Variation In Alcohol Intake Research Articles

Validation and characterisation of a DNA methylation alcohol biomarker across the life course

BackgroundRecently, an alcohol predictor was developed using DNA methylation at 144 CpG sites (DNAm-Alc) as a biomarker for improved clinical or epidemiologic assessment of alcohol-related ill health. We validate the performance and characterise the drivers of this DNAm-Alc for the first time in independent populations.ResultsIn N = 1049 parents from the Avon Longitudinal Study of Parents and Children (ALSPAC) Accessible Resource for Integrated Epigenomic Studies (ARIES) at midlife, we found DNAm-Alc explained 7.6% of the variation in alcohol intake, roughly half of what had been reported previously, and interestingly explained a larger 9.8% of Alcohol Use Disorders Identification Test (AUDIT) score, a scale of alcohol use disorder. Explanatory capacity in participants from the offspring generation of ARIES measured during adolescence was much lower. However, DNAm-Alc explained 14.3% of the variation in replication using the Head and Neck 5000 (HN5000) clinical cohort that had higher average alcohol consumption. To investigate whether this relationship was being driven by genetic and/or earlier environment confounding, we examined how earlier versus concurrent DNAm-Alc measures predicted AUDIT scores. In both ARIES parental and offspring generations, we observed associations between AUDIT and concurrent, but not earlier DNAm-Alc, suggesting independence from genetic and stable environmental contributions.ConclusionsThe stronger relationship between DNAm-Alcs and AUDIT in parents at midlife compared to adolescents despite similar levels of consumption suggests that DNAm-Alc likely reflects long-term patterns of alcohol abuse. Such biomarkers may have potential applications for biomonitoring and risk prediction, especially in cases where reporting bias is a concern.

P.2.021 - Functional changes in the dorsolateral striatum in loss of control over reward seeking

Substance addiction inflicts an enormous burden on patients with formidable costs to society. Loss of control over substance use is a hallmark of addiction. It marks the stage where substance use has progressed from casual to compulsive and persists despite negative consequences. It is thought that this progression arises after lengthy and excessive substance use, as a result of neurobiological dysfunctions. One of the neural mechanisms that has been proposed to contribute to loss of control use is exaggerated involvement of the dorsolateral striatum (DLS), which mediates habitual behaviour [1,2]. This study examines how changes in DLS functioning contribute to loss of control over reward seeking. First, we assessed the effect of long-term exposure to alcohol on synaptic plasticity in a cortical projection onto neurons in the DLS. To map cortical inputs towards the DLS, rats were bilaterally injected with a retrograde rabies virus (Rabies-SadDG-GFP) in the DLS. Using immunohistochemistry, we found GFP expression in different cortical areas, including the primary and secondary motor cortex. Next, voluntary home-cage alcohol consumption was monitored in outbred Lister-Hooded rats. We used a two-month intermittent alcohol access paradigm and found substantial individual variation in alcohol intake, consistent with our previous findings. Based on a rank score of their voluntary alcohol intake, low and high consuming animals were then selected and bilaterally injected with an adeno-associated Channelrhodopsin virus (AAV5-CamKII-Chr2-eYFP) targeted at the identified motor cortices that project onto neurons in the DLS. Whole-cell patch clamp recordings were performed to measure optically induced excitatory post-synaptic currents in neurons in the DLS. Our preliminary results indicate increased facilitation of paired-pulse responses in the DLS in rats that show a high voluntary alcohol consumption. This increase is caused by reduced amplitude of the first post-synaptic response, indicative of a reduced presynaptic release probability. In parallel, we assessed whether activation of the DLS is sufficient to drive habitual behaviour and loss of control over sucrose seeking. To investigate habitual behavior, changes in sensitivity for outcome devaluation were measured after pre-feeding animals with either sucrose or chow before operant training. Loss of control over sucrose seeking was examined in a task in which we measure continued responding during a conditioned cue that predicts probabilistic footshock punishment. To enhance neuronal activity of the DLS, rats received bilateral injections of an adeno-associated DREADD virus (AAV5-hSyn-hMD3q-mCherry). Systemic clozapine N-oxide (CNO) injections did not change the sensitivity to outcome devaluation. Furthermore, we show that the presentation of the footshock-predictive cue profoundly suppresses responding for sucrose, but this is unaffected by CNO injections. In sum, our data indicate that long-term ingestion of large quantities of alcohol modulates short-term synaptic plasticity in glutamatergic cortical inputs into the DLS. However, chemogenetic activation of the DLS does not seem sufficient to evoke habitual or compulsive behaviour.

Individual Variation in Alcohol Intake Predicts Reinforcement, Motivation, and Compulsive Alcohol Use in Rats.

Alcohol is one of the most commonly used psychoactive substances. Prolonged alcohol use can result in alcohol use disorder (AUD), characterized by excessive and compulsive alcohol consumption. Importantly, however, the development of AUD only happens in a minority of individuals who consume alcohol. To understand the individual vulnerability for AUD, models that capture both the individual variability in alcohol consumption and the transition from casual to compulsive alcohol use are essential. Individual variability in voluntary alcohol intake and the preference for alcohol were assessed under continuous alcohol access (CAA) and intermittent-every-other-day alcohol access (IAA) schedules in the home cage using outbred Lister Hooded rats. Subsequently, the reinforcing properties of alcohol were tested in an operant setting. In subsequent experiments, we performed a quinine adulteration experiment to assess inflexible alcohol consumption and blood alcohol levels (BALs) were assessed after voluntary alcohol consumption. We found marked individual differences in alcohol consumption and preference under both access schedules, whereby subgroups of high- and low-alcohol-drinking rats (HD and LD) could be identified. HD with IAA increased their alcohol intake over days in the first month, whereas LD did not. Moreover, when alcohol access time was extended from 7 to 24 h/d for rats with IAA, alcohol intake profoundly increased in HD with IAA, whereas LD with IAA maintained low levels of alcohol intake. Furthermore, HD earned more alcohol than LD under both fixed ratio and progressive ratio schedules of reinforcement. We further found that HD continued their intake of a quinine-adulterated alcohol solution to a larger extent than LD and HD showed higher BALs after 30 minutes of alcohol consumption. These profound individual differences in alcohol intake, reinforcement, motivation, and AUD-like behavior provide a promising tool to unravel the neurobehavioral underpinnings of individual vulnerability for AUD.

The enigma of 'harmful' alcohol consumption: evidence from a mixed methods study involving female drinkers in Scotland.

An appreciation of the drinking patterns of population subgroups may usefully inform tailored interventions. For this purpose, research has highlighted a need to better describe the drinking behaviour of UK women. This study aims to characterise the purchasing and consumption behaviour of female heavy, harmed, drinkers in contact with Scottish health services in two cities and to explore the factors that influence the link to harm. Mixed methods study involving cross-sectional survey questionnaires and one-to-one interviews (5). The questionnaires documented (1) demographic data (including derived deprivation score), last week's (or 'typical' weekly) consumption (type, brand, volume, price, place of purchase), self-reported illnesses, and (2) Alcohol-Related Problem Questionnaire score. A total of 181 patients with serious health problems linked to alcohol were recruited within National Health Service (NHS) hospital clinics (in- and outpatient settings), in two Scottish cities during 2012. Median consumption was 157.6 UK units for the recorded week, with almost exclusive purchase from 'off-sale' retail outlets. Preferred drinks were white cider, vodka and white wine. Increasing problems was positively associated with drinking more in the week, being younger and belonging to Glasgow. For Scottish women, the current definition of 'harmful' consumption likely captures a fourfold variation in alcohol intake, with gender differences less apparent. While current alcohol-related harm is positively associated with dose and being younger, there is clear evidence of an influence of the less tangible 'Glasgow effect'. Future harm concerns are warranted by data relating to pattern, alcohol dose and cigarette use.

Explaining Individual Differences in Alcohol Intake in Adults: Evidence for Genetic and Cultural Transmission?

The current study aimed to describe what proportion of variation in adult alcohol intake is attributable to genetic differences among individuals and what proportion to differences in environmental experiences individuals have been exposed to. Effects of age, gender, spousal resemblance, and cultural transmission of alcohol intake from parents to offspring were taken into account. In a twin-family design, the effects of genetic and cultural transmission and shared and nonshared environment on alcohol intake were estimated with genetic structural equation models. Data originated from adult twins, their siblings, parents (n = 12,587), and spouses (n = 429) registered with the population-based Netherlands Twin Register (63.5% female; ages 18-97 years). Alcohol intake (grams per day) was higher among men than women and increased with age. Broad-sense heritability estimates were similar across sex and age (53%). Spousal resemblance was observed (r = .39) but did not significantly affect the heritability estimates. No effects of cultural transmission were detected. In total, 23% of the variation in alcohol intake was explained by additive genetic effects, 30% by dominant (nonadditive) gene action, and 47% by environmental effects that were not shared among family members. Individual differences in adult alcohol intake are explained by genetic and individual-specific environmental effects. The same genes are expressed in males and females and in younger and older participants. A substantial part of the heritability of alcohol intake is attributable to nonadditive gene action. Effects of cultural transmission that have been reported in adolescence are not present in adulthood.

Pre‐diagnostic alcohol consumption and breast cancer recurrence and mortality: Results from a prospective cohort with a wide range of variation in alcohol intake

The association between pre-diagnostic alcohol consumption and breast cancer recurrence and breast cancer specific mortality was investigated in 1,052 women diagnosed with early breast cancer in a prospective cohort of 29,875 women. Known clinical, lifestyle and socioeconomic risk factors were evaluated and adjusted for in multivariate analysis. We found a modest but significant association between pre-diagnostic alcohol consumption and breast cancer recurrence with a median follow-up of six years after date of diagnosis, both when using baseline measures of alcohol intake (HR, 1.65; 95% CI, 1.02-2.67; >2 units/day vs. ≤1 unit/day) and cumulated alcohol intake (HR, 2.02; 95% CI, 1.06-3.85; >40 drinking years vs. 0<drinking years≤10). Results for breast cancer specific mortality were also suggestive of a higher risk but were not statistically significant. In addition to being a risk factor for breast cancer, a high pre-diagnostic alcohol intake also seems to have an effect on the course of the disease. We could not relate the finding to a specific tumor presentation.

A self-administered Timeline Followback to measure variations in underage drinkers' alcohol intake and binge drinking

Underage drinkers typically have not developed regular patterns of drinking and so are likely to exhibit situational variation in alcohol intake, including binge drinking. Information about such variation is not well captured by quantity/frequency (QF) measures, which require that drinkers blend information over time to derive a representative estimate of “typical” drinking. The Timeline Followback (TLFB) method is designed to retrospectively capture situational variations in drinking during a specific period of time. We compared our newly-developed Self-administered TLFB (STLFB) measure to a QF measure for reporting alcohol intake. Our sample of 429 (men = 204; women = 225) underage (i.e., age 18–20 years) drinkers completed the two drinking measures and reported on alcohol problems. The STLFB and QF measures converged in assessing typical daily intake, but the STLFB provided more information about situational variations in alcohol use and better identification of regular versus intermittent binge drinkers. Regular binge drinkers reported more alcohol problems. The STLFB is an easy-to-administer measure of variations in alcohol intake, which can be useful for understanding drinking behavior.

Effect of alcohol on risk of coronary heart disease and stroke: causality, bias, or a bit of both?

Epidemiological studies of middle-aged populations generally find the relationship between alcohol intake and the risk of coronary heart disease (CHD) and stroke to be either U- or J-shaped. This review describes the extent that these relationships are likely to be causal, and the extent that they may be due to specific methodological weaknesses in epidemiological studies. The consistency in the vascular benefit associated with moderate drinking (compared with non-drinking) observed across different studies, together with the existence of credible biological pathways, strongly suggests that at least some of this benefit is real. However, because of biases introduced by: choice of reference categories; reverse causality bias; variations in alcohol intake over time; and confounding, some of it is likely to be an artefact. For heavy drinking, different study biases have the potential to act in opposing directions, and as such, the true effects of heavy drinking on vascular risk are uncertain. However, because of the known harmful effects of heavy drinking on non-vascular mortality, the problem is an academic one. Studies of the effects of alcohol consumption on health outcomes should recognise the methodological biases they are likely to face, and design, analyse and interpret their studies accordingly. While regular moderate alcohol consumption during middle-age probably does reduce vascular risk, care should be taken when making general recommendations about safe levels of alcohol intake. In particular, it is likely that any promotion of alcohol for health reasons would do substantially more harm than good.

Alcohol Intake in Middle Age and Risk of Cardiovascular Disease and Mortality: Accounting for Intake Variation over Time

Moderate alcohol consumption is associated with a decreased risk of cardiovascular disease. However, the impact of variation in alcohol intake over time on estimated risk relations has not been adequately addressed. In this study, 6,544 middle-aged British men without previous cardiovascular disease were followed for cardiovascular events and all-cause mortality over 20 years from 1978/1980 to 1998/2000. Alcohol intake was ascertained at regular points throughout the study. A total of 922 men had a major coronary event within 20 years, 352 men had a stroke, and 1,552 men died of all causes. Baseline alcohol intake displayed U-shaped relations with cardiovascular disease and all-cause mortality, with light drinkers having the lowest risks and nondrinkers and heavy drinkers having similarly high risks. However, the nature of these relations changed after adjustment for intake variation; risks associated with nondrinking were lowered, and risks associated with moderate and heavy drinking increased. Regular heavy drinkers had a 74% higher risk of a major coronary event, a 133% higher risk of stroke, and a 127% higher risk of all-cause mortality than did occasional drinkers (these estimates were 8%, 54%, and 44% before adjustment for intake variation). The findings suggest that considerable caution may be needed before any recommendations regarding acceptable limits of alcohol consumption are made.

THE INTERACTION BETWEEN VOLUNTARY ALCOHOL CONSUMPTION AND DIETARY CHOICE

The influence of forced and voluntary alcohol intake on the choice by AA (heavy drinking) and ANA (light drinking) rats between carbohydrate, protein and fat was studied. Alcohol consumption reduced the carbohydrate intake but did not influence the total energy consumption. In AA rats on free choice, voluntary alcohol intake correlated negatively with carbohydrate consumption but positively with protein and water intake. It was also found that the day to day variation in alcohol intake was of the same order as those in carbohydrate, protein and water intake and smaller than that in fat consumption. These findings in addition to earlier observations point to a regulation of alcohol intake in rats which in many respects resembles the regulation of dietary choice.

The utility of self-report and biological measures of alcohol consumption in alcoholism treatment outcome studies

Despite the significant advances of the past 20 years, serious questions have been raised about the value of alcoholism treatment outcome research due to the purported invalidity of alcoholics' self-report data for which biological measures of alcohol consumption have been suggested as a solution. The literature does not support widespread skepticism of alcoholics' self-reports or the existence of a systematic underreporting bias except when alcoholics have a positive blood alcohol level. Available evidence shows good reliability and validity for reports of hospital/jail stays and frequency of drinking/abstinence; good reliability and modest agreement with collateral informants for measures of problem severity and alcohol dependence symptoms. For amount consumed, reliability is good for outpatient but not for inpatient or residential alcoholics and validity in the form of agreement with collateral reports is not good except in problem drinkers at followup. Unfortunately, currently available biological markers do not solve the problems of measuring alcohol consumption in outcome studies. Markers correlate only modestly with self-reported consumption, are affected by factors other than alcohol consumption, show large individual differences in response to variations in alcohol intake, have an overly long half-life in certain cases, provide a specific but not very sensitive indicator of poor outcome, and may present compliance problems especially among chronic alcoholics. Nonetheless, markers can be used as part of a convergent validity approach and as a measure of negative alcohol-related health consequences. Suggestions for current practices in the field and for future research directions are provided.

Zimelidine-induced variations in alcohol intake by nondepressed heavy drinkers.

The effect of zimelidine, a specific serotonin-reuptake inhibitor, on alcohol intake was tested in 13 healthy male, nondepressed heavy drinkers who were randomly allocated to receive zimelidine or placebo in a double-blind, crossover experiment. There were five 2-wk experimental periods (baseline, placebo 1 and 2, and zimelidine 1 and 2). Treatment was discontinued in three subjects due to a suspected adverse reaction and three other subjects dropped out. Thus, 13 subjects participated in at least two experimental drug periods and only 10 participated in all the periods. In the 13 subjects zimelidine increased the days of abstinence and decreased the daily number of drinks consumed, whereas in the 10 subjects only the number of days of abstinence increased. Subjects did not report aversive alcohol-sensitizing reactions. Spielberger state-anxiety test scores and depression scores (Montgomery/Asberg and Hamilton) were low at the beginning and throughout the study. Our data suggest that zimelidine modifies alcohol intake by a different mechanism than previously tested drugs, possibly by modulating the central neural mechanism that controls drinking of alcohol.