Alcohol (Hanover, York County, Pa.)最新文献

Background: The context of alcohol consumption can influence an individual's experience and subsequent motivation, representing a point of potential clinical intervention in alcohol use disorder (AUD). Despite strong evidence for context-dependent influences on drug-cue reactivity, craving, seeking, and use, how multimodal contextual features interact to promote or suppress these behaviors is not well understood.

Methods: In adult male C57BL6/J mice, we conducted an unbiased alcohol conditioned place preference (CPP) procedure to determine the effects of proximal (sensory characteristics of the training apparatus) and distal (spatial characteristics of the training room) features of the training context on motivation for alcohol.

Results: We found that alcohol place preference was uniquely influenced by proximal and distal context features. Specifically, training with alcohol, but not saline, resulted in a robust preference for a context with black walls, coarse floor, and coffee scent, as well as closest proximity to a wall of the room. Further analysis revealed a hierarchy of contextual influence, wherein the distal feature outweighed the proximal features. Context features also influenced the rate of change of alcohol-induced locomotor activity during training which correlated with the strength of context preference at testing, consistent with the link between alcohol experience and motivation seen from rodents to human.

Conclusions: Our findings indicate that both proximal and distal context features influence alcohol experience and subsequent motivation for alcohol. These findings highlight the importance of accounting for even subtle variations in training context, such as the location in a room. They further suggest that the varying motivational weight of different context levels could impact the development of AUD and be utilized to improve context-based treatment strategy outcomes. This approach offers a simple method to investigate the mechanisms by which multimodal context features influence appraisal and motivation.

Background: Prenatal alcohol exposure (PAE) is a risk factor for early-onset psychopathology. Low birthweight (LBW), one potential consequence of PAE, increases the vulnerability of children for externalizing disorders. This study investigates potential sex-specific indirect pathways linking PAE to behavioral symptoms in offspring, focusing on LBW as a mediating and moderating factor.

Methods: Participants were 9-10-year-old singleton children whose biological parents reported on pregnancy experiences in the Adolescent Brain Cognitive Development (ABCD) study. PAE was a binary variable, indicating any use during pregnancy. Externalizing behavioral problems were assessed with the Child Behavior Checklist and modeled continuously. LBW (<2500 g) was calculated based on parental reports. We applied a four-way decomposition analysis with stratification by sex. This causal framework allows to dissect the total effect into controlled direct effect (CDE), reference interaction (INTref), mediated interaction (INTmed), and pure indirect effect (PIE).

Results: The analytic sample (N = 7502) was evenly split by sex, and nearly 50% were non-Hispanic White children. A total of 2083 children were exposed to PAE. The adjusted total effect of PAE on externalizing behavioral problems was identified (β = 0.91; 95%CI: 0.38, 1.44), with slightly weaker effects observed in males (β = 0.88; 95%CI: 0.12, 1.64) than in females (β = 0.98; 95%CI: 0.25, 1.71). Decomposition analysis indicated potential interaction with a major difference in CDE in the presence of LBW and in its absence, specifically for males (β = 4.30, 95% CI: 1.97, 8.40 and β = 0.70, 95%CI:-0.17, 1.57, respectively). This indicates higher externalizing behavioral problems in males with a joint exposure to PAE and LBW, also confirmed with the INTref parameter (β = 0.18, 95%CI: 0.08, 0.4). We found no evidence for mediation (PIE) or mediated interaction (INTmed) via LBW.

Conclusion: Early identification and intervention for children with PAE have been shown to mitigate the risk of more severe secondary impacts. Our findings highlight the potential importance of birthweight as a factor that may exacerbate behavioral problems among PAE-exposed offspring, particularly males.

Background: Alcohol use disorder (AUD) is a chronic, relapsing condition and a major public health problem. However, few medications are approved to treat AUD, and those available show limited efficacy. Drug repurposing is a cost-effective strategy to identify novel therapeutic uses for existing medications. Here, we describe a pipeline that integrates genetic and electronic health record (EHR) data to identify and evaluate drugs to be repurposed for treating AUD.

Methods: Our approach comprises (1) alcohol-associated gene identification and biological network generation; (2) mapping drugs to target proteins; (3) filtering promising repurposing candidates; and (4) an exemplar pharmacoepidemiologic analysis of the effect of an identified drug (i.e., baclofen) on alcohol consumption.

Results: Linking loci to genes from a genome-wide association study (GWAS) of problematic alcohol use identified 94 genes, which we expanded to 327 alcohol-related genes through network-based analyses. Across these analyses, 52 genes were linked to 195 FDA-approved drugs, including four already approved or used off-label to treat AUD. After filtering for safety, relevance, and data availability, 26 candidate drugs, including baclofen, were selected for further evaluation. An evaluation of the real-world effectiveness of baclofen using national EHR data from the United States Department of Veterans Affairs provided evidence that baclofen-exposed patients reduced alcohol consumption more than propensity-score-matched unexposed patients.

Conclusions: This approach, which aligns genomic findings with real-world clinical data, provides an efficient method for identifying promising drug repurposing candidates and prioritizing those that merit evaluation in randomized trials to ultimately advance pharmacotherapies for AUD.

Background: Excessive alcohol consumption and stress are associated with structural and functional alterations in the brain and impaired cognition. However, the persistence of long-term neural impacts after alcohol and stress is less understood. This study investigated midlife cognition and neuropathological changes following a history of alcohol and stress exposure.

Methods: C57BL/6J mice acclimated to ethanol drinking (15% v/v) before exposure to four cycles of alternating chronic intermittent ethanol (CIE) vapor exposure and repeated forced swim stress (FSS), with control groups exposed to air and no stress (AIR/NS). After 3 months of abstinence, mice were evaluated at midlife (11 months old) on volitional drinking and a final CIE/FSS challenge for stress-induced drinking. Spatial learning and cognitive flexibility were assessed using the Barnes maze before brains were collected to evaluate locus coeruleus (LC) integrity at 12 months old.

Results: CIE/FSS increased volitional alcohol intake, and this drinking phenotype persisted through to midlife despite extended abstinence. CIE/FSS mice showed intact spatial learning but impaired flexibility in the Barnes maze reversal phase. Flexibility impairments were driven by decreased time in the target quadrant and increased errors during the reversal test compared with AIR/NS. Furthermore, CIE/FSS mice showed pathological measures of reduced LC integrity common to dementia-related disorders, including elevated markers of oxidative stress, apoptosis, and reduced autoinhibitory function.

Conclusions: Our findings highlight the long-lasting impact of alcohol and stress exposure on cognition, with flexibility impairments persisting into midlife. In addition to cognitive changes, alcohol and stress history produced pathological changes in the LC, an area known to mediate cognitive flexibility via its forebrain projections. Together, these results give insight into the long-lasting impacts of chronic alcohol and stress and how they may accelerate age-related cognitive decline.

Background: Young adults with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of experiencing alcohol use problems compared to peers without ADHD. Poorer parent-rated social functioning has been associated both positively and negatively with alcohol use among youth with ADHD. However, individuals' self-perceptions of their sociability, or comfort in social situations, could be more specifically linked to risky alcohol outcomes via drinking motives. We tested associations among ADHD, self-reported sociability, social and coping drinking motives, and alcohol use outcomes in young adulthood.

Method: A total of 333 young adults (53% with ADHD diagnosed in childhood; 80% non-Hispanic White; 10% female participants) reported their sociability, social and coping drinking motives, heavy alcohol use between ages 18 and 21, and their heavy alcohol use and alcohol-associated problems at age 23. Zero-inflated negative binomial path models were tested and mediation was evaluated using the joint significance test.

Results: Results supported the possibility of a social motives "protective" pathway, such that young adults with ADHD histories were less likely than peers to endorse social drinking motives and, in turn, reported better alcohol use outcomes. A low sociability-high coping motives association was also supported such that young adults with ADHD histories were more likely than peers to self-report low sociability and thus higher coping drinking motives, which were associated with worse alcohol use outcomes later.

Conclusions: Considering the perceptions of sociability among young adults with ADHD may help disentangle complex social pathways to alcohol use. Results highlight the need to develop healthy coping strategies among young adults with ADHD.

Background: Fetal alcohol spectrum disorders (FASD) encompass a range of phenotypes in offspring exposed to ethanol via maternal consumption during pregnancy. In a series of studies, our laboratory identified deleterious effects of prenatal ethanol exposure (PrEE) in our FASD mouse model. The first filial generation (F1) of PrEE offspring exhibited abnormal neocortical gene expression, ectopic intraneocortical connectivity, altered neuroanatomy, and disrupted behavior. Our results suggest that PrEE can induce transgenerational transmission of the abnormal phenotypes, potentially via epigenetic modifications.

Methods: Here, we investigated brain and behavioral development in the F1 (directly exposed), F2 (indirectly exposed), and F3 (non-exposed) generations of our PrEE model. Comparative analyses of body weight, brain weight, cortical length, thalamic nuclear areas, hippocampal structures, and corpus callosa were evaluated in control, F1, F2, and F3 newborn mice, with behavioral differences examined at wean age.

Results: All generations of PrEE newborns had decreased body weights, brain weights, and neocortical lengths compared with controls. Quantitative measures in F1, F2, and F3 newborn PrEE mice demonstrated altered neocortical thickness in F1 prelimbic, visual, and auditory cortices. Additionally, a transgenerational reduction was also observed in the auditory cortex in F3 mice when compared to controls. When compared to controls, all generations of PrEE mice demonstrated significant reductions in hippocampal CA3 thickness. While no control cases demonstrated corpus callosal agenesis, a majority of F1 cases did, as well as a lower but present percentage of F2 and F3 cases. Finally, we found that disrupted sensorimotor integration, motor control, and anxiety-like behavior persisted to at least the F2 generation.

Conclusions: Our data suggest that PrEE can result in abnormal brain and behavioral development with heritable effects that persist transgenerationally.

Traumatic brain injury (TBI) is a major global health concern, affecting over 30 million individuals annually and leading to significant disability and mortality. In the United States, the health burden of TBI is compounded by the high incidence of alcohol involvement, with up to 50% of cases occurring in intoxicated individuals and approximately 26% of patients consuming alcohol post-injury. This review synthesizes current research exploring the complex interplay between TBI and alcohol misuse, with a particular focus on their combined effects on mitochondrial function, energy metabolism, and cellular redox homeostasis. We discuss how TBI-induced mitochondrial dysfunction, manifested as impaired adenosine triphosphate (ATP) production, excessive reactive oxygen species (ROS) generation, and subsequent depletion of glutathione, intersects with alcohol-mediated metabolic reprogramming, resulting in disrupted glucose metabolism and a shift toward glutaminolysis. This metabolic perturbation predisposes neural tissue to lipid peroxidation and ferroptosis, an iron-dependent form of cell death that is characterized by the peroxidation of polyunsaturated fatty acid-containing phospholipids. Here we highlight how alterations in glutamate homeostasis in combination with exacerbated neuroinflammatory signaling contribute to post-TBI cognitive impairments and hinder the recovery process. Integrating findings from biomarker studies and preclinical models, we highlight the critical need for targeted therapies that address these interconnected molecular pathways. A comprehensive understanding of these pathways promises to uncover druggable targets leading to novel neuroprotective strategies, offering hope for improved clinical outcomes in patients suffering from TBI, particularly those with concurrent alcohol exposure.

Background: Fetal alcohol spectrum disorders (FASD) are among the most common developmental disorders but are underdiagnosed in part because of the inaccessibility of valid screening tools. The goal of this study was to test the ability of a novel online cognitive and behavioral screening tool to accurately distinguish youth with histories of prenatal alcohol exposure (PAE) from the comparison group.

Methods: Children were tested at home with an online cognitive and behavioral test battery, Brief Assessment of Individual Neurobehavior-online version (BRAIN-online). Participants included children with (n = 239) and without (n = 89) histories of PAE between the ages of 5 and 17 years. BRAIN-online includes a parent/caregiver-completed behavioral questionnaire and seven cognitive tasks completed by the child. Performance data were analyzed using ANOVA, ROC analysis, and logistic regression.

Results: Children in the alcohol-exposed group had more behavioral problems, as indicated by higher scores on the behavior rating, and performed more poorly on the cognitive tasks than children in the comparison group. Logistic regression results indicated that performance on BRAIN-online distinguished the groups with a high degree of accuracy (accuracy = 80%, sensitivity = 79%, specificity = 83%, positive predictive value = 92%, negative predictive value = 60%). Results were not affected by attention-deficit/hyperactivity disorder (ADHD) or overall intellectual ability.

Conclusion: BRAIN-online is a novel online screening tool that can distinguish individuals affected by prenatal alcohol exposure from typically developing children with a high degree of accuracy. The availability of an accessible, low-cost, efficient screening tool for fetal alcohol spectrum disorders (FASD) will improve diagnostic efficiency and reduce wait times and assessment costs.

Background: Although men have historically exhibited the higher levels of alcohol use and alcohol-related harm, sex differences in alcohol consumption have narrowed in recent decades. Whether similar convergence has occurred in the proportion of substance-related acute care encounters involving alcohol remains unclear.

Methods: We conducted a retrospective longitudinal cohort study using national administrative claims from the Merative MarketScan Commercial and Multi-State Medicaid databases (January 2016 to December 2023). Individuals aged 16-64 years with at least one emergency department (ED) or inpatient encounter involving a non-nicotine substance-related diagnosis (ICD-10-CM F10-F19, excluding F17) were included. Alcohol involvement was defined using multiple classifications: any alcohol-related diagnosis, alcohol-only encounters, inpatient admissions with alcohol as the primary diagnosis, and acute alcohol-related morbidity identified using CDC external cause codes. We estimated monthly sex-specific trends in the proportion of substance-related encounters involving alcohol using generalized estimating equation models with quadratic time terms.

Results: The cohort comprised 1,355,161 individuals (54.7% male, 45.3% female) with 5,190,680 substance-related ED and inpatient encounters. Among individuals with substance-related encounters, alcohol involvement was more common among males than females (61.5% vs. 43.2%). Across all alcohol-related outcomes, models demonstrated accelerating convergence in the sex gap over time (all p < 0.001). From 2016 to 2023, the male-female gap in the proportion of substance-related encounters involving alcohol narrowed by 6.0 percentage points (95% CI, 4.9-7.1), 4.7 points (95% CI, 3.6-5.8) for alcohol-only encounters, and 4.9 points (95% CI, 4.0-5.8) for inpatient admissions with alcohol as the primary diagnosis. Trends in total substance-related encounter volume did not differ by sex.

Conclusions: From 2016 to 2023, alcohol accounted for an increasing proportional share of substance-related acute care encounters among women relative to men, independent of changes in overall substance-related healthcare utilization volume.

Background: Alcohol use disorder (AUD) is a common substance use disorder associated with a range of sociodemographic, behavioral, and genetic factors. The current study characterizes variation in such factors as a function of ascertainment strategy in a sample of individuals with a lifetime history of severe AUD.

Methods: Participants (N = 10,804) were recruited through substance use treatment facilities or through online outreach/advertisement in the United States and completed a survey that assessed a range of alcohol-related variables, sociodemographics, psychopathology, and personality. Participants were asked to provide a saliva sample for DNA extraction and genotyping. Participants' survey responses and their polygenic risk for multiple alcohol outcomes were compared as a function of ascertainment strategy ("clinic" vs. "online") using t and chi-square tests.

Results: Ascertainment strategy was significantly associated with many phenotypic variables, although effect sizes were generally small. In general, clinic participants reported more adverse outcomes, such as higher AUDIT-C scores, longer duration of alcohol problems, antisocial behavior symptom counts, and four of five impulsivity facets. However, online participants reported more problems with depression. Polygenic risk scores differed by ascertainment strategy only for participants of European descent. Clinic participants' scores were higher for AUD, AUDIT-C, drinks per week, and problematic alcohol use. The groups' scores did not significantly differ for typical maximum drinks in 24 h.

Conclusions: Individuals with severe AUD exhibit heterogeneity across many risk domains, particularly for alcohol-related measures. This heterogeneity can be captured through the ascertainment of study participants via diverse modalities, improving representativeness and potentially facilitating gene identification efforts.