To support the free and open dissemination of research findings and information on alcoholism and alcohol-related problems. To encourage open access to peer-reviewed articles free for all to view.

For full versions of posted research articles readers are encouraged to email requests for "electronic reprints" (text file, PDF files, FAX copies) to the corresponding or lead author, who is highlighted in the posting.


Saturday, June 29, 2013

Physicians in Long-Term Recovery Who Are Members of Alcoholics Anonymous

 There is little empirical literature on the experience in sobriety of long-term, committed members of Alcoholics Anonymous (AA).
Studies on the experience of long-term members, however, can yield a better understanding of the role of spirituality in AA membership, and how the program helps stabilize abstinence.
We studied 144 physicians at a conference of doctors in AA.
Respondents had a mean period of sobriety of 140 months. Compared to normative populations, they scored higher on scales for depression and anxiety, and were more adherent to the spiritual character of AA, rather than a formally religious orientation. Those who reported “having a spiritual awakening” were more likely to “experience God's presence” on most days (81% vs. 19%) and were less likely to report craving for alcohol (21% vs. 41%) than those who did not. Respondents who had a history of being enrolled in State Physicians' Health Programs did not differ significantly on any of the aforesaid subjective variables from those who were not enrolled.
The experience of long-term AA members can be characterized in terms of abstinence, spirituality, and alcohol craving.

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The alcohol evidence matrix: evidence map of alcohol treatment

The Alcohol Matrix has been developed by Drug and Alcohol Findings for the Substance Misuse Skills Consortium. The Matrix is concerned with the treatment of alcohol-related problems among adults (a similar table deals with drug-related problems). The alcohol matrix can be found here.   > > > >  Read More

New onset alcohol dependence linked to treatment with selective serotonin reuptake inhibitors

Genetic and environmental factors influence the development of alcohol dependence and alcohol dependence increases the risk of developing Major Depressive Disorder-MDD (vice versa). Amongst antidepressants, the selective serotonin reuptake inhibitors (SSRIs) are likely the most frequently prescribed for MDD. However, findings on the role of SSRIs in alleviating alcoholism are conflicting. CASE DESCRIPTION: A review of the literature is highlighted with a case of middle-aged lady with new onset alcohol dependence syndrome after commencement of SSRI, which resolved following discontinuation of the SSRIs and the introduction of Mirtazapine. DISCUSSION: The serotonin transporter gene has been linked to excessive drinking, early-onset problem drinking, alcohol dependence, anxiety and impulsiveness. While the evidence for antidepressant use appears consistent in alleviating depressive symptoms in patients with comorbid alcohol dependence and depression, some groups of patients may show an increase in alcohol consumption. Alternatively, there are a series of studies suggesting that antagonism of S-3 receptors can lead to diminished cravings for alcohol. This case highlights the need for further research into the effects of SSRIs on alcohol consumption in those with and without previous alcohol dependence syndromes. It also indicates a need to monitor changes in alcohol consumption and behaviour while on SSRIs.

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Friday, June 28, 2013

Alcohol Consumption Is a Risk Factor for Colonic Diverticulosis

The exact factors predisposing to colonic diverticulosis other than age are unknown.

Cross-sectional study of asymptomatic subjects undergoing screening colonoscopy. A detailed dietary and social questionnaire was completed on all participants. A worldwide review of the literature was performed to further investigate any association between identified risk factors and diverticulosis.

Seven hundred forty-six consecutive individuals were enrolled (mean age, 61.1±8.3 y; female: male=0.98). Overall, the prevalence of diverticulosis was 32.8% (95% CI, 29.5-36.2). Diverticula were left-sided, right-sided, or both in 71.5%, 5.8%, and 22.7% of affected subjects, respectively. On univariate analysis, age, sex, adenomatous polyps, advanced neoplasia (adenoma≥1 cm, villous histology, or cancer), aspirin, and alcohol use were significantly associated with diverticulosis. Diet, body mass index, physical activity, and bowel habits were not associated with the disease. On multivariate analysis, increasing age , advanced neoplasia,  and alcohol consumption  were significantly associated with diverticulosis. The adjusted odds ratio for diverticulosis in alcohol users was 1.91 (1.36 to 2.69), with increasing prevalence with higher alcohol consumption When the prevalence of diverticulosis reported from 18 countries was analyzed against alcohol use, there was a strong correlation with national per-capita alcohol consumption rates.

Alcohol use is a significant risk factor for colonic diverticulosis and may offer a partial explanation for the existing East-West paradox in disease prevalence and phenotype. Further studies are needed to investigate this association and its putative pathophysiological mechanisms.

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Critique 115: Potential association of alcohol consumption with diverticulosis — 25 June 2013

Forum Comments

The etiology of diverticulosis of the colon is poorly understood. Many, but not all, studies suggest that low fiber intake and obesity increase the risk. The large Health Professional Follow-up Study of almost 50,000 subjects found a lower risk to be associated with increased physical exercise and the intake of soluble fiber, and no increase from alcohol consumption.

This paper tests the cross-sectional association of alcohol consumption with diverticulosis among 746 asymptomatic consecutive subjects undergoing screening colonoscopies in Lebanon. In a pre-screening questionnaire, subjects reported the intake of several dietary constituents, as well as alcohol, with about one-half of subjects being lifetime abstainers. Most of the “drinkers” stated that they consumed alcohol occasionally or < 1 drink/day; only about 10% reported one or more drinks/day. No data on type of beverage or pattern of drinking were available. From their cross-sectional analyses, the authors conclude that alcohol consumption raises the risk of diverticulosis.  > > > >  Read More 

Pretreatment Alcohol Drinking Goals are Associated with Treatment Outcomes

A large subset of patients who enter treatment for alcohol dependence report nonabstinent drinking goals (e.g., reduction in drinking) rather than abstinence, and this pretreatment goal choice may be associated with drinking outcomes and alcohol-related problems.
An analysis of the 16-week Combined Pharmacotherapies and Behavioral Interventions (COMBINE) study was conducted to determine the association between self-reported pretreatment drinking goal and drinking outcomes and alcohol-related problems. Participants who reported a nonabstinent drinking goal (n = 340) were matched with participants who reported an abstinent drinking goal (n = 340) on 3 variables believed to contribute to treatment outcomes: COMBINE experimental group, gender, and number of prebaseline heavy drinking days.
Analyses revealed no interaction between the COMBINE experimental group and drinking goal on outcome measures, so results were collapsed and examined as a function of drinking goal group. Participants who chose an abstinent drinking goal had significantly more weeks with no drinking or no heavy drinking, reported fewer heavy drinking days, reported fewer days with >1 drink, and were more likely to have a ≥50% decrease in drinks per day between baseline and week 16 of the intervention. However, both groups reported reductions over time in percent drinking days, mean drinks per day, number of heavy drinking days, and number of drinking days per week, and participants in both groups experienced significant reductions in alcohol-related problems and improvements in psychosocial functioning.
Results replicate and expand upon previous studies examining the association between drinking goal and treatment outcome. These data also provide support for the standard inclusion of drinking treatment goal as a stratification variable in study interventions or as a covariate in outcome analyses and highlight several areas that warrant additional research regarding patients who enter alcohol treatment with a nonabstinent drinking goal.

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Chronic Alcohol Consumption Increases the Expression of Uncoupling Protein-2 and -4 in the Brain

Chronic alcohol consumption leads to oxidative stress in a variety of cells, especially in brain cells because they have a reduced oxidative metabolism of alcohol. Uncoupling proteins (UCPs) are anion channels of the inner mitochondrial membrane, which can decouple internal respiration. “Mild uncoupling” of the mitochondrial respiratory chain leads to a reduced production of free radicals (reactive oxygen species) and a reduction in oxidative cell stress. The extent to which chronic alcohol consumption regulates UCP-2 and -4 in the brain is still unknown.
We examined the effects of a 12-week 5% alcohol diet in the brain of male Wistar rats (n = 34). Cerebral gene and protein expression of UCP-2, -4, as well as Bcl-2, and the release of cytochrome c out of the mitochondria were detected by real-time polymerase chain reaction and Western blot analysis. The percentage of degenerated cells was determined by Fluoro–Jade B staining of brain slices.
Brains of rats with a chronic alcohol diet showed an increased gene and protein expression of UCP-2 and -4. The expression of the antiapoptotic protein Bcl-2 in the brain of the alcohol-treated animals was decreased significantly, whereas cytochrome c release from mitochondria was increased. In addition increased neurodegeneration could be demonstrated in the alcohol-treated animals.
Chronic alcohol consumption leads to a cerebral induction of UCP-2 and -4 with a simultaneous decrease in the antiapoptotic protein Bcl-2, cytochrome c release from mitochondria and increased neurodegeneration. This study reveals a compensatory effect of UCP-2 and -4 in the brain during chronic alcohol consumption.

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Suppression and Epigenetic Regulation of MiR-9 Contributes to Ethanol Teratology: Evidence from Zebrafish and Murine Fetal Neural Stem Cell Models

Fetal alcohol exposure produces multiorgan defects, making it difficult to identify underlying etiological mechanisms. However, recent evidence for ethanol (EtOH) sensitivity of the miRNA miR-9 suggests one mechanism, whereby EtOH broadly influences development. We hypothesized that loss of miR-9 function recapitulates aspects of EtOH teratology.
Zebrafish embryos were exposed to EtOH during gastrulation, or injected with anti-miR-9 or nonsense control morpholinos during the 2-cell stage of development and collected between 24 and 72 hours postfertilization (hpf). We also assessed the expression of developmentally important, and known miR-9 targets, FGFR-1, FOXP2, and the nontargeted transcript, MECP2. Methylation at CpG islands of mammalian miR-9 genes was assessed in fetal murine neural stem cells (mNSCs) by methylation-specific PCR, and miRNA processing assessed by qRT-PCR for pre-miR-9 transcripts.
EtOH treatment and miR-9 knockdown resulted in similar cranial defects including microcephaly. Additionally, EtOH transiently suppressed miR-9, as well as FGFR-1 and FOXP2, and alterations in miR-9 expression were correlated with severity of EtOH-induced teratology. In mNSCs, EtOH increased CpG dinucleotide methylation at the miR-9-2 locus and accumulation of pre-miR-9-3.
EtOH exerts regulatory control at multiple levels of miR-9 biogenesis. Moreover, early embryonic loss of miR-9 function recapitulated the severe range of teratology associated with developmental EtOH exposure. EtOH also disrupts the relationship between miR-9 and target gene expression, suggesting a nuanced relationship between EtOH and miRNA regulatory networks in the developing embryo. The implications of these data for the expression and function of mature miR-9 warrant further investigation.

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The Acute Effects of Alcohol on Sleep Architecture in Late Adolescence

Alcohol consumption is prevalent in late adolescence; however, little is known about its effect on sleep in this group. In mature adults, alcohol decreases sleep onset latency (SOL) and sleep efficiency (SE) and increases wake after sleep onset (WASO). It also increases slow wave sleep (SWS) and decreases rapid eye movement (REM) sleep in the first half of the night, with the inverse occurring in the second half. Alcohol's effect on sleep during late adolescence is of interest given that this age group shows both dramatic increases in alcohol consumption and significant developmental changes in the central nervous system. This study examined the effect of alcohol on sleep architecture in women and men aged 18 to 21 years and whether previously reported sleep architecture effects may have been as an artificial result of changes to sleep cycle length.
Twenty-four (12 women) healthy 18- to 21-year-old light social drinkers (19.1 ± 1.0 years) underwent 2 conditions: presleep alcohol (target breath alcohol concentration [BAC] 0.10%) and placebo-administered under controlled conditions, followed by standard polysomnography.
In the alcohol condition, mean BAC at lights out was 0.084 ± 0.016%. Time in bed, total sleep time, and SOL (all p > 0.05) did not differ between conditions. However, there was less REM (p = 0.011) and more stage-2 sleep (p = 0.035) in the alcohol condition. Further, alcohol increased SWS (p = 0.02) and decreased REM sleep (p < 0.001) in the first half of the night and disrupted sleep in the second half, with increased WASO (interaction: p = 0.034), and decreased SE (p = 0.04) and SWS (p = 0.01) and no REM sleep rebound in the second half of the night (p = 0.262). Additionally, alcohol had no effect on sleep cycle length (p = 0.598).
The results were broadly consistent with the adult literature with the novel extension that half night sleep architecture effects could not be attributed to changes in sleep cycle length. However, alcohol did not reduce SOL, or result in a REM rebound following reduced REM in the first half of the night. The results suggest that the effects of alcohol on sleep are modified by sleep's prevailing developmental stage.

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Thursday, June 27, 2013

Global Actions: Commitments to Reduce Harmful Drinking. June 26, 2013

Global Actions in Focus
Global actions drink driving initiative: vietnam
As part of Phase Two of the Global Actions on Harmful Drinking Drink Driving Initiative work plan, two site surveys were completed on June 13 and 15, 2013 in Ho Chi Minh City and Long An Province, Vietnam. Working in conjunction with the Provincial Traffic Safety Council (TSC) executive office, members of the provincial traffic police department, youth unions, the Department of Health, and the Department of Transport, Global Actions addressed key issues concerning road safety and drink driving.
Issues included:
· The current traffic safety situation in the provinces and cities
· The drink driving situation and initiative measures and activities
· Participation from industry companies
· Leadership commitment to improving the drink driving initiative
· Participation by traffic police and health officials
· Challenges and successes during the recent drink driving initiative
Currently, the Global Actions Drink Driving Initiative in Vietnam has completed site surveys for four provinces and cities, including Thanh Hoan and Nghe An provinces in May 2013. Toward the end of June 2013, initiative leaders will meet with members from the National Transportation Safety Council to discuss implementing the Drink Driving Initiative in two more provinces in Vietnam. In July 2013, the first capacity building project will also be conducted.
Key Recent Milestones
· USA: CEOs from many of the signatory companies of the Beer, Wine and Spirits Producers’ Commitments to Reduce Harmful Drinking met in New York the week of June 17, 2013. In a discussion chaired by Heineken CEO Jean-François van Boxmeer, the CEOs reviewed progress made to date on the implementation of the Commitments and addressed how to best support action moving forward in the markets they serve around the world.
What's Happening Next
· China: On July 4, 2013, the Global Actions on Harmful Drinking Drink Driving Initiative Phase Two will be launched in Nanjing. The event is organized by the Nanjing Bureau of Traffic Management, the Jiangsu Center for Disease Control and Prevention, and ICAP. On July 5, the Drink Driving Initiative Phase Two, hosted by the Xi’an Institute for Health Education and ICAP, will hold a launch event in Xi’an. Representatives from ICAP, the Chinese Center for Disease Control and Prevention, industry members, local government agencies, media, and other stakeholders are expected to attend the events.

Investigating Parental Monitoring, School And Family Influences On Adolescent Alcohol Use

study report has been published by Alcohol Research UK which is based on the first five years of the Belfast Youth Development study which is a Longitudinal Study of Adolescent Drug Use . The findings of this study are of importance to the academic understanding of adolescent development and alcohol use, and to the field of alcohol harm reduction, family support, and youth alcohol policy> > > >   Read More

NIAAA Spectrum June 2013





  • Antismoking Medication Shows Promise for Treating Alcohol Dependence

  • Brain Patterns May Help Predict Relapse Risk for Alcoholism


  • Excessive Alcohol Use and Liver Disease


  • Children of Military Families at Increased Risk for Substance Use

  • How Does Drinking Alcohol Affect Food Choices?

  • Freshman-Year Spike in Alcohol May Change Connections in the Brain

  • Brain Images Used To Study Impact of Aerobic Exercise in Heavy Drinkers


  • Animal Models for Alcohol Research


  •  Ted George, M.D.

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Loss of Control of Alcohol Use and Severity of Alcohol Dependence in Non-Treatment-Seeking Heavy Drinkers Are Related to Lower Glutamate in Frontal White Matter

The development and maintenance of alcohol use disorders (AUD) have been hypothesized to be associated with an imbalance of glutamate (GLU) homeostasis. White matter (WM) loss, especially in anterior brain regions, has been reported in alcohol dependence, which may involve disturbances in both myelin and axonal integrity. Frontal lobe dysfunction plays an important role in addiction, because it is suggested to be associated with the loss of control over substance use. This study investigated magnetic resonance spectroscopy (MRS)-detectable Glu levels in frontal WM of non-treatment-seeking heavy drinkers and its associations with AUD symptoms.
Single-voxel MR spectra optimized for Glu assessment (TE 80 ms) were acquired at 3T from a frontal WM voxel in a group of heavy drinking, non-treatment-seeking subjects in comparison with a group of subjects with only light alcohol consumption.
The results corroborate previous findings of increased total choline in heavy drinking subjects. A negative association of Glu levels with severity of alcohol dependence and especially loss of control over time and amount of alcohol intake was observed.

In contrast to the rather unspecific rise in choline-containing compounds, low Glu in frontal WM may be specific for the shift from nondependent heavy drinking to dependence and does not reflect a simple effect of the amount of alcohol consumption alone.

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Binge Drinking–Induced Subtle Myocardial Injury

Most of the clinical, histopathological, and biochemical studies consider the effect of chronic alcohol intoxication on myocardial injury. Much less attention has been paid to acute alcohol (binge drinking)–induced cardiotoxicity, even though alcohol binging is much more common than alcohol dependence.
We briefly present some of the binge drinking–induced “holiday heart” effects. The literature was searched to find effects of alcohol on heart.
In binge drinking, the literature has demonstrated transient myocardial subtle changes in cardiac magnetic resonance, increased serological markers of myocardial injury and inflammation, abnormal cardiac rhythm, changes in other biochemical and ultrastructural indices of myocardial dysfunction, as well as changes in metabolism, blood pressure, heart rate, thrombosis/fibrinolysis processes, and coronary vasoconstriction.
Although acute low alcohol exposure has widely proven positive effect on myocardial function, heavy acute drinking frequent events are related to adverse cardiovascular effects.

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Alpha-Lipoic Acid Reduces Ethanol Self-Administration in Rats

The main system of central ethanol (EtOH) oxidation is mediated by the enzyme catalase. By reacting with H2O2, brain catalase forms compound I (the catalase-H2O2 system), which is able to oxidize EtOH to acetaldehyde (ACD) in the brain. We have previously shown that ACD regulates EtOH motivational properties and possesses reinforcing effects by itself. In this study, we investigate the effects of alpha-lipoic acid (ALA), a scavenging agent for H2O2, on oral EtOH self-administration.
To this end, we trained Wistar rats to orally self-administer EtOH (10%) by nose poking. The effect of intraperitoneal pretreatment with ALA was evaluated during (i) maintenance of EtOH self-administration, (ii) EtOH self-administration under a progressive ratio (PR) schedule of reinforcement, and (iii) oral EtOH priming to induce reinstatement of EtOH seeking behavior. Moreover, we tested the effect of ALA on saccharin (0.05%) reinforcement, as assessed by oral self-administration.
The results indicate that ALA dose-dependently reduced the maintenance, the break point of EtOH self-administration under a PR and the reinstatement of EtOH seeking behavior without suppressing saccharin self-administration.
These results support that ALA may have a potential use in alcoholism treatment.

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Emergency Department–Based Brief Intervention to Reduce Risky Driving and Hazardous/Harmful Drinking in Young Adults: A Randomized Controlled Trial

Risky driving and hazardous drinking are associated with significant human and economic costs. Brief interventions for more than one risky behavior have the potential to reduce health-compromising behaviors in populations with multiple risk-taking behaviors such as young adults. Emergency department (ED) visits provide a window of opportunity for interventions meant to reduce both risky driving and hazardous drinking.
We determined the efficacy of a Screening, Brief Intervention, and Referral to Treatment (SBIRT) protocol addressing risky driving and hazardous drinking. We used a randomized controlled trial design with follow-ups through 12 months. ED patients aged 18 to 44 who screened positive for both behaviors (n = 476) were randomized to brief intervention (BIG), contact control (CCG), or no-contact control (NCG) groups. The BIG (n = 150) received a 20-minute assessment and two 20-minute interventions. The CCG (n = 162) received a 20-minute assessment at baseline and no intervention. The NCG (n = 164) were asked for contact information at baseline and had no assessment or intervention. Outcomes at 3, 6, 9, and 12 months were self-reported driving behaviors and alcohol consumption.
Outcomes were significantly lower in BIG compared with CCG through 6 or 9 months, but not at 12 months: Safety belt use at 3 months (adjusted odds ratio [AOR], 0.22; 95% confidence interval [CI], 0.08 to 0.65); 6 months (AOR, 0.13; 95% CI, 0.04 to 0.42); and 9 months (AOR, 0.18; 95% CI, 0.06 to 0.56); binge drinking at 3 months (adjusted rate ratio [ARR] 0.84; 95% CI, 0.74 to 0.97) and 6 months (ARR, 0.81; 95% CI, 0.67 to 0.97); and ≥5 standard drinks/d at 3 months (AOR, 0.43; 95% CI, 0.20 to 0.91) and 6 months (AOR, 0.41; 95% CI, 0.17 to 0.98). No substantial differences were observed between BIG and NCG at 12 months.
Our findings indicate that SBIRT reduced risky driving and hazardous drinking in young adults, but its effects did not persist after 9 months. Future research should explore methods for extending the intervention effect.

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Wednesday, June 26, 2013

Institute of Alcohol Studies launch new website & latest Alcohol Alert

The Institure of Alcohol Studies (IAS) has launched a new website and twitter account to support its aim of 'advocating for the use of scientific evidence in policy-making to reduce alcohol-related harm'.

The IAS produce reports on key alcohol policy areas and also a regular 'Alcohol Alert' magazine - see below for some of the features in the current issue.  > > > >   Read More

The role of α-synuclein in the pathophysiology of alcoholism

Alcoholism has complex etiology and there is evidence for both genetic and environmental factors in its pathophysiology. Chronic, long-term alcohol abuse and alcohol dependence are associated with neuronal loss with the prefrontal cortex being particularly susceptible to neurotoxic damage.
This brain region is involved in the development and persistence of alcohol addiction and neurotoxic damage is likely to exacerbate the reinforcing effects of alcohol and may hinder treatment.

Understanding the mechanism of alcohol’s neurotoxic effects on the brain and the genetic risk factors associated with alcohol abuse are the focus of current research. Because of its well-established role in neurodegenerative and neuropsychological disorders, and its emerging role in the pathophysiology of addiction, here we review the genetic and epigenetic factors involved in regulating α-synuclein expression and its potential role in the pathophysiology of chronic alcohol abuse.

 Elucidation of the mechanisms of α-synuclein regulation may prove beneficial in understanding the role of this key synaptic protein in disease and its potential for therapeutic modulation in the treatment of substance use disorders as well as other neurodegenerative diseases.

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Alcohol Outlet Density and Violence: The Role of Risky Retailers and Alcohol-Related Expenditures

The aim of the study was to assess the association between alcohol outlet density and violence controlling for alcohol expenditures and the density of other retailers.

Cross-sectional ecological study of 1816 block groups in Philadelphia. We obtained 2010 data for aggravated assaults, alcohol outlets, alcohol expenditures, business points, land use and socioeconomic and demographic characteristics. We mapped the spatial distribution of alcohol outlets and aggravated assaults using a geographic information system. We estimated the association between assault density and total, on-premise and off-premise alcohol outlet densities using spatial regression models and controlling for the covariates of urban crime rates, alcohol expenditures, and the presence of other general and risky commercial retail outlets

The strong and positive association between alcohol outlet density and violence remained after controlling for alcohol expenditures and the density of other retailers.

Findings support the concept that off-premise alcohol outlets in the neighborhood environment may impact health and social outcomes. The positive outlet–violence association in the face of these controls means it is not an association due solely to alcohol availability or to retail density. It also suggests that there is something unique about alcohol outlets or their density that makes them crime generators and links them to violence.

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Metabolic Abnormalities in Lobar and Subcortical Brain Regions of Abstinent Polysubstance Users: Magnetic Resonance Spectroscopic Imaging

The aim of the study was to explore neurometabolic and associated cognitive characteristics of patients with polysubstance use (PSU) in comparison with patients with predominant alcohol use using proton magnetic resonance spectroscopy.

Brain metabolite concentrations were examined in lobar and subcortical brain regions of three age-matched groups: 1-month-abstinent alcohol-dependent PSU, 1-month-abstinent individuals dependent on alcohol alone (ALC) and light drinking controls (CON). Neuropsychological testing assessed cognitive function.

While CON and ALC had similar metabolite levels, persistent metabolic abnormalities (primarily higher myo-inositol) were present in temporal gray matter, cerebellar vermis and lenticular nuclei of PSU. Moreover, lower cortical gray matter concentration of the neuronal marker N-acetylaspartate within PSU correlated with higher cocaine (but not alcohol) use quantities and with a reduced cognitive processing speed.

These metabolite group differences reflect cellular/astroglial injury and/or dysfunction in alcohol-dependent PSU. Associations of other metabolite concentrations with neurocognitive performance suggest their functional relevance. The metabolic alterations in PSU may represent polydrug abuse biomarkers and/or potential targets for pharmacological and behavioral PSU-specific treatment.   

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Ethanol Consumption Increases Endothelin-1 Expression and Reactivity in the Rat Cavernosal Smooth Muscle

We investigated the effects of chronic ethanol consumption on the cavernosal smooth muscle (CSM) reactivity to endothelin-1 (ET-1) and the expression of ET system components in this tissue.

Male Wistar rats were treated with heavy dose of ethanol (20% v/v) for 6 weeks. Reactivity experiments were performed in the isolated rat CSM. Plasma and CSM nitrate generation and also superoxide anion generation in rat CSM were measured by chemiluminescence. Protein and mRNA levels of pre-pro-ET-1, endothelin-converting enzyme-1 (ECE-1), ETA and ETB receptors, eNOS, nNOS and iNOS were assessed by western immunoblotting and quantitative real-time polymerase chain reaction, respectively.

Chronic ethanol consumption increased plasma ET-1 levels and the contractile response induced by this peptide in the isolated CSM. The relaxation induced by acetylcholine, but not IRL1620, a selective ETB receptor agonist, was reduced in CSM from ethanol-treated rats. BQ123, a selective ETA receptor antagonist, produced a rightward displacement of the ET-1 concentration–response curves in CSM from control, but not ethanol-treated rats. Reduced levels of nitrate were found in the plasma and CSM from ethanol-treated rats. Ethanol consumption increased superoxide anion generation in the rat CSM. The mRNA levels of pre-pro-ET-1, ECE-1, ETA and ETB receptors, eNOS, nNOS and iNOS were not altered by ethanol consumption. Protein levels of ET-1, ETA receptor and iNOS were higher in the CSM from rats chronically treated with ethanol.

The major findings of the present study are that heavy ethanol consumption increases plasma ET-1 levels and the contraction induced by the peptide in the CSM. Increased CSM reactivity to ET-1 and altered protein levels of ET-1 and ETA receptors could play a role in the pathogenesis of erectile dysfunction associated with chronic ethanol consumption.                 

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The molecular features of tongue epithelium treated with the carcinogen 4-nitroquinoline-1-oxide (4-NQO) and alcohol as a model for HNSCC.

Cancer of the head and neck (HNSCC) is the sixth most common type of cancer affecting humans worldwide. To determine the potential mechanisms by which chronic tobacco and alcohol abuse lead to HNSCC of the oral cavity, we have used both the 4-nitroquinoline-1-oxide (4-NQO) murine oral carcinogenesis and the Meadows-Cook alcohol models.

In this study, we treated mice with 4-NQO in drinking water for 10 weeks and then administered 20%(w:v) ethanol for another 10 weeks. We observe increased levels and/or activation of signaling proteins (p38 MAP kinase, β-catenin, and Erk 1/2) that are typically altered during HNSCC initiation in humans.

We found that ethanol administration alone increased the expression of p38 MAP kinase, but not Erk 1/2 MAP kinase. Total β-catenin levels in the tongues increased by 2-3 fold after 4-NQO treatment, with or without ethanol. However, ethanol combined with 4-NQO reduced phosphorylated β-catenin levels, whereas 4-NQO treatment alone did not.

These data implicate ethanol as a regulator of β-catenin signaling in this HNSCC model. We also utilized K14-CreERTAM;ROSA26 mice to mark permanently stem/progenitor cells in the tongue epithelia.

We found that 4-NQO alone and 4-NQO plus ethanol treatment resulted in massive, horizontal expansion of stem/progenitor cell populations arising from single stem cells in the basal layer of the epithelia. This expansion is consistent with carcinogen associated, symmetric division of stem/progenitor cells.

Our data suggest that specific therapeutic targets for prevention of HNSCC of the oral cavity associated with both alcohol and tobacco use are p38 MAP kinase and β-catenin.

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Efficacy and the Strength of Evidence of U.S. Alcohol Control Policies


Public policy can limit alcohol consumption and its associated harm, but no direct comparison of the relative efficacy of alcohol control policies exists for the U.S.

To identify alcohol control policies and develop quantitative ratings of their efficacy and strength of evidence.\

In 2010, a Delphi panel of ten U.S. alcohol policy experts identified and rated the efficacy of alcohol control policies for reducing binge drinking and alcohol-impaired driving among both the general population and youth, and the strength of evidence informing the efficacy of each policy. The policies were nominated on the basis of scientific evidence and potential for public health impact. Analysis was conducted in 2010–2012.

Panelists identified and rated 47 policies. Policies limiting price received the highest ratings, with alcohol taxes receiving the highest ratings for all four outcomes. Highly rated policies for reducing binge drinking and alcohol-impaired driving in the general population also were rated highly among youth, although several policies were rated more highly for youth compared with the general population. Policy efficacy ratings for the general population and youth were positively correlated for reducing both binge drinking (r=0.50) and alcohol-impaired driving (r=0.45). The correlation between efficacy ratings for reducing binge drinking and alcohol-impaired driving was strong for the general population (r=0.88) and for youth (r=0.85). Efficacy ratings were positively correlated with strength-of-evidence ratings.

Comparative policy ratings can help characterize the alcohol policy environment, inform policy discussions, and identify future research needs.

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Tuesday, June 25, 2013

Elucidating the Biological Basis for the Reinforcing Actions of Alcohol in the Mesolimbic Dopamine System: The Role of Active Metabolites of Alcohol

The development of successful pharmacotherapeutics for the treatment of alcoholism is predicated upon understanding the biological action of alcohol. 

A limitation of the alcohol research field has been examining the effects of alcohol only and ignoring the multiple biological active metabolites of alcohol. The concept that alcohol is a ‘pro-drug’ is not new.  

Ethanol is readily metabolized to acetaldehyde within the brain. Acetaldehyde is a highly reactive compound that forms a number of condensation products, including salsolinol and iso-salsolinol (acetaldehyde and dopamine). 
Recent experiments have established that numerous metabolites of ethanol do have direct CNS action, and could, in part or whole, mediate the reinforcing actions of alcohol within the mesolimbic dopamine system. The mesolimbic dopamine system originates in the ventral tegmental area (VTA) and projects to forebrain regions that include the nucleus accumbens (Acb) and the medial prefrontal cortex (mPFC) and is thought to be the neurocircuitry governing the rewarding properties of drugs of abuse. 

Within this neurocircuitry there is convincing evidence that; 1) biologically active metabolites of ethanol can directly or indirectly alter the activity of VTA dopamine neurons, 2) ethanol and ethanol metabolites are reinforcing within the mesolimbic dopamine system, 3) altering the ethanol metabolic pathway alters the biological consequences of ethanol exposure, 4) ethanol consumption can be reduced by altering the ethanol metabolic pathway in the mesolimbic dopamine system, 5) ethanol metabolites can alter the neurochemical levels within the mesolimbic dopamine system, and 6) ethanol interacts with ethanol metabolites to enhance the actions of both compounds. 

The data indicate that there is complex relationship between ethanol and ethanol metabolites in regulating the biological consequences of consuming alcohol and the potential of alcohol use escalating to alcoholism.

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Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse

Relapse to alcohol abuse is an important clinical issue that is frequently caused by cue-induced drug craving. Therefore, disruption of the memory for the cue-alcohol association is expected to prevent relapse. It is increasingly accepted that memories become labile and erasable soon after their reactivation through retrieval during a memory reconsolidation process that depends on protein synthesis.

Here we show that reconsolidation of alcohol-related memories triggered by the sensory properties of alcohol itself (odor and taste) activates mammalian target of rapamycin complex 1 (mTORC1) in select amygdalar and cortical regions in rats, resulting in increased levels of several synaptic proteins.

Furthermore, systemic or central amygdalar inhibition of mTORC1 during reconsolidation disrupts alcohol-associated memories, leading to a long-lasting suppression of relapse.

Our findings provide evidence that the mTORC1 pathway and its downstream substrates are crucial in alcohol-related memory reconsolidation and highlight this pathway as a therapeutic target to prevent relapse.

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Acetaldehyde involvement in ethanol's postabsortive effects during early ontogeny

Clinical and biomedical studies sustains the notion that early ontogeny is a vulnerable window to the impact of alcohol. Experiences with the drug during these stages increase latter disposition to prefer, use or abuse ethanol.

This period of enhanced sensitivity to ethanol is accompanied by a high rate of activity in the central catalase system, which metabolizes ethanol in the brain. Acetaldehyde (ACD), the first oxidation product of ethanol, has been found to share many neurobehavioral effects with the drug. Cumulative evidence supports this notion in models employing adults.

Nevertheless very few studies have been conducted to analyze the role of ACD in ethanol postabsorptive effects, in newborns or infant rats. In this work we review recent experimental literature that syndicates ACD as a mediator agent of reinforcing aspects of ethanol, during early ontogenetic stages.

We also show a meta-analytical correlational approach that proposes how differences in the activity of brain catalase across ontogeny, could be modulating patterns of ethanol consumption.

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Gene specific modifications unravel ethanol and acetaldehyde actions

Ethanol is metabolized into acetaldehyde mainly by the action of alcohol dehydrogenase in the liver, while mainly by the action of catalase in the brain. Aldehyde dehydrogenase-2 metabolizes acetaldehyde into acetate in both organs. Gene specific modifications reviewed here show that an increased liver generation of acetaldehyde (by transduction of a gene coding for a high-activity liver alcohol dehydrogenase ADH1*B2) leads to increased blood acetaldehyde levels and aversion to ethanol in animals.

Similarly aversive is an increased acetaldehyde level resulting from the inhibition of liver aldehyde dehydrogenase-2 (ALDH2) synthesis (by an antisense coding gene against aldh2 mRNA).

The situation is diametrically different when acetaldehyde is generated in the brain. When the brain ventral tegmental area (VTA) is endowed with an increased ability to generate acetaldehyde (by transfection of liver rADH) the reinforcing effects of ethanol are increased, while a highly specific inhibition of catalase synthesis (by transduction of a shRNA anti catalase mRNA) virtually abolishes the reinforcing effects of ethanol as seen by a complete abolition of ethanol intake in rats bred for generations as high ethanol drinkers.

Data shows two divergent effects of increases in acetaldehyde generation: aversive in the periphery but reinforcing in the brain.

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