mTOR activation is required for the anti-alcohol effect of ketamine, but not memantine, in alcohol-preferring rats

 

Glutamate NMDA receptors mediate many molecular and behavioral effects of alcohol, and they play a key role in the development of excessive drinking. Uncompetitive NMDA receptor antagonists may, therefore, have therapeutic potential for alcoholism.

The first aim was to compare the effects of the NMDA antagonists memantine and ketamine on ethanol and saccharin drinking in alcohol-preferring rats. The second aim was to determine whether the effects of the two NMDA receptor antagonists were mediated by the mammalian target of rapamycin (mTOR).

TSRI Sardinian alcohol-preferring rats were allowed to self-administer either 10% w/v ethanol or 0.08% w/v saccharin, and water. Operant responding and motor activity were assessed following administration of either memantine (0–10 mg/kg) or ketamine (0–20 mg/kg). Finally, ethanol self-administration was assessed in rats administered with either memantine or ketamine but pretreated with the mTOR inhibitor rapamycin (2.5 mg/kg).

The uncompetitive NMDA receptor antagonists memantine and ketamine dose-dependently reduced ethanol drinking in alcohol-preferring rats; while memantine had a preferential effect on alcohol over saccharin, ketamine reduced responding for both solutions. Neither antagonist induced malaise, as shown by the lack of effect on water intake and motor activity. The mTOR inhibitor rapamycin blocked the effects of ketamine, but not those of memantine.

Memantine and ketamine both reduce alcohol drinking in alcohol-preferring rats, but only memantine is selective for alcohol. The effects of ketamine, but not memantine, are mediated by mTOR. The results support the therapeutic potential of uncompetitive NMDA receptor antagonists, especially memantine, in alcohol addiction.

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Request Reprint E-Mail:    vsabino@bu.edu

Alcohol hangover: Type and time-extension of motor function impairments

Alcohol hangover is defined as the unpleasant next-day state following an evening of excessive alcohol consumption. Hangover begins when ethanol is absent in plasma and is characterized by physical and psychological symptoms. During hangover cognitive functions and subjective capacities are affected along with inefficiency, reduced productivity, absenteeism, driving impairments, poor academic achievement and reductions in motor coordination.

The aim of this work was to study the type and length of motor and exploratory functions from the beginning to the end of the alcohol hangover.

Male Swiss mice were injected i.p. either with saline (control group) or with ethanol (3.8 g/kg BW) (hangover group). Motor performance, walking deficiency, motor strength, locomotion and exploratory activity were evaluated at a basal point (ZT0) and every 2 h up to 20 h after blood alcohol levels were close to zero (hangover onset).

Motor performance was 80% decreased at the onset of hangover (p < 0.001). Hangover mice exhibited a reduced motor performance during the next 16 h (p < 0.01). Motor function was recovered 20 h after hangover onset. Hangover mice displayed walking deficiencies from the beginning to 16 h after hangover onset (p < 0.05).

Moreover, mice suffering from a hangover, exhibited a significant decrease in neuromuscular strength during 16 h (p < 0.001). Averaged speed and total distance traveled in the open field test and the exploratory activity on T-maze and hole board tests were reduced during 16 h after hangover onset (p < 0.05).

Our findings demonstrate a time-extension between 16 to 20 h for hangover motor and exploratory impairments. As a whole, this study shows the long lasting effects of alcohol hangover.


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Request Reprint E-Mail:   analiakaradayian@conicet.gov.ar

Report to Congress on the Nation's Substance Abuse and Mental Health Workforce Issues

Provides an overview of the facts and issues affecting the substance abuse and mental health workforce in America. Presents demographic data on the workforce, major factors that impact the workforce, and efforts to address workforce challenges.


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Industry Use of Evidence to Influence Alcohol Policy: A Case Study of Submissions to the 2008 Scottish Government Consultation

 

Summary Points

• We examine how research evidence is used in alcohol industry submissions made to a Scottish Government consultation in 2008 to advocate policies in line with their commercial interests.
• Industry actors consistently oppose the approaches found in research to be most likely to be effective at a population level without actually engaging with the research literature in any depth.
• Strong evidence is misrepresented and weak evidence is promoted. Unsubstantiated claims are made about the adverse effects of unfavoured policy proposals and advocacy of policies favoured by industry is not supported by the presentation of evidence.
• The potential for corporations with vested interests to interfere with the evaluation of scientific evidence by policy makers needs to be restricted for effective policies to be designed.
• Studies of the nature of alcohol industry and other corporate influences on public policies can be informed by work already conducted on the tobacco industry.

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Briefing warns of sharp rise in admissions of older people with alcohol-related mental health problems

An Alcohol Concern briefing has warned of a 150% rise in hospital admissions for over 60’s with alcohol related mental health problems in the last decade. The briefing 'Trends in alcohol related admissions for older people with mental health problems: 2002 to 2012' finds a disproportionate rise amongst older adults, despite an overall rise in all adults and accounting for a growing older population.   > > > >  Read More

World Health Authorities meet in Istanbul to discuss alcohol policy

The Turkish Green Crescent Society will hold the first symposium on alcohol policies in Turkey with the World Health Organization. Margaret Chan, will be a guest speaker.

The Turkish Prime Minister, Recep Tayyip Erdogan, will attend the opening part of the symposium.

The “Global Alcohol Policy Symposium” will take place on April 26-27 and will bring together more than 1200 leading experts from 53 countries.   > > > >  Read More

Multi-cultural Association of the Serotonin Transporter Gene (SLC6A4) with Substance Use Disorder

 

 

A number of studies have reported associations between the serotonin transporter gene (SLC6A4) and alcohol, heroin, cocaine, or methamphetamine abuse. Other studies have yielded contrary results. There are a number of reasons for non-replication, including inadequate statistical power, population stratification, and poor phenotype definition.

 

This study was to test the association using a meta-analytic approach across a variety of racial and ethnic populations. Using the genotype data of 55 studies (7999 cases, 8264 controls, and 676 families or parent-offspring trios) published in the past 15 years, we have conducted comprehensive meta-analyses to examine the associations of the 5-HTTLPR and STin2 polymorphisms with substance use disorder.

 

The meta-analyses support the associations of 5-HTTLPR with alcohol, heroin, cocaine, and methamphetamine dependence and abuse (eg, the smallest P-values were 0.0058 with odds ratio (OR)=0.54 (0.35, 0.84); 0.0024 with OR=0.77 (0.66, 0.91); 0.018 with OR=1.38 (1.06, 1.81); and 0.028 with OR=0.46 (0.23, 0.92) for alcohol, heroin, cocaine, and methamphetamine dependence/abuse, respectively).

 

When all the phenotypes are combined, the P-value was 0.0006 with OR=0.86 (0.78, 0.94) in the combined European, Asian, and Mexican populations and P-value was 0.0028 with OR=1.41 (1.13, 1.78) in the African populations.

Evidence of significant associations was also identified in other subgroup analyses regarding differently combined substance and populations. The effect sizes of 5-HTTLPR were comparable among the European, Asian, and Mexican populations, however, the risk allele was more frequent in Asians than in Europeans and Mexicans. The opposite directions of risk allele in African population might be driven by the opposite directions of risk allele in cocaine dependence.

 

This meta-analysis supports that the association of the SLC6A4 gene with substance use disorder varies depending on substances with different risk allele frequencies in the multi-cultural populations. Further studies using larger sample size are warranted.

 

 

 

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Request Reprint E-Mail:  yctu_caojian@126.com.

Juvenile ethanol exposure increases rewarding properties of cocaine and morphine in adult DBA/2J mice

Convergent data showed that ethanol exposure during adolescence can alter durably ethanol-related behaviour at adulthood. However, the consequences of juvenile ethanol exposure on the reinforcing effects of other drugs of abuse remain unclear.

In the present work, we evaluated in adult male DBA/2J mice the effects of early ethanol exposure on the sensitivity to the incentive effects of cocaine and morphine, and on extracellular signal-regulated kinase (ERK) activation in response to cocaine. Juvenile male mice received intragastric administration of ethanol (2×2.5 g/kg/day) or water for 5 days starting on postnatal day 28. When reaching adult age (10 week-old), animals were subjected to an unbiased procedure to assess conditioned place preference (CPP) to cocaine or morphine. In addition, activation of ERK in response to an acute injection of cocaine was investigated using immunoblotting in the striatum and the nucleus accumbens.

Mice that have been subjected to early ethanol exposure developed CPP to doses of cocaine (5 mg/kg) or morphine (10 mg/kg) below the threshold doses to induce CPP in water pre-exposed mice. In addition, early ethanol administration significantly increased striatal ERK phosphorylation normally induced by acute cocaine (10 and 20 mg/kg) in adult mice.

These results show that, in DBA/2J mice, early exposure to ethanol enhanced the perception of the incentive effects of cocaine and morphine. Ethanol pre-exposure also induced a positive modulation of striatal ERK signalling, in line with the inference that juvenile ethanol intake may contribute to the development of addictive behaviour at adult age.


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Request Reprint E-Mail:    laurence.lanfumey@upmc.fr

Alcohol News - 16/2013

 

 

The Foreigner (Norway) - Norway Liberals liberate supermarket wine sales

It looks as though Norway might be moving towards a more (foreign) shopper-oriented alcohol policy just over five months before the general election. Last weekend’s national Party congress saw a majority vote in favour of wine and beer over 4.75 per cent alcohol by volume gracing the shelves of ordinary supermarkets and shops.

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The Local (Denmark/Sweden) - Danish beer bottles 'too sexy' for Sweden

A cartoon depiction of a topless woman has been deemed too sexy for Sweden's state run liquor store monopoly Systembolaget, forcing a brewery in Denmark to change the beer bottle's label for the Swedish stores.

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The Foriegner (Norway) - Supermarket wine will never work, says Norway trade organisation

Norwegian alcohol industry players think politicians and consumers will have a hangover after buying wine and strong beer in supermarkets.

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YLE.fi (Finland) - Alcohol industry claims higher taxes will mean tax losses

Finland's alcohol beverage industry says that a planned tax hike for its products will lead to more people buying cheaper drink in Estonia, depriving Finland of hundreds of millions in tax revenues.

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MedPage Today - Excess Alcohol Tied to Diabetes Precursor

Prediabetes in younger patients with early-stage hypertension may be one more risk to add to the list for heavy drinking, a study showed.

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Telegraph.co.uk (UK) - Minimum alcohol pricing may not happen over 'big, bossy government' fears

Minimum alcohol pricing may be scrapped over fears the Coalition would seem like a "big bossy government cracking down on people who don't have a problem", a health minister has admitted.

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U.S. News & World Report (USA) - Drunk Driving Not the Only Way Alcohol Leads to Teen Deaths: Study

Less than one-third of the 4,700 annual underage drinking-related deaths in the United States result from road crashes, according to a new study.

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Science Daily - Parents Can Help Their Children Avoid Alcohol Pitfalls During Transition from High School to College

Prior research has shown that the transition from high school to college is a particularly vulnerable time, associated with increased alcohol use and risk of negative alcohol-related consequences.

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Medical Xpress (Australia) - Australians drink to get drunk but want alcohol reforms

Australians are increasingly drinking alcohol to get drunk but just one in five believe they drink too much.

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UPI.com - Taste of beer, not alcohol, said trigger of urge to drink more

Just the taste of beer, even without alcohol, causes the release of brain chemicals that make us want to drink more and become intoxicated, U.S. scientists say.

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New Zealand Herald (New Zealand) - Alcohol most available in Chch's poorest suburbs

People living in Christchurch's poorest suburbs have the easiest access to booze and cause the most alcohol related harm.

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KYW Newsradio - Study: People Consume More Calories When Drinking Alcohol

If you feel like you’re eating more when you drink alcohol, you’re probably right. According to a study by the National Institute on Alcohol Abuse and Alcoholism, people consume more calories on days they drink than on days when they don’t imbibe.

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Irish Examiner (Ireland) - Expert: Ireland operates as ‘conveyor belt’ for alcohol industry

Ireland operates as a “conveyor belt” for the alcohol industry with 60,000 children starting to drink every single year, an Oireachtas committee has heard.

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aidsmap (EU) - Liver disease a major cause of illness and death across the EU: action needed to save lives

Liver disease is the cause of a considerable burden of illness across the European Union (EU), investigators report in The Journal of Hepatology. The authors calculate that 170,000 deaths each year are attributable to liver cirrhosis, with 47,000 of these caused by liver cancer. The main causes of liver disease were excess alcohol consumption, viral infections and obesity, all of which are “amenable to prevention and treatment”.

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Irish Independent (Ireland) - Doctors warn alcohol sponsorship of sports 'grooming' child drinkers

DOCTORS today demanded a ban on alcohol sponsorship of sporting events warning the drinks industry is “grooming” child drinkers.

Read more

 

 

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Common biological networks underlie genetic risk for alcoholism in African- and European-American populations

Alcohol dependence (AD) is a heritable substance addiction with adverse physical and psychological consequences, representing a major health and economic burden on societies worldwide. Genes thus far implicated via linkage, candidate gene and genome-wide association studies (GWAS) account for only a small fraction of its overall risk, with effects varying across ethnic groups.

Here we investigate the genetic architecture of alcoholism and report on the extent to which common, genome-wide SNPs collectively account for risk of AD in two US populations, African-Americans (AAs) and European-Americans (EAs).

Analyzing GWAS data for two independent case-control sample sets, we compute polymarker scores that are significantly associated with alcoholism (P=1.64 × 10^-3 and 2.08 × 10^-4 for EAs and AAs, respectively), reflecting the small individual effects of thousands of variants derived from patterns of allelic architecture that are population-specific.

Simulations show that disease models based on rare and uncommon causal variants best fit the observed distribution of polymarker signals. When scoring bins were annotated for gene location and examined for constituent biological networks, gene enrichment is observed for several cellular processes and functions in both EA and AA populations, transcending their underlying allelic differences.

Our results reveal key insights into the complex etiology of AD, raising the possibility of an important role for rare and uncommon variants, and identify polygenic mechanisms that encompass a spectrum of disease liability, with some, such as chloride transporters and glycine metabolism genes, displaying subtle, modifying effects that are likely to escape detection in most GWAS designs.


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Request Reprint E-Mail:    markz@txbiomedgenetics.org

Cognitive flexibility during breath alcohol plateau is associated with previous drinking measures

Although the biphasic effects of acute alcohol during ascending and descending Breath Alcohol Concentrations (BrACs) are well described, the plateau period between peak and steadily descending BrACs is generally unrecognized and under-studied by researchers. Naturalistic examinations indicate such periods persist for substantial intervals, with a time frame of onset suggesting BrAC plateaus may co-occur with potentially risky behaviors (e.g., driving).

The current pilot study examined neurocognitive performance during this period. Participants were healthy, community-residing moderate drinkers (n = 18). In the first phase of the study, the Digit Symbol Substitution and Trail Making Tasks were administered during BrAC plateau (M = 62 mg/dL).
BrACs were negatively correlated with Digit Symbol performance but unrelated to other tasks. In contrast, performance on a derived Trail Making measure of set-shifting was positively associated with the maximum alcohol doses consumed in the preceding 6 months.
Phase 2 analyses demonstrated that relationships between previous alcohol experience and cognitive performance were absent among individuals receiving placebo beverages.

Taken together, these data suggest a relationship worthy of investigation between previous drinking experiences and cognitive flexibility during the plateau phase.


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Request Reprint E-Mail:     benlewis@ufl.edu

Alcohol effects on synaptic transmission in periaqueductal gray dopamine neurons

The role of dopamine (DA) signaling in regulating the rewarding properties of drugs, including alcohol, has been widely studied. The majority of these studies, however, have focused on the DA neurons located in the ventral tegmental area (VTA), and their projections to the nucleus accumbens. DA neurons within the ventral periaqueductal gray (vPAG) have been shown to regulate reward but little is known about the functional properties of these neurons, or how they are modified by drugs of abuse. This lack of knowledge is likely due to the highly heterogeneous cell composition of the vPAG, with both γ-aminobutyric acid (GABA) and glutamate neurons present in addition to DA neurons.

In this study, we performed whole-cell recordings in a TH–eGFP transgenic mouse line to evaluate the properties of vPAG-DA neurons. Following this initial characterization, we examined how both acute and chronic alcohol exposure modify synaptic transmission onto vPAG-DA neurons.

We found minimal effects of acute alcohol exposure on GABA transmission, but a robust enhancement of glutamatergic synaptic transmission in vPAG-DA. Consistent with this effect on excitatory transmission, we also found that alcohol caused an increase in firing rate.

These data were in contrast to the effects of chronic intermittent alcohol exposure, which had no significant impact on either inhibitory or excitatory synaptic transmission on the vPAG-DA neurons.

These data add to a growing body of literature that points to alcohol having both region-dependent and cell-type dependent effects on function.


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

Cytisine modulates chronic voluntary ethanol consumption and ethanol-induced striatal up-regulation of ΔFosB in mice

 

Chronic administration of ethanol induces
persistent accumulation of ΔFosB, an important transcription factor, in the midbrain dopamine system. This process underlies the progression to addiction.

Previously, we have shown that cytisine, a neuronal nicotinic acetylcholine receptor (nAChR) partial agonist, reduces various ethanol-drinking behaviors and ethanol-induced striatal dopamine function. However, the effects of cytisine on chronic ethanol drinking and ethanol-induced up-regulation of striatal ΔFosB are not known.

Therefore, we examined the effects of cytisine on chronic voluntary ethanol consumption and associated striatal ΔFosB up-regulation in C57BL/6J mice using behavioral and biochemical methods. Following the chronic voluntary consumption of 15% (v/v) ethanol under a 24-h two-bottle choice intermittent access (IA; 3 sessions/week) or continuous access (CA; 24 h/d and 7 d/week) paradigm, mice received repeated intraperitoneal injections of saline or cytisine (0.5 or 3.0 mg/kg). Ethanol and water intake were monitored for 24 h post-treatment. Pretreatment with cytisine (0.5 or 1.5 mg/kg) significantly reduced ethanol consumption and preference in both paradigms at 2 h and 24 h post-treatment. The ΔFosB levels in the ventral and dorsal striatum were determined by Western blotting 18–24 h after the last point of ethanol access. In addition, cytisine (0.5 mg/kg) significantly attenuated up-regulation of ΔFosB in the ventral and dorsal striatum following chronic ethanol consumption in IA and CA paradigms.

The results indicate that cytisine modulates chronic voluntary ethanol consumption and reduces ethanol-induced up-regulation of striatal ΔFosB. Further, the data suggest a critical role of nAChRs in chronic ethanol-induced neurochemical adaptations associated with ethanol addiction.


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Request Reprint E-Mail:    shafiqur.rahman@sdstate.edu

Region-specific depression of striatal activity in Wistar rat by modest ethanol consumption over a ten-month period

The nucleus accumbens (nAc) is the primary target for the mesolimbic dopamine system and a key brain region for the reinforcing effects displayed by drugs of abuse, including ethanol. During the transition from recreational to compulsive consumption of reinforcing drugs, however, the dorsal striatum seems to be recruited. Understanding how synaptic activity is altered in a sub-region specific manner in the striatum during the course of long-term drug consumption thus could be essential for understanding the long-lasting changes produced by addictive substances, including ethanol.

Here we evaluated synaptic activity in the dorsolateral striatum (DLS) and ventral striatum (nucleus accumbens, nAc) of single-housed Wistar rats consuming water, or water and ethanol, for up to 10 months.

Even though ethanol intake was moderate, it was sufficient to decrease input/output function in response to stimulation intensity in the DLS, while recorded population spike (PS) amplitudes in the nAc were unaffected. Striatal disinhibition induced by the GABA_A receptor antagonist bicuculline had a slower onset in rats that had consumed ethanol for 2 months, and was significantly depressed in slices from rats that had consumed ethanol for 4 months. Bicuculline-induced disinhibition in the nAc, on the other hand, was not significantly altered by long-term ethanol intake. Changes in PS amplitude induced by taurine or the glycine receptor antagonist strychnine were not significantly altered by ethanol in any brain region.

Even though input/output function was not significantly affected by age, there was a significant decline in antagonist-induced disinhibition in brain slices from aged rats.

The data presented here suggest that even modest consumption of ethanol is sufficient to alter neurotransmission in the striatum, while synaptic activity appears to be relatively well-preserved in the nAc during the course of long-term ethanol consumption.


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Request Reprint E-Mail:   louise.adermark@neuro.gu.se

Shared risk: who engages in substance use with American homeless youth?

To identify characteristics of social network members with whom homeless youth engage in drinking and drug use.

 

A multi-stage probability sample of homeless youth completed a social network survey.

 

Forty-one shelters, drop-in centers and known street hangouts in Los Angeles County.

 

A total of 419 homeless youth, aged 13–24 years (mean age = 20.09, standard deviation = 2.80).

 

Respondents described 20 individuals in their networks, including their substance use and demographics, and the characteristics of the relationships they shared, including with whom they drank and used drugs. Dyadic, multi-level regressions identified predictors of shared substance use.

 

Shared drinking was more likely to occur with recent sex partners [odds ratio (OR) = 2.64, confidence interval (CI): 1.67, 4.18], drug users (OR = 4.57, CI: 3.21, 6.49), sexual risk takers (OR = 1.71, CI: 1.25, 2.33), opinion leaders (OR = 1.69, CI: 1.42, 2.00), support providers (OR = 1.41, CI: 1.03, 1.93) and popular people (those with high degree scores in the network) (OR = 1.07, CI: 1.01, 1.14). Shared drug use was more likely to occur with recent sex partners (OR = 2.44, CI: 1.57, 3.80), drinkers (OR = 4.53, CI: 3.05, 6.74), sexual risk takers (OR = 1.51, CI: 1.06, 2.17), opinion leaders (OR = 1.24, CI: 1.03, 1.50), support providers (OR = 1.83, CI: 1.29, 2.60) and popular people (OR = 1.16, CI: 1.08, 1.24).

 

Homeless youth in the United States are more likely to drink or use drugs with those who engage in multiple risk behaviors and who occupy influential social roles (popular, opinion leaders, support providers, sex partners). Understanding these social networks may be helpful in designing interventions to combat substance misuse.


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Request Reprint E-Mail:    hgreen@rand.org

Patterns of drug use in fatal crashes

To characterize drug prevalence among fatally injured drivers, identify significant associations (i.e. day of week, time of day, age, gender), and compare findings with those for alcohol.

 

Descriptive and logistic mixed-model regression analyses of Fatality Analysis Reporting System data.

 

US states with drug test results for >80% of fatally injured drivers, 1998–2010.

 

Drivers killed in single-vehicle crashes on public roads who died at the scene of the crash (n = 16 942).

 

Drug test results, blood alcohol concentration (BAC), gender, age and day and time of crash.

 

Overall, 45.1% of fatally injured drivers tested positive for alcohol (39.9% BAC ≥ 0.08) and 25.9% for drugs. The most common drugs present were stimulants (7.2%) and cannabinols (7.1%), followed by ‘other’ drugs (4.1%), multiple drugs (4.1%), narcotics (2.1%) and depressants (1.5%). Drug-involved crashes occurred with relative uniformity throughout the day while alcohol-involved crashes were more common at night (P < 0.01). The odds of testing positive for drugs varied depending upon drug class, driver characteristics, time of day and the presence of alcohol.


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Request Reprint E-Mail:    romano@pire.org

Conclusions

Fatal single-vehicle crashes involving drugs are less common than those involving alcohol and the characteristics of drug-involved crashes differ, depending upon drug class and whether alcohol is present. Concerns about drug-impaired driving should not detract from the current law enforcement focus on alcohol-impaired driving.

Relationship Between Alcohol Intake and Lipid Accumulation Product in Middle-aged Men

Lipid accumulation product (LAP), defined as a product of waist circumference and triglycerides, has recently been proposed as a predictor of cardiovascular disease and diabetes mellitus. The purpose of this study was to determine whether and how LAP is associated with alcohol drinking.

Subjects were 21,378 men aged 35–60 years and they were divided by alcohol intake into non-, light , heavy and very heavy drinkers. Relationships between alcohol intake and LAP were analyzed by using multivariate analyses with adjustment for age, smoking and habitual exercise.

Log-transformed LAP levels in light drinkers and very heavy drinkers were significantly (P< 0.01) lower and higher, respectively, than the level in non-drinkers, and the levels were comparable in non- and heavy drinkers (non-drinkers, 1.335 ± 0.005; light drinkers, 1.290 ± 0.009; heavy drinkers, 1.348 ± 0.005 and very heavy drinkers, 1.414 ± 0.006). The inverse association of alcohol intake with LAP was more prominent in smokers and subjects without regular exercise than in non-smokers and subjects with regular exercise, respectively, while the positive association of alcohol with LAP was more prominent in non-smokers than in smokers. Odds ratio for hyperglycemia of subjects with vs. subjects without high LAP was significantly higher than a reference level of 1.00, and this association was not different among the four alcohol groups.                    

There is a J-shaped relationship between alcohol intake and LAP, which is confounded by smoking and habitual exercise.


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Request Reprint E-Mail:   wakabaya@hyo-med.ac.jp

Prospective Effects of Adolescent Indicators of Behavioral Disinhibition on DSM-IV Alcohol, Tobacco, and Illicit Drug Dependence in Young Adulthood

To identify robust predictors of drug dependence.

This longitudinal study included 2361 male and female twins from an ongoing longitudinal study at the Center for Antisocial Drug Dependence (CADD) at the University of Colorado Boulder and Denver campuses. Twins were recruited for the CADD project while they were between the ages of 12 and 18. Participants in the current study were on average approximately 15 years of age during the first wave of assessment and approximately 20 years of age at the second wave of assessment. The average time between assessments was five years. A structured interview was administered at each assessment to determine patterns of substance use and Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; Fourth Edition) attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), and drug dependence symptoms. Cloninger’s Tridimensional Personality Questionnaire was also used to assess novelty seeking tendencies (NS). At the second wave of assessment, DSM-IV dependence symptoms were reassessed using the same interview. Path analyses were used to examine direct and indirect mechanisms linking psychopathology and drug outcomes.

Adolescent substance use, CD, and NS predicted young adult substance dependence, whereas the predictive effects of ADHD were few and inconsistent. Furthermore, CD and NS effects were partially mediated by adolescent substance use.

Adolescent conduct problems, novelty seeking, and drug use are important indices of future drug problems. The strongest predictor was novelty seeking.

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Request Reprint E-Mail:    Rohan_Palmer@Brown.edu   

An exploratory cluster randomised trial of a university halls of residence based social norms marketing campaign to reduce alcohol consumption among 1st year students

 

This exploratory trial examines the feasibility of implementing a social norms marketing campaign to reduce student drinking in universities in Wales, and evaluating it using cluster randomised trial methodology.

 

Fifty residence halls in 4 universities in Wales were randomly assigned to intervention or control arms. Web and paper surveys were distributed to students within these halls (n = 3800), assessing exposure/contamination, recall of and evaluative responses to intervention messages, perceived drinking norms and personal drinking behaviour. Measures included the Drinking Norms Rating Form, the Daily Drinking Questionnaire and AUDIT-C.

 

A response rate of 15% (n = 554) was achieved, varying substantially between sites. Intervention posters were seen by 80% and 43% of students in intervention and control halls respectively, with most remaining materials seen by a minority in both groups. Intervention messages were rated as credible and relevant by little more than half of students, though fewer felt they would influence their behaviour, with lighter drinkers more likely to perceive messages as credible. No differences in perceived norms were observed between intervention and control groups. Students reporting having seen intervention materials reported lower descriptive and injunctive norms than those who did not.

 

Attention is needed to enhancing exposure, credibility and perceived relevance of intervention messages, particularly among heavier drinkers, before definitive evaluation can be recommended. A definitive evaluation would need to consider how it would achieve sufficient response rates, whilst hall-level cluster randomisation appears subject to a significant degree of contamination.

 

 

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The First Case of Drug-Dependent Memory: The Biblical Lot in Talmudic and Midrashic Exegesis

The literature on alcohol and alcoholism has long noted how the effects of alcohol are reported in early sources, including religious texts such as the Bible and Talmud. In that vein, we suggest that the Bible, as elucidated according to long-established rabbinic interpretation, contains the earliest recorded case of drug-dependent memory, in the account of Lot's alcohol-facilitated incestuous relationships with his daughters (Genesis 19:29–38).

We posit that the Talmudic, Midrashic, and traditional rabbinic commentaries that support our reading of the Lot narrative convey keen understanding of the effects of alcohol on recall.

These Jewish sources, written centuries ago, demonstrate insight into the nature of alcohol-influenced cognitive function, which was thought to have been unknown prior to contemporary times.


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Request Reprint E-Mail:     schnall@yu.edu

Anandamide–CB1 Receptor Signaling Contributes to Postnatal Ethanol-Induced Neonatal Neurodegeneration, Adult Synaptic, and Memory Deficits

The transient exposure of immature rodents to ethanol during postnatal day 7 (P7), which is comparable with the third trimester in human pregnancy, induces synaptic dysfunctions. However, the molecular mechanisms underlying these dysfunctions are still poorly understood. Although the endocannabinoid system has been shown to be an important modulator of ethanol sensitivity in adult mice, its potential role in synaptic dysfunctions in mice exposed to ethanol during early brain development is not examined.

In this study, we investigated the potential role of endocannabinoids and the cannabinoid receptor type 1 (CB₁R) in neonatal neurodegeneration and adult synaptic dysfunctions in mice exposed to ethanol at P7. Ethanol treatment at P7, which induces neurodegeneration, increased anandamide (AEA) but not 2-arachidonylglycerol biosynthesis and CB₁R protein expression in the hippocampus and cortex, two brain areas that are important for memory formation and storage, respectively.                       

N-Arachidonoyl phosphatidylethanolamine–phospholipase D (NAPE–PLD), glycerophosphodiesterase (GDE1), and CB₁R protein expression were enhanced by transcriptional activation of the genes encoding NAPE–PLD, GDE1, and CB₁R proteins, respectively. In addition, ethanol inhibited ERK1/2 and AKT phosphorylation.

The blockade of CB₁Rs before ethanol treatment at P7 relieved ERK1/2 but not AKT phosphorylation and prevented neurodegeneration. CB₁R knock-out mice exhibited no ethanol-induced neurodegeneration and inhibition of ERK1/2 phosphorylation. The protective effects of CB₁R blockade through pharmacological or genetic deletion resulted in normal adult synaptic plasticity and novel object recognition memory in mice exposed to ethanol at P7.

The AEA/CB₁R/pERK1/2 signaling pathway may be directly responsible for the synaptic and memory deficits associated with fetal alcohol spectrum disorders.



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Request Reprint E-Mail:    Basavaraj@nki.rfmh.org

U.S. Alcohol Affordability and Real Tax Rates, 1950–2011

 

The affordability of alcoholic beverages, determined by the relationship of prices to incomes, may be an important factor in relation to heavy drinking, but little is known about how affordability has changed over time.

To calculate real prices and affordability measures for alcoholic beverages in the U.S. over the period from 1950 to 2011.

Affordability is calculated as the percentage of mean disposable income required to purchase 1 drink per day of the cheapest spirits, as well as popular brands of spirits, beer, and wine. Alternative income and price measures also are considered. Analyses were conducted in 2012.

One drink per day of the cheapest brand of spirits required 0.29% of U.S. mean per capita disposable income in 2011 as compared to 1.02% in 1980, 2.24% in 1970, 3.61% in 1960, and 4.46% in 1950. One drink per day of a popular beer required 0.96% of income in 2010 compared to 4.87% in 1950, whereas a low-priced wine in 2011 required 0.36% of income compared to 1.05% in 1978. Reduced real federal and state tax rates were an important source of the declines in real prices.

Alcoholic beverages sold for off-premises consumption are more affordable today than at any time in the past 60 years; dramatic increases in affordability occurred particularly in the 1960s and 1970s. Declines in real prices are a major component of this change. Increases in alcoholic beverage tax rates and/or implementing minimum prices, together with indexing these to inflation could be used to mitigate further declines in real prices.



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Nicotinic Acetylcholine Receptors Containing α6 Subunits Contribute to Alcohol Reward-Related Behaviors

Evidence is emerging that neuronal nicotinic acetylcholine receptors (nAChRs) in the mesolimbic dopamine (DA) system are involved in mediating the reinforcing effects of alcohol. Midbrain DA neurons express high levels of α6 subunit-containing nAChRs that modulate DA transmission, implicating their involvement in reward-related behaviors.

The present study assessed the role of α6-containing nAChRs in modulating alcohol reward using transgenic mice expressing mutant, hypersensitive α6 nAChR subunits (α6L9′S mice). α6L9′S mice and littermate controls were tested in three well-established models of alcohol reward: 24-hr two-bottle choice drinking, drinking in the dark (DID), and conditioned place preference (CPP). Confocal microscopy and patch-clamp electrophysiology were used to demonstrate the localization and function of hypersensitive α6 subunit-containing nAChRs.

Results indicate that female α6L9′S mice showed significantly higher alcohol intake at low concentrations of alcohol (3% and 6%) in the two-bottle choice procedure. Both male and female α6L9′S mice drank significantly more in the DID procedure and displayed an alcohol-induced place preference using a low dose of alcohol (0.5 g/kg) that was ineffective in littermate controls. Confocal microscopy showed that α6 subunit-containing nAChRs are selectively expressed on ventral tegmental area (VTA) DAergic, but not GABAergic neurons. Patch-clamp electrophysiology demonstrated that VTA DA neurons of α6L9′S mice are hypersensitive to ACh.

Collectively, these results suggest that α6L9′S mice are more sensitive to the rewarding effects of alcohol, and suggest that VTA α6 subunit-containing nAChRs modulate alcohol reward. Thus, α6 subunit-containing nAChRs may be a promising therapeutic target for treatment of alcohol use disorders.


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