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Background: Endophenotypes for alcohol use disorder are well known and may reflect paternal exposure effects passed down to offspring via epigenetic mechanisms. Previously, we showed that paternal alcohol exposure prior to conception attenuates the acquisition of operant alcohol self‐administration. We now test whether paternal alcohol exposure alters their offsprings' behavioral responses to alcohol (endophenotypes) and global DNA methylation levels in reward‐related brain regions. Methods: Adult male rats were exposed to alcohol vapors or air for 6 weeks and mated with alcohol‐naïve females 8 weeks later. Adult male and female offspring of the alcohol‐ and control‐sired litters were tested on three behaviors 30 m after gavage with water or alcohol (1.5 g/kg): open field, elevated plus maze, and accelerating rotarod. Global DNA methylation levels in sperm, nucleus accumbens, and prefrontal cortex were examined in male sires and in another group of offspring. Results: Alcohol‐sired males showed less anxiety‐like behavior in the elevated plus maze that was not affected by alcohol administration. By contrast, alcohol had anxiolytic effects in the open field in male offspring only with no paternal alcohol effect. Neither paternal alcohol exposure nor alcohol administration altered locomotor activity in either sex. Sex‐specific effects of paternal alcohol exposure were seen in the rotarod test. Alcohol‐sired male offspring showed blunted sensitivity to the alcohol's motor‐impairing effects, whereas alcohol‐sired female offspring showed enhanced sensitivity. Global DNA methylation was altered in the sperm of alcohol‐exposed males, but no changes were seen in their offspring. Conclusions: Paternal alcohol exposure prior to conception has sex‐ and task‐dependent effects on unconditioned behaviors in their offspring. [ABSTRACT FROM AUTHOR]

Background: Up to 15% of all visits to the Emergency Department (ED) are alcohol related. Identification of problematic alcohol use is important in this setting because it allows for intervention and prevention efforts. This study investigated the correlation between the objective phosphatidylethanol (PEth) marker and the subjective Alcohol Use Disorders Identification Test (AUDIT) and Timeline Followback Questionnaire (TLFB) as screening methods for hazardous alcohol use in the general ED population. Methods: This prospective cohort study included 301 ED patients (57% male) who were seen in the ED and required to give a blood sample. The correlation between the values of PEth (PEth 16:0/18:1 and PEth 16:0/18:2) and the scores on the AUDIT and TLFB were analyzed using Spearman's rank correlation coefficient. Differences between risk categories of PEth and AUDIT were also examined. Results: The Spearman correlation coefficients between PEth 16:0/18:1|PEth 16:0/18:2 values and the AUDIT scores were moderate (PEth 16:0/18:1: 0.67, p < 0.001; PEth 16:0/18:2: 0.67, p < 0.001). Of the patients who scored 'low risk drinking/abstinence' according to the AUDIT questionnaire, respectively 1% and 4% had PEth 16:0/18:1|PEth 16:0/18:2 values indicating excessive alcohol use, and another 10% and 12% had PEth 16:0/18:1|PEth 16:0/18:2 values indicating moderate alcohol consumption. Of the 12 (PEth 16:0/18:1) and 25 (PEth 16:0/18:2) patients with high‐risk values, respectively 25% and 40% scored in the lowest risk category on the AUDIT questionnaire. Spearman correlation coefficients between PEth 16:0/18:1|PEth 16:0/18:2 values and TLFB two‐week scores were high (PEth 16:0/18:1: 0.74, p < 0.001; PEth 16:0/18:2: 0.82, p < 0.001). Conclusions: AUDIT scores were moderately correlated with PEth values in the general ED population. In almost all cases where there was not a good correlation, patients had high PEth values with low AUDIT scores. We conclude that PEth identifies patients with problematic alcohol use who are missed by the AUDIT questionnaire and therefore PEth could be used as an additional screening method for hazardous alcohol use in this population. [ABSTRACT FROM AUTHOR]

Background: Mixing alcohol with caffeinated energy drinks is a common practice among young people. Consumption of alcohol mixed in energy drink is associated with increased risk of binge drinking and alcohol dependence. The purpose of this study was to determine whether voluntary intermittent access to alcohol mixed in energy drink in adolescent rats alters adult self‐administration of alcohol, anxiety, and memory. Methods: For 10 weeks in the home‐cage, two groups of adolescent female Sprague–Dawley rats had intermittent access to energy drink (ED) or 10% alcohol mixed in energy drink (AmED) with water concurrently available. Other rat groups had daily continuous access to ED or AmED. Anxiety was measured with an open field test and memory was assessed with a novel place recognition test. For self‐administration, rats pressed levers for 10% alcohol alone on a fixed ratio (FR1) and on a progressive ratio (PR). Results: Intermittent access to AmED generated greater intake during the initial 30 min of access (AmED 1.70 ± 0.04 g/kg vs. ED 1.01 ± 0.06 g/kg) and during the subsequent 24 h (AmED 7.04 ± 0.25 g/kg vs. ED 5.60 ± 0.29 g/kg). Intermittent AmED caused a significant but small decrease in anxiety while neither ED nor AmED altered memory. During alcohol self‐administration, group differences emerged only during PR testing during which intermittent AmED rats responded more than all other groups. Conclusions: These findings suggest that intermittent access to AmED generates binge‐like consumption that supports human findings that AmED generates greater alcohol consumption. Furthermore, experience with AmED may alter the motivational properties of alcohol into adulthood without necessarily causing a major impact on anxiety or memory. [ABSTRACT FROM AUTHOR]

Background: The primary cause of Wernicke–Korsakoff syndrome (WKS) is thiamine deficiency, and more than 90% of cases are reported in alcohol‐dependent patients. While observational studies show parenteral thiamine administration drastically reduced WKS‐related mortality, relevant treatment trials have never been conducted to determine the optimum thiamine dose. Methods: Two double‐blind, parallel groups, randomized controlled trials (RCTs) were conducted to determine the optimal thiamine dose required for (1) the prevention of Wernicke's encephalopathy (WE), the acute phase of WKS, in asymptomatic but "at‐risk" alcohol misuse patients (Study 1) and (2) the treatment of WE in symptomatic alcohol misuse patients (Study 2). Each study had a dosage regimen comprising three parenteral thiamine doses that were allocated at a ratio of 1:1:1. Study 1: Asymptomatic At‐Risk patients (N = 393) received either 100 mg daily, 100 mg thrice daily, or 300 mg thrice daily, for 3 days. Study 2: Symptomatic patients (N = 127) received either 100 mg thrice daily, 300 mg thrice daily, or 500 mg thrice daily, for 5 days. Cognitive function was the primary outcome, assessed using the Rowland Universal Dementia Assessment Scale, two Cogstate subtests, and an adapted Story Memory Recall test. Secondary analyses examined differences in neurological function (ataxia, oculomotor abnormalities, and confusion) at follow‐up. Results: No significant differences were observed between any of the dosage conditions for either Study 1 or Study 2 on cognition or neurological functioning. This real‐world study found that having a clinically unwell target population with high comorbidity and multiple presentations, coupled with challenges in cross‐cultural assessment is likely to complicate RCT findings. Conclusions: The results of this study showed no clear benefit of high dose thiamine over intermediate or lower doses of thiamine, over the time intervals examined, for the treatment and prevention of cognitive and neurological abnormalities related to WKS. Several study limitations temper the interpretation of these findings. Nevertheless, the absence of conclusive evidence for the superiority of high‐dose thiamine supports a recommendation for patient‐specific treatment, while ensuring that the potential impact of other biochemical factors (e.g., magnesium and other B vitamin deficiencies) are considered and corrected if necessary. [ABSTRACT FROM AUTHOR]

Background: Growing evidence indicates that sleep characteristics predict future substance use and related problems. However, most prior studies assessed a limited range of sleep characteristics, studied a narrow age span, and included few follow‐up assessments. Here, we used six annual assessments from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study, which spans adolescence and young adulthood with an accelerated longitudinal design, to examine whether multiple sleep characteristics in any year predict alcohol and cannabis use the following year. Methods: The sample included 831 NCANDA participants (423 females; baseline age 12–21 years). Sleep variables included circadian preference, sleep quality, daytime sleepiness, the timing of midsleep (weekday/weekend), and sleep duration (weekday/weekend). Using generalized linear mixed models (logistic for cannabis; ordinal for binge severity), we tested whether each repeatedly measured sleep characteristic (years 0–4) predicted substance use (alcohol binge severity or cannabis use) the following year (years 1–5), covarying for age, sex, race, visit, parental education, and previous year's substance use. Results: Greater eveningness, more daytime sleepiness, later weekend sleep timing, and shorter sleep duration (weekday/weekend) all predicted more severe alcohol binge drinking the following year. Only greater eveningness predicted a greater likelihood of any cannabis use the following year. Post‐hoc stratified exploratory analyses indicated that some associations (e.g., greater eveningness and shorter weekend sleep duration) predicted binge severity only in female participants, and that middle/high school versus post‐high school adolescents were more vulnerable to sleep‐related risk for cannabis use. Conclusions: Our findings support the relevance of multiple sleep/circadian characteristics in the risk for future alcohol binge severity and cannabis use. Preliminary findings suggest that these risk factors vary based on developmental stage and sex. Results underscore a need for greater attention to sleep/circadian characteristics as potential risk factors for substance use in youth and may inform new avenues to prevention and intervention. [ABSTRACT FROM AUTHOR]

Objective: Naltrexone is an effective treatment for heavy drinking among young adults. Laboratory‐based studies have shown that naltrexone dampens the subjective response to alcohol and craving. However, few studies have tested naltrexone's dynamic, within‐person effects on subjective response and craving among young adults in natural drinking environments. Methods: Using daily diary data from a randomized, placebo‐controlled study of naltrexone's efficacy in young adults, we examined the between‐person effects of treatment condition (i.e., naltrexone vs. placebo) and medication dosage (i.e., daily, targeted, and daily + targeted) on the subjective response to alcohol and craving on drinking days. Multilevel mediation models predicted subjective response and craving from treatment condition (between‐person) and medication dosage (within‐person), accounting for drinking levels. All effects were disaggregated within and between persons. Results: At the between‐person level, naltrexone directly blunted intense subjective effects (i.e., "impaired", "drunk") and indirectly blunted subjective effects through reduced drinking. Naltrexone was not associated with craving. Between‐person effects were not significant after alpha correction, but their effect sizes (bs = 0.14 to 0.17) exceeded the smallest effect size of interest. At the within‐person level, taking two (vs. 1) pills was associated with heavier drinking, and taking one (vs. 0) pill was associated with lighter drinking, and lighter drinking was associated with a lower subjective response and craving. Treatment condition did not moderate the within‐person effects of dosing on outcomes. Conclusions: Our findings suggest that the direct between‐person effect of naltrexone was largest on intense subjective responses, blunting feelings of being "drunk" and "impaired". Future research using momentary (rather than daily) assessments could confirm and extend these findings. [ABSTRACT FROM AUTHOR]

Background: The impact of alcoholic hepatitis (AH) on health‐related quality of life (HRQOL) remains inadequately described. We aimed to characterize HRQOL in AH and heavy drinkers (HD), and its associations with clinical variables and outcomes. Methods: This is a post hoc analysis of participants in the Translational Research and Evolving Alcoholic Hepatitis Treatment 001 study (NCT02172898). HRQOL was measured using Short Form Health Survey (SF‐36). Mean SF‐36 scores were compared in AH and HD with two‐sample t‐tests. Associations among clinical characteristics, 30‐day mortality, and SF‐36 mental and physical component scores (MC, PC) were investigated with generalized linear and logistic multivariate regression models. Trends of MC and PC scores were analyzed using one‐way ANOVA. Results: Participants with AH (n = 258) and HD (n = 181) were similar demographically. AH cases had a mean Model for End‐stage Liver Disease (MELD) score of 23 (7). AH cases had lower PC scores [37 (10) vs. 48 (11), p < 0.001] but higher MC scores [37 (13) vs. 32 (13), p < 0.001]. MC scores were independently associated with age, male gender, and daily alcohol consumption; PC scores were independently associated with age, BMI, alanine aminotransferase concentration, alkaline phosphatase concentration, white blood cell counts, and the presence of ascites. With each 5‐point decrease in the baseline PC score, the adjusted odds of dying within 30 days increased by 26.7% (95% CI 1% to 46%). Over time, HRQOL in AH improved (day 0 to day 180 delta PC score: 4.5 ± 1.7, p = 0.008; delta MC score: 9.8 ± 2.0, p < 0.001). Participants with a MELD score <15 by day 180 had greater increases in PC scores than those with MELD score ≥15 (delta PC score 7.1 ± 1.8 vs. −0.7 ± 2.3, p = 0.009), while those abstinent by day 180 had greater increases in MC scores than those who were not abstinent (delta MC score 9.1 ± 1.8 vs. 2.8 ± 2.4, p = 0.044). Conclusions: HRQOL is poor in AH and HD in a domain‐specific pattern. Independent of MELD score, lower baseline HRQOL is associated with higher 30‐day mortality. Over time, HRQOL improves with greater gains seen in individuals with improved MELD scores and those who were abstinent. [ABSTRACT FROM AUTHOR]

Background: Wearable transdermal alcohol concentration (TAC) sensors allow passive monitoring of alcohol concentration in natural settings and measurement of multiple features from drinking episodes, including peak intoxication level, speed of intoxication (absorption rate) and elimination, and duration. These passively collected features extend commonly used self‐reported drink counts and may facilitate the prediction of alcohol‐related consequences in natural settings, aiding risk stratification and prevention efforts. Method: A total of 222 young adults aged 21–29 (M age = 22.3, 64% female, 79% non‐Hispanic white, 84% undergraduates) who regularly drink heavily participated in a 5‐day study that included the ecological momentary assessment (EMA) of alcohol consumption (daily morning reports and participant‐initiated episodic EMA sequences) and the wearing of TAC sensors (SCRAM‐CAM anklets). The analytic sample contained 218 participants and 1274 days (including 554 self‐reported drinking days). Five features—area under the curve (AUC), peak TAC, rise rate (rate of absorption), fall rate (rate of elimination), and duration—were extracted from TAC‐positive trajectories for each drinking day. Day‐ and person‐level associations of TAC features with drink counts (morning and episodic EMA) and alcohol‐related consequences were tested using multilevel modeling. Results: TAC features were strongly associated with morning drink reports (r = 0.6–0.7) but only moderately associated with episodic EMA drink counts (r = 0.3–0.5) at both day and person levels. Higher peaks, larger AUCs, faster rise rates, and faster fall rates were significantly predictive of day‐level alcohol‐related consequences after adjusting for both morning and episodic EMA drink counts in separate models. Person means of TAC features added little above daily scores to the prediction of alcohol‐related consequences. Conclusions: These results support the utility of TAC sensors in studies of alcohol misuse among young adults in natural settings and outline the specific TAC features that contribute to the day‐level prediction of alcohol‐related consequences. TAC sensors provide a passive option for obtaining valid and unique information predictive of drinking risk in natural settings. [ABSTRACT FROM AUTHOR]

Introduction: Fetal alcohol spectrum disorders (FASD) are highly prevalent developmental disabilities associated with prenatal alcohol exposure. In addition to varied strengths and unique talents, people with FASD experience significant challenges, including in adaptive functioning. Adaptive functioning refers to skills related to everyday life such as communication, practical skills, and social skills. For the current review, we aimed to understand how adaptive functioning in FASD compares to that of alcohol nonexposed individuals and those with attention deficit‐hyperactivity disorder (ADHD). Additionally, we investigated how this relationship may change based on IQ, executive functioning, and age. Method: The current review was registered in the International Prospective Register of Systematic Reviews. Studies were eligible for inclusion if they measured adaptive functioning and included an FASD group and at least one eligible comparison group. Articles available in May 2021 in PubMed, PsycInfo, Scopus, and ProQuest Dissertations were searched. Publication bias was assessed using Egger's regression and three‐level random effects models were computed for all domains of adaptive functioning. Possible moderation by IQ, executive functioning, and age were investigated when heterogeneity analyses were significant. A post hoc moderation analysis of recruitment method was also completed. Results: Thirty studies were included. Individuals with FASD had significantly lower adaptive functioning than other groups, with effect sizes ranging from 1.04 to 1.35 compared to alcohol nonexposed groups and from 0.30 to 0.43 compared to ADHD groups. No significant moderating effects were found for IQ or age; executive functioning significantly moderated communication skills in FASD compared to the alcohol nonexposed group. Recruitment method significantly affected this relationship, with larger effect sizes on average found for clinically identified samples than at‐risk or population samples. Conclusions: Individuals with FASD have impairments in adaptive functioning relative to alcohol nonexposed and ADHD groups, regardless of IQ, executive functioning, or age. Limitations of the review include small sample sizes in some comparisons and a limited age range. [ABSTRACT FROM AUTHOR]

Background: Despite the social nature of most drinking experiences, prior work has largely failed to incorporate social context into the study of alcohol's effects on emotion. The present study provides an initial test of the effect of alcohol on mood among platonic friends drinking together in a non‐stress setting. We hypothesized that subjects would report more positive postdrink mood after consuming alcohol than after consuming a nonalcoholic control beverage. Methods: Dyads of platonic male friends (n = 36; 55.55% White, 38.88% Asian, 5.55% Black) attended two laboratory‐based experimental sessions, wherein their drink conditions (alcohol vs. no alcohol control) were randomized by dyad and counter‐balanced across sessions. They reported their mood before and after consuming their beverages together, using the Positive and Negative Affect Schedule and an 8‐item mood measure. Results: As hypothesized, alcohol enhanced positive mood (β = 0.26, p < 0.01). Although in the expected direction, the effect of alcohol on negative mood was not significant (β = −0.12, p = 0.17). Post hoc analyses revealed that alcohol yielded greater increases in both stimulation (β=0.26, p = 0.00) and sedation (β=0.40, p = 0.00) as compared to the control condition. Conclusion: This study highlights the positive mood‐enhancing and broader subjective effects of alcohol when drinking with a platonic friend and encourages further consideration of friendship contexts in the examination of alcohol's effects when developing models of the etiology of alcohol use disorder. [ABSTRACT FROM AUTHOR]

Background: Heavy alcohol consumption disrupts gut epithelial integrity, leading to increased permeability of the gastrointestinal tract and subsequent translocation of microbes. Regenerating islet‐derived protein 3α (REG3α) and Trefoil factor 3 (TFF3) are mainly secreted to the gut lumen by Paneth and Goblet cells, respectively, and are functionally linked to gut barrier integrity. Circulating levels of REG3α and TFF3 have been identified as biomarkers for gut damage in several human diseases. We examined whether plasma levels of REG3α and TFF3 were dysregulated and correlated with conventional markers of microbial translocation (MT) and pro‐inflammatory mediators in heavy drinkers with and without alcoholic hepatitis (AH). Methods: Cross‐sectional and longitudinal studies were performed to monitor plasma levels of REG3α and TFF3 in 79 AH patients, 66 heavy drinkers without liver disease (HDC), and 46 healthy controls (HC) at enrollment and at 6‐ and 12‐month follow‐ups. Spearman correlation was used to measure the relationships of REG3α and TFF3 levels with MT, disease severity, inflammation, and effects of abstinence from alcohol. Results: At enrollment, AH patients had significantly higher levels of REG3α and TFF3 than HDC and HC. The elevated REG3α levels were positively correlated with the 30‐day fatality rate. Plasma levels of REG3α and TFF3 in AH patients differentially correlated with conventional MT markers (sCD14, sCD163, and LBP) and several highly up‐regulated inflammatory cytokines/chemokines/growth factors. At follow‐ups, although REG3α and TFF3 levels were decreased in AH patients with alcohol abstinence, they did not fully return to baseline levels. Conclusions: Circulating levels of REG3α and TFF3 were highly elevated in AH patients and differentially correlated with AH disease severity, MT, and inflammation, thereby serving as potential biomarkers of MT and gut epithelial damage in AH patients. [ABSTRACT FROM AUTHOR]

Background: Prenatal alcohol exposure (PAE) is linked to a variety of neurodevelopmental challenges, including social functioning (SF) and executive functioning (EF) deficits. These deficits present differently across developmental stages from preschool age to adolescence. Methods: The post hoc analyses described here were conducted on data from 83 preschool‐age children with PAE (early childhood group; ages 2.5 to 5.0) and 95 adolescents (49 with PAE, 46 controls; ages 8 to 16). Each child completed EF tasks as part of several prior studies. Parents completed social and communication inventories about their child's abilities. Thirty‐three participants from the early childhood group returned for a 4‐year follow‐up and completed both SF and EF measures. Results: Both the early childhood and adolescent groups with PAE showed deficits in SF and EF. There was a relationship between SF and EF within the adolescent PAE group that was not present in the adolescent control group or the early childhood PAE group. However, at the 4‐year follow‐up (Mage = 8.45), participants originally in the early childhood PAE group also demonstrated this relationship. Conclusions: These findings support previous research on EF/SF deficits in adolescents with PAE while also addressing a gap in the literature concerning early childhood research on this topic. Additionally, these findings suggest that the relationship between EF and SF deficits may strengthen throughout development. This line of research highlights potential sensitive periods for SF and EF training in children with PAE and suggests that fetal alcohol spectrum disorders programs consider targeting EF training as a component of social skill interventions. [ABSTRACT FROM AUTHOR]

Background: Direct biomarkers such as phosphatidylethanol (PEth) have the capability to detect heavy alcohol use, but it is unclear how strongly self‐reported reduction in alcohol use correlates with reduction in PEth. We sought to explore the strength of correlation between reductions in self‐reported alcohol use and change in PEth among a sample of women living with HIV (WLWH) who participated in a clinical trial to reduce heavy alcohol use. We also sought to determine whether this correlation was stronger in women with lower body mass index (BMI) and women without an alcohol use disorder (AUD). Methods: 81 WLWH (mean age = 48.7, 80% Black) engaging in a randomized trial of naltrexone versus placebo with a positive baseline PEth (≥8 ng/ml), and alcohol use data at baseline, 2, and 7 months were included in this analysis. Spearman correlation coefficients were compared to measure the correlation between baseline PEth and number of drinks per week by demographic, biological, and alcohol use factors. Mini‐International Neuropsychiatric Interview was used to screen for AUD. Further analyses were stratified by BMI and AUD. Spearman correlation coefficients were calculated for the change in PEth and the change in number of drinks per week over 7 months, including 3 time‐points: baseline, 2, and 7 months. Results: At baseline, the correlation between baseline PEth and the number of drinks per week was significantly stronger for those with a BMI ≤25 compared to those with a BMI > 25 (r = 0.66; r = 0.26, respectively). Similarly, the correlation between baseline PEth and number of drinks was stronger for those who did not screen positive for AUD compared with those who did (r = 0.66; r = 0.25, respectively). When stratifying by BMI, a low‐to‐moderate correlation (r = 0.32, p = 0.02) was present for persons with a BMI > 25; when stratifying by AUD, a moderate correlation (r = 0.50, p < 0.01) was present for persons without an AUD between 0 and 2 months only. Conclusions: In this sample of WLWH, BMI and AUD affected the strength of correlation between PEth and drinks per week. Future work examining changes in PEth over time in broader populations is needed, particularly to understand the sex differences in PEth levels. [ABSTRACT FROM AUTHOR]

Background: We sought to compare self‐reported alcohol consumption using Timeline Followback (TLFB) to biomarker‐based evidence of significant alcohol use (phosphatidylethanol [PEth] > 20 ng/ml). Using data from patients with HIV (PWH) entering a clinical trial, we asked whether TLFB could predict PEth > 20 ng/ml and assessed the magnitude of association between TLFB and PEth level. Methods: We defined unhealthy alcohol use as any alcohol use in the presence of liver disease, at‐risk drinking, or alcohol use disorder. Self‐reported alcohol use obtained from TLFB interview was assessed as mean number of drinks/day and number of heavy drinking days over the past 21 days. Dried blood spot samples for PEth were collected at the interview. We used logistic regression to predict PEth > 20 ng/ml and Spearman correlation to quantify the association with PEth, both as a function of TLFB. Results: Among 282 individuals (99% men) in the analytic sample, approximately two‐thirds (69%) of individuals had PEth > 20 ng/ml. The proportion with PEth > 20 ng/ml increased with increasing levels of self‐reported alcohol use; of the 190 patients with either at‐risk drinking or alcohol use disorder based on self‐report, 82% had PEth > 20 ng/ml. Discrimination was better with number of drinks per day than heavy drinking days (AUC: 0.80 [95% CI: 0.74 to 0.85] vs. 0.74 [95% CI: 0.68 to 0.80]). The number of drinks per day and PEth were significantly and positively correlated across all levels of alcohol use (Spearman's R ranged from 0.29 to 0.56, all p values < 0.01). Conclusions: In this sample of PWH entering a clinical trial, mean numbers of drinks per day discriminated individuals with evidence of significant alcohol use by PEth. PEth complements self‐report to improve identification of self‐reported unhealthy alcohol use among PWH. [ABSTRACT FROM AUTHOR]

Background: Young adults typically drink in social settings and report high levels of episodic heavy drinking despite a range of adverse consequences. Behavioral economics posits that this may reflect a reinforcer pathology in which alcohol is overvalued relative to other reinforcers. Theoretically, the value of alcohol is related to both the direct pharmacological effects of alcohol (euphoria, sedation) and the associated social reinforcement, but to date no studies have differentiated the value of social vs. solitary drinking. The current study examines two modified hypothetical alcohol purchase tasks (APTs), one explicitly social and one explicitly solitary, in order to quantify the reward value of social vs. solitary drinking and to determine whether there are unique clinical correlates of solitary alcohol demand. Methods: Participants were young adults (N = 274, Mage = 25.15, SD = 4.10) recruited from Mturk and from a university subject pool. Participants completed a solitary and social APT, in addition to measures of alcohol consumption and problems. Results: Participants reported significantly greater demand in the social APT compared to the solitary APT across all demand indices. Elevated solitary and social demand were associated with elevated levels of alcohol use and problems. Using a residualized change approach, solitary demand amplitude (maximum consumption and expenditure) and persistence (price sensitivity) contributed additional variance above and beyond their social APT composite counterparts in predicting typical drinks per week and the self‐care, academic/occupational, and physical dependence subscales of the YAACQ. Conclusions: The presence of peers increases alcohol demand compared to a solitary scenario, and greater relative solitary drinking demand may be a risk factor for greater alcohol consumption and problems. [ABSTRACT FROM AUTHOR]

Background: Alcohol exposure alters the expression of a large number of genes, resulting in neuronal adaptions and neuronal loss, but the underlying mechanisms are largely unknown. miRNAs are gene repressors that are abundant in the brain. A recent study identified ~ 35 miRNAs that are up‐regulated in the prefrontal cortex of human alcoholics and predicted to target genes that are down‐regulated in the same region. Although interactions between alcohol‐responsive miRNAs and their target genes have been predicted, few studies have validated these predictions. Methods: We measured the expression of GABAAα5 mRNA in the prefrontal and motor cortices of human alcoholics and matched controls using real‐time PCR. The expression of miR‐203 was measured in a subset of these cases. The predicted interaction of miR‐203 and GABRA5 was validated for miR‐203 using a luciferase reporter assay. Results: In both frontal and motor cortices, the expression of GABAAα5 was significantly lower in cirrhotic alcoholics compared with controls. Further, the pattern of expression between the groups was significantly different between males and females. The expression of miR‐203 was higher in the prefrontal cortex of cirrhotic alcoholics compared with controls and uncomplicated alcoholics. These differences were particularly marked in female cases. Cotransfection of GABRA5 with miR‐203 in HEK293T cells reduced luciferase reporter activity. Conclusion: There are sex differences in the expression of GABAAα5 and miR‐203 in the brain of human alcoholics which are particularly marked in alcoholics with cirrhosis of the liver. Further, miR‐203 may mediate the changes in expression of this GABAA receptor isoform that is brought about by alcohol exposure. [ABSTRACT FROM AUTHOR]

Background: The study of alcohol use frequency utilizes alcohol‐related cue imagery. Although a number of alcohol‐image databases currently exist, they have several limitations: Many are not publicly available, some use stock images or clip art rather than real photographs, several eliminate any photographs displaying brand information, and predominantly they contain relatively few images. The aim of this project was to develop a large, open‐access database of alcohol‐related cue images, containing photographs with and without brand information, taken in real‐world environments, with images in a variety of orientations and dimensions. Methods: The study collected 1,650 images voluntarily from the larger community, to capture photographs with a wide range of content, environments, and relation to alcohol. All images were then rated on scales of valence, arousal, and relation to alcohol by 1,008 Amazon Mechanical Turk workers, using classical emotion validation methods based on the International Affective Picture System (IAPS). Survey respondents were screened with the Alcohol Use Disorders Identification Test (AUDIT), and Cronbach's alpha scores were calculated to determine the interrater reliability of scores across the whole sample, and within low‐risk, moderate‐risk, and high‐risk drinkers for each rating domain. Univariate ANOVAs were run to determine differences in ratings across drinking groups. Results: All Cronbach's alpha scores indicated high interrater reliability within the whole sample, and across drinking severity groups. Tukey's HSD post hoc results indicated greater arousal and affect in response to image viewing in moderate‐ and high‐risk drinkers, and higher relation‐to‐alcohol ratings in low‐risk drinkers. All images had categorization tags assigned by members of the study team. Conclusions: The established imagery set includes 1,650 alcohol‐related images, rated on scales of valence, arousal, and relation to alcohol, and categorized by type of alcohol depicted. The imagery database will be available for open‐access download and use through Google Photos. [ABSTRACT FROM AUTHOR]

Background: Human immunodeficiency virus (HIV) infection and heavy drinking independently promote microbial translocation and inflammation. However, it is not known how alcohol use may affect these processes in people living with HIV (PLWH). This study tested the hypothesis that alcohol exacerbates innate immune dysfunction in PLWH. Methods: Participants were 75 PLWH and 34 uninfected controls. Groups were recruited to have similar proportions of nondrinkers, moderate drinkers, and heavy drinkers. Substance use data and plasma samples were collected at up to 3 visits over a 5‐year study period. Recent alcohol use was assessed with the Timeline Followback Interview. Biomarkers of microbial translocation (lipopolysaccharide, LPS) and immune activation (lipopolysaccharide binding protein, LBP; soluble CD14, sCD14; soluble CD163, sCD163) were quantified using enzyme‐linked immunosorbent assays. Analyses tested 2 hypotheses: (i) that biomarker levels would be significantly higher in PLWH than controls with comparable alcohol use and (ii) that current alcohol use would exacerbate biomarker elevations in PLWH. The second analysis included the interaction of alcohol use with hepatitis C virus (HCV) coinfection. Results: Groups were matched on alcohol use, smoking, and other drug use. All biomarkers were significantly higher in PLWH relative to controls (LBP: p = 0.005; LPS: p = 0.014; sCD14: p < 0.001; sCD163: p < 0.001). In PLWH, alcohol use showed a significant, positive association with sCD163, but not with other biomarkers. However, the interaction of alcohol use with HCV coinfection was significant for all biomarkers (LBP: p = 0.002; LPS: p = 0.026; sCD14: p = 0.0004; sCD163: p = 0.001). In pairwise tests with sequential Bonferroni correction, HIV/HCV coinfected individuals who drank heavily had significantly higher sCD163 compared to coinfected nondrinkers and to HIV monoinfected nondrinkers, moderate drinkers, and heavy drinkers (ps < 0.005). Coinfected moderate drinkers had significantly higher sCD163 than each monoinfected group (ps < 0.003). In addition, sCD14 was significantly higher in coinfected moderate drinkers than coinfected nondrinkers (p = 0.027). Conclusions: As predicted, PLWH had higher levels of LBP, LPS, sCD14, and sCD163 than uninfected individuals with similar alcohol use. In PLWH, alcohol by itself was significantly associated only with higher sCD163. However, heavy or moderate alcohol use was associated with elevations in macrophage activation (sCD163) and monocyte activation (sCD14) in HIV/HCV coinfected individuals. [ABSTRACT FROM AUTHOR]

Background: Abstinence and no heavy drinking days are currently the only Food and Drug Administration–approved end points in clinical trials for alcohol use disorder (AUD). Many individuals who fail to meet these criteria may substantially reduce their drinking during treatment, and most individuals with AUD prefer drinking reduction goals. One‐ and two‐level reductions in World Health Organization (WHO) drinking risk levels have been proposed as alternative end points that reflect reduced drinking and are associated with reductions in drinking consequences, improvements in mental health, and reduced risk of developing alcohol dependence. The current study examined the association between WHO drinking risk level reductions and improvements in physical health and quality of life in a sample of individuals with alcohol dependence. Methods: Secondary data analysis of individuals with alcohol dependence (n = 1,142) enrolled in the longitudinal, prospective COMBINE study, a multi site randomized placebo‐controlled clinical trial, examining the association between reductions in WHO drinking risk levels and change in blood pressure, liver enzyme levels, and self‐reported quality of life following treatment for alcohol dependence. Results: One‐ and two‐level reductions in WHO drinking risk level during treatment were associated with significant reductions in systolic blood pressure (p < 0.001), improvements in liver enzyme levels (all p < 0.01), and significantly better quality of life (p < 0.001). Conclusions: One‐ and two‐level reductions in WHO drinking risk levels predicted significant improvements in markers of physical health and quality of life, suggesting that the WHO drinking risk level reduction could be a meaningful surrogate marker of improvements in how a person "feels and functions" following treatment for alcohol dependence. The WHO drinking risk levels could be useful in medical practice for identifying drinking reduction targets that correspond with clinically significant improvements in health and quality of life. At least 1‐ and 2‐level reductions in the World Health Organization (WHO) drinking risk levels by the end of treatment were associated with significant improvements at the end of treatment for physical health and quality of life outcomes. The WHO drinking risk level reductions capture considerable improvement in how patients feel and function in alcohol clinical trials. [ABSTRACT FROM AUTHOR]

Background: The older adult population is increasing worldwide, as is the number of older adults who consume alcohol. Although there is a growing body of research on alcohol consumption among older people, few studies focus on changes in at‐risk consumption over time across well‐defined birth cohorts of older adults. Methods: This study used a serial cross‐sectional design in order to compare alcohol consumption patterns among birth cohorts of Swedish 70‐year‐olds (total n = 2,268) examined in 1976 to 1977 (n = 393), 1992 to 1993 (n = 248), 2000 to 2002 (n = 458), and 2014 to 2016 (n = 1,169). Participants took part in a multidisciplinary study on health and aging. Face‐to‐face interviews were conducted by healthcare professionals. Protocols regarding alcohol consumption were similar for all cohorts. The volume of weekly alcohol consumption was estimated during the past month. At‐risk consumption was defined as ≥100 g alcohol/wk corresponding roughly to the National Institute on Alcohol Abuse and Alcoholism definition of heavy consumption. Results: The proportion of at‐risk consumers among men increased from 16.1% in 1976 to 1977 to 29.9% in 2000 to 2002 (p = 0.001) and 45.3% in 2014 to 2016 (p < 0.001). In women, proportions were low in 1976 to 1977 (0.5%) and 1992 to 1993 (2.0%; p = 0.134), but increased to 9.5% in 2000 to 2002 (p < 0.001) and 24.3% in 2014 to 2016 (p < 0.001). The male:female ratio regarding consumption of ≥100 g/wk decreased from 32.2:1 in 1976 to 1977 to 3.1:1 in 2000 to 2002 to 1.9:1 in 2014 to 2016. Spirit consumption decreased dramatically among men during the study period, while women reported very low spirit consumption at all examinations. Wine consumption increased in both sexes between 2000 to 2002 and 2014 to 2016. Beer consumption increased among men between 2000 to 2002 and 2014 to 2016. Conclusions: Recent cohorts of 70‐year‐olds in Sweden report significantly higher levels of alcohol consumption than previous cohorts. There was a dramatic increase in at‐risk consumption among 70‐year‐olds from the 1970s to the mid‐2010s, and this was particularly pronounced among women. This article compares alcohol consumption patterns among four birth cohorts of Swedish 70‐year‐olds born in different decades during the 20th century. The results show that later born cohorts are drinking more alcohol than earlier born cohorts. Also, sex differences in alcohol consumption decreased during the study period (1976–2016). The prevalence of non‐consumers and low consumers decreased among both men and women. Simultaneously, there was an increase in the prevalence of at‐risk consumers among both sexes. [ABSTRACT FROM AUTHOR]

Background: Most clinical trials evaluating treatments for alcohol use target individuals meeting diagnostic criteria for alcohol use disorder (AUD), but few address change in diagnostic status following treatment or as a potential outcome indicator. This study evaluated whether DSM-5 AUD total criteria count or severity category was sensitive to change over time and treatment effects. Methods: Data were drawn from a randomized clinical trial that evaluated the efficacy of computer-based cognitive behavioral therapy program (CBT4CBT) for AUD. Sixty-eight individuals were randomized to 1 of the 3 weekly outpatient treatments for an 8-week period: (i) treatment as usual (TAU), (ii) TAU+CBT4CBT, and (iii) CBT4CBT+brief monitoring. Structured clinical interviews were used to determine current (past 30 days) AUD diagnosis at baseline, end-of-treatment, and 6 months following end-of-treatment. Change in the total number of DSM criteria endorsed, as well as severity categories (mild, moderate, severe), was evaluated across time and by treatment condition. Results: Generalized Poisson's linear mixed models revealed a significant reduction in the number of DSMcriteria from baseline to treatment end point [time effect χ²(1) = 35.54, p < 0.01], but no significant interactions between time and treatment condition. Fewer total criteria endorsed, as well as achieving at least a 2-level reduction in AUD severity category at end-of-treatment, were associated with better outcomes during follow-up. Chi-square results indicated a greater proportion of individuals assigned to TAU+CBT4CBT had at least a 2-level reduction in severity category compared to TAU, at trend-level significance [χ²(2, 54) = 5.13, p = 0.07], consistent with primary alcohol use outcomes in the main trial. Conclusions: This is the first study to demonstrate change in DSM-5 AUD total criteria count, as well as severity category, in a randomized clinical trial. These findings offer support for their use as a potential clinically meaningful outcome indicator. [ABSTRACT FROM AUTHOR]

Background: Sleep disruptions are an important consequence of alcohol use disorders. There is a dearth of preclinical studies examining sex differences in sleep patterns associated with ethanol (EtOH) dependence despite documented sex differences in alcohol‐related behaviors and withdrawal symptoms. The purpose of this study was to investigate the effects of chronic intermittent EtOH on sleep characteristics in female and male mice. Methods: Female and male C57BL6/J mice had access to EtOH/water 2‐bottle choice (2BC) 2 h/d for 3 weeks followed by exposure to EtOH vapor (vapor‐2BC) or air for 5 cycles of 4 days. An additional group never experienced EtOH (naïve). Mice were implanted with electroencephalographic (EEG) electrodes, and vigilance states were recorded across 24 hours on the fourth day of withdrawal. The amounts of wakefulness, slow‐wave sleep (SWS), and rapid eye movement sleep were calculated, and spectral analysis was performed by fast Fourier transformation. Results: Overall, vapor‐2BC mice showed a decrease in the amount of SWS 4 days into withdrawal as well as a decrease in the power density of slow waves, indicating disruptions in both the amount and quality of sleep in EtOH‐dependent mice. This was associated with a decrease in duration and an increase in number of SWS episodes in males and an increase in latency to sleep in females. Conclusions: Our results revealed overall deficits in sleep regulation in EtOH‐dependent mice of both sexes. Female mice appeared to be more affected with regard to the triggering of sleep, while male mice appeared more sensitive to disruptions in the maintenance of sleep. [ABSTRACT FROM AUTHOR]

Background Biomarkers can play a key role in supplementing self-report information in alcohol research. In this study, we examined phosphatidylethanol (PEth) in comparison with self-reported alcohol use over time in a randomized controlled trial. Methods Participants were women living with HIV enrolled in a randomized placebo-controlled trial of naltrexone for reducing hazardous drinking. Drinking behavior was measured using Timeline Followback (TLFB), and PEth as a biomarker using dried blood spots. Data collected at baseline, and months 2 and 7 were analyzed. In addition to calculated Spearman's correlations, mixed-effects modeling was used to evaluate the changes in self-reported drinking and PEth, respectively, adjusting for body mass index (BMI). Results A total of 194 participants (83% black, mean age 48) were included in the analysis. PEth levels were significantly correlated with self-reported drinking via TLFB, Spearman's r = 0.21 at baseline, r = 0.29 at 2 months, and r = 0.28 at 7 months, respectively. No demographic or health factors, except for BMI, was associated with whether self-report was consistent with PEth. Mixed-effects model indicated that self-reported drinking showed significantly greater reductions in the naltrexone treatment group than the placebo group at the 2- and 7-month visits, whereas PEth measure only showed this difference at the 7-month follow-up. Conclusions The magnitude of the correlation between PEth and self-reported alcohol consumption was small. Caution is needed when using either self-report or PEth as a sole outcome measure for alcohol behavior changes in clinical trials. [ABSTRACT FROM AUTHOR]

Background Neuroactive steroids such as (3 α,5 α)3-hydroxypregnan-20-one (3 α,5 α- THP, allopregnanolone) are potent neuromodulators that enhance GABAergic neurotransmission and produce inhibitory neurobehavioral and anti-inflammatory effects. Chronic ethanol (EtOH) consumption reduces 3 α,5 α- THP levels in human plasma, but has brain region- and species-specific effects on central nervous system levels of 3 α,5 α- THP. We explored the relationship between 3 α,5 α- THP levels in the hippocampus and voluntary EtOH consumption in the cynomolgus monkey following daily self-administration of EtOH for 12 months and further examined the relationship with hypothalamic-pituitary-adrenal ( HPA) axis function prior to EtOH exposure. We simultaneously explored hippocampus levels of monocyte chemoattractant protein 1 ( MCP-1), a pro-inflammatory cytokine that plays an important role in the neuroimmune response to EtOH, following chronic self-administration. Methods Monkeys were subjected to scheduled induction of water and EtOH consumption (0 to 1.5 g/kg) over 4 months, followed by free access to EtOH or water for 22 h/d over 12 months. Immunohistochemistry was performed using an anti-3 α,5 α- THP or anti- MCP-1 antibody. Prolonged voluntary drinking resulted in individual differences in EtOH consumption that ranged from 1.2 to 4.2 g/kg/d over 12 months. Results Prolonged EtOH consumption increased cellular 3 α,5 α- THP immunoreactivity by 12 ± 2% ( p < 0.05) and reduced MCP-1 immunoreactivity by 23 ± 9% ( p < 0.05) in the hippocampus CA1. In both cases, the effect of EtOH was most pronounced in heavy drinkers that consumed ≥3 g/kg for ≥20% of days. 3 α,5 α- THP immunoreactivity was positively correlated with average daily EtOH intake (Spearman r = 0.76, p < 0.05) and dexamethasone inhibition of HPA axis function (Spearman r = 0.9, p < 0.05). In contrast, MCP-1 immunoreactivity was negatively correlated with average daily EtOH intake (Spearman r = −0.78, p < 0.05) and dexamethasone suppression of HPA axis function (Spearman r = −0.76, p < 0.05). Finally, 3 α,5 α- THP and MCP-1 immunoreactivity were inversely correlated with each other (Spearman r = −0.68, p < 0.05). Conclusions These data indicate that voluntary, long-term EtOH consumption results in higher levels of 3 α,5 α- THP, while decreasing levels of MCP-1 in the CA1 hippocampus, and that both changes may be linked to HPA axis function and the magnitude of voluntary EtOH consumption. [ABSTRACT FROM AUTHOR]

Background The heritable risk for alcohol use disorder ( AUD) is expressed partly through alterations in subjective alcohol response. In this study, we investigated the effects of 2 AUD-risk-associated single nucleotide polymorphisms, GABRA2 rs279858 and GRIK1 rs2832407, on the subjective response to alcohol administered intravenously to healthy social drinkers in a laboratory setting. Methods In total, 93 self-identified European American social drinkers underwent 3 blinded laboratory sessions in which they received intravenous infusions of ethanol at 3 target blood alcohol levels (0.00 mg%, 40 mg%, and 100 mg%) using a 'clamp' procedure. The self-reported Biphasic Alcohol Effects Scale ( BAES) stimulation and sedation subscales were the primary outcome measures. We examined the effects of these 2 genetic variants on subjective response to alcohol. Results For the BAES stimulation subscale scores, adjusting for age, baseline scores, and time effects, individuals with 2 copies of the GABRA2 rs279858 C 'risk' allele for AUD exhibited the greatest stimulant responses to high-dose alcohol compared to the other risk allele counts (dose-by-allele count interaction effect, p = 0.001, post hoc contrast for C-allele, p = 0.012). For the BAES sedation subscale scores, adjusting for the same covariates, we detected a dose-by-allele count interaction effect ( p = 0.0044) such that subjects with 2 copies of the GRIK1 C 'risk' allele reported the greatest sedative response to the higher alcohol dose. Conclusions This study suggests that gene variants contributing to the risk for AUD may alter features of the alcohol dose-response relationship in specific ways. GABRA2 rs279858*C enhances stimulant responses to higher levels of alcohol, while the GRIK1 rs2832407*C-allele increases sedative responses. In summary, GRIK1 and GABRA2 variants have distinct effects on the dose-related subjective response to intravenous alcohol in humans. [ABSTRACT FROM AUTHOR]

Background Hazardous drinking ( HD) is a serious health problem in people infected with human immunodeficiency virus type 1 ( HIV-1). Single nucleotide polymorphisms ( SNPs) in alcohol dehydrogenase ( ADH) genes have been associated with HD in different populations, but there were no data about this in HIV-1-positive individuals. This study investigated the association of 4 nonsynonymous SNPs in ADH genes (Arg48His and Arg370Cys in ADH1B gene; Arg272Gln and Ile350Val in ADH1C gene) with HD in people living with HIV-1. Methods This case-control study included 365 HIV-1-positive individuals (121 with HD and 244 without HD). Sociodemographic variables were collected with a standardized individual questionnaire. HD (score ≥8) and binge drinking ( BD) (drinks on the same occasion ≥5) were detected with the Alcohol Use Disorders Identification Test. The 4 SNPs were genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. Adjusted odds ratios ( aORs) and 95% confidence intervals ( CIs) were calculated using logistic regression analysis. The Bonferroni correction was used (considering the 4 SNPs studied). Results There were no significant differences in the frequencies of Arg370Cys, Arg272Gln, and Ile350Val polymorphisms between HD cases and controls. Otherwise, Arg/His genotype (rs1229984) in ADH1B gene showed a protective effect against HD ( aOR = 0.36; 95% CI: 0.14 to 0.90) and BD ( aOR = 0.49; 95% CI: 0.21 to 0.95). Nevertheless, these differences were no longer significant after Bonferroni correction. Conclusions The results of this study suggest a possible effect of the Arg48His genotype on the protection against HD in HIV-1-positive individuals. [ABSTRACT FROM AUTHOR]

Background Academic achievement was evaluated in children with heavy prenatal alcohol exposure to determine potential strengths and weaknesses, evaluate the utility of different definitions for identifying low academic performance, and explore the neural correlates that may underlie academic performance. Methods Children (8 to 16 years) were assessed using the WIAT- II. Patterns of performance were examined in 2 subject groups: children with heavy prenatal alcohol exposure ( n = 67) and controls ( n = 61). A repeated-measures MANCOVA examining group differences on academic domain (reading, spelling, math) scores was conducted. Post hoc comparisons examined within-group profiles. Numbers and percentage of children with low achievement were calculated using several criteria. In a subsample ( n = 42), neural correlates were analyzed using FreeSurfer v5.3 to examine relations between cortical structure (thickness and surface area) and performance. Results The alcohol-exposed group performed worse than controls on all domains and had a unique academic profile, supported by a significant group × academic domain interaction ( p < 0.001). For the alcohol-exposed group, math reasoning was significantly lower than numerical operations, which was significantly lower than spelling and word reading. Over half of the alcohol-exposed group (58.2%) demonstrated low achievement on 1 or more academic domains. The number and percentage of children meeting criteria for low achievement varied based on the domain and definition used. The imaging analysis identified several surface area clusters that were differentially related to math (L superior parietal and R lateral/middle occipital) and spelling (bilateral inferior and medial temporal) performance by group, with no relations for the other academic domains. Generally, scores improved as surface area decreased in controls, whereas no relation or a positive relation was observed in the alcohol-exposed group. Conclusions Alcohol-exposed children demonstrated deficits in academic performance across domains and definitions, with a relative weakness in math functioning. Atypical brain development may contribute to these impairments in academic achievement. Understanding academic difficulties can assist in advocating effectively for alcohol-exposed children. [ABSTRACT FROM AUTHOR]

Background Continued high alcohol consumption levels by college students highlight the need for more effective alcohol interventions and novel treatment engagement strategies. The purpose of this study was to investigate a behavioral sleep intervention as a means to engage heavy-drinking college students in treatment and reduce alcohol use and alcohol-related consequences. Methods Heavy-drinking college students ( N = 42) were assigned to 1 of 2 web-based interventions comprised of 4 modules delivered over 4 weeks. The experimental intervention focused primarily on sleep and included evidence-based sleep content (i.e., stimulus control instructions, sleep scheduling [consistent bed/rise times; ideal sleep duration for adolescents/young adults], sleep hygiene advice, relaxation training, cognitive strategies to target sleep-disruptive beliefs), and alcohol content (i.e., normative and blood alcohol level feedback, moderate drinking guidelines, controlled drinking strategies, effects of alcohol on sleep and the body, advice to moderate drinking for improved sleep) in young adults. The control condition Healthy Behaviors provided basic advice about nutrition, exercise, sleep (i.e., good sleep hygiene only), and drinking (i.e., effects of alcohol on the body, moderate drinking guidelines, advice to moderate drinking for sleep). Participants in both conditions monitored their sleep using daily web-based diaries and a wrist-worn sleep tracker. Results Recruitment ads targeting college students with sleep concerns effectively identified heavy-drinking students. The program generated a high number of inquiries and treatment completion rates were high. Both interventions significantly reduced typical week drinking and alcohol-related consequences and improved sleep quality and sleep-related impairment ratings. The control condition yielded greater reductions in total drinks in a heaviest drinking week. The effects on drinking were larger than those observed in typical brief alcohol intervention studies for college students. Greater sleep improvement tended to predict better subsequent drinking outcomes. Conclusions The results suggest that sleep treatment may be a promising strategy for targeting and treating heavy-drinking college students. [ABSTRACT FROM AUTHOR]

Background Negative emotional status and adverse emotional events increase vulnerability to alcohol abuse. Ultrasonic vocalizations ( USVs) emitted by rats are a well-established model of emotional status that can reflect positive or negative affective responses in real time. Most USV studies assess counts, yet each USV is a multidimensional data point characterized by several acoustic characteristics that may provide insight into the neurocircuitry underlying emotional response. Methods USVs emitted from selectively bred alcohol-naïve and alcohol-experienced alcohol-preferring and nonpreferring rats (P and NP rats) were recorded during 4-hour sessions on alternating days over 4 weeks. Linear mixed modeling ( LMM) and linear discriminant analysis ( LDA) were applied to USV acoustic characteristics (e.g., frequency, duration, power, and bandwidth) of negative affect (22 to 28 kilohertz [kHz])- and positive (50 to 55 kHz) affect-related USVs. Results Hundred percent separation between alcohol-naïve P and NP rats was achieved through a linear combination (produced by LDA) of USV acoustic characteristics of 22- to 28- kHz USVs, whereas poor separation (36.5%) was observed for 50- to 55- kHz USVs. 22- to 28- kHz LDA separation was high (87%) between alcohol-experienced P and NP rats, but was poor for 50- to 55- kHz USVs (57.3%). USV mean frequency and duration were the highest weighted characteristics in both the naïve and experienced 22- to 28- kHz LDA representations suggesting that alcohol experience does not alter the representations. LMM analyses of 22- to 28- kHz USV acoustic characteristics matched the LDA results. Poor LDA separation was observed between alcohol-naïve and alcohol-experienced P rats for both 22- to 28- kHz and 50- to 55- kHz USVs. Conclusions Advanced statistical analysis of negative affect-associated USV data predicts future behaviors of excessive alcohol drinking and alcohol avoidance in selectively bred rats. USV characteristics across rat lines reveal affect-related motivation to consume alcohol and may predict neural pathways mediating emotional response. Further characterization of these differences could delineate particular neurocircuitry and methods to ameliorate dysregulated emotional states often observed in human alcohol abusers. [ABSTRACT FROM AUTHOR]

Background Interactions between the liver, the gut, and the immune system are critical components of alcoholic liver disease (ALD). The aim of this study was to explore the associations between alcohol-induced liver injury, endotoxemia, and inflammation at admission and over time during abstinence, as well as to examine the sex-related differences in these parameters in alcohol-dependent individuals admitted to an alcohol treatment program. Methods A cohort of 48 otherwise healthy participants with alcohol use disorder, but no clinical signs of alcoholic liver injury (34 males [M]/14 females [F]) admitted to an alcohol detoxification program, was stratified into 2 groups based on baseline plasma alanine aminotransferase (ALT) levels (as a marker of liver injury). Group 1 (ALT < 40 U/l, 7M/8F) and Group 2 (ALT ≥ 40 U/l, 27M/6F) were identified. Plasma biomarkers of liver damage, endotoxemia, and inflammation were examined at baseline, day 8, and day 15 of the admission. The drinking history was also evaluated. Results Sixty-nine percent of patients had elevated ALT and other markers of liver damage, including aspartate aminotransferase and cytokeratin 18 (CK18 M65 and CK M30) at baseline, indicating the presence of mild ALD. Elevated CK18 M65:M30 ratio suggested a greater contribution of necrotic rather than apoptotic hepatocyte cell death in the liver injury observed in these individuals. Females showed greater elevations of liver injury markers compared to males, although they had fewer drinks per day and shorter lifetime duration of heavy drinking. Liver injury was associated with systemic inflammation, specifically, elevated plasma tumor necrosis factor-alpha levels. Compared to patients without liver injury, patients with mild ALD had greater endotoxemia (increased serum lipopolysaccharide levels), which decreased with abstinence and this decrease preceded the drop in CK18 M65 levels. Conclusions The study documented the association of mild alcohol-induced liver injury and endotoxemia, which improved with 2 weeks of abstinence, in a subset of individuals admitted to an alcohol detoxification program. [ABSTRACT FROM AUTHOR]

Background Alcohol use among adolescents is widespread and a growing concern due to long-term behavioral deficits, including altered Pavlovian behavior, that potentially contribute to addiction vulnerability. We tested the hypothesis that adolescent intermittent ethanol ( AIE) exposure alters Pavlovian behavior in males and females as measured by a shift from goal-tracking to sign-tracking. Additionally, we investigated GLT-1, an astrocytic glutamate transporter, as a potential contributor to a sign-tracking phenotype. Methods Male and female Sprague-Dawley rats were exposed to AIE (5 g/kg, intragastric) or water intermittently 2 days on and 2 days off from postnatal day (P) 25 to 54. Around P70, animals began 20 daily sessions of Pavlovian conditioned approach (PCA), where they learned that a cue predicted noncontingent reward delivery. Lever pressing indicated interaction with the cue, or sign-tracking, and receptacle entries indicated approach to the reward delivery location, or goal-tracking. To test for effects of AIE on nucleus accumbens (NAcc) excitatory signaling, we isolated membrane subfractions and measured protein levels of the glutamate transporter GLT-1 after animals completed behavior as a measure of glutamate homeostasis. Results Females exhibited elevated sign-tracking compared to males with significantly more lever presses, faster latency to first lever press, and greater probability to lever press in a trial. AIE significantly increased lever pressing while blunting goal-tracking, as indicated by fewer cue-evoked receptacle entries, slower latency to receptacle entry, and lower probability to enter the receptacle in a trial. No significant sex-by-exposure interactions were observed in sign- or goal-tracking metrics. Moreover, we found no significant effects of sex or exposure on membrane GLT-1 expression in the NAcc. Conclusions Females exhibited enhanced sign-tracking compared to males, while AIE decreased goal-tracking compared to control exposure. Our findings support the hypothesis that adolescent binge ethanol can shift conditioned behavior from goal- to cue-directed in PCA, especially in females. [ABSTRACT FROM AUTHOR]

Background Korsakoff syndrome ( KS), most frequently resulting from alcohol dependence (ALC), is characterized by severe anterograde amnesia. It has been suggested that these deficits may extend to other memory components, and notably source memory deficits involved in the disorientation and temporal confusion frequently observed in KS. However, the extent of this source memory impairment in KS and its usefulness for the differential diagnosis between ALC and KS remain unexplored. Methods Nineteen patients with KS were compared with 19 alcohol-dependent individuals and 19 controls in a source memory test exploring temporal context confusions ('continuous recognition task'). Episodic memory and psychopathological comorbidities were controlled for. Results While no source memory deficit was observed in ALC, KS was associated with a significant presence of temporal context confusion, even when the influence of comorbidities was taken into account. This source memory impairment did not appear to be related to performances on episodic memory or executive functions. Conclusions Patients with KS displayed source memory deficits, as indexed by temporal context confusions. The absence of a relationship with episodic memory performances seems to indicate that source memory impairment is not a mere by-product of amnesia. As ALC was associated with preserved source memory, the presence of temporal context confusion may serve as a complementary tool for the differential diagnosis between ALC and KS. [ABSTRACT FROM AUTHOR]

Background Increasing evidence suggests that levels of pro-inflammatory and anti-inflammatory cytokines are dysfunctional in alcohol dependence. Moreover, some initial findings demonstrate that these adaptations in peripheral inflammation may contribute to motivation for alcohol and problem drinking via possible direct effects or the indirect effects of stress responsivity. Importantly, the role of pro-inflammatory and anti-inflammatory cytokines in the progression from healthy to problem drinking is not well understood. The aim of this study was to assess whether alcohol-related peripheral immune system changes affect stress and alcohol cue-induced craving and anxiety and behavioral alcohol motivation and intake in the laboratory among problem drinkers compared with socially drinking controls. Methods Twenty-six problem drinkers and 38 moderate, social drinkers participated in a laboratory challenge procedure during which they were exposed to 3 personalized 5-minute imagery conditions (stress [S], relaxing [R], and alcohol cue [C]), followed by the 'alcohol taste test' ( ATT) as a measure of implicit alcohol motivation and intake, presented across 3 consecutive days, 1 per day in a randomized and counterbalanced order. Measures of tumor necrosis factor-alpha ( TNF α), interleukin-6 ( IL-6), interleukin-1 receptor antagonist ( IL-1ra), alcohol craving, and anxiety were assessed at baseline, immediately following imagery exposure and at discreet beer cue presentation in the ATT. Results Compared with moderate drinkers, problem drinkers demonstrated tonic attenuation of IL-6 and IL-1ra. In problem drinkers, these changes also accompanied elevated levels of stress- and cue-induced alcohol craving and anxiety and were predictive of provoked alcohol craving, behavioral alcohol motivation and intake, and severity of problem drinking. Conclusions Current findings indicate that selective immunosuppression in problem drinkers may play a key role in motivation for alcohol intake. [ABSTRACT FROM AUTHOR]

Background In our companion article, we examined the role of MyD88-dependent signaling in ethanol (EtOH) consumption in mice lacking key components of this inflammatory pathway and observed differential effects on drinking. Here, we studied the role of these same signaling components in the acute sedative, intoxicating, and physiological effects of EtOH. Toll-like receptor 4 (TLR4) has been reported to strongly reduce the duration of EtOH-induced sedation, although most studies do not support its direct involvement in EtOH consumption. We examined TLR4 and other MyD88 pathway molecules to determine signaling specificity in acute EtOH-related behaviors. We also studied other GABAergic sedatives to gauge the EtOH specificity and potential role for GABA in EtOH's sedative and intoxicating effects in the mutant mice. Methods Loss of righting reflex ( LORR) and recovery from motor incoordination were studied following acute injection of EtOH or other sedative drugs in male and female control C57 BL/6J mice versus mice lacking CD14, TLR2, TLR4 (C57 BL/10ScN), or MyD88. We also examined EtOH-induced hypothermia and blood EtOH clearance in these mice. Results Male and female mice lacking TLR4 or MyD88 showed reduced duration of EtOH-induced LORR and faster recovery from EtOH-induced motor incoordination in the rotarod test. MyD88 knockout mice had slightly faster recovery from EtOH-induced hypothermia compared to control mice. None of the mutants differed from control mice in the rate of blood EtOH clearance. All of the mutants showed similar decreases in the duration of gaboxadol-induced LORR, but only mice lacking TLR4 were less sensitive to the sedative effects of pentobarbital. Faster recovery from diazepam-induced motor impairment was observed in CD14, TLR4, and MyD88 null mice of both sexes. Conclusions TLR4 and MyD88 were key mediators of the sedative and intoxicating effects of EtOH and GABAergic sedatives, indicating a strong influence of TLR4-MyD88 signaling on GABAergic function. Despite the involvement of TLR4 in EtOH's acute behaviors, it did not regulate EtOH consumption in any drinking model as shown in our companion article. Collectively, our studies demonstrate differential effects of TLR-MyD88 components in the acute versus chronic actions of EtOH. [ABSTRACT FROM AUTHOR]

Background Molecular and behavioral studies support a role for innate immune proinflammatory pathways in mediating the effects of alcohol. Increased levels of Toll-like receptors (TLRs) have been observed in animal models of alcohol consumption and in human alcoholics, and many of these TLRs signal via the MyD88-dependent pathway. We hypothesized that this pathway is involved in alcohol drinking and examined some of its key signaling components. Methods Different ethanol (EtOH)-drinking paradigms were studied in male and female control C57BL/6J mice versus mice lacking CD14, TLR2, TLR4 (C57BL/10ScN), or MyD88. We studied continuous and intermittent access 2-bottle choice (2BC) and 1-bottle and 2BC drinking-in-the-dark (DID) tests as well as preference for saccharin, quinine, and NaCl. Results In the 2BC continuous access test, EtOH intake decreased in male TLR2 knockout (KO) mice, and we previously reported reduced 2BC drinking in male and female CD14 KO mice. In the intermittent access 2BC test, EtOH intake decreased in CD14 KO male and female mice, whereas drinking increased in MyD88 KO male mice. In the 2BC-DID test, EtOH drinking decreased in male and female mice lacking TLR2, whereas drinking increased in MyD88 KO male mice. In the 1-bottle DID test, EtOH intake decreased in female TLR2 KO mice. TLR2 KO and CD14 KO mice did not differ in saccharin preference but showed reduced preference for NaCl. MyD88 KO mice showed a slight reduction in preference for saccharin. Conclusions Deletion of key components of the MyD88-dependent pathway produced differential effects on EtOH intake by decreasing (TLR2 KO and CD14 KO) or increasing (MyD88 KO) drinking, while deletion of TLR4 had no effect. Some of the drinking effects depended on the sex of the mice and/or the EtOH-drinking model. [ABSTRACT FROM AUTHOR]

Background Recent reports have demonstrated that binge-like ethanol (EtOH) drinking leads to an increase in hypothalamic orexin ( OX) signaling and that suppressing this signaling via systemic administration of an orexin receptor ( OXR) antagonist blocks this behavior; however, the specific OX pathways that modulate this behavior remain unknown. The goal of this study was to further elucidate the role of the OX system in binge-like EtOH drinking using behavioral, molecular, and pharmacological techniques. Methods The drinking-in-the-dark ( DID) paradigm was used to model binge-like drinking behavior in male C57 BL/6J mice. Experiment 1 examined changes in the OX precursor, prepro-orexin, within the hypothalamus following multiple cycle EtOH or sucrose DID using polymerase chain reaction ( PCR) analysis. In experiments 2a and 2b, we used site-directed infusion of an OXR antagonist to examine the individual contribution of each OXR subtype within the ventral tegmental area ( VTA) and central nucleus of the amygdala (CeA), respectively, in binge-like EtOH or sucrose drinking. Results Findings from our PCR study revealed that multiple cycles of binge-like EtOH drinking did not lead to changes in prepro-orexin mRNA as a function of binge-like EtOH drinking. However, data from site-directed pharmacology studies indicate that the orexin-1 receptor (OX1R) is the predominate receptor subtype within the VTA and CeA that regulates binge-like EtOH drinking. Interestingly, inhibition of OX1Rs did not affect binge-like sucrose intake, which suggests that these OX circuits are specific for EtOH consumption. Conclusions As a whole, these data suggest that the VTA and CeA are important regions in which OX regulates binge-like EtOH drinking behavior. Moreover, these findings identify OXR antagonists as a potential treatment option that may be used to ameliorate problematic drinking behavior while leaving responding to natural rewards relatively intact. [ABSTRACT FROM AUTHOR]

Background Hyperalgesia or increased sensitivity to pain is often found in alcoholics during alcohol withdrawal and may contribute to relapse drinking. Alternative therapies such as acupuncture and electroacupuncture ( EA), through mechanisms involving opioid receptors, may reduce pain and substance dependence and withdrawal syndromes. The lateral habenula ( LHb), an epithalamic structure rich in mu opioid receptors ( MORs), is a critical target for both drugs of abuse and pain. We previously observed hyperalgesia in rats withdrawn from chronic ethanol (EtOH) drinking and found that EA at the acupoint Zusanli ( ST36) reduced EtOH intake. This raised question of whether EA can alleviate hyperalgesia during alcohol withdrawal and, if so, whether the mechanism involves MORs in the LHb. Methods We trained male rats to drink EtOH using the intermittent access 20% EtOH 2-bottle free-choice drinking paradigm for 8 weeks, after which the alcohol supply was discontinued. We measured pain sensitivity using radiant heat (a light beam directed at the hind paw of rats) and compared the paw withdrawal latencies ( PWLs) with and without EA at ST36. Results The PWLs were significantly shorter in rats at 24, 48, and 72 hours and 7 days after the discontinuation of EtOH when compared to EtOH-naïve rats. After a single administration of 2-Hz EA for 20 minutes at ST36, the PWLs at 24 hours after the withdrawal of EtOH were significantly greater than those of the sham group (2-Hz EA at the tail). Furthermore, the effect of EA on PWLs was significantly attenuated by bilateral intrahabenula infusion of the MOR antagonist naltrexone. Conclusions These results suggest that EA can alleviate hyperalgesia during EtOH withdrawal through a mechanism involving MORs in the habenula. Based on this, EA could be of potential value as a therapy for hyperalgesia in alcohol dependence. [ABSTRACT FROM AUTHOR]

Background Treatment for alcohol use disorders (AUDs) has traditionally been abstinence oriented, but new research and regulatory guidelines suggest that low-risk drinking may also be an acceptable treatment outcome. However, little is known about long-term outcomes for patients who become low-risk drinkers posttreatment. This study explores a posttreatment low-risk drinking outcome as a predictor of future drinking and psychosocial outcomes over 9 years. Methods Study participants were adults with AUDs at treatment entry who received follow-up interviews 6 months posttreatment intake ( N = 1,061) in 2 large randomized studies conducted at Kaiser Permanente Northern California, a large private, nonprofit, integrated health system. Six-month drinking status was defined as abstinent, low-risk (nonabstinent, no 5+ drinking days), or heavy drinking (1 or more days of 5+ drinks). Using logistic regression models, we explored the relationship between past 30-day drinking status at 6 months and odds of being abstinent or a low-risk drinker (compared to heavy drinking), and positive Addiction Severity Index psychosocial outcomes over 9 years (9-year follow-up rate of 73%). Results Abstainers and low-risk drinkers at 6 months had higher odds of recent abstinence/low-risk drinking over 9 years than heavy drinkers; abstainers had better drinking outcomes than low-risk drinkers. Additionally, among those with interview data, 95% of abstainers and 94% of low-risk drinkers at 6 months were abstinent/low-risk drinkers at 9 years; surprisingly, 89% of heavy drinkers at 6 months were also abstinent/low-risk drinkers although still significantly fewer than the other groups. Abstainers and low-risk drinkers at 6 months had better psychiatric outcomes, and abstainers had better family/social outcomes than heavy drinkers; medical outcomes did not differ. Low-risk drinkers and abstainers showed no reliable differences across psychosocial measures. Conclusions The findings suggest that a low-risk drinking outcome may be reasonable over the long-term for some alcohol-dependent individuals receiving addiction treatment. [ABSTRACT FROM AUTHOR]

Background Ethanol (EtOH) exposure during different phases of life may increase the risk of infections and cause alterations in the central nervous system. The present study investigated the effects of binge-like EtOH exposure in adolescent rats on the febrile response that was induced by lipopolysaccharide ( LPS) and interleukin-1 β ( IL-1 β). Methods Male rats were exposed to EtOH from postnatal days 25 to 38 in a binge-like pattern. Fever was induced by LPS (5 and 50 μg/kg, intraperitoneally) and evaluated on postnatal days 51 and 63, or by IL- β (3 ng) and evaluated on postnatal day 51. Hematological parameters, the status of peritoneal macrophages, and plasma and cerebrospinal IL-1 β levels were also evaluated on postnatal day 51. Results EtOH exposure during adolescence did not alter normal body temperature. However, a significant reduction in the febrile response that was induced by LPS at both doses was observed on postnatal day 51. However, no changes in the febrile response were observed on postnatal day 63 in EtOH-exposed animals. The febrile response that was induced by intracerebroventricular IL-1 β also significantly decreased in animals that received binge-like EtOH exposure during adolescence. Acute oral treatment with EtOH 24 h prior to LPS administration did not alter the febrile response that was induced by LPS. Binge-like EtOH exposure during adolescence did not alter hematological parameters or the number or viability of peritoneal macrophages. Binge-like EtOH exposure did not alter plasma IL-1 β levels but reduced the cerebrospinal fluid levels of this cytokine. Conclusions These results suggest that binge-like EtOH exposure during adolescence causes changes in the central nervous system that can impair the febrile response that can be observed after the cessation of EtOH exposure. These changes were reversible and appeared to involve the LPS/ IL-1 β system. [ABSTRACT FROM AUTHOR]

Background This study examined whether naltrexone ( NTX) or varenicline ( VAR), alone or in combination, can retard the phenotypic expression of a genetic predisposition toward high alcohol drinking in rats selectively bred for high alcohol intake when drug treatment is initiated prior to, or concomitantly with, the onset of alcohol drinking. Methods Alcohol-naïve P rats were treated daily with NTX (15.0 mg/kg BW), VAR (1.0 mg/kg BW), a combination of NTX (15.0 mg/kg BW) + VAR (1.0 mg/kg BW), or vehicle ( VEH) for 2 weeks prior to, or concomitantly with, their first opportunity to drink alcohol and throughout 21 days of daily 2-hour alcohol access. Drug treatment was then discontinued for 3 weeks followed by reinstatement of drug treatment for an additional 3 weeks. Results When P rats were pretreated with drug for 2 weeks prior to onset of alcohol access, only NTX + VAR in combination blocked the acquisition of alcohol drinking in alcohol-naïve P rats. When drug treatment was initiated concomitantly with the first opportunity to drink alcohol, NTX alone, VAR alone, and NTX + VAR blocked the acquisition of alcohol drinking. Following termination of drug treatment, NTX + VAR and VAR alone continued to reduce alcohol drinking but by the end of 3 weeks without drug treatment, alcohol intake in all groups was comparable to that seen in the vehicle-treated group as the expression of a genetic predisposition toward high alcohol drinking emerged in the drug-free P rats. After 3 weeks without drug treatment, reinstatement of NTX + VAR treatment again reduced alcohol intake. Conclusions A combination of NTX + VAR, when administered prior to, or concomitantly with, the first opportunity to drink alcohol, blocks the acquisition of alcohol drinking during both initial access to alcohol and during a later period of alcohol access in P rats with a genetic predisposition toward high alcohol intake. The results suggest that NTX + VAR may be effective in curtailing alcohol drinking in individuals at high genetic risk of developing alcoholism. [ABSTRACT FROM AUTHOR]

Background Conditioned responses to alcohol-associated cues can hinder recovery from alcohol use disorder ( AUD). Cue exposure (extinction) therapy ( CET) can reduce reactivity to alcohol cues, but its efficacy is limited by phenomena such as spontaneous recovery and reinstatement that can cause a return of conditioned responding after extinction. Using a preclinical model of alcohol cue reactivity in rats, we evaluated whether the efficacy of alcohol CET could be improved by conducting CET during the memory reconsolidation window after retrieval of cue-alcohol associations. Methods Rats were provided with intermittent access to unsweetened alcohol. Rats were then trained to predict alcohol access based on a visual cue. Next, rats were treated with either standard extinction ( n = 14) or postretrieval extinction ( n = 13). Rats were then tested for long-term memory of extinction and susceptibility to spontaneous recovery and reinstatement. Results Despite equivalent extinction, rats treated with postretrieval extinction exhibited reduced spontaneous recovery and reinstatement relative to rats treated with standard extinction. Conclusions Postretrieval CET shows promise for persistently attenuating the risk to relapse posed by alcohol cues in individuals with AUD. [ABSTRACT FROM AUTHOR]

Background Alcohol craving is a major cause of relapse in alcohol-dependent ( AD) patients. It is closely related to the high depression and anxiety symptoms that are frequently observed at the early stages of abstinence, and these comorbid symptoms might thus constitute a relapse factor when they persist after detoxification. As these negative affects are known to evolve during the detoxification process, the aim of this study was to investigate the course of the relation between affects and craving during detoxification, with a particular attention given to gender in light of the known differences in affects between AD men and women. Methods AD patients ( n = 256) undergoing a detoxification program were evaluated for positive ( PA) and negative affectivity ( NA), depression and anxiety symptoms, and craving, twice within a 3-week interval (on the first [T1] and the eighteenth day [T2] of abstinence). Results Detoxification course was associated with improvements regarding NA, depression and anxiety symptoms, and craving. Moreover, these negative affects were related to craving intensity. However, for men, the relation was only present at the beginning of detoxification, while, for women, it persisted at the end of detoxification as did high levels of depression. Furthermore, only with women was the level of craving at T2 proportional to negative affects reported at T1, and depression symptoms experienced at T1 were reliable predictors of craving at T2. Conclusions Given the importance of craving in relapse, special care should be given to improve depressive symptoms in AD women to promote long-term abstinence. Also, the remaining portion of AD women who still exhibit substantial symptoms of anxiety and depression at the end of detoxification could benefit from an integrated treatment simultaneously tackling mood and alcohol-dependence disorders. [ABSTRACT FROM AUTHOR]

Background Both chronic alcohol consumption and alcohol withdrawal lead to neural tissue damage which partly recovers during abstinence. This study investigated withdrawal-associated changes in glutamatergic compounds, markers of neuronal integrity, and gray matter volumes during acute alcohol withdrawal in the hippocampus, a key region in development and maintenance of alcohol dependence in humans and rats. Methods Alcohol-dependent patients ( N = 39) underwent magnetic resonance imaging ( MRI) and MR spectroscopy ( MRS) measurements within 24 hours after the last drink and after 2 weeks of abstinence. MRI and MRS data of healthy controls ( N = 34) were acquired once. Our thorough quality criteria resulted in N = 15 available spectra from the first and of N = 21 from the second measurement in patients, and of N = 19 from healthy controls. In a translational approach, chronic intermittent ethanol-exposed rats and respective controls (8/group) underwent 5 MRS measurements covering baseline, intoxication, 12 and 60 hours of withdrawal, and 3 weeks of abstinence. Results In both species, higher levels of markers of glutamatergic metabolism were associated with lower gray matter volumes in the hippocampus in early abstinence. Trends of reduced N-acetylaspartate levels during intoxication persisted in patients with severe alcohol withdrawal symptoms over 2 weeks of abstinence. We observed a higher ratio of glutamate to glutamine during alcohol withdrawal in our animal model. Conclusions Due to limited statistical power, we regard the results as preliminary and discuss them in the framework of the hypothesis of withdrawal-induced hyperglutamatergic neurotoxicity, alcohol-induced neural changes, and training-associated effects of abstinence on hippocampal tissue integrity. [ABSTRACT FROM AUTHOR]

Background We documented the dependence of ethanol (EtOH)-evoked myocardial dysfunction on estrogen (E2), and our recent estrogen receptor (ER) blockade study, in proestrus rats, implicated ERα signaling in this phenomenon. However, a limitation of selective pharmacological loss-of-function approach is the potential contribution of the other 2 ERs to the observed effects because crosstalk exists between the 3 ERs. Here, we adopted a 'regain'-of-function approach (using selective ER subtype agonists) to identify the ER subtype(s) required for unraveling the E2-dependent myocardial oxidative stress/dysfunction caused by EtOH in conscious ovariectomized (OVX) rats. Methods OVX rats received a selective ERα (PPT), ERβ (DPN), or GPER (G1) agonist (10 μg/kg; i.v.) or vehicle 30 minutes before EtOH (1.0 g/kg; infused i.v. over 30 minutes) or saline, and the hemodynamic recording continued for additional 60 minutes. Thereafter, left ventricular tissue was collected for conducting ex vivo molecular/biochemical studies. Results EtOH had no hemodynamic effects in OVX rats, but reduced the left ventricular contractility index, d P/d tmax, and MAP after acute ERα (PPT) or ERβ (DPN) activation. These responses were associated with increases in the phosphorylation of ERK1/2 and eNOS, and in reactive oxygen species (ROS) and malondialdehyde (MDA) levels in the myocardium. GPER activation (G1) only unraveled a modest EtOH-evoked hypotension and elevation in myocardial ROS. PPT enhanced catalase, DPN reduced ALDH2, while G1 had no effect on the activity of either enzyme, and none of the agonists influenced alcohol dehydrogenase or CYP2E1 activities in the myocardium. Blood EtOH concentration (96.0 mg/dl) was significantly reduced following ERα (59.8 mg/dl) or ERβ (62.9 mg/dl), but not GPER (100.3 mg/dl), activation in EtOH-treated OVX rats. Conclusions ERα and ERβ play major roles in the E2-dependent myocardial dysfunction caused by EtOH by promoting combined accumulation of cardiotoxic (ROS and MDA) and cardiodepressant (NOS-derived NO) molecules in female myocardium. [ABSTRACT FROM AUTHOR]

Background All stages of development of alcohol use disorder ( AUD) have not been equally studied. While initiation of drinking has been given considerable attention, other stages have not been as thoroughly investigated. It is not clear whether the same factors are associated consistently across early and late transitions in AUD involvement. High-risk family samples that are enriched for AUD vulnerability and transitions in AUD development offer an opportunity to examine influences across multiple stages of AUD development. Methods Data from adolescents and young adults from high-risk families were used to study 4 transitions in AUD development-time to first drink, first drink to first problem, first drink to first diagnosis, and first problem to first diagnosis. Cox modeling was used to compare associations of parental AUD, parental separation, peer substance use, offspring ever-use of cannabis, trauma exposures, and internalizing and externalizing psychopathology across transitions. Results Hazards of most transitions were elevated for those who had ever used cannabis, those who attributed substance use to their peers, those with externalizing disorders, and those with parents with AUD. Many risk factors were linked to early initiation of alcohol, particularly cannabis use. Internalizing disorders were associated with later stages. Nonassaultive trauma was associated only with early initiation; assaultive trauma was not associated with any transition. Conclusions In this large, ethnically diverse sample of high-risk youth, significant influences across transitions were fairly consistent, with externalizing disorders and cannabis ever-use elevating the likelihood of each stage, and peer and parental (and especially maternal AUD) influences linked to initiation and some later stages. Finally, in light of the increasingly permissive legal and social stances toward cannabis in the United States, the marked elevations of all alcohol outcomes observed for cannabis use underscore the importance of studying the underpinnings of this relationship. [ABSTRACT FROM AUTHOR]

Background A limited number of measures exist to assess alcohol problems during adolescence. Item response theory modeling was used to scale a measure of adolescent alcohol problems, including drinking and driving, and then related to alcohol and other psychiatric disorders that occurred over a 15-year period. Methods High school students ( N = 832) completed the 13-item Alcohol Problems Index ( API) at age 18 years as part of a long-term longitudinal study of predictors of alcohol use and alcohol disorders. Frequency of drinking and driving was also measured during adolescence. Lifetime psychiatric disorders, including alcohol disorders, were measured during young adulthood. Rasch modeling was used to scale the severity of alcohol problems, and the scaled total score was used to prospectively predict alcohol disorders. The area under the receiver operating characteristic ( ROC) curve was also computed between the adolescent alcohol problems and alcohol and other psychiatric disorders across a 15-year period. Results The prevalence of alcohol disorders was 38.7% (for alcohol dependence, it was 27.7%). Rasch modeling indicated that the API assessed a range of severity of alcohol problems and that drinking and driving were among the less severe indicators. Age 18 API scores significantly correlated with an alcohol diagnosis (0.34), and ROC curve analysis indicated that for adolescent alcohol problem scores, the diagnostic accuracy (or area under the curve) for an alcohol diagnosis by age 33 was 0.70. Conclusions Our findings supported the unidimensionality and reliability of the API, and statistically significant prospective prediction of young adult alcohol disorders. The measurement of alcohol problems during adolescence, in addition to drinking and driving, may be beneficial in understanding adverse consequences of drinking during adolescence as well as transitions in alcohol use and alcohol disorders across the lifespan. [ABSTRACT FROM AUTHOR]

Background Liver damage is a serious and sometimes fatal consequence of long-term alcohol intake, which progresses from early-stage fatty liver (steatosis) to later-stage steatohepatitis with inflammation and fibrosis/necrosis. However, very little is known about earlier stages of liver disruption that may occur in problem drinkers, those who drink excessively but are not dependent on alcohol. Methods We examined how repeated binge-like alcohol drinking in C57 BL/6 mice altered liver function, as compared with a single binge-intake session and with repeated moderate alcohol consumption. We measured a number of markers associated with early- and later-stage liver disruption, including liver steatosis, measures of liver cytochrome P4502E1 ( CYP2E1) and alcohol dehydrogenase ( ADH), alcohol metabolism, expression of cytokine mRNA, accumulation of 4-hydroxynonenal (4- HNE) as an indicator of oxidative stress, and alanine transaminase/aspartate transaminase as a measure of hepatocyte injury. Results Importantly, repeated binge-like alcohol drinking increased triglyceride levels in the liver and plasma, and increased lipid droplets in the liver, indicators of steatosis. In contrast, a single binge-intake session or repeated moderate alcohol consumption did not alter triglyceride levels. In addition, alcohol exposure can increase rates of alcohol metabolism through CYP2E1 and ADH, which can potentially increase oxidative stress and liver dysfunction. Intermittent, excessive alcohol intake increased liver CYP2E1 mRNA, protein, and activity, as well as ADH mRNA and activity. Furthermore, repeated, binge-like drinking, but not a single binge or moderate drinking, increased alcohol metabolism. Finally, repeated, excessive intake transiently elevated mRNA for the proinflammatory cytokine IL-1B and 4- HNE levels, but did not alter markers of later-stage liver hepatocyte injury. Conclusions Together, we provide data suggesting that even relatively limited binge-like alcohol drinking can lead to disruptions in liver function, which might facilitate the transition to more severe forms of liver damage. [ABSTRACT FROM AUTHOR]

Background Current estimates of the rates of alcohol-exposed pregnancies may underestimate prenatal alcohol exposure if alcohol consumption in early trimester 1, prior to awareness of pregnancy, is not considered. Extant literature describes predictors of alcohol consumption during pregnancy; however, alcohol consumption prior to awareness of pregnancy is a distinct behavior from consumption after becoming aware of pregnancy and thus may be associated with different predictors. The purpose of this study was therefore to examine prevalence and predictors of alcohol consumption by women prior to awareness of their pregnancy, and trajectories of change to alcohol use following pregnancy recognition. Methods Pregnant women ( n = 1,403) were prospectively recruited from general antenatal clinics of 4 public hospitals in Australian metropolitan areas between 2008 and 2013. Women completed detailed interviews about alcohol use before and after recognition of pregnancy. Results Most women ( n = 850, 60.6%) drank alcohol between conception and pregnancy recognition. Binge and heavy drinking were more prevalent than low-level drinking. The proportion of women who drank alcohol reduced to 18.3% ( n = 257) after recognition of pregnancy. Of women who drank alcohol, 70.5% ceased drinking, 18.3% reduced consumption, and 11.1% made no reduction following awareness of pregnancy. Socioeconomic status ( SES) was the strongest predictor of alcohol use, with drinkers more likely to be of high rather than low SES compared with abstainers ( OR = 3.30, p < 0.001). Factors associated with different trajectories (either cessation, reduction, or continuation of drinking) included level of alcohol use prior to pregnancy recognition, age, pregnancy planning, and illicit substance use. Conclusions In this sample of relatively high SES women, most women ceased or reduced drinking once aware of their pregnancy. However, the rate of alcohol-exposed pregnancies was higher than previous estimates when the period prior to pregnancy recognition was taken into account. [ABSTRACT FROM AUTHOR]

Background Breath alcohol responses may be affected by the presence of carbohydrate ( CHO) in a beverage. This study investigated the impact of consuming alcohol with mixers containing various doses of CHO or an artificial sweetener on breath alcohol concentration (Br AC), ratings of intoxication and impairment, and cognitive performance in females. Methods Twenty-six females (age 25.1 ± 0.7 years, mean ± standard deviation) completed a crossover study involving 4 trials. A dose of alcohol was consumed in each trial mixed with water (W), artificial sweetener (150 ± 1 mg aspartame [ AS]), or CHO (15 g sucrose [15 CHO] and 50 g sucrose [50 CHO]). Br AC was sampled for 210 minutes following beverage ingestion and analyzed for peak Br AC and other parameters using WinNonlin noncompartmental pharmacokinetic modeling ( cmax, tmax, area under the curve to the last measured time point [ AUClast]). An objective measure of cognitive performance was assessed using a 4-choice reaction time ( CRT) task. Estimation of Br AC, self-reported ratings of intoxication, and willingness to drive were recorded. Results Mean peak Br AC was reduced in a dose-response manner when alcohol was consumed with CHO compared to both W and AS treatments (W: 0.054 ± 0.015%, AS: 0.052 ± 0.011%, 15 CHO: 0.049 ± 0.008%, 50 CHO: 0.038 ± 0.007%). No difference in peak Br AC was observed between W and AS treatments. WinNonlin parameters revealed significant differences in cmax and AUClast (W: 4.80 ± 1.12 g/dl/h, AS: 4.61 ± 0.92 g/dl/h, 15 CHO: 4.10 ± 0.86 g/dl/h, 50 CHO: 3.11 ± 0.58 g/dL/h) when CHO-containing beverages were consumed compared to W and AS treatments. No difference in tmax or CRT was observed between treatments. Participants were able to detect subtle differences in peak Br AC and reported greater ability to drive after consuming 50 CHO compared to W. However, participant's willingness to drive and CRT did not differ between treatments. Conclusions Consuming alcohol with CHO-containing mixers attenuates peak Br AC and reduces total alcohol exposure in a dose-response manner compared to drinks containing artificial sweetener or no additives. The effect of adding CHO to alcoholic beverages may translate to reduced risk of alcohol-related harms. [ABSTRACT FROM AUTHOR]

Background The consumption of alcohol during pregnancy can result in abnormal fetal development and impaired brain function in humans and experimental animal models. Depending on the pattern of consumption, the dose, and the period of exposure to ethanol (EtOH), a variety of structural and functional brain deficits can be observed. Methods This study compared the effects of EtOH exposure during distinct periods of brain development on oxidative damage and endogenous antioxidant status in various brain regions of adult female and male Sprague Dawley rats. Pregnant dams and neonatal rats were exposed to EtOH during one of the following time windows: between gestational days ( GDs) 1 and 10 (first trimester equivalent); between GDs 11 and 21 (second trimester equivalent); or between postnatal days ( PNDs) 4 and 10 (third trimester equivalent). Results EtOH exposure during any of the 3 trimester equivalents significantly increased lipid peroxidation in both the cornus ammonis ( CA) and dentate gyrus ( DG) subregions of the hippocampus, while also decreasing the levels of the endogenous antioxidant glutathione in the hippocampal CA and DG subregions as well as the prefrontal cortex of young adult animals ( PND 60). Conclusions These results indicate that EtOH exposure during restricted periods of brain development can have long-term consequences in the adult brain by dysregulating its redox status. This dysfunction may underlie, at least in part, the long-term alterations in brain function associated with fetal alcohol spectrum disorders. [ABSTRACT FROM AUTHOR]