Levels Of Alcohol Exposure Research Articles

The neuroimmune system - Where aging and excess alcohol intersect.

As the percentage of the global population over age 65 grows, and with it a subpopulation of individuals with alcohol use disorder (AUD), understanding the effect of alcohol on the aged brain is of utmost importance. Neuroinflammation is implicated in both natural aging as well as alcohol use, and its role in alterations to brain morphology and function may be exacerbated in aging individuals who drink alcohol to excess. The neuroimmune response to alcohol in aging is complex. The few studies investigating this issue have reported heightened basal activity and either hypo- or hyper-reactivity to an alcohol challenge. This review of preclinical research will first introduce key players of the immune system, then explore changes in neuroimmune function with aging or alcohol alone, with discussion of vulnerable brain regions, changes in cytokines, and varied reactions of microglia and astrocytes. We will then consider different levels of alcohol exposure, relevant animal models of AUD, and neuroimmune activation by alcohol across the lifespan. By identifying key findings, challenges, and targets for future research, we hope to bring more attention and resources to this underexplored area of inquiry.

Using Geovisualization Tools to Examine Attitudes towards Alcohol Exposure in Urban Environments: A Pilot Study in Madrid, Spain.

Pervasiveness of alcohol products and their promotion in the urban landscape may normalize alcohol consumption. This study aims to utilize geovisualization-based methods to assess attitudes towards different levels of alcohol exposure in the urban environment. We selected a typical downtown location, Lavapiés Square in Madrid, Spain, to conduct our study. First, we designed and created realistic 3D models simulating three different urban scenes with varying degrees of exposure to alcohol in the environment. Second, we used a survey on 159 adults to explore the level of acceptance of, attitudes towards, and perceptions of alcohol exposure in each scene. Participants reported a higher level of comfort in the scene with null alcohol exposure compared with the other scenes (p < 0.001). Acceptance towards alcohol exposure decreased as the level of alcohol elements increased in the scenes (p < 0.01). Acceptance also decreased when children were present in the scenes (p < 0.01). This study demonstrated that geovisualization tools provide a useful and well-suited approach to analyze perceptions of the alcohol environment. The use of geovisualization can help understand attitudes and perceptions towards the alcohol environment and may offer a way to simulate different scenarios prior to development or retrofitting.

Effects of alcohol sensitivity on alcohol-induced blackouts and passing out: An examination of the alcohol sensitivity questionnaire among underage drinkers.

The role of alcohol sensitivity in the experience of blacking out and passing out has not been well established. Here, we examined the relation between individual differences in alcohol sensitivity (i.e., numbers of drinks required to experience various effects of alcohol) and reports of blacking out and passing out in the past year. Participants (925 healthy, underage college student drinkers) completed the Alcohol Sensitivity Questionnaire (ASQ) and reported on their past year blacking out and passing out experiences. The fit of the ASQ's 2-factor structure was fair (CFI=0.90, RMSEA=0.09) in this sample of underage drinkers. In unadjusted models, higher ASQ scores (i.e., requiring more drinks to experience effects, indicating lower alcohol sensitivity) were associated with experiencing more blackouts (IRR=1.68 [1.31-2.15]) and passing out (IRR=2.25 [1.59-3.18]) in the past year. After controlling for typical consumption, however, higher ASQ scores were associated with fewer past-year blackouts (IRR=0.76 [0.60-0.98]). Total ASQ scores moderated the relationship between typical alcohol consumption and blackout occurrence (interaction IRR=0.96 [0.93-0.98]), but not passing out occurrence (interaction IRR=0.95 [0.89-1.01]), with the quantity of alcohol consumed more strongly associated with blackout occurrence among higher-sensitivity than lower-sensitivity drinkers. These findings are consistent with prior work suggesting that low sensitivity may act as a paradoxical risk factor for certain heavy drinking effects, contributing to higher levels of alcohol consumption and more frequent negative consequences while also conferring protection (relative to high-sensitivity peers) at a given level of alcohol exposure.

Sex differences in cholinergic circuits and behavioral disruptions following chronic ethanol exposure with and without thiamine deficiency.

Few studies have investigated differences in the vulnerabilities of males and females to alcohol use disorder and alcohol-related brain damage (ARBD). According to epidemiological and clinical findings, females appear to be more sensitive to the effects of alcohol and thiamine deficiency and have a worse prognosis in recovery from neurocognitive deficits compared with males. This study aimed to characterize the effects of chronic ethanol (EtOH) toxicity and thiamine deficiency across the sexes using rodent models. Male and female Sprague Dawley rats were assigned to chronic forced EtOH treatment (CET), pyrithiamine-induced thiamine deficiency (PTD), combined CET-PTD, or pair-fed (PF) control treatment conditions. Following treatments, spatial working memory was assessed during a spontaneous alternation task while measuring acetylcholine (ACh) in the prefrontal cortex (PFC) and the hippocampus (HPC). The animals also underwent an operant-based attentional set-shifting task (ASST) for the analysis of behavioral flexibility. Female and male rats did not differ in terms of EtOH consumption; however, the CET and CET-PTD-treated female rats had lower BECs than male rats. Compared with the PF group, the CET, PTD, and CET-PTD groups exhibited spatial working memory impairments with corresponding reductions in ACh efflux in the PFC and HPC. The ASST revealed that CET-PTD-treated males and females displayed impairments marked by increased latency to make decisions. Thalamic shrinkage was prominent only in the CET-PTD and PTD treatment conditions, but no sex-specific effects were observed. Although the CET and CET-PTD-treated females had lower BECs than the males, they demonstrated similar cognitive impairments. These results provide evidence that female rats experience behavioral and neurochemical disruptions at lower levels of alcohol exposure than males and that chronic EtOH and thiamine deficiencies produce a unique behavioral profile.

Are there non-linear relationships between alcohol consumption and long-term health? Protocol for a systematic review of observational studies employing approaches to improve causal inference

IntroductionThere is a substantial literature finding that moderate alcohol consumption is protective against certain health conditions. However, more recent research has highlighted the possibility that these findings are methodological artefacts,...

Translating preclinical models of alcohol seeking and consumption into the human laboratory using intravenous alcohol self-administration paradigms.

Preclinical models of alcohol use disorder (AUD) have advanced theoretical, mechanistic, and pharmacological study of the human condition. "Liking" and "wanting" behaviors reflect core processes underlying several models of AUD. However, the development and application of translational models of these preclinical approaches are at an incipient stage. The goal of this study was to examine how intravenous free-access and progressive-ratio, operant-response human alcohol self-administration paradigms can be used as translational human model parallels of preclinical "liking" and "wanting." Participants were 40 adults (mean age=23.7, SD=2.0; 45% female) of European descent who reported 12.6 drinking days (SD=5.2) out of the previous 30 (average=4.1 drinks per drinking day [SD=1.7]). Individuals diverged in their alcohol self-administration behavior, such that free-access and progressive-ratio paradigm outcomes were not significantly correlated (p=0.44). Free-access alcohol seeking was related to enjoying alcohol (p<0.001), but not craving (p=0.48), whereas progressive-ratio seeking at similar levels of alcohol exposure was related to craving (p=0.02), but not enjoying (p=0.30). Family history of alcoholism, venturesomeness traits, and disinhibition traits were unrelated (ps>0.70) to preferred level of breath alcohol concentration (BrAC) in the free-access session, a measure of liking alcohol. Family history of alcoholism, disinhibition traits, and recent drinking history were significantly related (ps<0.05) to alcohol seeking in the progressive-ratio paradigm, a measure of wanting alcohol. We conclude that intravenous alcohol self-administration paradigms show promise in modeling behaviors that characterize and parallel alcohol "liking" and "wanting" in preclinical models. These paradigms provide a translational link between preclinical methods and clinical trials.

Association between alcohol intake, mild cognitive impairment and progression to dementia: a dose-response meta-analysis.

Mild cognitive impairment (MCI) is a cognitive state falling between normal aging and dementia. The relation between alcohol intake and risk of MCI as well as progression to dementia in people with MCI (PDM) remained unclear. To synthesize available evidence and clarify the relation between alcohol intake and risk of MCI as well as PDM. We searched electronic databases consisting of PubMed, EMBASE, Cochrane Library, and China Biology Medicine disc (CBM) from inception to October 1, 2019. Prospective studies reporting at least three levels of alcohol exposure were included. Categorical meta-analysis was used for quantitative synthesis of the relation between light, moderate and heavy alcohol intake with risk of MCI and PDM. Restricted cubic spline and fixed-effects dose-response models were used for dose-response analysis. Six cohort studies including 4244 individuals were finally included. We observed an unstable linear relation between alcohol intake (drinks/week) and risk of MCI (P linear = 0.0396). It suggested that a one-drink increment per week of alcohol intake was associated with an increased risk of 3.8% for MCI (RR, 1.038; 95% CI 1.002-1.075). Heavy alcohol intake (> 14 drinks/week) was associated with higher risk of PDM (RR = 1.76; 95% CI 1.10-2.82). And we found a nonlinear relation between alcohol intake and risk of PDM. Drinking more than 16 drinks/week (P nonlinear = 0.0038, HR = 1.42; 95% CI 1.00-2.02), or 27.5g/day (P nonlinear = 0.0047, HR = 1.46; 95% CI 1.00-2.11) would elevate the risk of PDM. There was a nonlinear dose-response relation between alcohol intake and risk of PDM. Excessive alcohol intake would elevate the risk of PDM.

Is burden of disease differentially linked to spirits? A systematic scoping review and implications for alcohol policy.

Most epidemiological research on alcohol as a risk factor is based on the assumption that outcomes are linked to pattern and level of alcohol exposure, where different beverages are converted into grams of ethanol. This review examines this basic assumption, that alcohol has the same impact, independent of beverage type. We conducted a systematic search on comparative research of beverage-specific alcohol exposure and consequences. Research was divided by methodology (survey, case-control, cohort, time-series analyses, interventional research). Overall, many studies showed higher risks for spirits compared to beer or wine; however, most research was not controlled adequately for confounders such as patterns of drinking. While there is no conclusive evidence for spirits being associated with more harm, given the same pattern and level of alcohol exposure, some evidence supports for certain outcomes such as injuries and poisonings, a potential excess risk with spirits consumption due to rapid ethanol intake and intoxication. Accordingly, encouraging people to opt for beverages with lower alcohol content via taxation strategies has the potential to reduce alcohol-attributable harm. This does not necessarily involve switching beverage type, but also can achieved within the same beverage category, by shifting from higher to lower concentration beverages.

Voluntary alcohol access during adolescence/early adulthood, but not during adulthood, causes faster omission contingency learning

In omission contingency training, rodents learn to suppress their natural tendency to approach or touch a reward-predictive cue (termed “autoshaping” or “sign-tracking” responses) if the approach/touching responses lead to the omission of the reward. Previous research has shown that high levels of alcohol exposure (through alcohol vapor exposure) or adolescent alcohol consumption (with some versions of the omission contingency task) can lead to faster omission contingency learning. However, the alcohol exposure procedures and/or omission contingency task parameters differed between these different demonstrations. It was unclear whether the same voluntary alcohol consumption procedures during adolescence/early adulthood and/or adulthood would lead to faster omission contingency learning in one or both age groups. Here, rats received 6 weeks of chronic intermittent access to 20% alcohol or water from PND 26–66 (adolescence/early adulthood in Exp. 1) or PND 68–108 (adulthood in Exp. 2) and began behavioral training (autoshaping training followed by omission contingency training) several days later. We found no evidence that alcohol access at either age altered the number of trials with a sign-tracking response on the levers during autoshaping training. However, alcohol access during adolescence/early adulthood, but not during adulthood, led to faster learning to withhold responding on the lever under omission contingencies during the subsequent phase. We also found no evidence that the level of alcohol consumption was correlated with sign-tracking behavior in the autoshaping phase or with the suppression of lever-pressing during the omission contingency phase. Our results suggest that adolescent/early adult rats have increased vulnerability, compared with adults, to some long-term behavioral effects of voluntary alcohol consumption.

Ghrelin receptor deletion reduces binge-like alcohol drinking in rats.

Ghrelin is a gastric hormone that has been implicated in the neurobiology of alcohol drinking. We have recently developed a ghrelin receptor (growth hormone secretagogue receptor; GHSR) knockout (KO) rat model, which exhibits reduced food consumption and body weight. In addition, recent preliminary work suggests that the gut-microbiome, which appears to interact with the ghrelin system, may modulate alcohol drinking. In the present study, we investigated the effects of GHSR deletion on alcohol consumption utilising GHSR KO and wild-type (WT) rats in three separate alcohol consumption paradigms: (i) operant self-administration (30-minute sessions); (ii) drinking in the dark (DID) (4-hour sessions); and (iii) intermittent access (24-hour sessions). These paradigms model varying degrees of alcohol consumption. Furthermore, we aimed to investigate the gut-microbiome composition of GHSR KO and WT rats before and after alcohol exposure. We found that the GHSR KO rats self-administered significantly less alcohol compared to WT rats in the operant paradigm, and consumed less alcohol than WT in the initial stages of the DID paradigm. No genotype differences were found in the intermittent access test. In addition, we found a significant decrease in gut-microbial diversity after alcohol exposure in both genotypes. Thus, the present results indicate that the ghrelin system may be involved in drinking patterns that result in presumably increased alcohol exposure levels. Furthermore, GHSR may constitute a potential pharmacological target for the reduction of binge-alcohol consumption. The potential functional role of the gut-microbiome in alcohol drinking, as well as interaction with the ghrelin system, is an interesting topic for further investigation.

Moderate developmental alcohol exposure reduces repetitive alternation in a zebrafish model of fetal alcohol spectrum disorders

The damaging effects of alcohol on a developing fetus are well known and cause a range of conditions known as fetal alcohol spectrum disorder (FASD). High levels of alcohol exposure lead to physical deformity and severe cognitive deficits, but more moderate exposure leads to a range of subtle cognitive effects such as reduced social behavior, higher propensity to develop addictions, and reduced spatial working memory. Previous studies have demonstrated that following exposure to relatively low levels of ethanol during early brain development (equivalent in humans to moderate exposure) zebrafish display a range of social and behavioral differences. Here, our aim was to test the hypothesis that moderate developmental ethanol exposure would affect aspects of learning and memory in zebrafish. In order to do this, we exposed zebrafish embryos to 20 mM [0.12% v/v] ethanol from 2 to 9 dpf to model the effects of moderate prenatal ethanol (MPE) exposure. At 3 months old, adult fish were tested for appetitive and aversive learning, and for spatial alternation in a novel unconditioned y-maze protocol. We found that MPE did not affect appetitive or aversive learning, but exposed-fish showed a robust reduction in repetitive alternations in the y-maze when compared to age matched controls. This study confirms that moderate levels of ethanol exposure to developing embryos have subtle effects on spatial working memory in adulthood. Our data thus suggest that zebrafish may be a promising model system for studying the effects of alcohol on learning and decision-making, but also for developing treatments and interventions to reduce the negative effects of prenatal alcohol.

Alcohol or Not: A Review Comparing Initial Mechanisms, Contributing Factors, and Liver Transplantation Outcomes Between Alcoholic and Nonalcoholic Steatohepatitis

Chronic liver diseases take many forms; alcohol-related liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are two common illnesses that potentially lead to cirrhosis, liver failure, and liver cancer. It is estimated that a quarter of heavy drinkers develop ALD and the same portion of people without heavy drinking habits have NAFLD. Alcohol intake is regularly used to differentiate NAFLD from ALD; however, diagnosis based on the discrimination threshold may be suboptimal when facing an obese patient with a high level of alcohol exposure. Therefore, understanding the common and/or different mechanism(s) driving each disease is extremely important. The ‘two-hit’ or ‘multi-hit’ hypothesis is used to explain the pathogenesis of both diseases. The ‘first hit’ refers to developing steatosis, the accumulation of fat components in the liver, and the ‘second hits’ are factors leading to oxidative stress, inflammation, and fibrosis, such as metabolic syndromes (e.g., morbid obesity, hyperglycaemia, hyperlipidaemia, disturbed circadian cycles, and altered intestinal microbiota) and environmental toxins (e.g., cigarette smoke and pollutants). Heritable factors also affect the probability and disease progression of both ALD and NAFLD. Whereas PNPLA3 and TM6SF2 variants are influential genetic risk factors for the diseases, epigenetic factors, such as DNA methylation, post-translational histone modifications, and small non-coding RNA, are of paramount importance. Moreover, considering that both ALD and NAFLD patients may eventually develop end-stage liver disease and require liver transplantation, the authors extensively investigated the worldwide outcomes from original literature for these two aetiologies, and the results showed no obvious differences in post-transplantation survival between them. Precise percentage determination of these two aetiologies contributing to steatohepatitis and its secondary injuries in the future would allow for better strategies for therapeutic and preventive intervention.

Prenatal alcohol consumption and infant and child behavior: Evidence from the Growing Up in New Zealand Cohort

BackgroundHigh levels of alcohol exposure during pregnancy can damage developing brains and influence child behavior and learning. AimTo examine the effects of lower levels of alcohol and very early exposure to alcohol on infant temperament and child behavior. Study design, subjects, and outcome measuresThe Growing Up in New Zealand study involves a prospective birth cohort of 6822 pregnant women of whom 6156 provided information on their child's temperament using the Infant Behavior Questionnaire-Revised (IBQ-R VSF) at 9 months and their child's behavior using the Strengths and Difficulties Questionnaire at 2 years. ResultsA series of adjusted linear regression models controlling for socio-demographic factors found alcohol consumption during pregnancy was most consistently related to Lower Positive Affect, Affiliation/Regulation, and Orienting Capacity temperament scores. Mothers who stopped drinking after becoming aware of their pregnancy, but had an unplanned pregnancy (hence may have a baby exposed to alcohol for longer), also reported infants with lower Orienting Capacity, Affiliation/Regulation, and Fear temperament scores compared to those that did not drink. Children whose mothers drank four or more drinks per week during pregnancy were more likely to report their child as having conduct problems, with higher total difficulties scores at age 2. ConclusionsAlcohol consumption during pregnancy has a negative effect especially on infant temperament, even if small amounts of alcohol are consumed. Our findings have implications for men and women who drink, medical professionals, and for the availability of contraception to those who drink, but do not plan to get pregnant.

Circadian Mechanisms in Alcohol Use Disorder and Tissue Injury.

Heavy use of alcohol can lead to addictive behaviors and to eventual alcohol-related tissue damage. While increased consumption of alcohol has been attributed to various factors including level of alcohol exposure and environmental factors such as stress, data from behavioral scientists and physiological researchers are revealing roles for the circadian rhythm in mediating the development of behaviors associated with alcohol use disorder as well as the tissue damage that drives physiological disease. In this work, we compile recent work on the complex mutually influential relationship that exists between the core circadian rhythm and the pharmacodynamics of alcohol. As we do so, we highlight implications of the relationship between alcohol and common circadian mechanisms of effected organs on alcohol consumption, metabolism, toxicity, and pathology.

Biomarkers for the Detection of Prenatal Alcohol Exposure: A Review.

Alcohol exposure during pregnancy can cause adverse effects to the fetus, because it interferes with fetal development, leading to later physical and mental impairment. The most common clinical tool to determine fetal alcohol exposure is maternal self-reporting. However, a more objective and useful method is based on the use of biomarkers in biological specimens alone or in combination with maternal self-reporting. This review reports on clinically relevant biomarkers for detection of prenatal alcohol exposure (PAE). A systematic search was performed to ensure a proper overview in existing literature. Studies were selected to give an overview on clinically relevant neonatal and maternal biomarkers. The direct biomarkers fatty acid ethyl esters (FAEEs), ethyl glucuronide (EtG), ethyl sulfate, and phosphatidylethanol (PEth) were found to be the most appropriate biomarkers in relation to detection of PAE. To review each biomarker in a clinical context, we have compared the advantages and disadvantages of each biomarker, in relation to its window of detectability, ease of collection, and the ease and cost of analysis of each biomarker. The biomarkers PEth, FAEEs, and EtG were found to be applicable for detection of even low levels of alcohol exposure. Meconium is an accessible matrix for determination of FAEEs and EtG, and blood an accessible matrix for determination of PEth.

Accidental Ethanol Ingestion in a 32 Day Old Infant

Alcohol exposure can occur in all age groups but occurs much less commonly in infants. Prior studies have shown that no level of alcohol exposure is safe, and can affect the brain and other areas of development. We report a 32 day old previously healthy male who presented to an outside hospital early morning for not acting normal. Earlier that morning, mom had fed him 3 ounces of formula mistakenly prepared with a clear liquid thought to be water, but later confirmed to be gin. The baby was mildly agitated on arrival, and the blood alcohol level 4 hrs post-ingestion was 230 mg/dl. This is one of the youngest documented cases of alcohol ingestion, and was remarkable for having a mild course with normal vital signs and electrolytes, and a non-focal physical exam. This case highlights the importance of having a high level of suspicion for alcohol exposure and a low threshold for checking blood ethanol levels in infants presenting with altered mental status, as there may be no hallmark signs, symptoms, or electrolyte abnormalities.

Cardiac Orienting Responses Differentiate the Impact of Prenatal Alcohol Exposure in Ukrainian Toddlers.

Prenatal alcohol exposure (PAE) has been found to impact neurophysiological encoding of environmental events negatively in the first year of life but has not been evaluated in older infants or toddlers. Cardiac orienting responses (ORs) collected duringa habituation/dishabituation learning paradigm were obtained from 12- to 18-month-olds to assess the impact of PAE beyond the first year of life. Participants included women and their toddlers who differed in PAE histories and enrolled in a randomized clinical trial of multivitamin/mineral usage during pregnancy. Those who were randomly assigned to the no intervention group were used for this analysis. The habituation/dishabituation paradigm consisted of 10 habituation and 5 dishabituation trials. Baseline heart rate (HR) was collected for 30seconds prior to stimulus onset, and responses to the stimuli were assessed by sampling HR for 12seconds poststimulus onset. The speed of the OR in response to auditory stimuli in the dishabituation condition was found to be altered as a function of maternal alcohol use around conception. For visual stimuli, positive histories of PAE were predictive of the magnitude but not the speed of the response on habituation and dishabituation trials. A history of binge drinking was associated with reduced magnitude of the OR response on visual encoding trials, and level of alcohol exposure at the time of conception was predictive of the magnitude of the response on visual dishabituation trials. Cardiac ORs collected in the toddler period were sensitive to the effects of PAE. The magnitude of the OR was more sensitive to the impact of PAE than in previous research with younger infants, and this may be a function of brain maturation. Additional research assessing the predictive utility of using ORs in making decisions about individual risk was recommended.

Effects of Moderate Prenatal Alcohol Exposure during Early Gestation in Rats on Inflammation across the Maternal-Fetal-Immune Interface and Later-Life Immune Function in the Offspring.

During early brain development, microglial activation can negatively impact long-term neuroimmune and cognitive outcomes. It is well-known that significant alcohol exposure during early gestation results in a number of cognitive deficits associated with fetal alcohol spectrum disorders (FASD). Additionally, microglia are activated following high levels of alcohol exposure in rodent models of FASD. We sought to examine whether moderate prenatal alcohol exposure (70mg/dL blood alcohol concentration) activates microglia in the fetal rat brain, and whether moderate fetal alcohol exposure has long-term negative consequences for immune function and cognitive function in the rat. We also measured inflammation within the placenta and maternal serum following moderate alcohol exposure to determine whether either could be a source of cytokine production in the fetus. One week of moderate prenatal alcohol exposure produced a sex-specific increase in cytokines and chemokines within the fetal brain. Cytokines were also increased within the placenta, regardless of the sex of the fetus, and independent of the low levels of circulating cytokines within the maternal serum. Adult offspring exposed to alcohol prenatally had exaggerated cytokine production in the brain and periphery in response to lipopolysaccharide (25μg/kg), as well as significant memory deficits precipitated by this low-level of inflammation. Thus the immune system, including microglia, may be a key link to understanding the etiology of fetal alcohol spectrum disorders and other unexplored cognitive or health risks associated with even low levels of fetal alcohol exposure.

Alcohol and Apoptosis: Friends or Foes?

Alcohol abuse causes 79,000 deaths stemming from severe organ damage in the United States every year. Clinical manifestations of long-term alcohol abuse on the cardiac muscle include defective contractility with the development of dilated cardiomyopathy and low-output heart failure; which has poor prognosis with less than 25% survival for more than three years. In contrast, low alcohol consumption has been associated with reduced risk of cardiovascular disease, however the mechanism of this phenomenon remains elusive. The aim of this study was to determine the significance of apoptosis as a mediating factor in cardiac function following chronic high alcohol versus low alcohol exposure. Adult rats were provided 5 mM (low alcohol), 100 mM (high alcohol) or pair-fed non-alcohol controls for 4–5 months. The hearts were dissected, sectioned and stained with cresyl violet or immunohistochemically for caspase-3, a putative marker for apoptosis. Cardiomyocytes were isolated to determine the effects of alcohol exposure on cell contraction and relaxation. High alcohol animals displayed a marked thinning of the left ventricular wall combined with elevated caspase-3 activity and decreased contractility. In contrast, low alcohol was associated with increased contractility and decreased apoptosis suggesting an overall protective mechanism induced by low levels of alcohol exposure.

Functional significance of subjective response to alcohol across levels of alcohol exposure.

Pre-clinical neurobiological models of addiction etiology including both the allostatic model and incentive sensitization theory suggest that alcohol consumption among alcohol-dependent (AD) individuals will be dissociated from hedonic reward as positive reinforcement mechanisms wane in later stage dependence. The aims of this study are to test this claim in humans by examining the relationship between dimensions of subjective responses to alcohol (SR) and alcohol craving across levels of alcohol exposure. Non-treatment-seeking drinkers (n = 205) completed an i.v. alcohol challenge (final target breath alcohol concentration = 0.06 g/dl) and reported on SR and craving. Participants were classified as light-to-moderate drinkers (LMD), heavy drinkers (HD) or AD. Analyses examined group differences in SR and craving response magnitude, as well as concurrent and predictive associations between SR domains and craving. At baseline, LMD and AD reported greater stimulation than HD, which carried over post-alcohol administration. However, stimulation was dose-dependently associated with alcohol craving in HD only. Furthermore, lagged models found that stimulation preceded craving among HD only, whereas this hypothesized pattern of results was not observed for craving preceding stimulation. Sedation was also positively associated with craving, yet no group differences were observed. In agreement with the prediction of diminished positive reinforcement in alcohol dependence, this study showed that stimulation/hedonic reward from alcohol did not precede craving in AD, whereas stimulation was dose-dependently associated with and preceded craving among non-dependent HD.