Search

Background We examined differences in response to self-reported alcohol use items by survey mode, whether self-report differences were the result of modality effects or self-selection, and whether these differences varied across the treatment and control arms of a preventative intervention trial. Methods Data from an existing alcohol prevention trial were used to estimate the effect of survey modality on adolescent's self-reported alcohol use at ages 17 to 18. Estimates were derived from regression models controlling for self-reported alcohol use during 8th grade, measured using a single survey modality, as well as time invariant selection factors. Results No statistically significant survey modality effects were found. No differential effects of survey modality were observed by assigned intervention group. Conclusions We provide initial evidence that adolescent alcohol prevention trials may use multiple survey modalities when necessary to increase response rates without harming interpretation of intervention effects. [ABSTRACT FROM AUTHOR]

Background Low levels of alcohol responses (low LRs) are genetically influenced phenotypes that are identified before alcohol dependence and predict future heavy drinking and alcohol problems. A recent paper described 13 LR-related blood oxygen level-dependent ( BOLD) response contrast patterns observed during an emotional face recognition task that might reflect cognitive processes contributing to LR and that might themselves predict adverse alcohol outcomes ( Paulus et al., Biol Psychiatry 2012; 72: 848). This paper evaluates the predictive implications of those functional magnetic resonance imaging (f MRI) patterns. Methods Of 120 subjects from Paulus and colleagues (2012), 114 (57 low and high LRs; ~50% females) were interviewed 5 years later at age 25. Correlations between baseline f MRI patterns and alcohol-related outcomes were evaluated, and regression analyses were used to determine if BOLD response contrasts incremented over LR in predicting outcomes. Results Baseline f MRI patterns in 5 of 13 baseline regions of interest correlated with adverse outcomes. Such patterns in insular regions, particularly the left anterior insula, and the right frontal gyrus, added to LR in predicting alcohol problems. The relationships remained robust when exact binomial procedures were used, but, reflecting the small sample size, it was not possible to adequately consider Bonferroni corrections. Conclusions The data suggest that f MRI BOLD response contrasts predicted heavier drinking and alcohol problems 5 years later, even after considering baseline low LRs. Future work will focus on whether f MRI results can predict outcomes in larger samples and among young nondrinkers, as well as how the imaging results increase understanding of the processes through which LR operates. [ABSTRACT FROM AUTHOR]

Background Over the past 60 years, the view that 'alcoholism' is a disease for which the only acceptable goal of treatment is abstinence has given way to the recognition that alcohol use disorders ( AUDs) occur on a continuum of severity, for which a variety of treatment options are appropriate. However, because the available treatments for AUDs are not effective for everyone, more research is needed to develop novel and more efficacious treatments to address the range of AUD severity in diverse populations. Here we offer recommendations for the design and analysis of alcohol treatment trials, with a specific focus on the careful conduct of randomized clinical trials of medications and nonpharmacological interventions for AUDs. Methods This paper provides a narrative review of the quality of published clinical trials and recommendations for the optimal design and analysis of treatment trials for AUDs. Results Despite considerable improvements in the design of alcohol clinical trials over the past 2 decades, many studies of AUD treatments have used faulty design features and statistical methods that are known to produce biased estimates of treatment efficacy. Conclusions The published statistical and methodological literatures provide clear guidance on methods to improve clinical trial design and analysis. Consistent use of state-of-the-art design features and analytic approaches will enhance the internal and external validity of treatment trials for AUDs across the spectrum of severity. The ultimate result of this attention to methodological rigor is that better treatment options will be identified for patients with an AUD. [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 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 All stages of development of alcohol use disorder ( AUD) have not been equally studied. While initiation of drinking has been given considerable attention, other stages have not been as thoroughly investigated. It is not clear whether the same factors are associated consistently across early and late transitions in AUD involvement. High-risk family samples that are enriched for AUD vulnerability and transitions in AUD development offer an opportunity to examine influences across multiple stages of AUD development. Methods Data from adolescents and young adults from high-risk families were used to study 4 transitions in AUD development-time to first drink, first drink to first problem, first drink to first diagnosis, and first problem to first diagnosis. Cox modeling was used to compare associations of parental AUD, parental separation, peer substance use, offspring ever-use of cannabis, trauma exposures, and internalizing and externalizing psychopathology across transitions. Results Hazards of most transitions were elevated for those who had ever used cannabis, those who attributed substance use to their peers, those with externalizing disorders, and those with parents with AUD. Many risk factors were linked to early initiation of alcohol, particularly cannabis use. Internalizing disorders were associated with later stages. Nonassaultive trauma was associated only with early initiation; assaultive trauma was not associated with any transition. Conclusions In this large, ethnically diverse sample of high-risk youth, significant influences across transitions were fairly consistent, with externalizing disorders and cannabis ever-use elevating the likelihood of each stage, and peer and parental (and especially maternal AUD) influences linked to initiation and some later stages. Finally, in light of the increasingly permissive legal and social stances toward cannabis in the United States, the marked elevations of all alcohol outcomes observed for cannabis use underscore the importance of studying the underpinnings of this relationship. [ABSTRACT FROM AUTHOR]

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

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

Background 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 Executive functioning and episodic memory impairment occur in HIV infection ( HIV) and chronic alcoholism ( ALC). Comorbidity of these conditions ( HIV + ALC) is prevalent and heightens risk of vulnerability to separate and compounded deficits. Age and disease-related variables can also serve as mediators of cognitive impairment and should be considered, given the extended longevity of HIV-infected individuals in this era of improved pharmacological therapy. Methods HIV, ALC, HIV + ALC, and normal controls ( NC) were administered traditional and computerized tests of executive function and episodic memory. Test scores were expressed as age- and education-corrected Z-scores; selective tests were averaged to compute Executive Function and Episodic Memory Composite scores. Efficiency scores were calculated for tests with accuracy and response times. Results HIV, ALC, and HIV + ALC had lower scores than NC on Executive Function and Episodic Memory Composites, with HIV + ALC even lower than ALC and HIV on the Episodic Memory Composite. Impairments in planning and free recall of visuospatial material were observed in ALC, whereas impairments in psychomotor speed, sequencing, narrative free recall, and pattern recognition were observed in HIV. Lower decision-making efficiency scores than NC occurred in all 3 clinical groups. In ALC, age and lifetime alcohol consumption were each unique predictors of Executive Function and Episodic Memory Composite scores. In HIV + ALC, age was a unique predictor of Episodic Memory Composite score. Conclusions Disease-specific and disease-overlapping patterns of impairment in HIV, ALC, and HIV + ALC have implications regarding brain systems disrupted by each disease and clinical ramifications regarding the complexities and compounded damping of cognitive functioning associated with dual diagnosis that may be exacerbated with aging. [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 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 To counteract the syndemics of HIV and alcohol in Sub-Saharan Africa, international collaborations have developed interventions to reduce alcohol consumption. Reliable and accurate methods are needed to estimate alcohol use outcomes. A direct alcohol biomarker called phosphatidylethanol ( PEth) has been shown to validate heavy, daily drinking, but the literature indicates mixed results for moderate and nondaily drinkers, including among HIV-infected populations. This study examined the associations of the PEth biomarker with self-report alcohol use at 2 time points in 127 HIV-infected outpatient drinkers in western Kenya. Methods Participants were consecutively enrolled in a randomized clinical trial to test the efficacy of a behavioral intervention to reduce alcohol use in Eldoret, Kenya. They endorsed current alcohol use, and a minimum score of 3 on the Alcohol Use Disorders Identification Test-Consumption or consuming ≥6 drinks per occasion at least monthly in the past year. Study interviews and blood draws were conducted at baseline and at 3 months post treatment from July 2012 through September 2013. Alcohol use was assessed using the Timeline Followback questionnaire. Blood samples were analyzed for the presence of the PEth biomarker and were compared to self-reported alcohol use. We also conducted semistructured interviews with 14 study completers in February through March 2014. Results Baseline data indicated an average of moderate-heavy alcohol use: 50% drinking days and a median of 4.5 drinks per drinking day. At baseline, 46% of women (31 of 67) and 8% of men (5 of 60) tested negative for PEth ( p < 0.001). At the 3-month follow-up, 93% of women (25 of 27) and 97% of men (30 of 31) who reported drinking tested positive, while 70% of women (28 of 40) and 35% of men (10 of 29) who denied drinking tested negative for PEth. Interviews were consistent with self-reported alcohol use among 13 individuals with negative baseline results. Conclusions These results add to the growing literature showing lack of agreement between self-report and PEth results among unhealthy and nondaily drinkers, particularly women. More research is needed to determine at what level of consumption over what period of time PEth becomes a reliable and accurate indicator of alcohol use. [ABSTRACT FROM AUTHOR]

Background Quantifying craving longitudinally during the course of withdrawal, early abstinence, and relapse is essential for optimal management of alcohol use disorder ( AUD). In an effort to identify biological correlates of craving, we used proton magnetic resonance spectroscopy (1H- MRS) to investigate the correlation between craving and glutamate levels in the left dorsolateral prefrontal cortex ( LDLPFC) of patients with AUD. Methods Participants underwent 1H- MRS of the LDLPFC with 2-dimensional J-resolved (2 DJ) averaged PRESS. MRS data were processed with LCModel and cerebrospinal fluid ( CSF)-corrected to generate metabolite concentrations. The Penn Alcohol Craving Scale ( PACS) and the 30-day time line follow-back ( TLFB 30) were used to quantify craving for alcohol and drinking patterns, respectively. Results There was a statistically significant positive correlation between CSF-corrected glutamate ([Glu]) levels and PACS scores ( n = 14; p = 0.005). When PACS scores were dichotomized (< or ≥median = 16), [Glu] levels were significantly higher in the high- versus low-craving group ( p = 0.007). In addition, there was a significant negative correlation between CSF-corrected N-acetyl aspartic acid ([ NAA]) levels and mean number of drinks per drinking day in the past month ( n = 13; TLFB 30; p = 0.012). When mean TLFB 30 was dichotomized (< or ≥median = 7.86), [ NAA] levels were significantly lower in subjects that consumed more alcoholic beverages. There was no significant correlation between [Glu] and [ NAA] levels with other measures of drinking behavior and or depression symptom severity. Conclusions While limited by small sample size, these data suggest that glutamate levels in LDLPFC are associated with alcohol craving intensity in patients with AUD. Further study with larger sample size is needed to replicate this finding and evaluate the merits of glutamate spectroscopy as a biological correlate of alcohol craving intensity and a guide to treatment interventions. [ABSTRACT FROM AUTHOR]

Background The Alcohol Use Disorder and Associated Disabilities Interview Schedule- IV ( AUDADIS- IV) and AUDADIS-5 are diagnostic interviews used in major epidemiological and other studies of alcohol use disorder ( AUD). Much of what we know regarding the prevalence of AUD in the United States is based upon this interview. However, past research and meta-analytic evidence suggest that differential operationalization of the AUD criteria across instruments can lead to differential endorsement of symptoms and resulting AUD diagnosis rates. In particular, studies employing the AUDADIS are observed to have markedly higher endorsement rates of withdrawal than other large epidemiological studies. One explanation for this is that when assessing withdrawal, the AUDADIS combines effects from the morning after drinking with those from the days following, thereby conflating hangover and withdrawal. Methods This study addresses whether this operationalization confounds rates of endorsement when compared to simpler, less ambiguous hangover or withdrawal stems. To this aim, 497 college student drinkers were randomized into 1 of 3 stem conditions: (i) hangover ( n = 164), (ii) withdrawal ( n = 167), or (iii) combined AUDADIS- IV ( n = 166). Results Across conditions, participants were more likely to report the occurrence of each withdrawal symptom in the combined stem condition than in the explicit withdrawal stem condition, but not in the explicit hangover stem condition. Within the combined stem condition, probed symptoms were more likely to be reported as a result of a hangover. Conclusions The AUDADIS potentially results in false positives for withdrawal, arguably a pathognomonic symptom of alcoholism and, in turn, likely affects rates of the diagnosis of AUD. [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 Alcoholism has been linked to deficits in cognitive, behavioral, and emotional functions, and the cerebellum is important for optimal functioning of these abilities. However, little is known about how individual differences such as gender and drinking history might influence regional cerebellar abnormalities. Methods Volumetric analyses of the cerebellum and its subregions were performed in relation to the interaction of gender and measures of drinking history. Structural magnetic resonance imaging scans of 44 alcoholic individuals (23 men) and 39 nonalcoholic controls (18 men) were obtained. In addition to measuring total cerebellar gray and white matter volumes, we measured 64 individual cerebellar parcellation units, as well as functionally defined a priori regions of interest that have been shown to correspond to functions impaired in alcoholism. Results Total cerebellar white matter volume was smaller in alcoholic relative to nonalcoholic participants. Moreover, volumes of parcellation units varied with drinking history, showing negative associations between years of heavy drinking and the anterior lobe, the vestibulocerebellar lobe, and the spinocerebellar subdivision. The negative association between anterior volume and years of heavy drinking was driven primarily by alcoholic men. Additionally, we observed larger white and gray matter volumes for alcoholic women than for alcoholic men. Conclusions The identification of drinking-related abnormalities in cerebellar subregions lays a foundation that can be utilized to inform how cerebro-cerebellar networks are perturbed in this pathological condition. These results also provide estimates of how gender and individual differences in drinking history can predict cerebellar volumes. [ABSTRACT FROM AUTHOR]

Background Despite the prevalence of fetal alcohol spectrum disorders (FASD) and the importance of accurate identification of patients, clinical diagnosis may not be consistent across sites due to the heterogeneous nature of FASD and the characteristics of different diagnostic systems used. Here, we compare 5 systems designed to operationalize criteria recommended for the diagnosis of effects of prenatal alcohol exposure ( PAE). We determined the extent of consistency among them as well as factors that may reduce intersystem reliability. Compared are: Emory Clinic, Seattle 4-Digit System (Diagnostic Guidelines for Fetal Alcohol Spectrum Disorders: The 4-Digit Diagnostic Code, Seattle, WA, University Publication Services, 2004), Centers for Disease Control and Prevention (Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis, Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA, 2004), Canadian Guidelines (CMAJ, 172, 2005, S1), and the Hoyme Modifications (Pediatrics, 115, 2005, 39). Methods Subjects were 1,581 consecutively registered patients applying for evaluation at a university-based clinic treating alcohol and drug-exposed children. Records of the multidisciplinary evaluation (pediatric, social, psychological) were abstracted. Diagnostic criteria for all 5 systems were applied, and patients were diagnosed according to each of the systems. We compared results using Cohen's Kappa to evaluate the extent of agreement. Results Percent of individuals diagnosed with FASD ranged from 4.74% ( CDC) to 59.58% (Hoyme). Examination using Cohen's Kappa found modest agreement among systems, particularly when individual diagnoses, Fetal Alcohol Syndrome ( FAS), partial FAS ( pFAS), and Alcohol-Related Neurodevelopmental Disorder ( ARND) were used. Examination of diagnostic criteria found almost perfect agreement on growth (weight; height), with limited overlap for physical features (palpebral fissures, hypoplastic philtrum, upper vermillion) and for neurobehavioral outcomes. Child's race and age influenced agreement among systems, with African American and older children more frequently diagnosed. Conclusions Results suggest problems in convergent validity among these systems, as demonstrated by a lack of reliability in diagnosis. Absence of an external standard makes it impossible to determine whether any system is more accurate, but outcomes do suggest areas for future research that may refine diagnosis. [ABSTRACT FROM AUTHOR]

Background Nutrition is an important factor that affects brain development. Nutritional deficiencies can exacerbate alcohol's damaging effects. Conversely, nutritional supplementation can serve a protective role against alcohol damage and may prove to be a worthwhile intervention strategy. This study investigated dietary intake in school-aged children with heavy prenatal alcohol exposure to understand their nutritional status, compared to a national sample of typically developing children and Dietary Reference Intakes. Methods Dietary intake data were collected from children with confirmed histories of heavy prenatal alcohol exposure (5 to 10 years, n = 55) using the Automated Self-Administered 24-Hour Dietary Recall ( ASA24). Observed nutrient levels were compared to the Dietary Reference Intakes to evaluate adequacy of nutrient intake as well as to national averages for same-aged children ( What We Eat in America, NHANES 2007-2008). Results Alcohol-exposed children exhibited poorer nutritional status compared to the typically developing NHANES sample, consuming lower levels of protein, omega-3 fatty acids, magnesium, potassium, zinc, vitamins C and K, niacin, and choline. Moreover, their diets did not meet Recommended Dietary Allowance or Adequate Intake for dietary fiber, potassium, vitamins E and K, omega-3 fatty acids, and choline. Conclusions The present findings are consistent with prior studies investigating nutritional intake in preschoolers with FASD, indicating that these children are vulnerable to nutritional inadequacies. Moreover, data suggest a specific profile of dietary intake in this population. As several nutrients are important for cognitive development, targeted interventions in clinical populations might be effective in boosting outcomes. Thus, further clinical investigation into the role of nutrition in improving cognitive outcomes is warranted. [ABSTRACT FROM AUTHOR]

Background Children exposed to alcohol prenatally may suffer from behavioral and cognitive alterations that adversely affect their quality of life. Animal studies have shown that perinatal supplementation with the nutrient choline can attenuate ethanol's adverse effects on development; however, it is not clear how late in development choline can be administered and still effectively reduce the consequences of prenatal alcohol exposure. Using a rodent model, this study examined whether choline supplementation is effective in mitigating alcohol's teratogenic effects when administered during adolescence/young adulthood. Methods Sprague- Dawley rats were exposed to alcohol (5.25 g/kg/d) during the third trimester equivalent brain growth spurt, which occurs from postnatal day ( PD) 4 to 9, via oral intubation. Sham-intubated and nontreated controls were included. Subjects were treated with 100 mg/kg/d choline chloride or vehicle from PD 40 to 60, a period equivalent to young adulthood in the rat. After the choline treatment had ceased, subjects were tested on a series of behavioral tasks: open field activity ( PD 61 to 64), Morris water maze spatial learning ( PD 65 to 73), and spatial working memory ( PD 87 to 91). Results Ethanol-exposed subjects were overactive in the activity chambers and impaired on both the spatial and the working memory versions of the Morris water maze. Choline treatment failed to attenuate alcohol-related overactivity in the open field and deficits in Morris water maze performance. In contrast, choline supplementation significantly mitigated alcohol-related deficits in working memory, which may suggest that choline administration at this later developmental time affects functioning of the prefrontal cortex. Conclusions The results indicate that adolescent choline supplementation can attenuate some, but not all, of the behavioral deficits associated with early developmental alcohol exposure. The results of this study indicate that dietary intervention may reduce some fetal alcohol effects, even when administered later in life, findings with important implications for adolescents and young adults with 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 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 detrimental effects of chronic heavy alcohol use on the cardiovascular system are well established and broadly appreciated. Integrated cardiovascular response to an acute dose of alcohol has been less studied. This study examined the early effects of an acute dose of alcohol on the cardiovascular system, with particular emphasis on system variability and sensitivity. The goal was to begin to understand how acute alcohol disrupts dynamic cardiovascular regulatory processes prior to the development of cardiovascular disease. Methods: Healthy participants (N = 72, age 21 to 29) were randomly assigned to an alcohol, placebo, or no-alcohol control beverage condition. Beat-to-beat heart rate (HR) and blood pressure (BP) were assessed during a low-demand cognitive task prior to and following beverage consumption. Between-group differences in neurocardiac response to an alcohol challenge (blood alcohol concentration ~ 0.06 mg/dl) were tested. Results: The alcohol beverage group showed higher average HR, lower average stroke volume, lower HR variability and BP variability, and increased vascular tone baroreflex sensitivity after alcohol consumption. No changes were observed in the placebo group, but the control group showed slightly elevated average HR and BP after beverage consumption, possibly due to juice content. At the level of the individual, an active alcohol dose appeared to disrupt the typically tight coupling between cardiovascular processes. Conclusions: A dose of alcohol quickly invoked multiple cardiovascular responses, possibly as an adaptive reaction to the acute pharmacological challenge. Future studies should assess how exposure to alcohol acutely disrupts or dissociates typically integrated neurocardiac functions. [ABSTRACT FROM AUTHOR]

Background: Chronic ethanol (EtOH) consumption decelerates the catabolism of long-lived proteins, indicating that it slows hepatic macroautophagy (hereafter called autophagy) a crucial lysosomal catabolic pathway in most eukaryotic cells. Autophagy and lysosome biogenesis are linked. Both are regulated by the transcription factor EB (TFEB). Here, we tested whether TFEB can be used as a singular indicator of autophagic activity, by quantifying its nuclear content in livers of mice subjected to acute and chronic EtOH administration. We correlated nuclear TFEB to specific indices of autophagy. Methods: In acute experiments, we gavaged GFP-LC3tg mice with a single dose of EtOH or with phosphate buffered saline (PBS). We fed mice chronically by feeding them control or EtOH liquid diets. Results: Compared with PBS-gavaged controls, livers of EtOH-gavaged mice exhibited greater autophagosome (AV) numbers, a higher incidence of AV-lysosome co-localization, and elevated levels of free GFP, all indicating enhanced autophagy, which correlated with a higher nuclear content of TFEB. Compared with pair-fed controls, livers of EtOH-fed mice exhibited higher AV numbers, but had lower lysosome numbers, lower AV-lysosome co-localization, higher P62/SQSTM1 levels, and lower free GFP levels. The latter findings correlated with lower nuclear TFEB levels in EtOH-fed mice. Thus, enhanced autophagy after acute EtOH gavage correlated with a higher nuclear TFEB content. Conversely, chronic EtOH feeding inhibited hepatic autophagy, associated with a lower nuclear TFEB content. Conclusions: Our findings suggest that the effect of acute EtOH gavage on hepatic autophagy differs significantly from that after chronic EtOH feeding. Each regimen distinctly affects TFEB localization, which in turn, regulates hepatic autophagy and lysosome biogenesis. [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 In clinical practice as well as research situations, it is of great importance to get reliable information about a patient's alcohol consumption. The aim of the study was to investigate the correlation of alcohol biomarkers (phosphatidylethanol [PEth], carbohydrate-deficient transferrin [ CDT], γ-glutamyltransferase, aspartate aminotransferase, and alanine aminotransferase) to retrospective as well as diary-based alcohol self-reports and to examine whether it is possible to correlate a biomarker result to a more precise level of alcohol consumption. Methods One hundred and sixty alcohol-dependent patients were included in a randomized, placebo-controlled clinical trial of pharmacotherapy for alcohol dependence, of which 115 (76 men and 39 women) completed the study. Retrospective alcohol consumption data were collected at baseline, and alcohol diaries were used during the study. Blood samples for determination of alcohol biomarkers were collected on 5 occasions during the study. Results PEth and CDT showed a better correlation with alcohol consumption documented in the diary ( PEth rs = 0.56 and CDT rs = 0.35) than with retrospective consumption data ( PEth rs = 0.23 and CDT rs = 0.22). An even higher correlation ( rs = 0.63) was seen between the 2 alcohol biomarkers PEth and CDT. At all consumption levels, PEth had the highest sensitivity of all biomarkers studied. Conclusions PEth was the biomarker with the best correlation to self-reported alcohol consumption. PEth was superior to CDT owing to its substantially higher sensitivity but also due to its closer correlation to self-report. PEth values can be translated into an approximate level of alcohol consumption and PEth appears to be a more reliable measure of alcohol consumption than self-reports. [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 Deficits in neuronal plasticity underlie many neurobehavioral and cognitive problems presented in fetal alcohol spectrum disorder ( FASD). Our laboratory has developed a ferret model showing that early alcohol exposure leads to a persistent disruption in ocular dominance plasticity ( ODP). For instance, a few days of monocular deprivation results in a robust reduction of visual cortex neurons' responsiveness to stimulation of the deprived eye in normal animals, but not in ferrets with early alcohol exposure. Previously our laboratory demonstrated that overexpression of serum response factor ( SRF) exclusively in astrocytes can improve neuronal plasticity in FASD. Here, we test whether neuronal overexpression of SRF can achieve similar effects. Methods Ferrets received 3.5 g/kg alcohol intraperitoneally (25% in saline) or saline as control every other day between postnatal day 10 to 30, which is roughly equivalent to the third trimester of human gestation. Animals were given intracortical injections of a Herpes Simplex Virus-based vector to express either green fluorescent protein or a constitutively active form of SRF in infected neurons. They were then monocularly deprived by eyelid suture for 4 to 5 days after which single-unit recordings were conducted to determine whether changes in ocular dominance had occurred. Results Overexpression of a constitutively active form of SRF by neurons restored ODP in alcohol-treated animals. This effect was observed only in areas near the site of viral infection. Conclusions Overexpression of SRF in neurons can restore plasticity in the ferret model of FASD, but only in areas near the site of infection. This contrasts with SRF overexpression in astrocytes which restored plasticity throughout the visual cortex. [ABSTRACT FROM AUTHOR]

Background Dual process models posit that problem drinking is maintained by an imbalance between relatively strong automatic processes and weak controlled processes, a combination of executive functions and motivation. Few studies have examined how the interplay between automatic processes and executive functions is affected by motivation to change. This study examined this relationship in problem drinkers seeking online help to change their alcohol use. It was expected that executive functions (i.e., working memory, response inhibition) would moderate the relationship between automatic (valence and approach) associations and alcohol use and that this effect would be stronger in individuals with strong motivation to change. Methods A sample of 302 problem drinkers (mean age: 51.7 years) participated in this study as part of the baseline assessment before an Internet intervention. Participants completed an online version of the brief Implicit Association Test (valence and approach associations), the self-ordered pointing task (working memory), the Stroop task (response inhibition), the Readiness to Change Questionnaire (motivation to change), and the Timeline Follow-Back Questionnaire (alcohol use). Hierarchical moderated regression analysis was used to test the 4 hypothesized 3-way interactions. Results As expected, the interaction between valence associations and working memory only predicted alcohol use among individuals with strong motivation. This pattern was neither found for response inhibition nor for approach associations. Conclusions Results provide partial support for the moderating role of motivation in the interplay between automatic processes and executive functions. Future studies should investigate this relationship in participants with the full range of motivation and alcohol use. [ABSTRACT FROM AUTHOR]

Background Our goal was to assess the prevalence of 9 different types of precipitating circumstances among suicide decedents, and examine the association between circumstances and postmortem blood alcohol concentration ( BAC ≥ 0.08 g/dl) across U.S. ethnic groups. Methods Data come from the restricted 2003 to 2011 National Violent Death Reporting System, with postmortem information on 59,384 male and female suicide decedents for 17 U.S. states. Results Among men, precipitating circumstances statistically associated with a BAC ≥ 0.08 g/dl were physical health and job problems for Blacks, and experiencing a crisis, physical health problems, and intimate partner problem for Hispanics. Among women, the only precipitating circumstance associated with a BAC ≥ 0.08 g/dl was substance abuse problems other than alcohol for Blacks. The number of precipitating circumstances present before the suicide was negatively associated with a BAC ≥ 0.08 g/dl for Whites, Blacks, and Hispanics. Conclusions Selected precipitating circumstances were associated with a BAC ≥ 0.08 g/dl, and the strongest determinant of this level of alcohol intoxication prior to suicide among all ethnic groups was the presence of an alcohol problem. [ABSTRACT FROM AUTHOR]

Background For over 2 decades, brief motivational interventions ( BMIs) have been implemented on college campuses to reduce heavy drinking and related negative consequences. Such interventions include in-person motivational interviews ( MIs), often incorporating personalized feedback ( PF), and stand-alone PF interventions delivered via mail, computer, or the Web. Both narrative and meta-analytic reviews using aggregate data from published studies suggest at least short-term efficacy of BMIs, although overall effect sizes have been small. Methods This study was an individual participant-level data ( IPD) meta-analysis of 17 randomized clinical trials evaluating BMIs. Unlike typical meta-analysis based on summary data, IPD meta-analysis allows for an analysis that correctly accommodates the sampling, sample characteristics, and distributions of the pooled data. In particular, highly skewed distributions with many zeroes are typical for drinking outcomes, but have not been adequately accounted for in existing studies. Data are from Project INTEGRATE, one of the largest IPD meta-analysis projects to date in alcohol intervention research, representing 6,713 individuals each with 2 to 5 repeated measures up to 12 months postbaseline. Results We used Bayesian multilevel over dispersed Poisson hurdle models to estimate intervention effects on drinks per week and peak drinking, and Gaussian models for alcohol problems. Estimates of overall intervention effects were very small and not statistically significant for any of the outcomes. We further conducted post hoc comparisons of 3 intervention types (individual MI with PF, PF only, and group MI) versus control. There was a small, statistically significant reduction in alcohol problems among participants who received an individual MI with PF. Short-term and long-term results were similar. Conclusions This study questions the efficacy and magnitude of effects of BMIs for college drinking prevention and intervention and suggests a need for the development of more effective intervention strategies. [ABSTRACT FROM AUTHOR]

Background Much is unknown about the relationship between socioeconomic status ( SES) and alcohol use, including the means by which SES may influence risk for alcohol use. Methods Using a sample of 672 twin pairs (aged 25 to 74) derived from the MacArthur Foundation Survey of Midlife Development in the United States, this study examined whether SES, measured by household income and educational attainment, moderates genetic and environmental influences on 3 indices of alcohol use: amount used, frequency of use, and problem use. Results We found significant moderation for amount of alcohol used. Specifically, genetic effects were greater in low- SES conditions, shared environmental effects (i.e., environmental effects that enhance the similarity of twins from the same families) tended to increase in high- SES conditions, and nonshared environmental effects (i.e., environmental effects that distinguish twins) tended to decrease with SES. This pattern of results was found for both income and education, and it largely replicated at a second wave of assessment spaced 9 years after the first. There was virtually no evidence of moderation for either frequency of alcohol use or alcohol problems. Conclusions Our findings indicate that genetic and environmental influences on drinking amount vary as a function of the broader SES context, whereas the etiologies of other drinking phenomena are less affected by this context. Efforts to find the causes underlying the amount of alcohol used are likely to be more successful if such contextual information is taken into account. [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 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 Few studies assess reliability and validity of lifetime alcohol measures. We undertook extended test-retest analyses of retrospective lifetime drinking measures and of incremental predictive ability of lifetime heavy drinking (days 5+ drinks) in teens, 20s, and 30s for current (12-month) alcohol use disorders ( AUDs). Methods A subset (31.4%; 962 men, 1,220 women) of the 2005 U.S. National Alcohol Survey ( NAS; N11) completed a follow-up survey ( N11 T) by phone or mail (mean delay of 2.7 years). Both surveys assessed lifetime drinking. Results In N11 T, drinking status was reported consistently by 94.7% of N11 current drinkers, 85.5% of ex-drinkers, and 74.4% of lifetime abstainers (93.5% overall). Cumulative number of prior heavy drinking days (teens through 30s) were moderately consistent (Pearson's ρ = 0.6, p < 0.001, n = 1,636). Reliability was lower for younger respondents under 30 and higher for Whites versus Blacks and Hispanics ( ρ = 0.68 vs. ρ = 0.56 vs. ρ = 0.56, both p = 0.01), but did not differ by gender. Heavy drinking days in teens correlated 0.63 ( p < 0.001) for those aged 20 or older, higher for women than men and for Whites versus ethnic minorities. Heavy drinking days in the 20s and 30s reported by those 30 and older and 40 and older correlated at 0.63 and 0.67, respectively, being higher for Whites. Age of drinking onset and of lifetime maximum quantity reports were also consistent (0.65, 0.73), higher for women versus men, for those older than 29 versus younger, and for Whites versus Blacks and Hispanics. In N11, controlling for gender, age, ethnicity, and current 5+ frequency, cumulative prior 5+ days (teens to age 39) predicted current alcohol-related consequences and dependence (both p = 0.003). Conclusions Measurements of earlier heavy drinking are feasible, efficient, and reasonably reliable, albeit with some individual imprecision. Prior drinking data improve prediction of current AUDs, adjusting for demographics and current drinking. [ABSTRACT FROM AUTHOR]

Background Procedural learning allows for the acquisition of new behavioral skills. Previous studies have shown that chronic alcoholism is characterized by impaired cognitive procedural learning and brain abnormalities affecting regions that are involved in the automation of new cognitive procedures in healthy individuals. The goal of the present study was to investigate the brain structural substrates of cognitive procedural learning in alcoholic patients (ALs) early in abstinence. Methods Thirty-one ALs and 31 control participants (NCs) performed the Tower of Toronto task (4 daily learning sessions, each comprising 10 trials) to assess cognitive procedural learning. We also assessed episodic and working memory, executive functions, and visuospatial abilities. ALs underwent 1.5T structural magnetic resonance imaging. Results The initial cognitive phase was longer in the AL group than in the NC group, whereas the autonomous phase was shorter. In ALs, the longer cognitive phase was predicted by poorer planning and visuospatial working memory abilities, and by smaller gray matter ( GM) volumes in the angular gyrus and caudate nucleus. ALs' planning abilities correlated with smaller GM volume in the angular gyrus. Conclusions Cognitive procedural learning was impaired in ALs, with a delayed transition from the cognitive to the autonomous phase. This slowdown in the automation of the cognitive procedure was related to lower planning abilities, which may have hampered the initial generation of the procedure to be learned. In agreement with this neuropsychological finding, a persistent relationship was found between learning performance and the GM volumes of the angular gyrus and caudate nucleus, which are usually regarded as markers of planning and initial learning of the cognitive procedure. [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]