Alcohol related deaths in young women rising in three UK cities but causes unclear

Research from the Glasgow Centre for Population Health has shown that alcohol-related deaths in women born in the 1970's have risen sharply in Glasgow, Manchester and Liverpool. The rise is much faster than in young men and goes against a national trend of stable alcohol-related deaths.

The research was recently published online in the Journal of Epidemiology and Community Health and has been widely reported in the press; see also an NHS choices review of the reporting and a comment piece on the Addaction blog.  > > > >   Read More

Policy Statement The Role of Recovery Residences in Promoting Long-term Addiction Recovery

Addiction and the larger arena of alcohol and other drug (AOD) abuse and related problems exact an enormous toll on individuals, families, organizations, local neighborhoods, and whole communities in the United States. Although a great number of advances have been made in AOD treatment, far too few individuals who could benefit from treatment receive it, and many who do receive treatment will resume AOD use following their discharge from it. New recovery support institutions are emerging beyond the arenas of traditional addiction treatment to support individuals hoping to initiate and to sustain long term recovery from addiction. One promising mechanism is the recovery residence.

Recovery residences (e.g., sober living houses, recovery homes, and Oxford HousesTM) are sober, safe, and healthy living environments that promote recovery from AOD use and associated problems. At a minimum, recovery residences offer peer-to-peer recovery support with some providing professionally delivered clinical services all aimed at promoting abstinence-based, long-term recovery. Recovery residences are sober living environments, meaning that residents are expected to abstain from alcohol and illegal drug use. Each credentialed recovery residence publishes policies on relapse sanctions and readmission criteria and other rules governing group living. Recovery residences may require abstinence from particular types of medications according to individual policy. Although the exact number is currently unknown, many thousands exist in the United States.

A small but growing body of research supports the effectiveness of recovery residences in sustaining abstinence and promoting gains in a variety of other domains, and the National Association of Recovery Residences has developed guidelines to define levels of care and standards to ensure the quality of care received. Yet, despite these advances, recovery residences face innumerable challenges. Critical questions regarding the operations and effects of recovery residence participation remain unanswered, and research scientists wishing to study recovery residences face considerable funding challenges given the prevailing funding emphasis on the neuroscience of addiction. Efforts to establish or relocate recovery residences face challenges with start-up funding and often face considerable neighborhood and political opposition. Also of importance, many health and human professionals are unaware of recovery residences and their benefits on long-term recovery outcomes.


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Alcohol questionnaires and HDL: Screening scores as scaled markers of alcohol consumption

Improving the quality of alcohol-related care requires practical approaches to assessing alcohol consumption to guide management and monitor outcomes. Given the increasing use of alcohol screening questionnaires to identify alcohol misuse it would be ideal if scores on screening questionnaires were also indicators of average alcohol consumption. However, the questionnaires were not designed for this purpose and include dimensions of drinking that may not reflect average consumption (e.g. heavy episodic drinking, alcohol-related problems).

In a general population sample, scores on the AUDIT-C screen correlated with reports of alcohol consumption in detailed interviews, but the relationship is unknown for clinical populations and other questionnaires. Serum high-density lipoprotein cholesterol (HDL) is a biomarker routinely obtained in clinical care and is known to rise with average alcohol consumption. This cross-sectional study of 11,175 male U.S. Veterans Affairs patients enrolled in a primary care study used HDL as an objective biomarker to evaluate whether average alcohol consumption increased as scores increased on 3 brief alcohol screens – the AUDIT-C, AUDIT Question #3 (a single-item screen), and the CAGE questionnaire.

Mean HDL progressively increased as screening scores increased for the AUDIT-C and AUDIT Question #3: about 12 mg/dL from the lowest to the highest scores. The association was much weaker for the CAGE questionnaire.

Results were minimally affected by adjustment for covariates (e.g. age, race, medical comorbidity, smoking, medication count, and depression) but the association was modified (p = 0.008) and mildly attenuated by adherent use of lipid-lowering medications.

This study using HDL as a biomarker of average alcohol consumption adds to evidence that some alcohol screening scores may also serve as scaled markers of average alcohol consumption.




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Request Reprint E-Mail:    douglas.berger@va.gov

Long-Term Ethanol and Corticosterone Co-Exposure Sensitize the Hippocampal CA1 Region Pyramidal Cells to Insult During Ethanol Withdrawal in an NMDA GluN2B Subunit-Dependent Manner

Chronic ethanol (EtOH) exposure produces neuroadaptations in NMDA receptor function and/or abundance and alterations in hypothalamic–pituitary–adrenal (HPA) axis functioning that contribute to neuronal excitation and neurotoxicity during ethanol withdrawal (EWD). Both EtOH and corticosterone (CORT) promote synthesis of polyamines, which allosterically potentiate NMDA receptor function at the GluN2B subunit. The current studies investigated the effect of 10-day EtOH and CORT co-exposure on toxicity during EWD in rat hippocampal explants and hypothesized that alterations in function and/or density of GluN2B subunits contribute to the toxicity.

 

Organotypic hippocampal slice cultures were exposed to CORT (0.01–1.0 μM) during 10-day EtOH exposure (50 mM) and 1 day of EWD. EtOH-naïve cultures were exposed to CORT for 11 days. Additional cultures were exposed to a membrane impermeable form of CORT (BSA-CORT) with and without 10-day EtOH exposure and EWD. Cytotoxicity (uptake of propidium iodide) was assessed in the pyramidal cell layer of the CA1 region. Western blot analysis was employed to assess the density of GluN2B subunits following EtOH and CORT exposure.

 

EWD did not produce overt neurotoxicity. However, co-exposure to EtOH/EWD and CORT produced significant neurotoxicity in the CA1 region pyramidal cell layer. Ifenprodil, a GluN2B polyamine site antagonist, significantly reduced toxicity from EtOH and CORT (0.1 μM) co-exposure during EWD. However, Western blots did not reveal differences in GluN2B subunit density among groups. Exposure to BSA-CORT did not produce toxicity, suggesting that membrane-bound CORT receptors did not significantly contribute to the observed toxicity.

 

These data suggest that CORT and EtOH co-exposure result in increased function of polyamine-sensitive GluN2B subunits, but this toxicity does not appear dependent on the abundance of hippocampal NMDA GluN2B subunits or membrane-bound CORT receptor function.


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Genetic Studies of Acute Tolerance, Rapid Tolerance, and Drinking in the Dark in the LXS Recombinant Inbred Strains

We hypothesized that rapid tolerance (1-day tolerance) for the duration of the loss of righting reflex (“sleep time” [ST]) was mediated by an increase in acute functional tolerance (AFT). We also hypothesized that increased AFT would correspond to increased drinking. These questions were addressed using the LXS recombinant inbred mouse strain panel.

Mice were given a pretreatment dose of either saline or 5 g/kg alcohol on day 1. On day 2, mice were tested for ST (4.1 g/kg) using a method with which it is possible to accurately assess AFT. Genetic correlation analysis was conducted among the ST-related variables and also with “drinking in the dark” (DID) which was previously measured by Saba and colleagues ().

 

Saline-pretreated mice showed a continuous distribution of ST ranging from ~40 minutes to over 3 hours. Of the 43 strains tested, 9 showed significantly decreased ST after alcohol pretreatment, while in 3 strains, ST was significantly increased. AFT scores ranged from 0 to over 200 mg% in the saline group, and in the alcohol group, 8 strains showed a significant increase in AFT and 2 strains showed significant decrease in AFT. In the saline group, AFT was significantly correlated with ST (r = −0.47), but not in the alcohol group (r = −0.22). DID was significantly correlated with only AFT in the alcohol pretreated group (r = 0.64).

 

The results suggest that AFT is an important component of the overall ST response, but that the alcohol pretreatment–induced change in AFT does not contribute to rapid ST tolerance. The significant correlation between DID and AFT in the alcohol group suggests that AFT may be a more relevant predictor of drinking behavior than the static measurement of ST. Moreover, preexposure to alcohol seems to change AFT in a way that makes it an even stronger predictor of drinking behavior.



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Request Reprint E-Mail:      Richard.Radcliffe@ucdenver.edu

Missing Data in Alcohol Clinical Trials: A Comparison of Methods

 


The rate of participant attrition in alcohol clinical trials is often substantial and can cause significant issues with regard to the handling of missing data in statistical analyses of treatment effects. It is common for researchers to assume that missing data is indicative of participant relapse, and under that assumption, many researchers have relied on setting all missing values to the worst-case scenario for the outcome (e.g., missing = heavy drinking). This sort of single-imputation method has been criticized for producing biased results in other areas of clinical research, but has not been evaluated within the context of alcohol clinical trials, and many alcohol researchers continue to use the missing = heavy drinking assumption.
 

Data from the COMBINE study, a multisite randomized clinical trial, were used to generate simulated situations of missing data under a variety of conditions and assumptions. We manipulated the sample size (n = 200, 500, and 1,000) and dropout rate (5, 10, 25, 30%) under 3 missing data assumptions (missing completely at random, missing at random, and missing not at random). We then examined the association between receiving naltrexone and heavy drinking during the first 10 weeks following treatment using 5 methods for treating missing data (complete case analysis [CCA], last observation carried forward [LOCF], missing = heavy drinking, multiple imputation [MI], and full information maximum likelihood [FIML]).

 

CCA, LOCF, and missing = heavy drinking produced the most biased naltrexone effect estimates and standard errors under conditions that are likely to exist in randomized clinical trials. MI and FIML produced the least biased naltrexone effect estimates and standard errors.

 

Assuming that missing = heavy drinking produces biased results of the treatment effect and should not be used to evaluate treatment effects in alcohol clinical trials.



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Request Reprint E-Mail:     khallg@unm.edu

Trait Aggression and Problematic Alcohol Use Among College Students: The Moderating Effect of Distress Tolerance

Trait aggression has been linked to alcohol-related problems among college students. However, the individual conditions underlying this association are unknown. Empirical evidence and theory suggest the importance of distress tolerance, defined as an individual's ability to withstand negative affective states, in the relationship between trait aggression and alcohol use. Therefore, the purpose of the current study was to examine whether distress tolerance moderates the relationship between trait aggression and problematic alcohol use.

 

Participants were 646 undergraduate students in a large university, who reported any lifetime alcohol use. The dependent variable, problematic alcohol use, was measured using the Alcohol Use Disorders Identification Test total score. The main independent variable, trait aggression, was assessed on the negative emotionality scale of the Multidimensional Personality Questionnaire, and the moderator, distress tolerance, was determined using the Distress Tolerance Scale.

 

Hierarchical linear regression analyses indicated a significant interaction between trait aggression and distress tolerance in predicting problematic alcohol use, adjusting for demographic variables, regular substance use, depressive symptoms, and anxiety symptoms. Specifically, a significant positive relationship between trait aggression and problematic alcohol use was present among those with low, but not high, distress tolerance.

 

Results provide evidence that college students with high levels of trait aggression are more likely to engage in problematic alcohol use if they also evidence an inability to tolerate negative affective states. Study implications are discussed, including the development of prevention and intervention programs that target distress tolerance skills.


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Request Reprint E-Mail:     daughter@unc.edu
 

The Placebo Effect in Clinical Trials for Alcohol Dependence: An Exploratory Analysis of 51 Naltrexone and Acamprosate Studies

The placebo effect often undermines efforts to determine treatment effectiveness in clinical trials. A significant placebo response occurs in alcohol trials, but it is not well understood. The purpose of this study was to characterize the placebo response across multiple naltrexone and acamprosate studies.

 

Fifty-one trials, 3 with a naltrexone and an acamprosate arm, 31 with at least 1 naltrexone arm, and 17 with at least 1 acamprosate arm, were identified from Cochrane reviews and PubMed search. To be included in this study, patients had to be at least 18 years old, abstinent from alcohol before randomization, and meet a diagnosis of alcohol dependence. Pearson correlation coefficients (r_p) and simple linear regression were used to describe the strength of linear relationships between placebo response and treatment effect size. Spearman's rank correlation coefficients (r_s) were used to examine the strength of associations between study characteristics and placebo response.

 

For the end point measures of percent days abstinent and total abstinence, a negative relationship was evident between placebo response and treatment effect size in the naltrexone trials (r_p = −0.55, p < 0.01 and r_p = −0.20, p = 0.35, respectively) as well as in the acamprosate trials (r_p = −0.45, p = 0.09 and r_p = −0.56, p = 0.01, respectively). The placebo response for percent days abstinent was negatively correlated with mean age of participants (r_s = −0.42, p = 0.05) across naltrexone trials and positively correlated with publication year (r_s = 0.57, p = 0.03) across acamprosate trials. However, these 2 study characteristics were not significantly correlated with treatment effect size.

 

The placebo response varied considerably across trials and was negatively correlated with the treatment effect size. Additional studies are required to fully understand the complex nature of the placebo response and to evaluate approaches to minimize its effects.


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

Global Actions: Commitments to Reduce Harmful Drinking. - July 24, 2013

 

 

 

Global Actions in Focus Brewers Association of Japan: STOP! Underage Drinking Campaign Twice a year, the Brewers Association of Japan launches the STOP! Underage Drinking Campaign, which raises awareness about the consequences of underage drinking. The STOP! campaign utilizes statistics and images to provide beverage alcohol education to youth, parents, and retailers. Advertisements are placed in newspapers and in transit stations where there are large populations of commuting youth. Stickers are also placed above train doors. In an effort to increase the campaign’s reach, large posters are featured in major city intersections and display the STOP! campaign logo and additional information about underage drinking. In 2011, the campaign was expanded to include internet advertisements and video advertisements on trains in an attempt to strengthen communication with youth. Internet campaign advertisements are featured as banner ads on sites such as Yahoo! Japan and are in the form of a game to actively engage underage viewers. In addition to visual media, the Brewers Association of Japan collaborates with several retail associations, including supermarkets and convenience stores, and the Karaoke Restaurant Association to deliver point of purchase (POP) posters with the STOP! logo. Surveys are conducted after each campaign to evaluate its effectiveness and gather suggested improvements. Since 2005, the Brewers Association of Japan has conducted seven STOP! Underage Drinking Campaigns and according to their latest post-campaign survey, have achieved a 90% recognition rate. In collaboration with the STOP! campaign, the Brewers Association of Japan also conducts the Prevention of Underage Drinking- Posters, Slogans and School Activities Contest. Started in 2002, the contest has been continued for 12 consecutive years. This initiative asks middle and high school students to submit posters, slogans, and school activities that promote the theme of anti-underage drinking. The contest is supported by the Ministry of Health, Ministry of Education, National Tax Agency, Cabinet Office, National Police Agency, PTA, Nursing Teachers Association, and Principles Association. Key Recent Milestones · India: Three life skills workshops promoting responsible drinking were hosted in India in June and July 2013. Two workshops in June involved approximately 200 participants from the Mumbai Police Department. Partnering with CII Bangalore for the third workshop in July, Global Actions provided information and training to approximately 35 Infosys employees. A fourth workshop for Blue Star Infotech employees will take place on July 26, 2013. What's Happening Next · Nigeria: A health education intervention will take place in Nigeria beginning the week of August 5, 2013. Volunteers will distribute fliers, hang posters, and host carnival-like events that promote “Don't Drink and Drive” to petroleum tanker drivers in Apapa, Lagos.

Commentary - Research Opportunities for Medications to Treat Alcohol Dependence: Addressing Stakeholders' Needs

During the past decade, significant advances have been made in the development of medications to treat alcohol dependence. Four medications have been approved by the U.S. Food and Drug Administration for treating alcohol dependence—naltrexone, injectable naltrexone, acamprosate, and disulfiram—and several others show promise.

The fact remains, however, that because of the heterogeneity of alcohol dependence, these medications will not work for all people, in all circumstances. Moreover, clinicians are not routinely prescribing these medications for alcohol treatment.

This commentary poses a number of issues that must be addressed in order to advance the alcohol research field and to make medications a mainstream treatment for problematic drinking.

These issues are framed from the perspective of the various stakeholders involved, including clinicians, patients, regulatory agencies, the pharmaceutical industry, and third-party payers.

Addressing these issues will not only help to improve treatment but, as further described, will also open up many new research opportunities for alcohol investigators in the coming decade.

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

A Daily Process Examination of the Bidirectional Relationship Between Craving and Alcohol Consumption as Measured Via Interactive Voice Response

Craving is a central component to alcohol use disorders, although there are contradictory findings in the literature regarding the importance of craving in alcohol use. The study goal was to examine the bidirectional relationship between craving and alcohol consumption in heavy drinkers.

 

Participants received brief alcohol interventions from their primary care physicians and then were asked to make daily reports of craving and alcohol consumption to an interactive voice response (IVR) telephone system for 180 days. The study sample included 246 participants (166 men) with mean age of 46. Ninety-seven percent were Caucasian and 66% met criteria for alcohol dependence. Analysis used generalized estimating equations (GEE) to evaluate whether craving intensity predicted next day alcohol consumption and whether alcohol consumption predicted next day craving intensity. Significant interactions with gender led to stratified analyses.

 

GEE analyses revealed a significant bidirectional relationship between craving and drinking, where craving intensity predicted next day total drinks consumed (p = 0.001), and total drinks predicted next day craving intensity (p = 0.02). Exploratory analysis found that gender significantly moderated the craving–drinking relationship (p = 0.002) with men increasing next day alcohol use more (b = 0.19) than women (b = 0.08).

 

Findings suggest a bidirectional relationship between craving and drinking may contribute to the development or maintenance of heavy drinking, particularly for men. Based on our findings, we recommend that during brief interventions, physicians address both drinking and craving and provide advice for coping with craving.


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Request Reprint E-Mail:  tfazzino@uvm.edu 

Altered Neural Processing of Threat in Alcohol-Dependent Men

Stress-response biological systems are altered in alcohol-dependent individuals and are reported to predict future relapse. This study was designed to assess neural disruptions in alcohol-dependent participants when exposed to a conditioned stimulus (CS) warning of the impending onset of a universal, nonpersonalized stressor.

 

Fifteen alcohol-dependent men abstinent for 3 to 5 weeks and 15 age- and race-similar healthy controls were studied. Anticipatory anxiety was induced by a CS paired with an uncertain, physically painful unconditioned stressor. Neural response was assessed using functional magnetic resonance imaging.

 

Both groups experienced significant, similar levels of anticipatory anxiety in response to the high-threat relative to the low-threat CS. Whereas control participants markedly increased the blood oxygen level-dependent (BOLD) amplitude in cortical–limbic–striatal regions during the high-threat, relative to low-threat, stimulus, alcohol-dependent participants decreased BOLD amplitude in the pregenual anterior cingulate cortex (pgACC), medial prefrontal cortex (mPFC), medial orbitofrontal cortex, posterior cingulate cortex (PCC), bilateral parietal/occipital cortex, and right hippocampus. Alcohol-dependent participants significantly deactivated pgACC/mPFC and PCC clusters, relative to controls, during the high- versus low-threat stimulus. This difference was due to a decrease in %BOLD amplitude during the high-threat stimulus in the alcohol-dependent, but not the control, participants.

 

Alcohol-dependent men show cortical–limbic–striatal deactivation during anticipatory anxiety, particularly in regions associated with emotional regulation. These findings suggest a lack of engagement of affective regulatory mechanisms during high-stress situations in alcohol-dependent men.


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Request Reprint E-Mail:  bryon.adinoff@utsouthwestern.edu
 

Alcohol, Other Drugs, and Health: Current Evidence

 

Table of Contents: July-August 2013

INTERVENTIONS & ASSESSMENTS

Screening and Brief Intervention: USPSTF Update Affirms Recommendations and Highlights Evidence Gapshttp://www.bu.edu/aodhealth/issues/issue_july13/saitz_moyer.html

Smoking During Medically Managed Opioid Withdrawal is Associated with Increased Craving for Opioids and Nicotinehttp://www.bu.edu/aodhealth/issues/issue_july13/walley_mannelli.html

Trends in Ambulatory Care for People with Substance Use Disordershttp://www.bu.edu/aodhealth/issues/issue_july13/kraemer_frank.html


HEALTH OUTCOMES

Alcohol Use Disorders: More Deadly Than Previously Thoughthttp://www.bu.edu/aodhealth/issues/issue_july13/friedmann_roerecke.html

Heavy Episodic Drinking in Young, Healthy Adults Increases Risk for Cardiovascular Diseasehttp://www.bu.edu/aodhealth/issues/issue_july13/tetrault_goslawski.html

Participation in Football and Wrestling is Associated with Nonmedical Use of Opioid Medications Among Adolescentshttp://www.bu.edu/aodhealth/issues/issue_july13/rastegar_veliz.html

Reporting of Methadone-Associated Cardiac Arrhythmias has Increasedhttp://www.bu.edu/aodhealth/issues/issue_july13/kraemer_kao.html

Relation of Alcohol Intake to the Risk of Dying from Cancerhttp://www.bu.edu/aodhealth/issues/issue_july13/ellison_jin.html

Systematic Review of Opioids for Pain and Opioid Dependence: The Risks Cannot be Estimatedhttp://www.bu.edu/aodhealth/issues/issue_july13/friedmann_minozzi.html

Subarachnoid Hemorrhage after Cocaine Use Associated with Aneurysm Re-Rupture and Deathhttp://www.bu.edu/aodhealth/issues/issue_july13/fairbairn_chang.html


HIV AND HCV

Daily Tenofovir Pre-Exposure Prophylaxis Reduces HIV Transmission among People with Injection Drug Use in Drug Treatmenthttp://www.bu.edu/aodhealth/issues/issue_july13/walley_choopanya.html

Persons Coinfected with HIV and Hepatitis C have Liver Fibrosis Measures Equal to Those with Hepatitis C Only who are Nearly a Decade Olderhttp://www.bu.edu/aodhealth/issues/issue_july13/rastegar_kirk.html

Response to HCV Treatment Among People with Heavy Alcohol Use is Similar to Those Who Abstainhttp://www.bu.edu/aodhealth/issues/issue_july13/bertholet_costentin.html


FEATURE ARTICLE: ETHICAL CONDUCT OF ALCOHOL AND OTHER DRUG RESEARCH

Confidentiality Protections in Research Involving People with Substance Use Disordershttp://www.bu.edu/aodhealth/issues/issue_july13/feature072013.html


SLIDE PRESENTATIONS

Update on Alcohol, Other Drugs, and Healthhttp://www.bu.edu/aodhealth/update.html

Journal Clubhttp://www.bu.edu/aodhealth/club/therapy.html



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Increased Receptor for Advanced Glycation End Product Expression in the Human Alcoholic Prefrontal Cortex is Linked to Adolescent Drinking.

Adolescence is characterized behaviorally by increased impulsivity and risk-taking that declines in parallel with maturation of the prefrontal cortex and executive function. In the brain, the receptor for advanced glycation end products (RAGE) is critically involved in neurodevelopment and neuropathology. In humans, the risk of alcoholism is greatly increased in those who begin drinking between 13 and 15 years of age, and adolescents binge drink more than any other age group. We have previously found that alcoholism is associated with increased expression of neuroimmune genes.

This manuscript tested the hypothesis that adolescent binge drinking upregulates RAGE and Toll-like receptor (TLR) 4 as well as their endogenous agonist, high-mobility group box 1 (HMGB1).

Immunohistochemistry, Western blot, and mRNA analyses found that RAGE expression was increased in the human post-mortem alcoholic orbitofrontal cortex (OFC). Further, an earlier age of drinking onset correlated with increased expression of RAGE, TLR4, and HMGB1.

To determine if alcohol contributed to these changes, we used an adolescent binge ethanol model in rats (5.0 g/kg, i.g., 2-day on/2-day off from postnatal day [P] 25 to P55) and assessed neuroimmune gene expression.

We found an age-associated decline of RAGE expression from late adolescence (P56) to young adulthood (P80). Adolescent intermittent ethanol exposure did not alter RAGE expression at P56, but increased RAGE in the young adult PFC (P80). Adolescent intermittent ethanol exposure also increased TLR4 and HMGB1 expression at P56 that persisted into young adulthood (P80).

Assessment of young adult frontal cortex mRNA (RT-PCR) found increased expression of proinflammatory cytokines, oxidases, and neuroimmune agonists at P80, 25 days after ethanol treatment.

Together, these human and animal data support the hypothesis that an early age of drinking onset upregulates RAGE/TLR4-HMGB1 and other neuroimmune genes that persist into young adulthood and could contribute to risk of alcoholism or other brain diseases associated with neuroinflammation.


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Request Reprint E-Mail:    rvetreno@email.unc.edu

Scrutiny of the CHRNA5-CHRNA3-CHRNB4 smoking behavior locus reveals a

 

 

The CHRNA5-CHRNA3-CHRNB4 gene cluster on chromosome 15q25.1 encoding the cholinergic nicotinic receptor subunits is robustly associated with smoking behavior and nicotine dependence. Only a few studies to date have examined the locus with alcohol related traits and found evidence of association with alcohol abuse and dependence. Our main goal was to examne the role of three intensively studied single nucleide polymorphisms, rs16969968, rs578776 and rs588765, tagging three distinct loci, in alcohol use.

 

Our sample was drawn from two independent Finnish population-based surveys, the National FINRISK Study and the Health 2000 (Health Examination) Survey. The combined sample included a total of 32,592 adult Finns
(54% women) of whom 8,356 were assessed for cigarettes per day (CPD). Data on alcohol use were available for 31,812 individuals.

We detected a novel association between rs588765 and alcohol use defined as abstainers and low-frequency drinkers versus drinkers (OR=1.15, p=0.00007). Additionally, we provide precise estimates of strength of the association between the three loci and smoking quantity in a very large population based sample.

As a conclusion, our results provide further evidence for the nicotine-specific role of rs16969968 (locus 1). Further, our data suggest that the effect of rs588765  (locus 3) may be specific to alcohol use as the effect is seen also in never smokers

 

 

 

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Selective Inhibition by Ethanol of Mitochondrial Calcium Influx Mediated by Uncoupling Protein-2 in Relation to N-Methyl-D-Aspartate Cytotoxicity in Cultured Neurons

We have shown the involvement of mitochondrial uncoupling protein-2 (UCP2) in the cytotoxicity by N-methyl-D-aspartate receptor (NMDAR) through a mechanism relevant to the increased mitochondrial Ca²⁺ levels in HEK293 cells with acquired NMDAR channels. Here, we evaluated pharmacological profiles of ethanol on the NMDA-induced increase in mitochondrial Ca²⁺ levels in cultured murine neocortical neurons.

In neurons exposed to glutamate or NMDA, a significant increase was seen in mitochondrial Ca²⁺ levels determined by Rhod-2 at concentrations of 0.1 to 100 µM. Further addition of 250 mM ethanol significantly inhibited the increase by glutamate and NMDA in Rhod-2 fluorescence, while similarly potent inhibition of the NMDA-induced increase was seen after exposure to ethanol at 50 to 250 mM in cultured neurons. Lentiviral overexpression of UCP2 significantly accelerated the increase by NMDA in Rhod-2 fluorescence in neurons, without affecting Fluo-3 fluorescence for intracellular Ca²⁺ levels. In neurons overexpressing UCP2, exposure to ethanol resulted in significantly more effective inhibition of the NMDA-induced increase in mitochondrial free Ca²⁺ levels than in those without UCP2 overexpression, despite a similarly efficient increase in intracellular Ca²⁺ levels irrespective of UCP2 overexpression. Overexpression of UCP2 significantly increased the number of dead cells in a manner prevented by ethanol in neurons exposed to glutamate. In HEK293 cells with NMDAR containing GluN2B subunit, more efficient inhibition was similarly induced by ethanol at 50 and 250 mM on the NMDA-induced increase in mitochondrial Ca²⁺ levels than in those with GluN2A subunit. Decreased protein levels of GluN2B, but not GluN2A, subunit were seen in immunoprecipitates with UCP2 from neurons with brief exposure to ethanol at concentrations over 50 mM.

Ethanol could inhibit the interaction between UCP2 and NMDAR channels to prevent the mitochondrial Ca²⁺ incorporation and cell death after NMDAR activation in neurons.


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MicroRNA expression profile and functional analysis reveal that miR-382 is a critical novel gene of alcohol addiction

Alcohol addiction is a major social and health concern. Here, we determined the expression profile of microRNAs (miRNAs) in the nucleus accumbens (NAc) of rats treated with alcohol. The results suggest that multiple miRNAs were aberrantly expressed in rat NAc after alcohol injection. Among them, miR-382 was down-regulated in alcohol-treated rats.

In both cultured neuronal cells in vitro and in the NAc in vivo, we identified that the dopamine receptor D1 (Drd1) is a direct target gene of miR-382. Via this target gene, miR-382 strongly modulated the expression of DeltaFosB. Moreover, overexpression of miR-382 significantly attenuated alcohol-induced up-regulation of DRD1 and DeltaFosB, decreased voluntary intake of and preference for alcohol and inhibited the DRD1-induced action potential responses.

The results indicated that miRNAs are involved in and may represent novel therapeutic targets for alcoholism.


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Neonatal ethanol exposure results in dose-dependent impairments in the acquisition and timing of the conditioned eyeblink response and altered cerebellar interpositus nucleus and hippocampal CA1 unit activity in adult rats

Exposure to ethanol in neonatal rats results in reduced neuronal numbers in the cerebellar cortex and deep nuclei of juvenile and adult animals. This reduction in cell numbers is correlated with impaired delay eyeblink conditioning (EBC), a simple motor learning task in which a neutral conditioned stimulus (CS; tone) is repeatedly paired with a co-terminating unconditioned stimulus (US; periorbital shock). Across training, cell populations in the interpositus (IP) nucleus model the temporal form of the eyeblink-conditioned response (CR). The hippocampus, though not required for delay EBC, also shows learning-dependent increases in CA1 and CA3 unit activity.

In the present study, rat pups were exposed to 0, 3, 4, or 5 mg/kg/day of ethanol during postnatal days (PD) 4–9. As adults, CR acquisition and timing were assessed during 6 training sessions of delay EBC with a short (280 ms) interstimulus interval (ISI; time from CS onset to US onset) followed by another 6 sessions with a long (880 ms) ISI. Neuronal activity was recorded in the IP and area CA1 during all 12 sessions.

The high-dose rats learned the most slowly and, with the moderate-dose rats, produced the longest CR peak latencies over training to the short ISI. The low dose of alcohol impaired CR performance to the long ISI only. The 3E (3 mg/kg/day of ethanol) and 5E (5 mg/kg/day of ethanol) rats also showed slower-than-normal increases in learning-dependent excitatory unit activity in the IP and CA1. The 4E (4 mg/kg/day of ethanol) rats showed a higher rate of CR production to the long ISI and enhanced IP and CA1 activation when compared to the 3E and 5E rats.

The results indicate that binge-like ethanol exposure in neonatal rats induces long-lasting, dose-dependent deficits in CR acquisition and timing and diminishes conditioning-related neuronal excitation in both the cerebellum and hippocampus.


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Request Reprint E-Mail:      lindquist.40@osu.edu