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Background Although most people are aware of government guidelines for alcohol consumption, few have accurate knowledge of these and fewer still use these guidelines to monitor their drinking. Most people also lack accurate knowledge of the alcohol content of the drinks they consume. The aim of the study reported here was to examine whether or not personalized feedback on alcohol consumption based on performance in a drink-pouring task and self-reported alcohol intake would improve university students' knowledge of alcohol consumption guidelines and reduce their alcohol intake. Methods A quasi-randomized control trial with a 2-month follow-up was conducted with 200 students aged 18 to 37 in the south of England. Participants were allocated to a 'pour + feedback' group that completed a drink-pouring task and received personalized feedback, a 'pour only' group that completed the drink-pouring task but did not receive feedback, and a control group. Results At follow-up, participants in the 'pour + feedback' group had significantly better knowledge of government guidelines, and significantly lower weekly alcohol intake when compared to the 'control' and 'pour only' groups. Conclusions Further refinement of the drink-pouring intervention and feedback is reported in this paper, and assessment of their impact in various populations may lead to better understanding of which elements of personalized feedback have the greatest influence on young people's alcohol use. [ABSTRACT FROM AUTHOR]

Background Prenatal alcohol exposure can kill developing neurons, leading to microencephaly and mental retardation. However, not all fetuses are equally vulnerable to alcohol's neurotoxic effects. While some fetuses are severely affected and are ultimately diagnosed with fetal alcohol syndrome (FAS), others have no evidence of neuropathology and are behaviorally normal. These widely different outcomes among alcohol-exposed fetuses are likely due, in part, to genetic differences. Some fetuses possess genotypes that make them much more vulnerable than others to alcohol's teratogenic effects. However, to date, only 1 gene has been identified whose mutation can worsen alcohol-induced behavioral deficits in an animal model of FAS. That gene is neuronal nitric oxide synthase ( nNOS). The purpose of this study was to determine whether mutation of nNOS can likewise worsen alcohol-induced microencephaly and lead to permanent neuronal deficits. Methods Wild-type and nNOS−/− mice received alcohol (0.0, 2.2, or 4.4 mg/g) daily over postnatal days (PDs) 4 to 9. Beginning on PD 85, the mice underwent a series of behavioral tests; the results of which are reported in the companion paper. The brains were then weighed, and stereological cell counts were performed on the cerebral cortex and hippocampal formation, which are the brain regions that mediate the aforementioned behavioral tasks. Results Alcohol caused dose-dependent microencephaly, but only in the nNOS−/− mice and not in wild-type mice. Alcohol-induced neuronal losses were more severe in the nNOS−/− mice than in the wild-type mice in all of the brain regions examined, including the cerebral cortex, hippocampal CA3 subregion, hippocampal CA1 subregion, and dentate gyrus. Conclusions Targeted mutation of the nNOS gene increases the vulnerability of the developing brain to alcohol-induced growth restriction and neuronal losses. This increased neuropathology is associated with worsened behavioral dysfunction. The results demonstrate the critical importance of genotype in determining the outcome of developmental alcohol exposure. [ABSTRACT FROM AUTHOR]

Background Alcohol-related blackouts ( ARBs) are reported by ~50% of drinkers. While much is known about the prevalence of ARBs in young adults and their cross-sectional correlates, there are few prospective studies regarding their trajectories over time during mid-adolescence. This paper reports latent trajectory classes of ARBs between age 15 and 19, along with predictors of those patterns. Methods Latent class growth analysis ( LCGA) was used to evaluate the pattern of occurrence of ARBs across 4 time points for 1,402 drinking adolescents from the Avon Longitudinal Study of Parents and Children ( ALSPAC). Multinomial regression analyses evaluated age-15 demography, substance-related items, externalizing characteristics, and estimated peer substance use as predictors of latent class membership. Results ARBs were reported at age 15 in 30% and at age 19 in 74% of these subjects. Four latent trajectory classes were identified: Class 1 (5.1%) reported no blackouts; for Class 2 (29.5%), ARBs rapidly increased with age; for Class 3 (44.9%), blackouts slowly increased; and for Class 4 (20.5%), ARBs were consistently reported. Using Class 2 (rapid increasers) as the reference, predictors of class membership included female sex, higher drinking quantities, smoking, externalizing characteristics, and estimated peer substance involvement (pseudo R2 = 0.22). Conclusions ARBs were common and repetitive in these young subjects, and predictors of their trajectories over time involved multiple domains representing diverse characteristics. [ABSTRACT FROM AUTHOR]

Background: This paper examines differences in drinking and binge drinking between Mexican Americans living along the U.S.-Mexico border and those living in 2 metropolitan areas away from the border (Houston, Texas and Los Angeles, California). Methods: Respondents in the non-border area (Houston and Los Angeles) constitute a multistage probability sample ( N = 1,288), who were interviewed as part of the 2006 Hispanic Americans Baseline Alcohol Survey (HABLAS). Respondents in the border area ( N = 1,307) constitute a household probability sample of Mexican Americans living on the U.S.-Mexico border. In both surveys, data were collected during computer-assisted interviews conducted in respondents' homes. The HABLAS and the border sample response rates were 76 and 67%, respectively. Results: There were no differences between border and non-border Mexican American men in the proportion of drinkers, the proportion who binge drink at least once a year, and volume of alcohol consumption. However, within each location, there were significant differences in drinking by age, indicating that younger men drank more than men who were older. Border women showed significant differences across age-groups in the proportion of drinkers, in binge drinking, and volume of alcohol consumption, which were not seen among non-border women. Conclusions: Women's drinking seems to be more affected than men's by their residence on or off the U.S.-Mexico border. This is seen most clearly among young women 18 to 29 years old, and it is associated with an increased proportion of drinkers, a higher volume of drinking, and an increased proportion of women who report binge drinking. Increased drinking in this group of younger women seems to be associated with drinking in Mexico. [ABSTRACT FROM AUTHOR]

Although we know a great deal about the percentage of youth who drink alcohol, we know very little about the specific brands they choose to drink. This information gap needs to be addressed if public health officials are to develop more effective interventions. Unfortunately, there are no national youth surveys that collect data on alcohol brand consumption. In this paper, we describe the development and pilot testing of what we believe to be the first comprehensive, Internet-based youth survey of brand-specific alcohol use. We used online advertising in 3 U.S. cities to recruit a convenience sample of 241 respondents, ages 16 to 18 years. We used Craigslist, a network of online communities that features local classified advertisements, to recruit the sample. We used SurveyGizmo, an online software program for designing Internet surveys, collecting data, and performing basic analysis, to survey these respondents about their brand-specific alcohol consumption patterns. The survey instrument assessed each respondent's 30-day drinking history, including the frequency of consumption for each alcohol brand. Using Internet survey technology, we were able to collect information on 366 brands and still have respondents complete the instrument quickly and easily. The total number of brands consumed in the past 30 days ranged from 1 to 18, with a median of 4 brands. The top 5 brands consumed were beer brands, as were eleven of the top 15 brands. The remaining 4 brands in the top 15 included 3 brands of flavored alcoholic beverages and 1 brand of mixed drink. Among the top 15 alcohol brands consumed during heavy drinking episodes were 8 brands of beer, 4 brands of flavored alcoholic beverages, 2 brands of wine, and 1 brand of mixed drink. This pilot study helps establish the feasibility of including brand-specific questions on federal or other national youth alcohol surveys. [ABSTRACT FROM AUTHOR]

Previous research has documented a relationship between child sexual abuse and alcohol dependence. This paper extends that work by providing a comprehensive description of past year and lifetime alcohol consumption patterns, consequences, and dependence among women reporting either physical and sexual abuse in a national sample. This study used survey data from 3,680 women who participated in the 2005 U.S. National Alcohol Survey. Information on physical and sexual child abuse and its characteristics were assessed in relation to 8 past year and lifetime alcohol consumption measures. Child physical or sexual abuse was significantly associated with past year and lifetime alcohol consumption measures. In multivariate analyses, controlling for age, marital status, employment status, education, ethnicity, and parental alcoholism or problem drinking, women reporting child sexual abuse vs. no abuse were more likely to report past year heavy episodic drinking (OR = 1.7; 95% CI 1.0 to 2.9), alcohol dependence (OR = 7.2; 95% CI 3.2 to 16.5), and alcohol consequences (OR = 3.6; 95% CI 1.8 to 7.3). Sexual abuse (vs. no abuse) was associated with a greater number of past year drinks (124 vs. 74 drinks, respectively, p = 0.002). Sexual child abuse was also associated with lifetime alcohol-related consequences (OR = 3.5; 95% CI 2.6 to 4.8) and dependence (OR = 3.7; 95% CI 2.6 to 5.3). Physical child abuse was associated with 4 of 8 alcohol measures in multivariate models. Both physical and sexual child abuse were associated with getting into fights, health, legal, work, and family alcohol-related consequences. Alcohol-related consequences and dependence were more common for women reporting sexual abuse compared to physical abuse, 2 or more physical abuse perpetrators, nonparental and nonfamily physical abuse perpetrators, and women reporting injury related to the abuse. Both child physical and sexual abuse were associated with many alcohol outcomes in adult women, even when controlling for parental alcohol problems. The study results point to the need to screen for and treat underlying issues related to child abuse, particularly in an alcohol treatment setting. [ABSTRACT FROM AUTHOR]

Background: While drinking alcohol, one must choose between the immediate rewarding effects and the delayed reward of a healthier lifestyle. Individuals differ in their devaluation of a delayed reward based on the time required to receive it, i.e., delay discounting (DD). Previous studies have shown that adolescents discount more steeply than adults and that steeper DD is associated with heavier alcohol use in both groups. Methods: In a large‐scale longitudinal study, we investigated whether higher rates of DD are an antecedent or a consequence of alcohol use during adolescent development. As part of the IMAGEN project, 2220 adolescents completed the Monetary Choice Questionnaire as a DD measure, the Alcohol Use Disorders Identification Test, and the Timeline Follow Back interview at ages 14, 16, 18, and 22. Bivariate latent growth curve models were applied to investigate the relationship between DD and drinking. To explore the consequences of drinking, we computed the cumulative alcohol consumption and correlated it with the development of discounting. A subsample of 221 participants completed an intertemporal choice task (iTeCh) during functional magnetic resonance imaging at ages 14, 16, and 18. Repeated‐measures ANOVA was used to differentiate between high‐risk and low‐risk drinkers on the development of neural processing during intertemporal choices. Results: Overall, high rates of DD at age 14 predicted a greater increase in drinking over 8 years. In contrast, on average, moderate alcohol use did not affect DD from ages 14 to 22. Of note, we found indicators for less brain activity in top‐down control areas during intertemporal choices in the participants who drank more. Conclusions: Steep DD was shown to be a predictor rather than a consequence of alcohol use in low‐level drinking adolescents. Important considerations for future longitudinal studies are the sampling strategies to be used and the reliability of the assessments. [ABSTRACT FROM AUTHOR]

Background: There are gaps in the literature on service use (help‐seeking and treatment utilization) for alcohol problems among those with alcohol use disorder (AUD). First, policy changes and cultural shifts (e.g., insurance) related to AUD have occurred over the last few decades, making it important to study generational differences. Second, multiple studies have found that females receive fewer services than males, and exploring whether these sex differences persist across generations can inform public health and research endeavors. The current study examined service use for alcohol problems among individuals with AUD. The aims were as follows: (i) to describe service use for alcohol problems; (ii) to assess generational differences (silent [b. 1928 to 1945], boomer [b. 1946 to 1964], generation X [b. 1965 to 1980], millennial [b. 1981 to 1996]) in help‐seeking and treatment utilization; and (iii) to examine sex differences across generations. Methods: Data were from affected family members of probands who participated in the Collaborative Study on the Genetics of Alcoholism (N = 4,405). First, frequencies for service use variables were calculated across generations. Pearson chi‐square and ANOVA were used to test for differences in rates and types of service use across generations, taking familial clustering into account. Next, Cox survival modeling was used to assess associations of generation and sex with time to first help‐seeking and first treatment for AUD, and time from first onset of AUD to first help‐seeking and first treatment. Interactions between generation and sex were tested within each Cox regression. Results: Significant hazards were found in all 4 transitions. Overall, younger generations used services earlier than older generations, which translated into higher likelihoods of these behaviors. Regardless of generation, younger females were less likely to use services than males. Conclusions: There are generational and sex differences in service use for alcohol problems among individuals with AUD. Policy and clinical implications are discussed. [ABSTRACT FROM AUTHOR]

Background: Rodent studies have consistently shown that prenatal alcohol exposure (PAE) impairs performance on the Morris water maze (MWM), a test of spatial navigation. A previous study comparing boys with fetal alcohol syndrome (FAS) to controls found poorer performance on the virtual water maze (VWM), a human analogue of the MWM. We examined PAE effects on virtual navigation in both sexes using the VWM in a moderately exposed Detroit cohort (N = 104; mean = 19.4 year) and a heavily exposed Cape Town, South African cohort (N = 62; mean = 10.4 year). Methods: The task requires the participant to learn the location of a hidden platform in a virtual pool of water. The set of acquisition trials requires the participant to learn the location of the hidden platform and to return to that location repeatedly. The single‐probe trial requires the participant to return to that location without knowing that the platform has been removed. Results: No effects of FASD diagnostic group or PAE were detected on virtual navigation in the Detroit moderately exposed cohort. By contrast, in the more heavily exposed Cape Town cohort, the FAS/partial FAS (PFAS) group took longer to locate the hidden platform during acquisition than nonsyndromal heavily exposed (HE) and control groups, an effect that persisted even after controlling for IQ. Among boys, both the FAS/PFAS and HE groups performed more poorly than controls during acquisition, and both boys and girls born to women who binge drank performed more poorly than those born to abstainers/light drinkers. Both amount and frequency of PAE were related to poorer performance during the probe trial at 10 years of age. Conclusions: These data demonstrate deficits in spatial navigation among heavily exposed syndromal boys and girls and in nonsyndromal exposed boys. [ABSTRACT FROM AUTHOR]

Background: Youth with heavy prenatal alcohol exposure have high rates of behavioral concerns and psychopathology, including increased oppositional and conduct behaviors. The relation between those concerns and executive function (EF) deficits is unknown. We investigated the association of oppositional and conduct behavior and EF in adolescents to inform targeted intervention. Methods: Subjects (N = 267) ages 10 to 17 years comprised 3 groups: alcohol‐exposed with oppositional/conduct behaviors (AE+), alcohol‐exposed without oppositional/conduct behaviors (AE−), and controls (CON). Group differences on direct neuropsychological (Delis‐Kaplan Executive Function System [D‐KEFS]) and indirect parent‐report (Behavior Rating Inventory of Executive Function [BRIEF]) EF measures were tested with multivariate analysis of covariances, followed by univariate analysis of variances and pairwise comparisons. The contribution of attention‐deficit/hyperactivity disorder (ADHD) within the AE groups was assessed in secondary analyses. Results: On the D‐KEFS, there was an omnibus main effect of group, with significant main effects on 3 of 6 variables (CON>AE+, AE−). Within the AE groups, ADHD did not alter the results. On the BRIEF, there was an omnibus significant main effect of group, with significant main effects on all scales (CON

Background Although studies have shown that alcohol expectancies are prominent predictors of alcohol initiation and subsequent drinking levels, the questionnaires used to assess these expectancies among young adolescents have been criticized as being time-intensive, biased, and inappropriate. Methods In response, we developed the Alcohol Expectancy Task ( AET), in which 8 scenarios featuring adults in everyday situations and in different emotional states, accompanied by photographs of a range of beverages (4 alcoholic, 8 nonalcoholic), are displayed on a tablet screen, and participants are then asked to tap on the beverage they think the given person had been drinking. Results In a first study among 184 adults (75.1% women; mean age = 37.8, SD = 12.2), results from a repeated-measures analysis of variance revealed a strong correspondence between the emotions depicted in the scenarios and how the participants interpreted them. In a second study, this time among 283 third and fourth graders (50.2% girls; mean age = 10.6, SD = 0.69), a confirmatory factor analysis confirmed the 4-factor structure of the AET. The results from a logistic regression analysis showed that the more often young adolescents assigned alcohol to the adults in an arousal-positive mood than to those in a sedation-negative mood, the more likely they were to have already consumed alcohol more than twice. Questionnaire-assessed expectancies were unrelated to adolescents' drinking and did not affect the associations of the AET. Conclusions The AET has the advantage of being time-efficient and convenient and could overcome certain limitations associated with questionnaire-based assessments of alcohol expectancy. [ABSTRACT FROM AUTHOR]

Background Several psychometrically sound measures of alcohol use have been developed to assess drinking. The Alcohol Use Disorders Identification Test (AUDIT) and its shorter counterpart the AUDIT-C, which contains the first 3 AUDIT questions, were developed by the World Health Organization and have become the preferred brief measures for screening and evaluating problem severity. This study compared the first 3 questions on the AUDIT with another psychometrically sound brief measure of alcohol use, the Quick Drinking Screen (QDS). Methods Data were obtained from a randomized controlled trial of a mail-based intervention promoting self-change with 472 alcohol abusers ( n = 280, no prior alcohol treatment; n = 192, prior alcohol treatment). Participants' retrospective self-reports of alcohol consumption were collected using the QDS and the 3 AUDIT-C questions and compared. Although both measures contain similar questions (2 quantity-frequency and 1 binge drinking), they differ in 2 important ways: (i) temporal interval over which data are collected, and (ii) formatting of response options (i.e., a continuous number vs. categorical). Results Intraclass correlations for drinking variables were moderate to moderately high. A repeated-measures MANOVA using treatment condition and gender as variables revealed significant differences in absolute values between the 2 drinking measures with the QDS showing greater consumption on almost all variables. Participants' numerical answers on the QDS were compared to their categorical answers to the similar alcohol use questions on the AUDIT-C. The comparison revealed that participants' answers on the AUDIT-C were associated with extreme variability compared to their QDS answers. This variability suggests the AUDIT-C would be unreliable as a quantitative measure of alcohol consumption. Conclusions The differences between the 3 alcohol use questions on the AUDIT-C and the same questions on the QDS may reflect the imprecision of the AUDIT-C's drinking response categories. Results suggest that the QDS can be used to identify risky drinking and to provide a more informative characterization of a drinker's alcohol consumption than that provided by the AUDIT-C. [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 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 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 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 Physicians have long reported that patients with chronic pain show higher tendencies for alcohol use disorder ( AUD), and AUD patients appear to have higher pain sensitivities. The goal of this study was to test 2 hypotheses: (i) binge alcohol consumption increases inflammatory pain and mechanical and cold sensitivities; and (ii) tigecycline is an effective treatment for alcohol-mediated-increased pain behaviors and sensitivities. Both female and male mice were used to test the additional hypothesis that important sex differences in the ethanol (EtOH)-related traits would be seen. Methods 'Drinking in the Dark' ( DID) alcohol consuming and nondrinking control, female and male, adult C57 BL/6J mice were evaluated for inflammatory pain behaviors and for the presence of mechanical and cold sensitivities. Inflammatory pain was produced by intraplantar injection of formalin (10 μl, 2.5% in saline). For cold sensation, a 20 μl acetone drop was used. Mechanical withdrawal threshold was measured by an electronic von Frey anesthesiometer. Efficacy of tigecycline (80 mg/kg i.p.) to reduce DID-related pain responses and sensitivity was tested. Results DID EtOH consumption increased inflammatory pain behavior, while it also produced sustained mechanical and cold sensitivities in both females and males. Tigecycline produced antinociceptive effects in males; a pro-nociceptive effect was seen in females in the formalin test. Likewise, the drug reduced both mechanical and cold sensitivities in males, but females showed an increase in sensitivity in both tests. Conclusions Our results demonstrated that binge drinking increases pain, touch, and thermal sensations in both sexes. In addition, we have identified sex-specific effects of tigecycline on inflammatory pain, as well as mechanical and cold sensitivities. The development of tigecycline as an AUD pharmacotherapy may need consideration of its pro-nociceptive action in females. Further studies are needed to investigate the mechanism underlying the sex-specific differences in nociception. [ABSTRACT FROM AUTHOR]

Background The chronic intermittent ethanol ( CIE) paradigm is valuable for screening compounds for efficacy to reduce drinking traits related to alcohol use disorder ( AUD), as it measures alcohol consumption and preference under physical dependence conditions. Air control-treated animals allow simultaneous testing of similarly treated, nondependent animals. As a consequence, we used CIE to test the hypothesis that tigecycline, a semisynthetic tetracycline similar to minocycline and doxycycline, would reduce alcohol consumption regardless of dependence status. Methods Adult C57 BL/6J female and male mice were tested for tigecycline efficacy to reduce ethanol (EtOH) consumption using a standard CIE paradigm. The ability of tigecycline to decrease 2-bottle choice of 15% EtOH (15E) versus water intake in dependent ( CIE vapor) and nondependent (air-treated) male and female mice was tested after 4 cycles of CIE vapor or air exposure using a within-subjects design and a dose-response. Drug doses of 0, 40, 60, 80, and 100 mg/kg in saline were administered intraperitoneally (0.01 ml/g body weight) and in random order, with a 1-hour pretreatment time. Baseline 15E intake was re-established prior to administration of subsequent injections, with a maximum of 2 drug injections tested per week. Results Tigecycline was found to effectively reduce high alcohol consumption in both dependent and nondependent female and male mice. Conclusions Our data suggest that tigecycline may be a promising drug with novel pharmacotherapeutic characteristics for the treatment of mild-to-severe AUD in both sexes. [ABSTRACT FROM AUTHOR]

Background New pharmacotherapies to treat alcohol use disorders ( AUD) are needed. Given the complex nature of AUD, there likely exist multiple novel drug targets. We, and others, have shown that the tetracycline drugs, minocycline and doxycycline, reduced ethanol (EtOH) drinking in mice. To test the hypothesis that suppression of high EtOH consumption is a general property of tetracyclines, we screened several derivatives for antidrinking activity using the Drinking-In-the-Dark ( DID) paradigm. Active drugs were studied further using the dose-response relationship. Methods Adult female and male C57 BL/6J mice were singly housed and the DID paradigm was performed using 20% EtOH over a 4-day period. Mice were administered a tetracycline or its vehicle 20 hours prior to drinking. Water and EtOH consumption was measured daily. Body weight was measured at the start of drug injections and after the final day of the experiment. Blood was collected for EtOH content measurement immediately following the final bout of drinking. Results Seven tetracyclines were tested at a 50 mg/kg dose. Only minocycline and tigecycline significantly reduced EtOH drinking, and doxycycline showed a strong effect size trend toward reduced drinking. Subsequent studies with these 3 drugs revealed a dose-dependent decrease in EtOH consumption for both female and male mice, with sex differences in efficacy. Minocycline and doxycycline reduced water intake at higher doses, although to a lesser degree than their effects on EtOH drinking. Tigecycline did not negatively affect water intake. The rank order of potency for reduction in EtOH consumption was minocycline > doxycycline > tigecycline, indicating efficacy was not strictly related to their partition coefficients or distribution constants. Conclusions Due to its effectiveness in reducing high EtOH consumption coupled without an effect on water intake, tigecycline was found to be the most promising lead tetracycline compound for further study toward the development of a new pharmacotherapy for the treatment of AUD. [ABSTRACT FROM AUTHOR]

Background Cognitive bias modification ( CBM) can be used to retrain automatic approach tendencies for alcohol. We investigated whether changing cortical excitability with transcranial direct current stimulation ( tDCS) could enhance CBM effects in hazardous drinkers. We also studied the underlying mechanisms by including behavioral (craving, implicit associations, approach tendencies) and electrophysiological (event-related potentials) measurements. Methods The analytical sample consisted of 78 hazardous drinkers (Alcohol Use Disorders Identification Test >8) randomly assigned to 4 conditions in a 2-by-2 factorial design (control/active CBM and sham/active tDCS). The intervention consisted of 3 sessions of CBM, specifically alcohol approach bias retraining, combined with 15 minutes 1 mA tDCS over the left dorsolateral prefrontal cortex. There was a pre- and postassessment before and after the intervention that included experimental tasks (Approach Avoidance Task, Implicit Association Task) and an electroencephalogram with an oddball and cue-reactivity task. Results tDCS decreased cue-induced craving (but not overall craving) on postassessment. CBM did not induce an avoidance bias during assessment. During the training, active and control- CBM only differed in bias score during the first session. We found no enhancement effects of tDCS on CBM. Electrophysiological data showed no clear effects of active tDCS or CBM on the P300. Conclusions There were no electrophysiological or behavioral effects of repeated CBM and/or tDCS, except for an effect of tDCS on craving. Applied in these specific ways these techniques appear to have limited effects in a hazardous drinking population. [ABSTRACT FROM AUTHOR]

Background This was a proof-of-concept study to evaluate the efficacy of LY2940094, a nociceptin/orphanin FQ peptide receptor antagonist, in reducing alcohol consumption in actively alcohol-drinking patients with alcohol dependence. Methods Eighty-eight patients, 21 to 66 years of age, diagnosed with alcohol dependence, reporting 3 to 6 heavy drinking days per week, were randomized (1:1) to 8 weeks of treatment with once-daily oral placebo ( N = 44) or 40 mg/d of LY2940094 ( N = 44). The primary efficacy analysis was the change from baseline in number of drinks per day ( NDD) utilizing mixed-model repeated measures comparing LY2940094 and placebo in Month 2 of the 8-week double-blind treatment period. The probability that the difference relative to placebo in NDD was ≤0 at endpoint was calculated, and a probability ≥80% was considered to be evidence that LY2940094 was associated with the reduction in NDD. Results After 8 weeks of treatment, reduction in mean NDD did not differ between LY2940094 versus placebo (−1.4 vs. −1.5, respectively, 44% probability of greater reduction relative to placebo), but there was a greater reduction in the mean percentage of heavy drinking days in a month with LY2940094 versus placebo (−24.5 vs. −15.7%, respectively, 93% probability of a greater reduction relative to placebo), and an increase in the mean percentage of abstinent days in a month compared to placebo (9.1 vs. 1.9%, respectively, 91% probability of a greater increase relative to placebo). Patients who were treated with LY2940094 showed decreased plasma levels of gamma-glutamyl transferase with probabilities ≥98% for greater reduction compared with placebo at Weeks 1, 4, 6, and 8. Treatment-emergent adverse events in ≥5% of patients treated with LY2940094 included insomnia, vomiting, and anxiety. There were no serious adverse events or significant changes in laboratory assessments or vital signs with LY2940094. Conclusions Although not reducing the NDD, LY2940094, compared to placebo, did reduce heavy drinking days and increased abstinence days in patients with alcohol dependence. [ABSTRACT FROM AUTHOR]

Background Neurobehavioral consequences of heavy prenatal alcohol exposure are well documented; however, the role of age or sex in these effects has not been studied. The current study examined the effects of prenatal alcohol exposure, sex, and age on neurobehavioral functioning in children. Methods Subjects were 407 youth with prenatal alcohol exposure ( n = 192) and controls ( n = 215). Two age groups (child [5 to 7 years] or adolescent [10 to 16 years]) and both sexes were included. All subjects completed standardized neuropsychological testing, and caregivers completed parent-report measures of psychopathology and adaptive behavior. Neuropsychological functioning, psychopathology, and adaptive behavior were analyzed with separate 2 (exposure history) × 2 (sex) × 2 (age) multivariate analyses of variance (MANOVAs). Significant effects were followed by univariate analyses. Results No 3-way or 2-way interactions were significant. The main effect of group was significant in all 3 MANOVAs, with the control group performing better than the alcohol-exposed group on all measures. The main effect of age was significant for neuropsychological performance and adaptive functioning across exposure groups with younger children performing better than older children on 3 measures (language, communication, socialization). Older children performed better than younger children on a different language measure. The main effect of sex was significant for neuropsychological performance and psychopathology; across exposure groups, males had stronger language and visual spatial scores and fewer somatic complaints than females. Conclusions Prenatal alcohol exposure resulted in impaired neuropsychological and behavioral functioning. Although adolescents with prenatal alcohol exposure may perform more poorly than younger exposed children, the same was true for nonexposed children. Thus, these cross-sectional data indicate that the developmental trajectory for neuropsychological and behavioral performance is not altered by prenatal alcohol exposure, but rather, deficits are consistent across the 2 age groups tested. Similarly, observed sex differences on specific measures were consistent across the groups and do not support sexually dimorphic effects in these domains. [ABSTRACT FROM AUTHOR]

Background Relapse is common in alcohol-dependent individuals and can be triggered by alcohol-related cues in the environment. It has been suggested that these individuals develop cognitive biases, in which cues automatically capture attention and elicit an approach action tendency that promotes alcohol seeking. The study aim was to examine whether cognitive bias modification ( CBM) training targeting approach bias could be delivered during residential alcohol detoxification and improve treatment outcomes. Methods Using a 2-group parallel-block (ratio 1:1) randomized controlled trial with allocation concealed to the outcome assessor, 83 alcohol-dependent inpatients received either 4 sessions of CBM training where participants were implicitly trained to make avoidance movements in response to pictures of alcoholic beverages and approach movements in response to pictures of nonalcoholic beverages, or 4 sessions of sham training (controls) delivered over 4 consecutive days during the 7-day detoxification program. The primary outcome measure was continuous abstinence at 2 weeks postdischarge. Secondary outcomes included time to relapse, frequency and quantity of alcohol consumption, and craving. Outcomes were assessed in a telephonic follow-up interview. Results Seventy-one (85%) participants were successfully followed up, of whom 61 completed all 4 training sessions. With an intention-to-treat approach, there was a trend for higher abstinence rates in the CBM group relative to controls (69 vs. 47%, p = 0.07); however, a per-protocol analysis revealed significantly higher abstinence rates among participants completing 4 sessions of CBM relative to controls (75 vs. 45%, p = 0.02). Craving score, time to relapse, mean drinking days, and mean standard drinks per drinking day did not differ significantly between the groups. Conclusions This is the first trial demonstrating the feasibility of CBM delivered during alcohol detoxification and supports earlier research suggesting it may be a useful, low-cost adjunctive treatment to improve treatment outcomes for alcohol-dependent patients. [ABSTRACT FROM AUTHOR]

Background: Exposure to ethanol (EtOH) in utero alters the disposition of tangentially migrating GABAergic interneurons in the fetal brain. The medial ganglionic eminence (MGE) gives rise to a large portion of cortical GABAergic interneurons, including the parvalbumin-expressing interneurons that shape and contribute to inhibitory/excitatory (I/E) balance of the intracortical circuit. Here, we investigated in the mouse medial prefrontal cortex (mPFC) the hypothesis that low levels of maternal EtOH consumption from closure of the neural tube embryonic day (E) 9.5 until birth result in an enduring interneuronopathy. Methods: Pregnant mice were subjected to a 2%w/w EtOH consumption regimen starting at neural tube closure and ending at parturition. Neurogenesis in theMGE was assessed by 5-bromo-2-deoxyuridine (BrdU) immunofluorescence at E12.5. The count and distribution of parvalbumin-expressing interneurons were determined in adult animals, and patch clamp electrophysiology was performed to determine GABAergic function and I/E balance. Open-field behavior in adult mice was assessed to determine whether the EtOH-exposed cohort displayed a lasting alteration in exploratory behavior. Results: In embryos exposed to EtOH in utero, we found increased BrdU labeling in the MGE, pointing to increased neurogenesis. Adult mice prenatally exposed to EtOH were hyperactive, and this was associated with an increase in parvalbumin-expressing GABAergic interneurons in the mPFC. In addition, prenatal EtOH exposure altered the balance between spontaneous inhibitory and excitatory synaptic input and attenuated GABAergic tone in layer V mPFC pyramidal neurons in juvenile mice. Conclusions: These findings underscore that altered migration of GABAergic interneurons contributes to the EtOH-induced aberration of cortical development and that these effects persist into adulthood as altered cortical form and function. [ABSTRACT FROM AUTHOR]

Background Prenatal alcohol exposure ( PAE) can result in an array of morphological, behavioral, and neurobiological deficits that can range in their severity. Despite extensive research in the field and a significant progress made, especially in understanding the range of possible malformations and neurobehavioral abnormalities, the molecular mechanisms of alcohol responses in development are still not well understood. There have been multiple transcriptomic studies looking at the changes in gene expression after PAE in animal models; however, there is a limited apparent consensus among the reported findings. In an effort to address this issue, we performed a comprehensive re-analysis and meta-analysis of all suitable, publically available expression data sets. Methods We assembled 10 microarray data sets of gene expression after PAE in mouse and rat models consisting of samples from a total of 63 ethanol (EtOH)-exposed and 80 control animals. We re-analyzed each data set for differential expression and then used the results to perform meta-analyses considering all data sets together or grouping them by time or duration of exposure (pre- and postnatal, acute and chronic, respectively). We performed network and Gene Ontology enrichment analysis to further characterize the identified signatures. Results For each subanalysis, we identified signatures of differential expressed genes that show support from multiple studies. Overall, the changes in gene expression were more extensive after acute EtOH treatment during prenatal development than in other models. Considering the analysis of all the data together, we identified a robust core signature of 104 genes down-regulated after PAE, with no up-regulated genes. Functional analysis reveals over representation of genes involved in protein synthesis, mRNA splicing, and chromatin organization. Conclusions Our meta-analysis shows that existing studies, despite superficial dissimilarity in findings, share features that allow us to identify a common core signature set of transcriptome changes in PAE. This is an important step to identifying the biological processes that underlie the etiology of fetal alcohol spectrum disorders. [ABSTRACT FROM AUTHOR]

Background In the accompanying article, we showed that activation of peroxisome proliferator-activated receptor alpha (PPARα) signaling by fenofibrate and tesaglitazar decreases ethanol (EtOH) consumption in mice. In this study, we determined the role of these PPAR agonists in EtOH-related behaviors and other actions that may be important in regulating EtOH consumption. Methods The effects of fenofibrate (150 mg/kg) and tesaglitazar (1.5 mg/kg) were examined on the following responses in male and female C57BL/6J (B6) and B6 × 129S4 mice: preference for saccharin, EtOH-induced conditioned place preference (CPP), conditioned taste aversion (CTA), loss of righting reflex, and withdrawal, acoustic startle reflex, response to novelty, and EtOH clearance. Because the B6 inbred strain usually displays weak EtOH-induced CPP and weak EtOH-induced acute withdrawal, B6 × 129S4 mice were also studied. Results Fenofibrate and tesaglitazar decreased the novelty response and increased acute EtOH withdrawal severity, and fenofibrate increased EtOH-induced CTA. Two important factors for EtOH consumption (saccharin preference and EtOH-induced CPP) were not altered by fenofibrate or tesaglitazar. EtOH clearance was increased by both fenofibrate and tesaglitazar. Response to novelty, acute withdrawal, and EtOH clearance show sex differences and could contribute to the reduced EtOH consumption following fenofibrate administration. Conclusions These studies indicate the complexity of EtOH-dependent and EtOH-independent behaviors that are altered by PPAR agonists and provide evidence for novel behavioral actions of these drugs that may contribute to PPAR-mediated effects on alcohol drinking. [ABSTRACT FROM AUTHOR]

Background Prenatal alcohol exposure ( PAE) enhances the risk for alcoholism by increasing the propensity to consume alcohol and altering neurophysiological response to alcohol challenge. Trans-generationally transmittable genetic alterations have been implicated in these behavioral changes. To date, transgenerational transmission of PAE-induced behavioral responses to alcohol has never been experimentally investigated. Therefore, we explored the transgenerational transmission of PAE-induced behavioral effects across 3 generations. Methods Pregnant Sprague Dawley dams received 1 g/kg ethanol (EtOH) or water daily on gestational days 17 through 20 via gavage, or remained untreated in their home cages. To produce second filial (F2) or F3 generations, similarly treated adult F1 or F2 offspring were mated and left undisturbed through gestation. On postnatal day ( PND) 14, male and female F1, F2, and F3 offspring were tested for consumption of 5% (w/v) EtOH (in water), or water. Using the loss of righting reflex ( LORR) paradigm on PND 42, F1 and F2 adolescent male offspring were tested for sensitivity to acute EtOH-induced sedation-hypnosis at 3.5 or 4.5 g/kg dose. F3 male adolescents were similarly tested at 3.5 g/kg dose. Blood EtOH concentration ( BEC) was measured at waking. Results EtOH exposure increased EtOH consumption compared to both water and untreated control groups in all generations. EtOH-treated group F1 and F2 adolescents displayed attenuated LORR duration compared to the water group. No attenuated LORR was observed in the F3 generation. BEC at waking corroborated with the significant LORR duration differences while also revealing differences between untreated control and water groups in F1 and F2 generations. Conclusions Our results provide novel behavioral evidence attesting that late gestational moderate EtOH exposure increases EtOH intake across 3 generations and may alter sensitivity to EtOH-induced sedation-hypnosis across 2 generations. [ABSTRACT FROM AUTHOR]

Background Posttraumatic stress disorder (PTSD) is an important and timely clinical issue particularly for combat veterans. Few pharmacologic options are available to treat PTSD, particularly among military personnel, and they are not based on rational neurobiology. The evidence for noradrenergic dysregulation in PTSD is strong, and the alpha-adrenergic agonist prazosin is one of the most promising medications to treat sleep disturbances associated with PTSD as well as PTSD symptoms among both veterans and civilians. Evidence also implicates noradrenergic dysregulation in the pathophysiology of alcohol dependence (AD); prazosin also may have efficacy in treating this disorder. The use of prazosin represents a rational and compelling approach for the treatment of PTSD and comorbid AD. Given the high rates of comorbid AD in trauma survivors with PTSD, and the enormous impact that these comorbid disorders have on psychosocial function and well-being, finding effective treatments for this population is of high clinical importance. Methods Ninety-six veterans with PTSD and comorbid AD were randomized to receive prazosin (16 mg) or placebo in an outpatient, randomized, double-blind, clinical trial for 13 weeks. Main outcomes included symptoms of PTSD, sleep disturbances, and alcohol use. Results Symptoms of PTSD improved over time, but contrary to the hypothesis, there was no medication effect on PTSD symptoms, or on sleep. Alcohol consumption also decreased over time, but there were no significant differences in outcomes between medication groups. Conclusions Prazosin was not effective in treating PTSD symptoms, improving sleep, or reducing alcohol consumption overall in this dually diagnosed group. This does not support the use of prazosin in an actively drinking population and suggests that the presence of a comorbid condition affects the efficacy of this medication. This study highlights the importance of conducting clinical trials in 'real-world' patients, as results may vary based on comorbid conditions. [ABSTRACT FROM AUTHOR]

Background: The role of neuroimmune activation in withdrawal from chronic alcohol (ethanol) has been established in both adolescent and adult models, but direct comparisons across age are sparse. Studies need to elucidate age-dependent neuroimmune effects of alcohol and to focus research attention on age-dependent mechanisms and outcomes. Methods: Adult and adolescent rats from 2 commonly used strains, Wistar and Sprague Dawley (SD), were maintained on continuous 7%, 5.35%, 4.5%alcohol diet (CAD) or cycled 7%w/v alcohol diet for 15 days. Cortical tissue was collected at 0, 8, 16, and 24 hours postwithdrawal followed by measurement of chemokine (C-C motif) ligand 2 (CCL2), tumor necrosis factor alpha, and interleukin 1 beta mRNA with quantitative real-time polymerase chain reaction. Results: Both age groups and strains showed a strong cytokine mRNA response at 7%CAD. Further, a greater increase in CCL2 mRNA was observed in the cortex of adolescents at 7% CAD, which correlated with higher blood alcohol levels (BALs). Adolescents exposed to 5.35%CAD exhibited similar blood levels and cytokine responses as adults exposed to 7%CAD. Substantial variability in CCL2 mRNA responses was found only in adolescent rats exposed to 7%CAD. In this group, data could be segregated into high-responding and low-responding groups. Moreover, the data from the high-responding group were associated with seizures. Conclusions: Relative to other cytokine mRNAs, CCL2 exhibits a unique response profile during withdrawal from CAD. This profile is shown in adolescents, where CCL2 is uniquely influenced by the effects of seizures. Additionally, this profile is shown by the fact that only CCL2 expression correlated with BAL that transcended age groups. These data emphasize the importance of BALs and treatment regimen on developmental neuroimmune responses and suggest that select components of the neuroimmune system are more responsive to CAD withdrawal and that neurobiological mechanisms differentiating these responses should be further explored. [ABSTRACT FROM AUTHOR]

Background Many alcoholics display moderate to severe cognitive dysfunction accompanied by brain pathology. A factor confounded with prolonged heavy alcohol consumption is poor nutrition, and many alcoholics are thiamine deficient. Thus, thiamine deficiency ( TD) has emerged as a key factor underlying alcohol-related brain damage ( ARBD). TD in humans can lead to Wernicke Encephalitis that can progress into Wernicke-Korsakoff syndrome and these disorders have a high prevalence among alcoholics. Animal models are critical for determining the exact contributions of ethanol (EtOH)- and TD-induced neurotoxicity, as well as the interactions of those factors to brain and cognitive dysfunction. Methods Adult rats were randomly assigned to 1 of 6 treatment conditions: chronic EtOH treatment ( CET) where rats consumed a 20% v/v solution of EtOH over 6 months; severe pyrithiamine-induced TD ( PTD-moderate acute stage); moderate PTD ( PTD-early acute stage); moderate PTD followed by CET ( PTD- CET); moderate PTD during CET ( CET- PTD); and pair-fed (PF) control. After recovery from treatment, all rats were tested on spontaneous alternation and attentional set-shifting. After behavioral testing, brains were harvested for determination of mature brain-derived neurotrophic factor ( BDNF) and thalamic pathology. Results Moderate TD combined with CET, regardless of treatment order, produced significant impairments in spatial memory, cognitive flexibility, and reductions in brain plasticity as measured by BDNF levels in the frontal cortex and hippocampus. These alterations are greater than those seen in moderate TD alone, and the synergistic effects of moderate TD with CET lead to a unique cognitive profile. However, CET did not exacerbate thalamic pathology seen after moderate TD. Conclusions These data support the emerging theory that subclinical TD during chronic heavy alcohol consumption is critical for the development of significant cognitive impairment associated with ARBD. [ABSTRACT FROM AUTHOR]

Background Alcohol research may benefit from controlled and validated picture sets. We have constructed the Amsterdam Beverage Picture Set ( ABPS), which was designed for alcohol research in general and cognitive bias measurement and modification in particular. Here, we first formulate a position on alcohol stimulus validity that prescribes that alcohol-containing pictures, compared to nonalcohol-containing pictures, should induce a stronger urge to drink in heavy drinkers than in light drinkers. Because a perceptually simple picture might induce stronger cognitive biases but the presence of a drinking context might induce a stronger urge to drink, the ABPS contains pictures with and without drinking context. By limiting drinking contexts to simple consumption scenes instead of real-life scenes, complexity was minimized. A validation study was conducted to establish validity, to examine ABPS drinking contexts, and to explore the role of familiarity, valence, arousal, and control. Methods Two hundred ninety-one psychology students completed the Alcohol Use Disorders Identification Test, as well as rating and recognition tasks for a subset of the ABPS pictures. Results The ABPS was well-recognized, familiar, and heavy drinkers reported a greater urge to drink in response to the alcohol-containing pictures only. Alcohol presented in drinking context did not elicit a stronger urge to drink but was recognized more slowly than alcohol presented without context. Conclusions The ABPS was found to be valid, although pictures without context might be preferable for measuring cognitive biases than pictures with context. We discuss how an explicit approach to picture construction may aid in creating variations of the ABPS. Finally, we describe how ABPS adoption across studies may allow more reproducible and comparable results across paradigms, while allowing researchers to apply picture selection criteria that correspond to a wide range of theoretical positions. The latter is exemplified by ABPS derivatives and adoptions that are currently under way. [ABSTRACT FROM AUTHOR]

Background Models of drug addiction emphasize the reciprocal influence of incentive-motivational properties of drug-related cues and poor impulse control resulting in drug use. Recent studies have shown that alcohol-related cues can impair response inhibition. What is unknown is whether these cues also disrupt learning of inhibitory associations. Methods Participants performed a conditioned inhibition ( CI) task and were required to learn that a neutral image was a conditioned inhibitor when presented in the context of either an alcohol image intended to draw their attention away from the to-be-trained inhibitor, or a control condition in which the alcohol image was absent. After training, subjects in each condition rated the likelihood that the neutral image would signal the outcome. Eye tracking was used to verify that attention to the neutral image was in fact reduced when the alcohol image was present. Results Compared with controls those trained in the alcohol image condition reported a greater likelihood that the presence of the inhibitor would be followed by the outcome and thus were less able to acquire CI. Measures of eye tracking verified that attention to the alcohol cue was associated with this maladaptive behavior. Conclusions When alcohol cues are present, there is a reduced ability to learn that such information is irrelevant to an outcome, and this impairs ones' ability to inhibit perseveration of a response. This has implications for persistence of a drinking episode. [ABSTRACT FROM AUTHOR]

Background Our previous work showed that binge drinking in the rat induced hepatic steatosis which correlated with reduced expression of AMP-activated protein kinase ( AMPK). In this study, we used the rat model to investigate the role of adiponectin (Adip), sirtuin 1 ( SIRT1), AMPK, and lipin 1 ( LIP 1) signaling, a central controlling pathway of lipid metabolism in hepatic steatosis. Methods The serum Adip and tumor necrosis factor-alpha ( TNF- α) as well as liver Adip receptors (AdipoR1 and AdipoR2) SIRT1, AMPK, phosphorylated AMPK (p- AMPK), sterol regulatory element-binding proteins ( SREBPs), acetyl-CoA carboxylase ( ACC), LIP 1, lipocalin-2 ( LCN2), and serum amyloid A1 were assessed in the rat model where 16 weeks of gavaged alcohol were administered. Results In this model of ethanol (EtOH) administration, hepatic steatosis, necrosis, as well as inflammation were increased over the 16-week period. The level of TNF- α in the serum was increased while the Adip content decreased significantly, and there was an inverse relationship between the content of TNF- α and Adip. The mRNA and protein expression of AdipoR2, SIRT1, and AMPK was suppressed by EtOH in the rats' hepatic tissue. Additionally, EtOH significantly decreased p- AMPK by 90% over the 16-week period. In parallel, there was a 2.53- and 1.82-fold increase of lipogenic genes SREBP1c and ACC, and a 3.22- and 4.12-fold increase of LIP 1 and LIP 1 β mRNA expression, respectively, in the hepatic tissue of the rats. Conclusions Our present observations demonstrate that the impaired Adip- SIRT1- AMPK signaling pathway contributes, at least in part, to the development of alcoholic fatty liver disease in EtOH binge rats. [ABSTRACT FROM AUTHOR]

Background Heavy drinking is common during transitions from high school to college. Optimal programs for diminishing risks for high alcohol consumption often tailor the approach to the specific needs of students. This study describes the results of an Internet-based prevention protocol that tailors the information to the risk associated with a pre-existing phenotype, the Low level of Response (Low LR) to alcohol. Methods Using stratified random assignment, 454 freshmen with Low and High LR values were assigned to 2 education groups (LR-based where all examples were given the context of the Low LR model of heavy drinking or a State Of The Art (SOTA) Group where the same lessons were taught but without an emphasis on LR) or a no-intervention Control Group. Individuals in the 2 education groups viewed 50-minute online videos once per week for 4 weeks. Changes in drinking patterns were assessed at Baseline, 4 weeks, and 8 weeks using a 2 (LR status) by 3 (education group) by 3 (time points) analysis of variance, with additional tests for ethnicity and sex. Results Low LR participants tended to decrease their usual ( p < 0.06) and maximum ( p < 0.05) drinks per occasion most prominently when assigned to the LR-based protocol, while those with High LRs improved more in the SOTA Group. The most robust differences were seen when controlling for ethnicity. The effect sizes were small to medium. Conclusions These results support the advantages of carrying out prevention via the Internet and in tailoring the approach to a pre-existing phenotype. [ABSTRACT FROM AUTHOR]

Background Alcohol's effect on sleep electroencephalogram ( EEG) power spectra during late adolescence is of interest given that this age group shows both dramatic increases in alcohol consumption and major sleep-related developmental changes in quantitative EEG measures. This study examined the effect of alcohol on sleep EEG power spectra in 18- to 21-year-old college students. Methods Participants were 24 (12 female) healthy 18- to 21-year-old social drinkers. Participants underwent 2 conditions: presleep alcohol and placebo, followed by standard polysomnography with comprehensive EEG recordings. Results After alcohol, mean breath alcohol concentration at lights-out was 0.084%. Interaction effects indicated simultaneous increases in frontal non-rapid eye movement sleep ( NREM) delta ( p = 0.031) and alpha ( p = 0.005) power in the first sleep cycles following alcohol consumption which was most prominent at frontal scalp sites ( p < 0.001). A decrease in sigma power ( p = 0.001) was also observed after alcohol. Conclusions As hypothesized, alcohol increased slow wave sleep-related NREM delta power. However, there was a simultaneous increase in frontal alpha power. Results suggest that alcohol may exert an arousal influence which may compete with the sleep maintenance influence of increased delta activity. The phenomenon is similar to, or the same as, alpha-delta sleep which has been associated with the presence of disruptive stimuli during sleep. This may have negative implications for the impact of presleep alcohol consumption on sleep and consequent daytime functioning. [ABSTRACT FROM AUTHOR]

Background Alcohol abuse during pregnancy often induces neuropsychological problems in the offspring, including learning disorders, attention deficits, and behavior problems, all of which are prominent components of fetal alcohol spectrum disorders (FASD). However, not all children who were exposed to alcohol in utero are equally affected by it. While some children have major deficits, others are spared. This unequal vulnerability is likely due largely to differences in fetal genetics. Some fetuses appear to have certain genotypes that make them much more prone to FASD. However, to date, no gene has been identified that worsens alcohol-induced brain dysfunction. Nitric oxide (NO) is a gaseous molecule that can protect developing neurons against alcohol-induced death. In the brain, NO is produced by neuronal nitric oxide synthase ( nNOS). In this study, we examined whether homozygous mutation of the nNOS gene in mice worsens the behavioral deficits of developmental alcohol exposure. Methods Wild-type and nNOS−/− mice received alcohol (0.0, 2.2, or 4.4 mg/g) daily over postnatal days (PDs) 4 to 9. Beginning on PD 85, the mice underwent a series of behavioral tests, including open field activity, the Morris water maze, and paired pulse inhibition. Results For the wild-type mice, alcohol impaired performance only in the water maze. In contrast, for the nNOS−/− mice, alcohol impaired performance on all 3 tasks. Furthermore, the nNOS−/− mice were substantially more impaired than wild-type mice in their performance on all 3 of the behavioral tests and at both the low (2.2) and high (4.4) doses of alcohol. Conclusions Targeted disruption of the nNOS gene worsens the behavioral impact of developmental alcohol exposure and allows alcohol-induced learning problems to emerge that are not seen in wild type. This is the first demonstration that a specific genotype can interact with alcohol to worsen functional brain deficits in an animal model of FASD. [ABSTRACT FROM AUTHOR]

Background Anxiety disorders predispose individuals to the development of alcohol dependence in humans. Surprisingly, whether anxiety is a trait influencing the development of alcohol-related behaviors in rodents remains controversial. Here, we addressed the hypothesis of a relationship between basal anxiety levels and the development of ethanol (Et OH)-induced behavioral sensitization ( EIBS), a model of neuroadaptations occurring after repeated Et OH exposure which is proposed to play a role in early and recurring steps of addiction. Methods Et OH-naïve DBA/2J mice were submitted to the elevated plus maze and light/dark box tests to evaluate their basal anxiety levels. Then, mice received daily intraperitoneal injection of saline or 2 g/kg Et OH for 10 days and locomotor activity was immediately monitored. Mice were then split into resistant and sensitized phenotypes based on their increase in locomotion. The relationship between basal anxiety and the development of sensitization was investigated. In addition, we tested the effect of an 8-day-long treatment with 4 mg/kg diazepam, a broad-spectrum benzodiazepine anxiolytic, on the expression of sensitization in both resistant and sensitized mice. Results For the first time, we showed that vulnerability to EIBS is negatively correlated with basal anxiety. Moreover, a diazepam treatment during EIBS procedure increased Et OH-induced hyperlocomotion of resistant mice after 1 week of withdrawal (but not immediately after) without any effect in the group of sensitized mice. Conclusions This study shows that, in mice, basal anxiety predicts the vulnerability to EIBS. Mice exhibiting low basal anxiety will develop higher EIBS than mice with elevated anxiety levels. Modulation of anxiety by a diazepam treatment during the development of EIBS enhances its expression after 1 week postinduction. Altogether, we demonstrated an inverse relationship between basal anxiety-like behaviors and EIBS vulnerability and that resistance to EIBS vanishes after anxiolytic treatment. [ABSTRACT FROM AUTHOR]

Background In human adolescents, heavy drinking is often predicted by high sociability in males and high social anxiety in females. This study assessed the impact of baseline levels of social activity and social anxiety-like behavior in group-housed adolescent and adult male and female Sprague- Dawley rats on ethanol ( Et OH) intake when drinking alone or in a social group. Methods Social activity and anxiety-like behavior initially were assessed in a modified social interaction test, followed by 6 drinking sessions that occurred every other day in animals given ad libitum food and water. Sessions consisted of 30-minute access to 10% Et OH in a 'supersac' (3% sucrose + 0.1% saccharin) solution given alone as well as in groups of 5 same-sex littermates, with order of the alternating session types counterbalanced across animals. Results Adolescent males and adults of both sexes overall consumed more Et OH under social than alone circumstances, whereas adolescent females ingested more Et OH when alone. Highly socially active adolescent males demonstrated elevated levels of Et OH intake relative to their low and medium socially active counterparts when drinking in groups, but not when tested alone. Adolescent females with high levels of social anxiety-like behavior demonstrated the highest Et OH intake under social, but not alone circumstances. Among adults, baseline levels of social anxiety-like behavior did not contribute to individual differences in Et OH intake in either sex. Conclusions The results clearly demonstrate that in adolescent rats, but not their adult counterparts, responsiveness to a social peer predicts Et OH intake in a social setting-circumstances under which drinking typically occurs in human adolescents. High levels of social activity in males and high levels of social anxiety-like behavior in females were associated with elevated social drinking, suggesting that males ingest Et OH for its socially enhancing properties, whereas females ingest Et OH for its socially anxiolytic effects. [ABSTRACT FROM AUTHOR]

Background Binge-like ethanol (EtOH) exposure during the early rat neonatal period results in acute cell loss in specific brain regions, but such acute cell death has not been well established in the hippocampus. Binge alcohol exposure can also result in protein expression changes in the cerebellum that could alter cell fate, but this has not been reported for the hippocampal subregions. This study investigates acute apoptotic cell death in hippocampal regions CA1, CA3, and dentate gyrus ( DG) following a binge EtOH exposure on postnatal day ( PN) 6, PN8, or PN6 + 8 and the alteration in pro- and anti-apoptotic proteins following a single EtOH binge on PN6. Methods Apoptotic cell death was quantified 12 hours after Et OH binge exposure using the optical fractionator method. Western blot analysis determined expression of pro-apoptotic Bax and anti-apoptotic Bcl-2, 12, 24, and 48 hours after binge Et OH exposure on PN6. The Bcl-2:Bax ratio was used as a measure of vulnerability to apoptosis. Results Acute apoptosis increased significantly 12 hours following PN6 or 8 Et OH exposure in CA1, CA3, and DG, but the magnitude of apoptotic cell death was significantly greater in CA1 than in CA3 and DG, which did not differ. Significant cell death was not detected when a PN8 Et OH exposure was preceded by exposure on PN6. Binge Et OH exposure on PN6 resulted in a significant increase in expression of Bcl-2 and the Bcl-2:Bax ratio in the CA1/ DG region at 24 hours after Et OH exposure on PN6. The Bcl-2:Bax ratio in the CA3 region was not altered. Conclusions This study shows that repeated binge exposure does not have a cumulative effect on the magnitude of acute apoptotic cell death. This finding may be explained in part by changes in the Bcl-2:Bax ratio after a single binge Et OH exposure. [ABSTRACT FROM AUTHOR]

Background Fetal alcohol spectrum disorders are the result of alcohol-exposed pregnancies ( AEP) and believed to be the leading known cause of developmental disabilities in the United States. Our objective was to determine whether a culturally targeted Screening, Brief Intervention, and Referral to Treatment ( SBIRT) intervention may reduce risky drinking and vulnerability to AEP among American Indian/Alaska Native ( AIAN) women in Southern California. Methods Southern California AIAN women of childbearing age who completed a survey including questions regarding alcohol consumption and contraceptive use were randomized into intervention or treatment as usual groups where the former group completed an online SBIRT intervention, and were followed up at 1, 3, and 6 months postintervention. Results Of 263 women recruited and 247 with follow-up data, one-third were at high risk of having an AEP at baseline. Both treatment groups decreased self-reported risky drinking behavior (drinks per week, p < 0.001; frequency of heavy episodic [binge] drinking episodes per 2 weeks, p = 0.017 and risk of AEP p < 0.001 at 6 months postintervention) in the follow-up period. There was no difference between treatment groups. Baseline factors associated with decreased risk of an AEP at follow-up included the perception that other women in their peer group consumed a greater number of drinks per week, having reported a greater number of binge episodes in the past 2 weeks, and depression/impaired functionality. Conclusions Participation in assessment alone may have been sufficient to encourage behavioral change even without the web-based SBIRT intervention. Randomization to the SBIRT did not result in a significantly different change in risky drinking behaviors. The importance of perception of other women's drinking and one's own depression/functionality may have implications for future interventions. [ABSTRACT FROM AUTHOR]

Background The long-term consequences of adolescent alcohol abuse that persist into adulthood are poorly understood and have not been widely investigated. We have shown that intermittent exposure to alcohol during adolescence decreased the amplitude of GABAA receptor (GABAAR)-mediated tonic currents in hippocampal dentate granule cells in adulthood. The aim of this study was to investigate the enduring effects of chronic intermittent alcohol exposure during adolescence or adulthood on the expression of hippocampal GABAARs. Methods We used a previously characterized tissue fractionation method to isolate detergent resistant membranes and soluble fractions, followed by Western blots to measure GABAAR protein expression. We also measured mRNA levels of GABAAR subunits using quantitative real-time polymerase chain reaction. Results Although the protein levels of α1-, α4-, and δ-GABAAR subunits remained stable between postnatal day (PD) 30 (early adolescence) and PD71 (adulthood), the α5-GABAAR subunit was reduced across that period. In rats that were subjected to adolescent intermittent ethanol (AIE) exposure between PD30 and PD46, there was a significant reduction in the protein levels of the δ-GABAAR, in the absence of any changes in mRNA levels, at 48 hours and 26 days after the last ethanol (EtOH) exposure. Protein levels of the α4-GABAAR subunit were significantly reduced, but mRNA levels were increased, 26 days (but not 48 hours) after the last AIE exposure. Protein levels of α5-GABAAR were not changed by AIE, but mRNA levels were reduced at 48 hours but normalized 26 days after AIE. In contrast to the effects of AIE, chronic intermittent ethanol (CIE) exposure during adulthood had no effect on expression of any of the GABAAR subunits examined. Conclusions AIE produced both short- and long-term alterations of GABAAR subunits mRNA and protein expression in the hippocampus, whereas CIE produced no long-lasting effects on those measures. The observed reduction of protein levels of the δ-GABAAR, specifically, is consistent with previously reported altered hippocampal GABAAR-mediated electrophysiological responses after AIE. The absence of effects of CIE underscores the emerging view of adolescence as a time of distinctive vulnerability to the enduring effects of repeated EtOH exposure. [ABSTRACT FROM AUTHOR]

Background The effects of stress, including neuroendocrine and behavioral sequelae aimed at maintaining homeostasis, are associated with increased alcohol consumption. Because both stress and drinking are multifactorial, the mechanisms underlying the relationship are difficult to elucidate. We therefore employed an animal model investigating the influence of blocked access to a running wheel on drinking in C57 BL/6J (B6) mice. Methods In the first experiment, naïve, adult male and female subjects were individually housed for 2 weeks with 24-hour access to a running wheel and 12% ethanol (EtOH) in a 2-bottle, free choice paradigm. After determining baseline consumption and preference, experimental subjects had the running wheel placed in a locked position for 6 hours, and the Et OH bottle was removed during the first half of this period. Two subsequent experiments, again in adult, naïve B6 mice, examined the influence of locked running wheels on self-administration of 20% Et OH in a limited access paradigm, and blood Et OH concentrations ( BECs) were determined on the final day of this protocol. Results In all 3 studies, using both between- and within-subject analyses, females showed transient yet reliable increases in alcohol drinking during blocked access to a rotating activity, while drinking in male mice was largely insensitive to this manipulation, although both sexes showed appreciable BECs (>130 mg/dl in females and 80 mg/dl in males) following a 2-hour EtOH access period. Conclusions These data add to a burgeoning literature suggesting that the factors contributing to excessive alcohol use differ between males and females and that females may be especially sensitive to the influence of wheel manipulation. Elucidating the sex-dependent mechanisms mediating differences in alcohol sensitivity and response is critical to understanding the causes of alcoholism and in developing effective treatments and interventions. [ABSTRACT FROM AUTHOR]

Background Sleep disturbances are both common and well-characterized in adults with alcohol use disorders ( AUDs), but have received little study in adolescents with AUDs. Furthermore, a handful of studies suggest that sleep complaints are a risk factor for AUDs. However, no published studies have yet examined the longitudinal course of sleep complaints in adolescents with AUDs; in particular, it remains unclear how persistent AUD-associated sleep complaints are in this age group, and what types of sleep complaints are most relevant to alcohol-use symptoms. We investigated these questions in a 5-year longitudinal study of adolescents with and without AUDs at baseline. Methods Participants were 696 adolescents (age 12 to 19) from a longitudinal study at the Pittsburgh Adolescent Alcohol Research Center. At baseline, 347 participants had a current AUD ( AUD+), while 349 had no current or past AUD ( AUD−). We examined sleep and alcohol involvement at baseline as well as 1-, 3-, and 5-year follow-up visits. Sleep variables included self-reported insomnia and hypersomnia, as well as variability in weekday-weekend sleep duration, all at baseline. Covariates included sex, age, current alcohol symptoms, and depression severity. Results The AUD+ group reported more overall sleep disturbance at baseline, including greater insomnia and hypersomnia complaints, and greater variability in weekday-weekend sleep duration. Group differences in insomnia and hypersomnia complaints persisted to the 5- and 3-year follow-ups, respectively. In the AUD− group, greater insomnia complaints at baseline predicted an increase in alcohol symptoms at the 1-year follow-up, while greater variability in sleep duration at baseline predicted an increase in alcohol symptoms at the 3- and 5-year follow-ups. Conclusions These results complement previous findings in other samples, indicating that insomnia and other sleep problems are a chronic predicament for adolescents with AUDs. The findings also suggest that sleep disturbances may place adolescents without AUDs at an elevated risk of developing alcohol problems. [ABSTRACT FROM AUTHOR]

Background Aging and chronic alcohol consumption are both modifiers of DNA methylation, but it is not yet known whether chronic alcohol consumption also alters DNA hydroxymethylation, a newly discovered epigenetic mark produced by oxidation of methylcytosine. Furthermore, it has not been tested whether aging and alcohol interact to modify this epigenetic phenomenon, thereby having an independent effect on gene expression. Methods Old (18 months) and young (4 months) male C57BL/6 mice were pair-fed either a Lieber- De Carli liquid diet with alcohol (18% of energy) or an isocaloric Lieber- De Carli control diet for 5 weeks. Global DNA hydroxymethylation and DNA methylation were analyzed from hepatic DNA using a new liquid chromatography-tandem mass spectrometry method. Hepatic m RNA expression of the Tet enzymes were measured via quantitative real-time polymerase chain reaction. Results In young mice, mild chronic alcohol exposure significantly reduced global DNA hydroxymethylation compared with control mice (0.22 ± 0.01 vs. 0.29 ± 0.06%, p = 0.004). Alcohol did not significantly alter hydroxymethylcytosine levels in old mice. Old mice fed the control diet showed decreased global DNA hydroxymethylation compared with young mice fed the control diet (0.24 ± 0.02 vs. 0.29 ± 0.06%, p = 0.04). This model suggests an interaction between aging and alcohol in determining DNA hydroxymethylation ( pinteraction = 0.009). Expression of Tet2 and Tet3 was decreased in the old mice relative to the young ( p < 0.005). Conclusions The observation that alcohol alters DNA hydroxymethylation indicates a new epigenetic effect of alcohol. This is the first study demonstrating the interactive effects of chronic alcohol consumption and aging on DNA hydroxymethylation. [ABSTRACT FROM AUTHOR]

Background Binge alcohol drinking is among the most common pattern of alcohol consumption in our society. Binge alcohol consumption has serious negative consequence on mental and physical health. Although alcohol consumption is known to have profound impact on sleep, it is yet unknown as to how binge alcohol affects/alters sleep-wakefulness. The objective of this study was to examine the effect of acute binge alcohol administration on sleep-wakefulness. Methods Male Sprague Dawley rats were used in the study. Under standard aseptic surgical conditions, rats ( N = 7) were implanted with sleep-recording electrodes. After postoperative recovery and habituation, baseline sleep-wakefulness was recorded. Subsequently, rats were exposed to binge alcohol treatment as follows: One hour before light onset, a priming dose of 5 g/kg of alcohol was administered followed by 2 subsequent doses (adjusted based on the intoxication level of the rat) approximately 8 hours apart. Sleep-wakefulness was continuously recorded for 3 days post-binge. Results Acute binge alcohol administration had no significant effect on sleep-wakefulness on post-binge Day 1. However, on post-binge Day 2, after blood alcohol concentration (BAC) was 0, sleep disruptions were observed manifested by a reversal of sleep-wakefulness as evident from insomnia-like symptoms (significant increase in wakefulness; significant reduction in nonrapid eye movement [ NREM] sleep) during the normal sleep (light) period and excessive sleep (significant increase in NREM sleep) during the normal active (dark) period similar to excessive daytime sleepiness in humans. All sleep-wakefulness changes were normalized on Day 3 post-binge. Conclusions Alcohol hangover is defined as the presence of unpleasant symptoms that peak when BAC is 0. Our results suggest that the reversal of sleep-wakefulness accompanies alcohol hangover after binge alcohol administration. [ABSTRACT FROM AUTHOR]

Background Ethanol (Et OH) exposure alters gene expression in the cerebral cortex ( CCx); however, mechanisms of Et OH-induced gene regulation are not well understood. We hypothesized that Et OH regulates gene expression by differentially altering histone modifications at gene promoters that are up- and down-regulated by Et OH. Such epigenetic mechanisms may ultimately contribute to Et OH-induced neuro-adaptations that underlie tolerance, dependence, and Et OH-use disorders. Methods Eight-week-old, male C57 BL/6J mice were treated with 3 g/kg Et OH (intraperitoneally) or saline and sacrificed 6 hours after injection; the CCx and hippocampus ( HC) were immediately removed and flash frozen. Chromatin immunoprecipitation was used to study the association of model gene promoters with histone modifications. Western blot was used to detect global changes in the histone modifications studied. We also used a polymerase chain reaction (PCR) array to identify changes in expression of chromatin-modifying enzymes. Results In CCx, acute Et OH decreased expression of Gad1, Hdac2, and Hdac11, which was associated with decreased histone acetylation at the Gad1 and Hdac2 promoters; we also identified increased expression of Mt1, Mt2, Egr1, which was associated with increased H3K4me3 levels at the Mt2 promoter and decreased H3K27me3 levels at the Mt1 promoter. We identified an increase in global levels of H3K4me3 in CCx as well as a global increase in H3K9ac and H3K14ac in HC. The PCR array identified decreased expression of Csrp2 bp, Hdac2, and Hdac11 as well as increased expression of Kat2b in CCx. Conclusions Acute Et OH induces chromatin remodeling at model up- and down-regulated genes in CCx. Different patterns of histone modifications at these gene promoters indicate that Et OH may be acting through multiple histone-modifying enzymes to alter gene expression; in particular, differential expression of Kat2b, Hdac2, Hdac11, and Csrp2 bp in CCx may mediate Et OH-induced chromatin remodeling. Additional studies are necessary to determine the relationship between Et OH-induced changes in histone-modifying enzymes, specific Et OH-induced histone modifications, and gene expression. [ABSTRACT FROM AUTHOR]

Background It has been known that ADH1B*2 allele has a protective effect against the development of alcohol dependence. However, the protection mechanism is still unknown. We investigated whether ADH1B gene polymorphism affects ethanol (EtOH) metabolism. Methods In a parent study, we conducted a randomized crossover trials on 24 healthy male subjects who were selected by genotyping: 12 with ALDH2*1/*1 (active form) and 12 with ALDH2*1/*2 (inactive form). In the present study, the 24 subjects were reclassified into 2 groups of 11 with ADH1B*1/*2 and 13 with ADH1B*2/*2 according to the ADH1B genotypes. Each subject was administered 1 of 3 doses of EtOH (0.25, 0.5, 0.75 g/kg) or a placebo in 4 trials. After the administration of alcohol, blood EtOH and acetaldehyde concentrations were measured 9 times over 4 hours. Results In the case of EtOH, the area under the concentration-time curve from 0 to 4 hours ( AUC0-4) and the peak blood concentration of EtOH ( Cmax) in subjects with ADH1B*2/*2 were significantly higher than those in subjects with ADH1B*1/*2 at all 3 dosages before stratifying by ALDH2 genotype. However, after stratifying by ALDH2 genotype, a statistically significant difference between ADH1B*2/*2 and ADH1B*1/*2 was found only at the 0.5 g/kg dosage regardless of ALDH2 genotype. In the case of acetaldehyde, the AUC0-4 and Cmax of acetaldehyde of ADH1B*2/*2 after administration of 0.25 g/kg alcohol and the AUC0-4 of acetaldehyde of ADH1B*2/*2 at 0.5 g/kg were significantly higher than corresponding values of ADH1B*1/*2 only in the group of ALDH2*1/*2. Conclusions Our findings indicate that the blood EtOH concentrations of ADH1B*2/*2 group are higher than those of ADH1B*1/*2 group regardless of ALDH2 genotype, and the blood acetaldehyde concentrations of ADH1B*2/*2 are also higher than those of ADH1B*1/*2 only in the ALDH2*1/*2 group. To our knowledge, this is the first report to demonstrate the association of ADH1B*2 allele with blood EtOH and acetaldehyde levels in humans, and these results suggest that higher blood EtOH and acetaldehyde concentrations in ADH1B*2/*2 may constitute the mechanism of protection against alcoholism by ADH1B*2/*2. [ABSTRACT FROM AUTHOR]

Background Alcoholism is associated with specific brain abnormalities revealed through postmortem studies, including a reduction in glial cell number and dysregulated glutamatergic neurotransmission. Whether these abnormalities contribute to the etiology of alcoholism, are consequences of alcohol use, or both is still unknown. Methods We investigated the role of astrocytic glutamate uptake in ethanol (Et OH) binge drinking in mice, using the 'drinking in the dark' ( DID) paradigm by blocking the astrocytic glutamate transporter ( GLT-1) with intracerebroventricular ( ICV) administration of dihydrokainic acid ( DHK). To determine whether astrocytic glutamate uptake regulates the conditioned rewarding effects of Et OH, we examined the effects of ICV DHK on the acquisition and expression of Et OH-induced conditioned place preference. Results Blocking central astrocytic glutamate uptake selectively attenuated Et OH binge drinking behavior in mice. DHK did not alter the acquisition or expression of preference for Et OH-associated cues, indicating that reduced astrocytic glutamate trafficking may decrease binge-like drinking without altering the conditioned rewarding effects of Et OH. Conclusions Several alternative conclusions are plausible, however, interpreting these data in the context of the human literature, these findings suggest that the reduction of glia in the alcoholic brain may not be a predisposing factor to developing alcoholism and could be a consequence of Et OH toxicity that decreases excessive Et OH intake. [ABSTRACT FROM AUTHOR]

Background Heavy prenatal alcohol exposure and attention-deficit/hyperactivity disorder ( ADHD) are associated with adaptive behavior deficits. This study examined the interaction between these 2 factors on parent ratings of adaptive behavior. Methods As part of a multisite study, primary caregivers of 317 children (8 to 16 years, M = 12.38) completed the Vineland Adaptive Behavior Scales-Second Edition ( VABS- II). Four groups of subjects were included: children with prenatal alcohol exposure with ADHD ( AE+, n = 82), children with prenatal alcohol exposure without ADHD ( AE−, n = 34), children with ADHD ( ADHD, n = 71), and control children ( CON, n = 130). VABS- II domain scores (Communication, Daily Living Skills, Socialization) were examined using separate 2 (Alcohol Exposure [ AE]) × 2 ( ADHD diagnosis) between-subjects analyses of covariance. Results There were significant main effects of AE ( p < 0.001) and ADHD ( p < 0.001) on all VABS- II domains; alcohol-exposed children had lower scores than children without prenatal alcohol exposure and children with ADHD had lower scores than those without ADHD. There was a significant AE × ADHD interaction effect for Communication, F(1, 308) = 7.49, p = 0.007, partial η2 = 0.024, but not Daily Living Skills or Socialization domains ( ps > 0.27). Follow-up analyses in the Communication domain indicated the effects of ADHD were stronger in comparison subjects ( ADHD vs. CON) than exposed subjects ( AE+ vs. AE−), and the effects of alcohol exposure were stronger in subjects without ADHD ( AE− vs. CON) than in subjects with ADHD ( AE+ vs. ADHD). Conclusion As found previously, both prenatal alcohol exposure and ADHD increase adaptive behavior deficits in all domains. However, these 2 factors interact to cause the greatest impairment in children with both prenatal alcohol exposure and ADHD for communication abilities. These results further demonstrate the deleterious effects of prenatal alcohol exposure and broaden our understanding of how ADHD exacerbates behavioral outcomes in this population. [ABSTRACT FROM AUTHOR]

Background An acute ethanol (EtOH) challenge prior to fear conditioning typically disrupts fear retention to contextual cues to a greater degree than fear retention to a discrete tone cue, and adolescent rats are less sensitive than adults to these EtOH-induced disruptions of context fear memory. Given that some research suggests that repeated EtOH exposure during adolescence may 'lock-in' adolescent-typical EtOH sensitivity into adulthood, the purpose of this study was to determine whether adults exposed to EtOH as adolescents would be less sensitive to EtOH-induced disruptions of context fear. Methods Male Sprague-Dawley rats were given 4 g/kg intragastric EtOH (25% v/v) or water every 48 hours for a total of 11 exposures during adolescence (postnatal day [P] 28 to 48) or adulthood (P70-90). After a 22-day non-EtOH period, animals were acutely challenged with 1 g/kg intraperitoneal EtOH or saline 10 minutes prior to tone or context (noncued) fear conditioning. Tone and context fear retention was subsequently examined. Results Regardless of age or exposure history, typical deficits in context fear retention were evident after EtOH challenge during conditioning. Similarly, tone fear retention was disrupted in all animals that were trained in the presence of EtOH, which was somewhat surprising given the relative resistance of tone fear retention to an acute EtOH challenge. Conclusions These results do not support the notion of a 'lock-in' of adolescent-typical EtOH sensitivity as there was no influence of exposure age on sensitivity to the disruptive effects of an acute EtOH challenge. Thus, it appears that not all adolescent-like EtOH sensitivities persist into adulthood after prior EtOH exposure during adolescence. [ABSTRACT FROM AUTHOR]