Many of the women who desisted from substance use while pregnant returned to use after their child was born.

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Drinking and Driving 2007: Prevalence, Decision Making and Attitudes
- Scottish Government - March 2007

• While much progress has been made in the field of drink-driving, road safety statistics and conviction statistics show that the area still requires further work. In 2007, the Scottish Government commissioned research from TNS System Three into this issue. This followed on from research on this topic carried out on 2001 ( NFO, 2001) and was designed to allow comparisons to be made over time.

• Both quantitative research, in the form of a survey of a representative sample of 1034 current drivers in Scotland, and qualitative research, in the form of 6 focus groups and 6 depth interviews with those who admitted to driving after consuming alcohol, was undertaken. The purpose of the research was to measure prevalence of driving after consuming alcohol, both within and above the legal limit, and to provide insight into attitudes to drink-driving and the thought process behind the decision either to do or not to do so.

Read Full Report (PDF)
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The DASIS Report: Employment Status and Substance Abuse Treatment Admissions, 2006

Highlights

• Of the substance abuse treatment admissions aged 18 to 64 reported to SAMHSA's Treatment Episode Data Set (TEDS), 31% in 2006 were employed full- or part-time at the time of admission, 33% were unemployed, and 36% were not in the labor force (i.e., not employed and not looking for work).

• Full time employed substance abuse treatment admissions were more likely to report alcohol as their primary substance of abuse (58%) than substance abuse treatment admissions who were homemakers (35%), unemployed (39%), labor force dropouts (39%), or disabled (46%).

• Substance abuse treatment admissions who were labor force dropouts were more than twice as likely as admissions who were employed full time to report daily use of their primary substance in the past month (56% vs. 26%).

Substance abuse treatment admissions who were homemakers (59%) or who were employed full time (57%) were more likely to report entering treatment for the first time than admissions who were unemployed (40%), labor force dropouts (47%), or disabled (41%)

Read Full Report (PDF)
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Leading questions
Jean Collingwood, chief executive, Drinkaware Trust

• Interview by Alexandra Topping
• Wednesday March 19 2008

What is the aim of the Drinkaware Trust?

To positively change the UK drinking culture and minimise and reduce alcohol-related harm.

What challenges do you face?

The biggest challenge is getting Britain's drinkers to take stock of their own attitudes toward alcohol, encouraging them to be more personally responsible. This needs a large-scale cultural shift because of the unique relationship Britain has with alcohol, which for centuries has been a major part of our lives and part of our societal DNA.

Why is the work of the trust important?

The long-term harm caused by alcohol misuse is significant, so our work in educating consumers is very important.

Do you think there is an alcohol crisis?

Sensationalism in the media is not helpful, simply because most of the public would struggle to identify what constitutes binge drinking. Young people, in particular, seem to be associated with the "crisis" we are facing, but we must recognise that peer pressure and social anxiety are key drivers in their approach to alcohol, which can sometimes mean drinking to excess.

How can we tackle the problem in Britain?

Education is key to creating an open and honest dialogue. This will encourage people to think and talk - and to play a responsible role in our society.

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Read Full Interview

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Development of an outcome prediction measure for alcoholism therapy by multimodal monitoring of treatment processes
Journal of Psychiatric Research Article in Press, Corrected Proof 14 Mar 2008

Outcome prediction in alcoholism therapy is of major sociopolitical and economic significance. Instruments based on psychotherapeutic processes are lacking.

Therefore, treatment processes of 64 chronic alcohol dependent patients have been investigated at three time-points, t₁ (week 3), t₂ (month 6), and t₃ (month 12) during the first year of a comprehensive outpatient treatment program, guaranteeing strictly controlled alcohol abstinence.

Main focus of the study was the prediction of cumulative abstinence probability over a follow-up period of up to 4 years based on these treatment processes.

One hundred and seventy-five video recordings of therapy sessions were analyzed with the behavior observational system VAMP (Video-Assisted Monitoring of Psychotherapeutic Processes in Chronic Psychiatric Disease). Patients’ self-rating of treatment processes was measured with questionnaires for self-efficacy, abstinence confidence, self-consciousness and stress coping. Prediction of cumulative abstinence probability was determined with Cox regression analysis.

By integrating the observer rated process variables with the highest predictive validity, the composite score TOPPS (Therapy Orientation by Process Prediction Score) was constructed. It includes the process variables experience of resources, abstinence self-efficacy, implicit craving, relapse alertness, relapse risk, disease concept, dysfunctional therapeutic engagement, and dysfunctional problem solving of current problems.

Whereas patients’ self-rating of treatment processes was insufficiently predictive, the TOPPS strongly predicted four-year abstinence probability at any of the 3 time-points (p < 0.001). The results suggest to validate the item combination described in the TOPPS in addiction therapy as a treatment guideline of individual relapse prevention strategies.

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Request Reprint E-Mail: ehrenreich@em.mpg.de
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Phenomic, Convergent Functional Genomic, and biomarker studies in a stress-reactive genetic animal model of bipolar disorder and co-morbid alcoholism
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Volume 147B, Issue 2 , Pages 134 - 166

We had previously identified the clock gene D-box binding protein (Dbp) as a potential candidate gene for bipolar disorder and for alcoholism, using a Convergent Functional Genomics (CFG) approach.

Here we report that mice with a homozygous deletion of DBP have lower locomotor activity, blunted responses to stimulants, and gain less weight over time.

In response to a chronic stress paradigm, these mice exhibit a diametric switch in these phenotypes. DBP knockout mice are also activated by sleep deprivation, similar to bipolar patients, and that activation is prevented by treatment with the mood stabilizer drug valproate.

Moreover, these mice show increased alcohol intake following exposure to stress.

Microarray studies of brain and blood reveal a pattern of gene expression changes that may explain the observed phenotypes. CFG analysis of the gene expression changes identified a series of novel candidate genes and blood biomarkers for bipolar disorder, alcoholism, and stress reactivity.

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Request Reprint E-Mail: anicules@iupui.edu
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Low level of harm avoidance is associated with serotonin transporter functional haplotype in alcohol-dependent individuals.
Psychiatric Genetics. 18(2):59-63, April 2008.

The serotonin transporter gene (SLC6A4) encodes a trans-membrane protein (5-HTT) that plays an important role in regulating serotonergic neurotransmission, which is known to be involved in many psychiatric disorders. A polymorphism in the transcriptional control region containing long (L) and short (S) variants (5-HTTLPR) as well as alleles of the variable number tandem repeats (VNTR) region were demonstrated.

Higher serotonin levels among carriers of the S allele might exhibit increased liability of serotonin-mediated, psychopathology-like anxiety and depression and may impair social skills reflected by harm avoidance.

To analyze the data of alcohol-dependent, unrelated German individuals for a significant association between serotonin transporter gene and history of depression as well as TCI scales.

We characterized 368 alcohol-dependent participants by TCI and SSAGA/history of depression. HHT and VNTR genes were amplified by polymerase chain reaction.

No significant association was found between history of depression and 5-HTTLPR (F=0.42, P=0.65, d.f.=2) as well as between history of depression and VNTR (F=0.24, P=0.91, d.f.=2). As harm avoidance is often associated with history of depression, the TCI was used.

Regarding the TCI temperament and character scale scores, no significant association was found between harm avoidance and this genetic variant 5-HTTLPR (F=0.55, P=0.57, d.f.=2), and between harm avoidance and VNTR (F=0.39, P=0.81, d.f.=2).

Haplotype analysis showed significant relationship between low level of harm avoidance and haplotype S/12 ([chi]2=7.01, P=0.00). Haplotype analysis of history of depression ([chi]2=2.04, P=0.742) showed no significant result.

Our results indicate an association between S/12 haplotype of SLC6A4 and low level of harm avoidance

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Request Reprint E-Mail: gabi.koller@med.uni-muenchen.de
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ADHD and Co-Occuring Substance Use Disorders: New Clinical Insights and Emerging Therapies


Attention-deficit/hyperactivity disorder (ADHD)—a disorder of inattention, impulsivity, and hyperactivity—affects anywhere from 3% to 5% of all children in the United States. The course of the disorder is often chronic, and at least half of those affected will have prominent symptoms and impairment spanning into adulthood. In addition to learning dysfunction, ADHD is associated with psychiatric comorbidity—anxiety, mood disorders (eg, unipolar and bipolar depression), disruptive disorders (eg, oppositional and conduct disorders), and substance use disorders (SUDs). Studies have shown that young adults with ADHD are significantly more likely to have SUDs (eg, alcohol, drug, nicotine dependence) than their peers without ADHD.

Recent genetic and imaging studies, neuropsychologic data, and neurochemical findings support the biologic underpinningof ADHD. Despite the burden ADHD represents, it is a treatable disorder. Medication (eg, stimulants, antidepressants, antihypertensives) and psychotherapy are key to the management of ADHD across the lifespan. Because of the overlap between
ADHD and SUDs, appropriate treatment of ADHD is important to help reduce the risk for future SUDs.

This newsletter will provide an overview of the latest research on ADHD and co-occurring SUD. It will review factors that contribute to an increased risk of SUD in ADHD individuals. Treatment of comorbid individuals requires management of both ADHD and SUD, and this newsletter will review new approaches in ADHD pharmacotherapy and their implications for effectively treating individuals with ADHD and co-occurring SUD.

Downlod Monograph (PDF)

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Battle against teenage binge drinking 'must begin at home'
14 Mar 2008

A leading medical journal called on parents today to bear most of the responsibility for steering teenagers away from binge drinking and drunkenness.

Learning to enjoy alcohol without misusing it was "an important part of growing up" in many societies, said an editorial in The Lancet.

But the lesson did not appear to be taught in the UK, where young people were drinking more alcohol than ever before.
. . . . . .

Read Full Article

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Violent Behavior and DSM-IV Psychiatric Disorders: Results From the National Epidemiologic Survey on Alcohol and Related Conditions
J Clin Psychiatry 2008;69:12-22

To present nationally representative data on the lifetime prevalence and population estimates of violent behavior among individuals with DSM-IV psychiatric disorders.

After controlling for sociodemographic characteristics and other comorbidity, it was found that the odds of violent behavior were significantly increased (p < .05) among individuals with substance use disorders; pathological gambling; major depressive disorder; bipolar disorders; panic disorder without agoraphobia; specific phobia; and paranoid, schizoid, histrionic, and obsessive-compulsive personality disorders. Percentages of violent behavior among individuals with each comorbid disorder were, with few exceptions, significantly greater (p < .05-p < .001) than the corresponding percentages among those presenting with the pure form of each disorder. Alcohol and drug use disorders were the most significant contributors to the public health burden of violent behavior.

The majority of individuals with psychiatric disorders do not engage in violent behavior, and public perception associated with stereotypic violence among individuals with psychiatric disorders appears unwarranted. Elevated risks and burden of violent behavior were not equally shared across the spectrum of psychiatric disorders, with particular disorders, especially substance use disorders, contributing disproportionately to the burden. Future research should examine the circumstances under which violence among individuals with psychiatric disorders occurs with a view toward improving clinical prediction and developing more effective prevention strategies.

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Request Reprint E-Mail: bgrant@willco.niaaa.nih.gov

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Memantine enhances the inhibitory effects of naltrexone on ethanol consumption
European Journal of Pharmacology
Article in Press, Corrected Proof 14 Feb 2008


Effects of the opioid receptor antagonist naltrexone (0.1; 0.3; 1.0 mg/kg i.p.) on operant ethanol self-administration alone and in combination with the non-competitive NMDA antagonist memantine (0.5 and 1 mg/kg, i.p.) were studied in rats.

Acute administration of naltrexone (0.1; 0.3; 1.0 mg/kg i.p.) inhibited ethanol self-administration in a dose-dependent manner. Memantine (1.0 mg/kg) significantly enhanced the effects of naltrexone at 0.1 mg/kg, failing per se to inhibit ethanol consumption.

Thus, low, sub-effective dose of memantine in combination with low doses of naltrexone blocked the reinforcing properties of ethanol in rats.

It is suggested that the combination of sub-effective doses of memantine and naltrexone may have therapeutic value in the treatment of alcoholism particularly in a subgroup of alcoholic patients who have high sensitivity to the adverse side effects of naltrexone.

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Request Reprint E-Mail: alexander.kuzmin@neuro.ki.se
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A Haplotype of the DRD1 Gene Is Associated With Alcohol Dependence
Alcoholism: Clinical and Experimental Research, Early Online, 13 Mar 2008

The D1 dopamine receptor has been involved in a number of brain functions, including motor control, inattentive symptoms and reward and reinforcement mechanisms. Indeed, DRD1 antagonists may reduce cocaine-seeking behavior and the acquisition of cocaine-cue associations. The D1.1/r4532 marker of the DRD1 gene has been associated with a large set of phenotypes including addictive behaviors, but none with alcohol dependence per se.

We analyzed a population of 134 patients with alcohol dependence, also assessing more homogeneous (severe) phenotypes, comparing this sample with a healthy control population, assessing two SNPs within the DRD1 gene in order to depict the role of DRD1 polymorphisms and haplotypes.

The T allele of the rs686 polymorphism within DRD1 gene was significantly more frequent in patients with alcohol dependence (p = 0.0008), with a larger excess for patients with severe dependence (p = 6 × 10⁻⁶), and even more for patients with severe complications such as withdrawal seizures (p = 7 × 10⁻⁷). A specific haplotype rs686*T-rs4532*G within the DRD1 gene was significantly more precisely associated with alcohol dependence in our sample (p = 5 × 10⁻⁶).

Even though chance finding cannot be ruled out, convergent evidence is given that the DRD1 gene is a susceptibility gene in alcohol dependence, regarding the fact that relying on more homogeneous phenotypes (i.e., more severe patients) and more informative genetic markers (i.e., haplotypes) reinforce the initial association.

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Request Reprint E-Mail: philippe.batel@bjn.aphp.fr

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Strain Differences in Alcohol-Induced Neurochemical Plasticity: A Role for Accumbens Glutamate in Alcohol Intake
Alcoholism: Clinical and Experimental Research, Online early, 13 Mar 2008

Repeated alcohol administration alters nucleus accumbens (NAC) basal glutamate content and sensitizes the capacity of alcohol to increase NAC extracellular glutamate levels. However, the relevance of alcohol-induced changes in NAC glutamate for alcohol drinking behavior is under-investigated.

While strain differences were not apparent for NAC basal levels of dopamine, serotonin or γ-amino butyric acid (GABA), repeated alcohol treatment elevated NAC basal glutamate content only in B6 mice. Strain differences in both the acute and the sensitized neurochemical responses to 2 g/kg alcohol were observed for all neurotransmitters examined. While the alcohol-induced rise in NAC dopamine and glutamate levels sensitized in B6 mice, a sensitization was not observed in D2 animals. Moreover, B6 mice exhibited a sensitized serotonin and GABA response to alcohol followed repeated treatment, whereas neither tolerance nor sensitization was observed in D2 animals. An intra-NAC APDC infusion reduced alcohol intake in both B6 and D2 mice by approximately 50%. In contrast, TBOA infusion elevated alcohol intake selectively in B6 mice.

These data indicate an active role for NAC glutamate in regulating alcohol consumption in mice and support the hypothesis that predisposition to high alcohol intake involves genetic factors that facilitate alcohol-induced adaptations in glutamate release within the NAC.

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Request Reprint E-Mail: szumlinski@psych.ucsb.edu

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Adult Transition From At-Risk Drinking to Alcohol Dependence: The Relationship of Family History and Drinking Motives
Alcoholism: Clinical and Experimental Research, Early Online, 13 Mar 2008

Prospective studies have not previously examined whether a family history of alcoholism and drinking motives conjointly predict a diagnosed DSM-IV alcohol abuse or dependence in adults, despite a large literature that each is associated with alcohol consumption.

The focus of this study is the conjoint, prospective examination of these risk factors in a 10-year longitudinal study of adults who were at-risk drinkers at baseline.

Prospective, population-based cohort of drinkers aged 18 or older from a Northeastern U.S. area initially evaluated for history of alcohol use disorders and drinking motives in 1991 to 1992. New onset dependence was studied in those who never met the criteria for alcohol dependence at baseline (n = 423), and new onset abuse was studied in those who never met the criteria for alcohol abuse at baseline (n = 301) and who did not develop dependence during the follow-up.

Family history significantly interacted with 2 baseline drinking motives in predicting new onsets of DSM-IV alcohol dependence: drinking to reduce negative affect (OR 3.38; 95% CI 1.05, 10.9) and drinking for social facilitation (OR 3.88; CI 1.21, 12.5). Effects were stronger after conditioning the drinking motives on having a positive family history of alcoholism. In contrast, in predicting new onsets of alcohol abuse, drinking motives did not have direct effects or interact with family history.

Those who drank to reduce negative affect or for social facilitation at baseline were at greater risk of alcohol dependence 10 years later if they also had a family history of alcoholism.

These results suggest an at-risk group that can be identified prior to the development of alcohol dependence.

Further, the findings suggest utility in investigating the interaction of drinking motives with measured genetic polymorphisms in predicting alcohol dependence.

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Request Reprint E-Mail: dsh2@columbia.edu

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Patterns of Alcohol Consumption and Alcohol-Impaired Driving in the United States
Alcoholism: Clinical and Experimental Research, Early Online, 13 Mar 2008

Alcohol-related motor vehicle crashes kill approximately 17,000 Americans annually and were associated with more than $51 billion in total costs in 2000. Relatively little is known about the drinking patterns of alcohol-impaired (AI) drivers in the United States.

2006 Behavioral Risk Factor Surveillance System (BRFSS) was analyzed for alcohol consumption and self-reported AI driving among U.S. adults aged ≥18 years for all states. Alcohol consumption was divided into 4 categories: binge/heavy, binge/nonheavy, nonbinge/heavy, and nonbinge/nonheavy. Binge drinking was defined as ≥5 drinks for men or ≥4 drinks for women on one or more occasions in the past month, and heavy drinking was defined as average daily consumption of >2 drinks/day (men) or >1 drink/day (women). The prevalence of AI driving was examined by drinking pattern and by demographic characteristics. Logistic regression analysis was used to assess the association between drinking patterns and AI driving.

Five percent of drinkers were engaged in AI driving during the past 30 days. Overall, 84% of AI drivers were binge drinkers and 88% of AI driving episodes involved binge drinkers. By drinking category, binge/nonheavy drinkers accounted for the largest percentage of AI drivers (49.4%), while binge/heavy drinkers accounted for the most episodes of AI driving (51.3%). The adjusted odds of AI driving were 20.1 (95% CI: 16.7, 24.3) for binge/heavy, 8.2 (6.9, 9.7) for binge/nonheavy, and 3.9 (2.4, 6.3) for nonbinge/heavy drinkers, respectively.

There is a strong association between binge drinking and AI driving. Most AI drivers and almost half of all AI driving episodes involve persons who are not heavy drinkers (based on average daily consumption).

Implementing effective interventions to prevent binge drinking could substantially reduce AI driving.

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Ethanol Selectively Attenuates NMDAR-Mediated Synaptic Transmission in the Prefrontal Cortex
Alcoholism: Clinical and Experimental Research, Online early, 13 Mar 2008

Brain imaging studies have revealed abnormal function in the prefrontal cortex (PFC) of alcoholics that may contribute to the impulsive behavior and lack of control over drinking that characterizes this disorder. Understanding how ethanol affects the physiology of PFC neurons may help explain this loss of control and lead to better treatments for alcohol addiction.

In a previous study from this laboratory, we showed that ethanol inhibits complex patterns of persistent activity (known as "up-states") in medial PFC (mPFC) neurons in a reversible and concentration-dependent manner.

In deep-layer mPFC pyramidal neurons, ethanol reversibly attenuated electrically evoked N-methyl-d-aspartate-type glutamate receptor (NMDAR)-mediated EPSCs. Significant inhibition was observed at concentrations as low as 22 mM, equivalent to a blood ethanol concentration (0.1%) typically associated with legal limits for intoxication. In contrast to NMDA responses, neither evoked nor spontaneous EPSCs mediated by α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-type glutamate receptor were affected by ethanol at concentrations as high as 88 mM, a concentration that can be fatal to non-tolerant individuals. At similar concentrations, ethanol also had little effect on spontaneous or evoked IPSCs mediated by a-type γ-aminobutyric acid receptor. Finally, mPFC neurons showed little evidence of GABAR-mediated tonic current and this was unaffected by ethanol.

Together, these results suggest that NMDAR-mediated processes in the mPFC may be particularly susceptible to disruption following the acute ingestion of ethanol.

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Request Reprint E-Mail: woodward@musc.edu

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Alcoholic Beverages and Incidence of Dementia: 34-Year Follow-up of the Prospective Population Study of Women in Göteborg
American Journal of Epidemiology 2008 167(6):684-691;



The objective of this study was to assess the association between different types of alcoholic beverages and 34-year incidence of dementia.

Among a random sample of 1,462 women aged 38–60 years and living in Göteborg, Sweden, in 1968–1969, 164 cases of dementia were diagnosed by 2002. At baseline as well as in 1974–1975, 1980–1981, and 1992–1993, the frequency of alcohol intake, as well as other lifestyle and health factors, was recorded and related to dementia with Cox proportional hazard regression, by use of both baseline and updated covariates.

Wine was protective for dementia (hazard ratio (HR) = 0.6, 95% confidence interval (CI): 0.4, 0.8) in the updated model, and the association was strongest among women who consumed wine only (HR = 0.3, 95% CI: 0.1, 0.8).

After stratification by smoking, the protective association of wine was stronger among smokers. In contrast, consumption of spirits at baseline was associated with slightly increased risk of dementia (HR = 1.5, 95% CI: 1.0, 2.2). Results show that wine and spirits displayed opposing associations with dementia.

Because a protective effect was not seen for the other beverages, at least part of the association for wine may be explained by components other than ethanol.

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Request Reprint E-Mail: kirsten.mehlig@gu.se
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Alcohol empire strikes back
The Sydney Morning Herald

March 15, 2008

Alcopops are flying off the bar but binge drinking by young people has put the alcohol industry under new scrutiny. They are well prepared for the fight to come, writes Julian Lee.
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Scripps Research Scientists Launch International Conference on Alcoholism and Stress
By Mika Ono Benedyk

Scripps Research Institute investigators Marisa Roberto and George Koob are launching a new international conference, "Alcoholism and Stress: A Framework for Future Treatment Strategies," to be held in Volterra, Italy, Tuesday, May 6 to Thursday, May 8, 2008.

"This conference is the first international meeting of its kind," said Roberto. "Its primary purpose is to establish an international effort among both basic researchers and clinicians to develop preventive strategies and pharmacotherapeutic remedies."

Roberto notes that the growing health burdens of alcohol addiction and stress-related disorders affect the worldwide population, demanding novel treatment strategies and new advances in biomedical research.

The meeting will provide a platform for the world's preeminent scientists in alcoholism and stress research to present their latest findings through symposia, posters, discussions, and plenary lectures. Presentations will represent research in molecular and cellular biology, biobehavioral and clinical alcohol research, and epidemiology. An area of emphasis for the conference will be translational research for future treatment strategies.
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Nucleotide Sequence Variation within the PI3K p85 Alpha Gene Associates with Alcohol Risk Drinking Behaviour in Adolescents
PLoS ONE 3(3): e1769.

While the phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway is typically known to regulate cell growth and survival, emerging evidence suggest a role for this pathway in regulating the behavioural responses to addictive drugs.

To investigate whether PI3K contributes to patterns of risky alcohol drinking in human, we investigated genetic variations in PIK3R1, encoding the 85 kD regulatory subunit of PIK, in 145 family trios consisting of 15–16 year old adolescents and their parents.

Screening for mutations in exons, exon-intron boundaries and regulatory sequences, we identified 14 single nucleotide polymorphisms (SNPs) in the PIK3R1 gene region from exon 1 to the beginning of the 3′ untranslated region (UTR). These SNPs defined haplotypes for the respective PIK3R1 region. Four haplotype tagging (ht)SNPs (rs706713, rs2302975, rs171649 and rs1043526), discriminating all haplotypes with a frequency ≥4.5% were identified.

These htSNPs were used to genotype adolescents from the “Mannheim Study of Risk Children” (MARC). Transmission disequilibrium tests in these adolescents and their parents demonstrated sex-specific association of two SNPs, rs2302975 and rs1043526, with patterns of risky alcohol consumption in male adolescents, including lifetime prevalence of drunkenness (p = 0.0019 and 0.0379, respectively) and elevated maximum amount of drinking (p = 0.0020 and 0.0494, respectively), as a measure for binge drinking pattern.

Our findings highlight a previously unknown relevance of PIK3R1 genotypes for alcohol use disorders and might help discriminate individuals at risk for alcoholism.

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Mortality rates in subjects with fetal alcohol spectrum disorders and their siblings
Birth Defects Research (Part A), Early View 12 Mar 2008


Our objective was to estimate the mortality rate in subjects with fetal alcohol spectrum disorders (FASD) and their siblings whose FASD status was unknown.

We used the state FASD Registry to link subjects with FASD to a North Dakota birth certificate. We were able to link 304 of 486 cases (63%). We used the birth certificates to identify the mother and children born to the mother (siblings). We then searched for death certificates for both the FASD cases and their siblings. We then calculated the annual and age-adjusted mortality rates for the siblings of the Registry cases and compared them with mortality rates from North Dakota.

The FASD case mortality rate was 2.4%, with a 4.5% mortality rate for their sibings, accounting for 14% of all deaths when compared to the North Dakota residents matched by age and year of death. The sibling deaths accounted for 21.5% of all cause mortality matched by age and year of death. The age-standardized mortality ratios were 4.9 for the FASD cases and 2.6 for their siblings whose FASD status was unknown.

Mortality rates for FASD cases and their siblings were increased and represent a substantial proportion of all cause mortality in North Dakota. Prevention of FASD may be a useful strategy to decrease mortality.

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Request Reprint E-Mail: laburd@medicine.nodak.edu
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Paradoxical increase of positive answers to the Cut-down, Annoyed, Guilt, Eye-opener (CAGE) questionnaire during a period of decreasing alcohol consumption: results from two population-based surveys in Île-de-France, 1991 and 2005
Addiction 103 (4) , 598–603

To describe trends of responses to the Cut-down, Annoyed, Guilt, Eye-opener (CAGE) questionnaire during a period of declining alcohol consumption, in a country with no temperance history.

The proportion of subjects giving at least two positive answers has increased by 4.2 times; the biggest increase was observed for the Guilt question (4.8 times) and the smallest for the Eye-opener question (2.6 times). Several increases were higher for women than for men: 12.9 times versus 3.3 times for two or more positive answers, 9.8 times versus 3.8 times for the Guilt question. Increases did not vary consistently by age.

These paradoxical trends do not support the use of CAGE in general population surveys. They confirm previous reports suggesting that CAGE was sensitive to community temperance level. They might reflect the emergence of a temperance movement in France, with stronger impact among women. This movement might be responsible for the fall in alcohol consumption.

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Request Reprint E-Mail: antoine.messiah@isped.u-bordeaux2.fr

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Neurobiology and Treatment in Alcoholism—Recent Findings Regarding Lesch's Typology of Alcohol Dependence
Alcohol and Alcoholism Advance Access published online on March 13, 2008

Subtyping in alcohol dependence has become an important issue as studies have proposed different neurobiological mechanisms in alcoholism in the recent years.

Studies have shown that alcohol dependence reflects a wide range of different phenotypes, including psychological, social, and neurobiological factors. Different ways of subtyping have been proposed in the last decades, one of them being Lesch's typology of alcohol dependence.

Recent investigations have shown that different subtypes of Lesch's typology are associated with specific neurobiological factors which may have important implications for clinical practice.

This applies in particular for genetic and neuroendocrinological factors, differences in the regulation of NMDA receptor-mediated glutamatergic neurotransmission, and in response to acamprosate and naltrexone treatment.

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Request Repint E-Mail: thomas.hillemacher@uk-erlangen.de

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News Release - 60,000 new doctors will target problem drinkers

Friday 14 March 2008
Department of Health (National)

Sixty thousand new doctors will be specifically trained in the next ten years to identify and treat people who are drinking too much, Public Health Minister Dawn Primarolo will announce today.

Medical schools have been allocated £650,000 to do a scoping exercise next financial year to see how alcohol misuse training can be added to the curriculum.

The findings will enable a first tranche of medical schools to make the necessary changes - and test them - before full roll out. Within three years, every medical school in the country will have alcohol training on the curriculum.
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The ISAJE/WHO Young Scholars Award

The ISAJE Board is pleased to announce the first winner of the ISAJE/WHO Young Scholars Award. Dr Jaeuk Hwang, a research scientist from Seoul National University Hospital, Korea, receives the award for a paper published in Drug and Alcohol Dependence on decreased cerebral blood flow in former methamphetamine users. Dr Hwang wins travel support to attend an international scientific meeting of his choice.

ISAJE ONLINE

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ISAJE/WHO YOUNG SCHOLARS AWARD SCHEME (2008)

International Society of Addiction Journal Editors (ISAJE)

World Health Organization (WHO)

Purpose of the award

The award scheme aims to provide appropriate recognition for the contributions to addiction science of young scholars from developing countries and to promote their involvement in research and publication in the field.

Eligibility for the award

The criteria for eligibility will be as follows:

• The applicant should be less than 35 years old
• He/she should be the lead author of the published paper being submitted for the award
• He/she should hold a current academic or research position in a low or middle income country (as defined by the World Bank); or should have held such a position at the time the research for the paper was being carried out
• The research reported should have been carried out predominantly in a low or middle income country
• The paper should be based on a topic of relevance to the country or region of origin, or should have broad implications for the field of addiction research
• The paper submitted for the award should have been published either online or in print form in a peer-reviewed scholarly journal between 1 July 2007 and 30 June 2008.

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