ADH SNP ASSOCIATIONS WITH ALCOHOL METABOLISM IN VIVO

Human Molecular Genetics Advance Access published online on February 4, 2009

We have previously found that variation in alcohol metabolism in Europeans is linked to the chromosome 4q region containing the ADH gene family.

We have now typed 103 SNPs across this region to test for allelic associations with variation in blood and breath alcohol concentrations after an alcohol challenge.

In vivo alcohol metabolism was modelled with three parameters that identified the absorption and rise of alcohol concentration following ingestion, and the rate of elimination. Alleles of ADH7 SNPs were associated with the early stages of alcohol metabolism, with additional effects in the ADH1A, ADH1B and ADH4 regions.

Rate of elimination was associated with SNPs in the intragenic region between ADH7 and ADH1C, and across ADH1C and ADH1B.

SNPs affecting alcohol metabolism did not correspond to those reported to affect alcohol dependence or alcohol-related disease.

The combined SNP associations with early and late stage metabolism only account for about 20% of the total genetic variance linked to the ADH region, and most of the variance for in vivo alcohol metabolism linked to this region has yet to be explained.

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Request Reprint E-Mail: John.Whitfield@qimr.edu.au

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4-Containing GABAA Receptors in the Nucleus Accumbens Mediate Moderate Intake of Alcohol

The Journal of Neuroscience, January 14, 2009, 29(2):543-549;

Alcohol has subjective and behavioral effects at the pharmacological levels typically reached during the consumption of one or two alcoholic drinks.

Here we provide evidence that an 4-subunit-containing GABAA receptor contributes to the consumption of low-to-moderate levels of alcohol.

Using viral-mediated RNA interference (RNAi), we found that reduced expression of the 4 subunit in the nucleus accumbens (NAc) shell of rats decreased their free consumption of and preference for alcohol. The time course for the reduced alcohol intake paralleled the time course of 4 mRNA reductions achieved after viral-mediated RNAi for 4.

Furthermore, the reduction in drinking was region- and alcohol-specific: there was no effect of reductions in 4 expression in the NAc core on alcohol intake, and reductions in 4 expression in the NAc shell did not alter sucrose or water intake.

These results indicate that the GABAA receptor 4 subunit in the NAc shell mediates alcohol intake.

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Review: Should ethanol be scheduled as a drug of high risk to public health?

Journal of Psychopharmacology, Vol. 23, No. 1, 94-100 (2009)

Six criteria described in the New Zealand Misuse of Drugs Act and used by the Expert Advisory Committee on Drugs (EACD) for determining the risk of a drug to public health were examined in relation to ethanol, using -hydroxybutyric acid (GHB) as a comparator drug.

GHB is an ideal candidate for use as a comparator because it is a sedative substance very similar to ethanol and has been previously investigated by the EACD using these six criteria. GHB was subsequently classified as a Class B1 drug under the Misuse of Drugs Act, that is, as a prohibited drug of high risk to public health.

The dangerousness level of ethanol was found to be at least similar to that of GHB in this analysis. This highlights a major discrepancy in public policy.

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Request Reprint E-Mail: doug.sellman@otago.ac.nz
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Effects of acute alcohol consumption on processing of perceptual cues of emotional expression

Journal of Psychopharmacology, Vol. 23, No. 1, 23-30 (2009)

Alcohol consumption has been associated with increases in aggressive behaviour. However, experimental evidence of a direct association is equivocal, and mechanisms that may underlie this relationship are poorly understood. One mechanism by which alcohol consumption may increase aggressive behaviour is via alterations in processing of emotional facial cues.

We investigated the effects of acute alcohol consumption on sensitivity to facial expressions of emotion. Participants attended three experimental sessions where they consumed an alcoholic drink (0.0, 0.2 or 0.4 g/kg), and completed a psychophysical task to distinguish expressive from neutral faces.

The level of emotion in the expressive face varied across trials the threshold at which the expressive face was reliably identified and measured. We observed a significant three-way interaction involving emotion, participant sex and alcohol dose. Male participants showed significantly higher perceptual thresholds for sad facial expressions compared with female participants following consumption of the highest dose of alcohol.

Our data indicate sex differences in the processing of facial cues of emotional expression following alcohol consumption. There was no evidence that alcohol altered the processing of angry facial expressions.

Future studies should examine effects of alcohol expectancy and investigate the effects of alcohol on the miscategorisation of emotional expressions.

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Request Reprint E-Mail: Angela.Attwood@bris.ac.uk

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Alcohol Consumption Behaviours and Social Mobility in Men and Women of the Midspan Family Study
Alcohol and Alcoholism Advance Access published online on January 23, 2009

The aim of this study was to investigate relationships between alcohol consumption and social mobility in a cohort study in Scotland.

More downwardly mobile men exceeded the weekly limit, the daily limit, were defined as binge drinkers and drank the most units per week of the four social mobility groups. Stable non-manual women were more likely to consume alcohol on 5+ days a week but very few were binge drinkers. Stable non-manual and upwardly mobile men and women were more likely to drink wine, and downwardly mobile men to drink beer.

Downward mobility was associated with less favourable alcohol behaviours, especially in men. Wine consumption was more closely related to the social mobility groups than beer and spirits consumption. Drinking patterns could both influence and be influenced by social mobility.

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Psychiatrist Directed Army, VA Programs For Substance Abuse

By Patricia Sullivan Washington Post Staff Writer February 6, 2009; Page B06

Stewart L. Baker, 88, a psychiatrist who developed comprehensive drug abuse and alcoholism treatment programs for the Army in 1971 and later directed similar programs for the Veterans Administration, died Jan. 13 at the Riderwood Village retirement community in Silver Spring after a stroke.

. . . . .

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Alcohol, young people and the media: a study of radio output in six radio stations in England
Journal of Public Health Advance Access first published online on January 13, 2009

This research investigated the representation of alcohol in radio output. The study was prompted by concerns that media output might be part of a developing culture of excessive drinking among young people.

Alcohol comments were examined across six radio stations in England. 1200 h of weekend output was screened and the sampling frame included periods when references to alcohol would be expected, such as the Christmas period. Statistical analysis identified the volume and proportion of comments, whereas qualitative analysis explored these in more depth, focusing on the themes and discourses surrounding alcohol talk.

Of 703 alcohol comments identified, 244 involved presenters. The volume of comments about alcohol varied between stations, being lower on BBC than on commercial stations and being influenced by music genre. Seventy-three percent of comments initiated by presenters, compared with 45% of comments from all sources, encouraged drinking. The majority of comments by presenters support drinking in relation to partying and socializing. Alcohol comments seem to create identity for programmes and forge connections between presenters and audiences, although some presenters achieve this without mentioning drinking. The assumption that alcohol is necessary to have a good time is seldom directly challenged.

While it may be unsurprising that much of this content reflected themes of weekend drinking and partying, the study suggests that alcohol comments play a particular role in marketing and branding of radio output. Comments about alcohol are shaped by broadcasting conventions that make it difficult to challenge discourses surrounding excessive drinking. Further research is needed on the influence that radio output may have on drinking behaviour among young people.

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Sweet Liking Phenotype, Alcohol Craving and Response to Naltrexone Treatment in Alcohol Dependence
Alcohol and Alcoholism Advance Access published online on February 3, 2009

To investigate the relationship between the sweet liking/sweet disliking phenotype (a putative probe of brain opioid function), craving for alcohol and response to treatment with naltrexone in individuals with alcohol dependence.

Forty individuals with alcohol dependence were enrolled in a 12-week open-label study of 50 mg of naltrexone with four sessions of motivational enhancement therapy. Prior to treatment, individuals completed a sweet preference test and the Penn Alcohol Craving Scale. Subjects were categorized as sweet liking (SL), n = 15, or sweet disliking (SDL), n = 25, via a standard sweet tasting paradigm. The sweet tasting results were blinded to the subjects and to treatment staff. SL status, pretreatment craving and their interaction were examined as predictors of frequency of abstinent days and heavy drinking days during treatment with naltrexone.

SL and SDL subjects achieved similar reductions in percent heavy drinking days with treatment. During treatment, SDL subjects had 48% abstinent days compared to 30% for SL subjects (P = 0.034). Pretreatment craving did not predict % heavy drinking days or % abstinent days. An interaction effect was found between the SL/SDL phenotype and pretreatment craving such that SL subjects with high craving demonstrated higher rates of percent abstinent days whereas SDL subjects with high craving demonstrated lower rates of percent abstinent days, P < 0.001.

These findings indicate that the SL/SDL phenotype may predict variation in response to naltrexone and/or counseling treatment. Furthermore, the SL/SDL phenotype may interact with craving to provide a more robust prediction of outcome with naltrexone or counseling.

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Request Reprint E-Mail: jc_garbutt@med.unc.edu
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Chronic ethanol consumption resulting in the downregulation of insulin receptor-β subunit, insulin receptor substrate-1, and glucose transporter 4 expression in rat cardiac muscles

The objective of this study was to investigate the effect of chronic ethanol intake on the expression of insulin receptor β subunit (IR-β), insulin receptor substrate-1 (IRS-1), and glucose transporter 4 (Glut4) in rat cardiac muscle.

Forty-eight male Wistar rats were randomly classified into four groups and to each group, ethanol was administered daily at the respective doses of 0 (control, C), 0.5 g kg−1 (low ethanol, L), 2.5 g kg−1 (middle ethanol, M), and 5 g kg−1 (high ethanol, H). Twenty-two weeks later, the rats were anesthetized, and the left ventricle muscles were excised. The IR-β, IRS-1, and Glut4 mRNA levels in the cardiac muscle tissues were detected by reverse-transcription polymerase chain reaction (RT-PCR); The IR-β, tyrosine phosphorylation of IR-β (PY-IR-β), IRS-1, tyrosine phosphorylation of IRS-1 (PY-IRS-1), and Glut4 protein levels were measured by Western blotting.

Compared to the control group, the IR-β, IRS-1, and Glut4 mRNA levels in groups H and M decreased remarkably. In addition, the protein levels of IR-β, IRS-1, and Glut4 showed a corresponding decline in ethanol-treated groups, especially in group H. Moreover, the PY-IR-β and PY-IRS-1 protein levels decreased in the hearts of ethanol-treated rats with corresponding changes in the IR-β and IRS-1 protein levels.

The present study showed that chronic ethanol intake could downregulate the expression levels of IR-β, IRS-1, and Glut4 in rat cardiac muscles.

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Request Reprint E-Mail: jjzhao@medmail.com.cn
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ICAP Reviews 3. Noncommercial Alcohol in Three Regions

A significant portion of alcohol produced, sold, and consumed around the world is not reflected in official statistics. This ICAP Review focuses on the prevalence of "noncommercial alcohol" in sub-Saharan Africa, central and eastern Europe, and southern Asia. "Noncommercial alcohol" is defined as traditional drinks produced for home consumption or limited local trade, unregistered and counterfeit products, and nonbeverage, or surrogate, alcohols.

The Review papers are written by regional experts familiar with local research and regional trends. Each paper provides a literature review and introduces new data. This ICAP Review contributes to a better understanding of the informal alcohol sector, identifies available local and international research, and highlights areas for further work.

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Excessive alcohol consumption is blocked by glial cell line–derived neurotrophic factor
Alcohol Volume 43, Issue 1, February 2009, Pages 35-43

We previously found that activation of the glial cell line–derived neurotrophic factor (GDNF) pathway in the ventral tegmental area (VTA) reduces moderate alcohol (ethanol) intake in a rat operant self-administration paradigm.

Here, we set out to assess the effect of GDNF in the VTA on excessive voluntary consumption of ethanol.

Long–Evans rats were trained to drink large quantities of a 20% ethanol solution in an intermittent-access two-bottle choice drinking paradigm. The rats were given three 24-h sessions per week, and GDNF's actions were measured when rats achieved a baseline of ethanol consumption of 5.5 g/kg/24 h.

We found that microinjection of GDNF into the VTA 10 min before the beginning of an ethanol-drinking session significantly reduced ethanol intake and preference, but did not affect total fluid intake.

We further show that GDNF greatly decreased both the first bout of excessive ethanol intake at the beginning of the session, and the later consummatory activity occurring during the dark cycle.

These data suggest that GDNF is a rapid and long-lasting inhibitor of “binge-like” ethanol consumption.

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Request Reprint E-Mail: dorit.ron@ucsf.edu
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Ethanol disrupts NMDA receptor and astroglial EAAT2 modulation of Kv2.1 potassium channels in hippocampus
Alcohol Volume 43, Issue 1, February 2009, Pages 45-50

Delayed-rectifier Kv2.1 channels are the principal component of voltage-sensitive K+ currents (IK) in hippocampal neurons and are critical regulators of somatodendritic excitability.

In a recent study, we demonstrated that surface trafficking and phosphorylation of Kv2.1 channels is modulated by NMDA-type glutamate receptors and that astroglial excitatory amino acid transporters 2 (EAAT2) regulate the coupling of NMDA receptors and Kv2.1 channels.

Because ethanol is known to acutely inhibit NMDA receptors, we sought to determine if NMDA receptor and astroglial EAAT2 modulation of Kv2.1 channels is impaired by ethanol in the rodent hippocampus.

As expected, bath application of NMDA to hippocampal cultures reduced the size of Kv2.1 clusters and produced a hyperpolarizing shift in the voltage-dependent activation of IK that was associated with dephosphorylated Kv2.1 channels.

Ethanol, applied acutely, prevented the hyperpolarizing shift in activation of IK induced by NMDA and restored Kv2.1 clustering and phosphorylation to near control levels. Ethanol also attenuated the dephosphorylation of Kv2.1 channels produced by the EAAT2 selective inhibitor dihydrokainic acid.

These data demonstrate that acute ethanol disrupts changes in Kv2.1 channels that follow NMDA receptor activation and impairs astroglial regulation of the functional coupling between NMDA receptors and Kv2.1 channels.

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Request Reprint E-Mail: chandj@musc.edu
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Chronic ethanol consumption resulting in the downregulation of insulin receptor-β subunit, insulin receptor substrate-1, and glucose transporter 4 expression in rat cardiac muscles
Alcohol Volume 43, Issue 1, February 2009, Pages 51-58

The objective of this study was to investigate the effect of chronic ethanol intake on the expression of insulin receptor β subunit (IR-β), insulin receptor substrate-1 (IRS-1), and glucose transporter 4 (Glut4) in rat cardiac muscle.

Forty-eight male Wistar rats were randomly classified into four groups and to each group, ethanol was administered daily at the respective doses of 0 (control, C), 0.5 g kg−1 (low ethanol, L), 2.5 g kg−1 (middle ethanol, M), and 5 g kg−1 (high ethanol, H). Twenty-two weeks later, the rats were anesthetized, and the left ventricle muscles were excised. The IR-β, IRS-1, and Glut4 mRNA levels in the cardiac muscle tissues were detected by reverse-transcription polymerase chain reaction (RT-PCR); The IR-β, tyrosine phosphorylation of IR-β (PY-IR-β), IRS-1, tyrosine phosphorylation of IRS-1 (PY-IRS-1), and Glut4 protein levels were measured by Western blotting.

Compared to the control group, the IR-β, IRS-1, and Glut4 mRNA levels in groups H and M decreased remarkably. In addition, the protein levels of IR-β, IRS-1, and Glut4 showed a corresponding decline in ethanol-treated groups, especially in group H. Moreover, the PY-IR-β and PY-IRS-1 protein levels decreased in the hearts of ethanol-treated rats with corresponding changes in the IR-β and IRS-1 protein levels.

The present study showed that chronic ethanol intake could downregulate the expression levels of IR-β, IRS-1, and Glut4 in rat cardiac muscles.

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Request Reprint E-Mail: jjzhao@medmail.com.cn
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Effect of exercise training on ethanol-induced oxidative damage in aged rats

Alcohol Volume 43, Issue 1, February 2009, Pages 59-64

It is well known that lipid peroxidation increases with age, and alcohol drinking further exacerbates this damage.

The present study determined the effect of regular exercise training on alcohol-induced oxidative damage and antioxidant status in the liver of aged animals.

The age-matched Wistar albino rats (3 months young, n = 24; 18 months old, n = 24) were evenly divided into four groups: control (C), exercise trained (Ex), ethanol drinking (Et), and exercise plus ethanol drinking (Ex + Et).

With ethanol drinking, hepatic malondialdehyde (MDA) level was significantly elevated above control (P < .001), whereas glutathione (GSH) and ascorbic acid (vitamin C) contents were significantly decreased below control. These changes were found to be greater in the aged rats than those of the young rats. For both age groups, exercise training significantly reversed the increase in MDA and decreases in GSH and ascorbic acid induced by ethanol drinking.

The present study showed that ethanol-induced deterioration in lipid peroxidation and reduction in antioxidant status in the liver were exacerbated with age. Here, we found that exercise training significantly reversed the adverse conditions that were caused by ethanol in aged rats.

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Request Reprint E-Mail: sathyakreddy@hotmail.com

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Alcohol consumption and lipodystrophy in HIV-infected adults with alcohol problems

Alcohol Volume 43, Issue 1, February 2009, Pages 65-71

Lipodystrophy is a common long-term complication of HIV infection that may lead to decreased quality of life and less adherence to antiretroviral therapy (ART). A complete understanding of the etiology of HIV-associated lipodystrophy has not yet been achieved, although factors related to the virus, per se, and use of ART appear to be related.

Alcohol use is common among HIV-infected patients and has biological effects on fat distribution, yet alcohol's relationship to HIV-associated lipodystrophy has not been examined.

The goal of this clinical study was to assess the effect of alcohol consumption on lipodystrophy in HIV-infected adults with alcohol problems. This was a prospective study (2001–2006) of 289 HIV-infected persons with alcohol problems. The primary outcome was self-reported lipodystrophy, which was assessed at one time point (median 29 months after enrollment). Alcohol use was assessed every 6 months and classified as: abstinent at all interviews; ≥1 report of moderate drinking but no heavy drinking; 1 or 2 reports of heavy drinking; or ≥3 reports of heavy drinking. Multivariable logistic regression models were fit to the data.

Fifty-two percent (150/289) of subjects reported lipodystrophy. Alcohol consumption was: 34% abstinent at all interviews; 12% ≥1 report of moderate drinking, but no heavy drinking; 34% 1–2 reports of heavy drinking; and 20% ≥3 reports of heavy drinking. Although not statistically significant, subjects with alcohol use had a higher odds of lipodystrophy (adjusted odds ratios and 95% confidence interval: ≥1 report of moderate drinking, 2.36 [0.89, 6.24]; 1–2 reports of heavy drinking, 1.34 [0.69, 2.60]; ≥3 reports of heavy drinking, 2.07 [0.90, 4.73]).

Alcohol use may increase the odds of developing HIV-associated lipodystrophy among subjects with alcohol problems. However, larger studies are needed to fully elucidate the role and impact of alcohol consumption on the development of this common long-term complication of HIV infection and its treatment.

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Request Reprint E-Mail: dmcheng@bu.edu

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HTR3B is associated with alcoholism with antisocial behavior and alpha EEG power—an intermediate phenotype for alcoholism and co-morbid behaviors

Alcohol Volume 43, Issue 1, February 2009, Pages 73-84

Alcohol use disorders (AUD) with co-morbid antisocial personality disorder (ASPD) have been associated with serotonin (5-HT) dysfunction. 5-HT3 receptors are potentiated by ethanol and appear to modulate reward. 5-HT3 receptor antagonists may be useful in the treatment of early-onset alcoholics with co-morbid ASPD. Low-voltage alpha electroencephalogram (EEG) power, a highly heritable trait, has been associated with both AUD and ASPD.

A recent whole genome linkage scan in one of our samples, Plains American Indians (PI), has shown a suggestive linkage peak for alpha power at the 5-HT3R locus. We tested whether genetic variation within the HTR3A and HTR3B genes influences vulnerability to AUD with comorbid ASPD (AUD + ASPD) and moderates alpha power.

Our study included three samples: 284 criminal alcoholic Finnish Caucasians and 234 controls; two independent community-ascertained samples with resting EEG recordings: a predominantly Caucasian sample of 191 individuals (Bethesda) and 306 PI. In the Finns, an intronic HTR3B SNP rs3782025 was associated with AUD + ASPD (P = .004).

In the Bethesda sample, the same allele predicted lower alpha power (P = 7.37e−5). Associations between alpha power and two other HTR3B SNPs were also observed among PI (P = .03). One haplotype in the haplotype block at the 3′ region of the gene that included rs3782025 was associated with AUD + ASPD in the Finns (P = .02) and with reduced alpha power in the Bethesda population (P = .00009). Another haplotype in this block was associated with alpha power among PI (P = .03). No associations were found for HTR3A.

Genetic variation within HTR3B may influence vulnerability to develop AUD with comorbid ASPD. 5-HT3R might contribute to the imbalance between excitation and inhibition that characterize the brain of alcoholics.

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Request Reprint E-Mail: Francesca.Ducci@iop.kcl.uk

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