Alcoholism: Clinical and Experimental Research

Stress exposure contributes to the development of drug and alcohol use disorders. In animal models, stress exacerbates escalations in alcohol consumption in alcohol-dependent animals. The nucleus of the solitary tract (NTS) is a critical brainstem region for integrating and relaying peripheral signals to regulate stress responses. To define the molecular adaptions within this brain region that may contribute to stress-induced alcohol drinking, we exposed animals to chronic intermittent bouts of ethanol vapor (CIE), forced swim stress (FSS), or both (CIE + FSS) and then transcriptionally profiled the NTS at three different timepoints after the last vapor exposure (0-hr, 72-hr, and 186-hr). We identified interferon (IFN) signaling as a critical gene network correlated with alcohol consumption levels. Using a likelihood ratio test, we identified genes that were differentially expressed across time and between groups. Clustering analysis of these genes to identify unique expression patterns identified a subset of genes that fail to normalize in the CIE + FSS group, but not the others. These genes were enriched for cell-to-cell interaction and cellular movement pointing to long-term structural and functional changes in this brain region caused by the unique interaction of alcohol dependence and stress. Specific genes of interest identified in this group include Aqp4, Il16, Reln, Grm4, Gabrd, and Gabra6. We also compared gene expression changes in the NTS to the PFC and found a significant overlap of genes between the two brain regions. Overlapping NTS/PFC genes in the CIE + FSS group were enriched for type I IFN signaling. Finally, we tested the hypothesis that activation of type I IFN signaling increases alcohol consumption based on the three lines of evidence identifying type I IFN signaling as critical for escalations in alcohol intake. Mice treated with recombinant IFN{beta} showed significantly elevated levels of alcohol intake in a two-bottle choice procedure compared to saline-treated controls. Overall, these results define the transcriptomic changes across time in the NTS that may be critical to the development of stress-induced increases in alcohol consumption and alcohol dependence.

BackgroundChronic alcohol use disorder (AUD) is associated with profound dysregulation of immune function, neuroinflammation, and systemic stress responses, which contribute to both the maintenance of addiction and alcohol-related organ damage. While brain transcriptomic studies have established neuroimmune signaling and synaptic remodeling as central features of AUD, peripheral blood signatures during early withdrawal and recovery remain underexplored. Understanding the dynamic transcriptional changes in peripheral blood accompanying supervised withdrawal therapy is critical for identifying reversible molecular processes versus persistent trait-like alterations. MethodsRNA sequencing (RNA-seq) was performed on peripheral blood from individuals with alcohol use disorder (AUD, n = 100) and healthy controls (n = 74) at baseline and after three weeks of supervised withdrawal therapy. Differentially expressed genes (DEGs) were identified using linear mixed models assessing main effects of group, time, and their interaction. Functional enrichment and co-expression network analyses were performed to identify coordinated biological processes. ResultsAt baseline, more than 1,000 genes were differentially expressed between AUD and control participants, showing robust dysregulation of immune-related pathways. After three weeks of withdrawal, the number of DEGs decreased markedly to 141, indicating partial transcriptomic normalization. Nevertheless, immune dysregulation persisted despite treatment, particularly linked to B cell activation and cell-cell junctions. Interaction analyses (group x time) identified 16 genes whose expression dynamically changed with therapy, highlighting strong enrichment for fatty acid pathways. Co-expression network analysis revealed that baseline modules were enriched for genes associated with secretory granules and immune signaling, while therapy-related co-expression shifts involved coagulation and platelet activation processes. ConclusionsAUD is associated with widespread but partly reversible transcriptomic dysregulation in peripheral blood. These findings support a system-level view of AUD as a disorder of intertwined immune, metabolic, and coagulation biology and suggest that longitudinal blood transcriptomics may help identify both rapidly therapy-responsive and more stable molecular targets for relapse prevention.

Alcohol use disorder (AUD) imposes a significant global health burden, yet effective treatments remain limited due to the scarcity of well-characterized biological sample repositories. To address this gap, we established the UCSD Alcohol BioBank, a comprehensive resource containing thousands of samples from over 700 genetically diverse heterogeneous stock (HS) rats. Modeled after successful cocaine and oxycodone biobanks, this repository utilizes the chronic intermittent ethanol vapor exposure (CIE) model, paired with oral self-administration, to characterize AUD-like behaviors, including ethanol consumption, preference, motivation, and withdrawal symptoms such as allodynia and anxiety-like behavior. Longitudinal samples (blood, urine, and feces) are collected before, during, and after ethanol exposure, while terminal samples (brain, heart, liver, kidneys, cecum, reproductive organs, adrenal glands, peripheral blood mononuclear cells) are obtained at intoxication, acute withdrawal, protracted abstinence, or from naive controls. Samples are preserved via snap-freezing or paraformaldehyde fixation to support diverse applications, including genomics, transcriptomics, proteomics, and neuroanatomy. The genetic diversity of HS rats enables genome-wide association studies (GWAS) to identify AUD-related genetic variants. Freely available to non-profit organizations at www.alcoholbiobank.org, with genetic and behavioral data deposited in public repositories, the Alcohol BioBank facilitates collaborative research to uncover biomarkers and develop novel therapies for AUD, addressing a critical need in addiction science.

BackgroundStudies show that Black and Hispanic Veterans have a higher prevalence of alcohol use disorder (AUD) than White Veterans. We examined whether the relationship between self-reported race/ethnicity and AUD diagnosis varies by self-reported alcohol consumption. MethodsThe sample included 700,013 Black, Hispanic, and White Veterans enrolled in the Million Veteran Program cohort. Alcohol consumption was defined as an individuals maximum score on the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire, a screen for hazardous or harmful drinking. The primary outcome, AUD, was defined by the presence of ICD-9/10 codes in the electronic health record. We used logistic regression with interactions to assess the association between race/ethnicity and AUD by maximum AUDIT-C score. ResultsBlack and Hispanic Veterans were more likely to have an AUD diagnosis than White Veterans despite similar levels of alcohol consumption. The difference was greatest between Black and White men. At all but the lowest and highest levels of alcohol consumption, Black men had 24%-111% greater odds of an AUD diagnosis. The association between race/ethnicity and AUD diagnosis remained after adjustment for alcohol consumption, alcohol-related disorders, and other potential confounders. ConclusionsThe large discrepancy in AUD diagnosis across groups despite a similar distribution of alcohol consumption measures suggests that Veterans are differentially assigned an AUD diagnosis by race/ethnicity. Efforts are needed to examine the causes of the observed differences and to implement changes, such as structured diagnostic methods, to address a likely contributor to racial differences (i.e., bias) in AUD diagnosis.

This study explores the neurobiological underpinnings of alcohol use disorder (AUD) by integrating bulk and single-cell transcriptomic data from humans, primates, and mice across three brain regions associated with addiction (i.e., prefrontal cortex (PFC), nucleus accumbens (NAc), and central amygdala (CeA)). We compared AUD RNA expression and cell-type abundance from 92 human brain to data from 53 primates and 90 mice engaged in diverse alcohol use paradigms. The findings revealed significant and reproducible correlations between human AUD and mammalian models of alcohol use that vary by tissue, species, and behavioral paradigm. The strongest correlations occurred between primate and mouse models of binge drinking (i.e., high drinking in the dark). Certain primate models demonstrated that the brain RNA correlations with human alcohol use disorder (AUD) were approximately 40% as strong as the correlations observed within human samples themselves. By integrating single-cell transcriptomic data, this study observed decreased oligodendrocyte proportions in the PFC and NAc of human AUD with similar trends in animal models. Gene co-expression network analyses revealed conserved systems associated with human AUD and animal models of heavy/binge alcohol consumption. Gene co-expression networks were enriched for pathways related to inflammation, myelination, and synaptic plasticity and the genes within them accounted for [~]20% of the heritability in human alcohol consumption. Identified hub genes were associated with relevant traits (e.g., impulsivity, motivation) in humans and mice. This study sheds light on conserved biological entities underlying AUD and chronic alcohol use, providing insights into the cellular, genetic, and neuromolecular basis across species.

BackgroundAlcohol is the most widely consumed psychoactive substance worldwide. In Portugal, alcohol consumption is deeply embedded in social and cultural practices, contributing to high prevalence rates among university students, with binge drinking emerging as a predominant consumption pattern. Despite the associations between this drinking behaviour and numerous social, physical, and psychological problems, research on alcohol consumption in Portuguese university populations remains limited. Thus, this study aimed to provide a comprehensive description of alcohol use patterns among a large sample of Portuguese university students, focusing on adolescents and young adults. MethodsA total of 1,746 students, aged 17-24 years, were surveyed using the Alcohol Use Disorders Identification Test (AUDIT) and additional questionnaires regarding socio-demographic information, alcohol and illicit drug use, smoking habits, and alcohol cravings. Students were classified into five drinking groups: Abstainers (16.8%), Moderate Drinkers (35.1%), Hazardous Drinkers (25.8%), Binge Drinkers (20.8%), and Dependent Drinkers (1.5%). Statistical analyses included descriptive statistics, group comparisons, and multinomial logistic regressions to obtain Odds Ratios (ORs) for group membership. ResultsAlcohol consumption was reported by 83.2% of students over the past year. Nearly 47% of students revealed harmful drinking patterns, and 1.5% exhibited symptoms of alcohol dependence. A progressive increase in the severity of alcohol consumption characteristics was observed across the groups, with Dependent Drinkers reporting the highest levels overall. Significant predictors of group membership included polydrug use, standard weekly consumption, earlier drinking onset, and higher levels of alcohol craving. Polydrug use, reported by 27.3% of students, was the strongest predictor for being a Hazardous Drinker (OR = 10.75), Binge Drinker (OR = 13.20), and Dependent Drinker (OR = 21.40). Binge Drinkers displayed standard weekly consumption and craving levels comparable to Dependent Drinkers, while Moderate Drinkers exhibited the least risky patterns, including a later age of onset of drinking. Male students reported significantly greater consumption and craving levels than their female peers. ConclusionsThis study highlights the prevalence of harmful drinking behaviours among Portuguese university students and identifies critical risk factors, such as polydrug use and early drinking onset. These findings underscore the need for prevention programmes focused on delaying the onset of alcohol use, reducing polydrug use, and promoting healthier behaviours within academic settings.

BackgroundGenetic influences account for a substantial proportion of individual differences in alcohol use behaviors (AUBs). However, multiple distinct sets of genes are linked to different AUBs, which may explain their dramatic variability in risk factors and manifestations. In this study, we explore whether intermediate neurobiological traits and alcohol-related cognitions mediate the relationship between polygenic scores (PGS) and multiple AUBs, with the aim to better understand processes captured by different genetic profiles. MethodsUsing results from prior genome-wide association studies, we derived PGS for 6 AUBs in participants from Spit for Science, a longitudinal study of college students in the U.S. (n=4,549). Self-report measures included personality traits, alcohol expectancies, drinking motivations, and alcohol sensitivity measures as well as drinking frequency, drinking quantity, alcohol use disorder (AUD) symptoms, and maximum drinks in 24 hours. Using linear regression and multiple mediation models, we investigated the direct and indirect effects of PGS on AUBs. ResultsIn univariable regression results, PGSs indexing broad AUB dimensions such as drinks per week (DPW) and AUD predicted higher levels of sensation-seeking and multiple drinking motives, while BeerPref PGSs (indexing a variable pattern of alcohol problems associated with a preference for beer) predicted higher negative urgency and lower alcohol sensitivity. Mediational models indicated strong direct and indirect effects of DPW PGSs on multiple AUBs via social/enhancement drinking motives and alcohol sensitivity, indirect effects of AUD PGSs on AUD symptoms via coping motives, and indirect effects of BeerPref PGS on all AUBs via the joint effect of mediators including alcohol sensitivity. ConclusionsThese findings provide initial evidence that the genetic influences on different AUBs are associated with and partially mediated by intermediate neurobiological and cognitive factors, which may be more amenable to intervention. Greater focus on drinking motives and alcohol sensitivity is warranted in genetic research, as well as attention to the heterogeneous pathways linking genes to alcohol use outcomes.

BackgroundMethamphetamine addiction remains a significant public health concern, primarily affecting the central nervous system by disrupting dopamine and serotonin signaling. Epigenetic modifications, especially DNA methylation in the catechol-O-methyltransferase (COMT) and serotonin transporter (SLC6A4) genes, are implicated in addiction-related behavioral changes. While previous research has examined these genes, this study provides a novel perspective by analyzing methylation patterns in relation to aggression subtypes and methamphetamine use behaviors within a Middle Eastern cohort--an underrepresented population in addiction genetics. AimsTo investigate the genetic and epigenetic factors associated with methamphetamine addiction and aggression, with a specific focus on methylation profiles of the SLC6A4 and COMT genes. MethodsSixty male patients with methamphetamine addiction and aggression, and thirty age-matched healthy controls were enrolled. Peripheral blood samples were collected for RNA and DNA extraction. Methylation levels were assessed via bisulfite sequencing, and gene expression was evaluated using qRT-PCR. Behavioral data and substance use patterns were recorded through structured assessments. ResultsPatients showed significantly higher methylation levels in the SLC6A4 (63.29% vs. 7.84%, p = 0.0001) and COMT(50.98% vs. 19.77%, p = 0.0001) genes compared to controls. A strong correlation was observed between dopamine and methamphetamine levels (r = 0.846, p < 0.001). Methylation levels varied by aggression subtype and drug use frequency, suggesting epigenetic involvement in addiction severity and behavioral traits. ConclusionsThis study supports the role of SLC6A4 and COMT gene methylation in methamphetamine addiction and aggression. While causality cannot be inferred, the findings encourage further investigation into epigenetic biomarkers for behavioral risk profiling. Broader, longitudinal studies are needed to evaluate therapeutic potential and inform ethically sound applications in personalized addiction treatment.

RationaleIn humans, alcohol drinking is a significant driver of violent behaviors such as assaults and homicides. While acute intoxication is known to produce heightened aggression, little is known about alcohols long-term effects. Emerging evidence, however, suggests that chronic alcohol intake can promote heightened aggression, including during abstinence and may also sensitize individuals to alcohols acute aggression-heightening effects. ObjectivesThe goal of this study was to test the effects of chronic binge-like ethanol drinking on both alcohol-involved and alcohol-uninvolved aggression in male CFW mice. We aimed to model individual differences in binge drinking and assess changes in aggression during both acute and protracted abstinence. ResultsAfter 5 weeks of Drinking in the Dark (DID), CFW mice that showed higher levels of EtOH drinking ( high drinkers, 1.33 g/kg/h) became more aggressive than low drinkers (0.45 g/kg/h) and H2O controls, as measured via frequency of attack bites during resident-intruder fighting. In the first aggressive encounter following 1 week of abstinence, animals with an alcohol drinking history initiate a fight more rapidly and with greater consistency than H2O controls. We also found that a single session of binge-like alcohol drinking acutely heightened aggression regardless of drinking history. ConclusionsThese results suggest that repeated binge-like alcohol drinking causes escalations in alcohol-uninvolved aggression during acute (in high drinkers) and protracted abstinence (in all alcohol drinkers). However, chronic alcohol intake does not appear to sensitize animals to alcohol-involved aggression. These findings support the utility of genetically heterogeneous CFW mice for modeling individual variability in alcohol-related aggression.

ObjectiveFetal alcohol spectrum disorders affect approximately 1 in 20 school age children in the United States of America. To study fetal alcohol spectrum disorders, mouse models are commonly used. Of the many approaches of gestational exposure, voluntary drinking paradigms represent the most similar mechanism of drinking as human exposure. These exposures can be done through low-tech solutions such as test tubes (TT), or more high-tech methods such as a volumetric drinking monitor (VDM). Here were compare the TT method and the VDM directly, to evaluate their effect on female mouse drinking. MethodWe adapted a drinking in the dark, active cycle, limited access (4 hr.) voluntary drinking paradigm first described by Brady et al. (2012) to test tubes and the volumetric drinking monitor. 8 mice were placed in either drinking method and we evaluated their drinking volume and blood alcohol concentrations (BACs). We compared the values for each group using t-tests. ResultsAfter 2 weeks of drinking 10% ethanol with 0.4% saccharine, BACs were not significantly different [t(14)=0.2681, p=0.7935] between the VDM (81.56 {+/-} 21.16 mg/dL) vs.TT (73.14 {+/-} 23.20 mg/dL) groups. Calculated intake of ethanol (g/kg) on the day of blood draw for BAC analysis was also not significantly different [t(14)=0.4308, p=0.6732] between VDM (2.985 {+/-} 0.4127) vs.TT (3.260 {+/-} 0.4863; Fig 1B) groups. O_FIG O_LINKSMALLFIG WIDTH=139 HEIGHT=200 SRC="FIGDIR/small/658718v1_fig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@5f3ad4org.highwire.dtl.DTLVardef@f45edorg.highwire.dtl.DTLVardef@b7d7f8org.highwire.dtl.DTLVardef@1c40c63_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig 1.C_FLOATNO C_FIG ConclusionsTest tube or VDM resulted in similar average daily ethanol consumption and resultant BACs in female mice

AbstractDespite decades of research, no new FDA-approved medications for alcohol use disorder (AUD) have emerged in over 25 years. Enhancing the translational relevance of preclinical models by more precisely capturing the behavioral and neurobiological features of AUD offers a promising path toward identifying novel therapeutic targets. Operant self-administration paradigms are essential for modeling voluntary ethanol intake in rodents, yet traditional approaches often confound appetitive (seeking) and consummatory (intake) behaviors. The sipper model addresses this limitation by allowing extended, uninterrupted access to ethanol following operant responding, enabling a clearer dissociation between seeking and consumption. In this review, we synthesize key findings from studies employing the sipper model to investigate the behavioral and neurobiological mechanisms underlying alcohol use. We emphasize how over two decades of research employing the sipper model have demonstrated that ethanol- directed behaviors are dynamic processes, shaped by internal states, environmental cues, and prior experience. Finally, we introduce medparser, a new open-source R package designed to standardize the analysis of high-resolution licking data generated by sipper paradigms. By promoting reproducibility and cross-study comparability, this tool supports rigorous behavioral phenotyping. Together, these methodological and analytical advances enhance the translational potential of preclinical models and may ultimately aid in the discovery of novel therapeutic targets for AUD.

BackgroundContrary to previous findings, emerging studies support the increased likelihood of hazardous alcohol consumption in autistic adults when compared to neurotypical individuals. However, support services specifically for autistic people drinking hazardously are lacking. Examining the relationship of autistic features with alcohol consumption patterns longitudinally is essential to identify appropriate developmental points to offer support. MethodsWe investigated this using both phenotypic and genetic exposures measured in participants from the Avon Longitudinal Study of Parents and Children (ALSPAC). Our exposures included three measures of autistic traits (a broad autism phenotype measure, Social Communication Disorders Checklist score and polygenic score reflecting genetic liability for autism). Our outcome was alcohol consumption, measured across five timepoints between the ages of 17 to 28 years. We used multilevel piecewise linear spline analyses to model both the mean and 10th, 50th (median) and 90th quantiles of alcohol consumption longitudinally. ResultsThere was little evidence that genetic liability for autism influenced alcohol consumption. However, we found that individuals with higher autistic traits drank less at the mean and 10th, 50th (median) and 90th percentiles of alcohol consumption compared to those with lower autistic traits. We did not find evidence of a relationship between social communication differences and alcohol consumption at the mean, 10th and 50th (median) percentiles. Conversely, there was evidence to suggest that individuals with greater social communication differences drank more at the 90th percentile compared to those with fewer social communication differences. ConclusionOur findings indicate that social communication differences are associated with increased alcohol consumption in heavy drinkers, and that the relationship between autistic traits and alcohol consumption varies dependent on how traits are measured. This may explain the plurality of previous findings. Further research is needed to develop a more nuanced understanding of these associations across subpopulations of autistic traits and alcohol consumption.

Excessive alcohol (ethanol) consumption is a hallmark of alcohol use disorder (AUD). Activation of innate immune system and proinflammatory signaling in the brain may play a key role in promoting alcohol consumption and development of AUD in humans. Innate immune activation by toll-like receptor (TLR) agonists in rodents is associated with release of proinflammatory cytokines and changes in alcohol consumption, and these effects are genotype- and sex-dependent. For example, C57BL/6J male, but not female mice increase alcohol intake after TLR3 activation. In order to better understand the interactions between neuroimmune signaling, genotype, and sex and their effects on ethanol drinking, males and females of more genotypes need to be tested. The goal of this study was to test the effects of innate immune activation on ethanol consumption and neuroimmune molecular profiles of F1 hybrid mice from reciprocal crosses between C57BL/6J (B6) and FVB/NJ (FVB) mouse strains, which are animals with high levels of ethanol intake. Animals were randomly assigned to receive intraperitoneal injections of either saline, Poly(I:C) (PIC, 2 or 10 mg/kg), a TLR3 agonist, or lipopolysaccharide, (LPS, 0.1 mg/kg), a TLR4 agonist, administered every 4 days for a total of 10 injections and subjected to a 2-bottle choice every-other-day ethanol drinking paradigm for a total of 18 dinking sessions, which generated high levels of voluntary ethanol consumption. Six and 24 hours after the last injection, brains were removed, frontal cortex dissected, and levels of 3 proinflammatory cytokines (Tnfa, Il1b, Ccl5), as well as Tlr3, and Tlr4 were measured using qPCR. Immune activation by PIC produced escalation of ethanol drinking, while LPS resulted in a reduction of ethanol consumption or a trend to reduce drinking in males but not females of both FVB/B6 and B6/FVB crosses. Furthermore, activation of TLR3 by PIC produced sex-specific time course responses of pro-inflammatory cytokines, which may, at least in part, explain behavioral differences. Taken together, these results validate previous findings that the effects of immune activation on ethanol consumption depend on genotype, sex, and mode of activation (TLR3 vs TLR4) and suggest that FVB/B6J and B6J/FVB F1 males are a suitable model to study TLR3-dependent escalation of alcohol drinking. HighlightsO_LIImmune activation by Toll-like receptor 3 (TLR3) agonist, Poly(I:C), produced an escalation of ethanol drinking, while immune activation by TLR4 agonist, LPS, reduced ethanol intake in male but not female FVB/NJ x C57BL/6J hybrid mice. C_LIO_LIPoly(I:C)-induced escalation of alcohol consumption in males was reproducible and consistent across different Poly(I:C) doses. C_LIO_LIActivation of TLR3 by Poly(I:C) produced sex-specific time course responses of pro-inflammatory cytokines, which may, at least in part, explain sex differences in alcohol consumption. C_LIO_LIOur data suggest that FVB/NJ x C57BL/6J hybrid male mice are a suitable model to study TLR3-dependent escalation of alcohol drinking. C_LI

BackgroundVariation in genes involved in ethanol metabolism has been shown to influence risk for alcohol dependence (AD) including protective loss of function alleles in ethanol metabolizing genes. We therefore hypothesized that people with severe AD would exhibit different patterns of rare functional variation in genes with strong prior evidence for influencing ethanol metabolism and response when compared to genes not meeting these criteria. ObjectiveLeverage a novel case only design and Whole Exome Sequencing (WES) of severe AD cases from the island of Ireland to quantify differences in functional variation between genes associated with ethanol metabolism and/or response and their matched control genes. MethodsFirst, three sets of ethanol related genes were identified including those a) involved in alcohol metabolism in humans b) showing altered expression in mouse brain after alcohol exposure, and altering ethanol behavioral responses in invertebrate models. These genes of interest (GOI) sets were matched to control gene sets using multivariate hierarchical clustering of gene-level summary features from gnomAD. Using WES data from 190 individuals with severe AD, GOI were compared to matched control genes using logistic regression to detect aggregate differences in abundance of loss of function, missense, and synonymous variants, respectively. ResultsThree non-independent sets of 10, 117, and 359 genes were queried against control gene sets of 139, 1522, and 3360 matched genes, respectively. Significant differences were not detected in the number of functional variants in the primary set of ethanol-metabolizing genes. In both the mouse expression and invertebrate sets, we observed an increased number of synonymous variants in GOI over matched control genes. Post-hoc simulations showed the estimated effects sizes observed are unlikely to be under-estimated. ConclusionThe proposed method demonstrates a computationally viable and statistically appropriate approach for genetic analysis of case-only data for hypothesized gene sets supported by empirical evidence.

BackgroundDopamine and serotonin are key regulators of reward sensitivity, yet their distinct roles in motivating natural (e.g., sucrose) versus drug (e.g., ethanol) rewards remain unclear. Understanding these mechanisms could help explain individual variability in reward processing relevant to substance use vulnerability. MethodsWe assessed reward sensitivity in dopamine transporter (DAT) and serotonin transporter (SERT) knockout (KO) rats using both home cage (two-bottle choice for sucrose and ethanol) and operant paradigms (Pavlovian and instrumental learning). ResultsDAT KO rats showed lower sucrose preference (-27% for 2%, -13% for 4%) and intake (-42% for 4%), diminished Pavlovian responding for sucrose (-68%), and slower acquisition of sucrose-taking behavior ([~]+30 days) compared to WT rats. DAT KO rats also showed reduced ethanol preference in the home cage (-16%) despite an unchanged intake. Furthermore, operant performed was markedly reduced operant performance after the sucrose-to-ethanol transition (-83%), with no increase in ethanol-taking following sucrose exposure (0% change), unlike WT controls (+41%). SERT KO rats presented reduced sucrose preference (-5%) and intake (-46%) for the 4% solution only. In addition, SERT KO rats also showed reduced Pavlovian sucrose responding (- 28%) and slower acquisition of sucrose-taking ([~]+30 days) but intact responding and learning for ethanol. In the home cage, they displayed lower ethanol preference (-35%) without significant change in operant ethanol performance. A modest overall increase in ethanol-taking was seen post-sucrose in both SERT KO and WT, but without genotype-specific effects. Conclusion and ImplicationsDAT deletion broadly impaired sensitivity for both natural sucrose and ethanol rewards, particularly under effortful or devalued conditions. In contrast, SERT deletion produced more selective impairments by disrupting sucrose operant responding and moderately reducing ethanol reward preference. These findings reveal distinct but overlapping roles of DAT and SERT in regulating reward sensitivity, with implications for understanding individual vulnerability to substance use.

Both prenatal alcohol exposure (PAE) and adolescent alcohol exposure (AAE) persistently impair executive function in humans and animal models. Executive function encompasses multiple interrelated domains including working memory, inhibitory control, and behavioral flexibility. We hypothesized that a developmental "double hit" of PAE and AAE would produce more severe behavioral deficits associated with these executive domains compared to alcohol-naive and single-exposed animals. We tested this hypothesis in rats by assessing disinhibition (low-light elevated plus maze; LL-EPM), behavioral flexibility (attentional set shift test; ASST), and working memory (spontaneous alternations in a T-maze); we also tested behavioral flexibility (ASST) in mice. Pregnant Sprague Dawley rats received water or 5 g/kg alcohol from gestational day (GD)13.5-GD20.5, and offspring received water or 5 g/kg alcohol on a 2-day-on, 2-day-off paradigm from postnatal day (PD)25 to PD54. Pregnant C57BL/6J mice received water or 4.5 g/kg alcohol from GD13.5-GD17.5, and offspring received water or 4.5 g/kg alcohol on a 2-day-on, 2-day-off paradigm from PD25 to PD42. Offspring underwent behavioral testing in young adulthood. Double hit rats showed more exploration in the LL-EPM than controls and fewer alternations in the T-maze than AAE-only rats, suggesting deficits in disinhibition and spatial working memory, respectively. Double hit rats and mice exhibited more errors and/or more trials to criterion in the ASST, indicative of decreased behavioral flexibility. Overall, double hit animals showed altered performance on tests related to executive function, suggesting that the combined exposure alters executive function in a manner distinct from single-exposure models.

Any increase in alcohol use is associated with an increase in risk of illness and mortality and consequences of chronic alcohol use include cancer, hypertension, heart and liver disease, and Alcohol Use Disorder. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective anti-glycemic and weight-loss medications with a strong safety record. There is substantial preclinical evidence and mounting retrospective and prospective randomized controlled trial evidence that GLP-1RAs could be effective for reducing alcohol consumption. However, the mechanism by which GLP-1RAs reduce alcohol intake remains unclear. While medications that reduce alcohol intake such as naltrexone and acamprosate have central nervous system action, disulfiram reduces alcohol intake through peripheral mechanisms. Here, we test whether GLP- 1RAs alter alcohols peripheral pharmacokinetics as a potential mechanism of action for their alcohol intake suppressive effects. In this pilot study, twenty participants with obesity in the GLP-1RA or control group consumed a challenge dose of alcohol, and we measured breath alcohol (BrAC) and the subjective effects of alcohol. We observed a delayed rise in BrAC and subjective effects in the GLP-1RA group as compared to controls, that was not explained by nausea. These data provide preliminary evidence that GLP-1RAs could act through peripheral mechanisms to suppress alcohol intake.

Binge drinking (BD) during emerging adulthood increases the risk of developing alcohol use disorders, yet not all individuals follow this trajectory. Deficits in emotion regulation has been identified as a risk factor for psychopathology, but its specific role in shaping long-term alcohol severity among young binge drinkers remains insufficiently understood. This study investigates the role of emotion regulation difficulties as a mediator in the relationship between binge BD and future alcohol severity in young people and the moderator role of emerging psychopathological symptoms. We followed a cohort of 192 university students (53% female) over two years, from ages 18 to 20 We measured alcohol consumption and emotion regulation (Difficulties in Emotion Regulation Scale), as well as psychopathological symptoms (Brief Symptom Inventory). Mediation and moderated mediation models were conducted with PROCESS. Results show that BD predicts future alcohol severity, with emotion regulation difficulties, specifically challenges in goal-directed behaviour, partially mediating this relationship. Psychopathological symptoms moderated the effects, with difficulties in emotion regulation being a significant predictor of future alcohol severity only in individuals with emerging psychopathological symptoms. Additionally, the association between BD and future alcohol severity was amplified in those with emerging psychopathological symptoms. These findings offer new insights into the risk factors underlying the escalation of problematic alcohol use and the interplay between BD, emotion regulation, and psychopathology. They also stress the importance of early interventions focused on enhancing emotion regulation abilities in young binge drinkers, especially those displaying early psychopathological symptoms.

AimsTo estimate polygenic and polygene x environment contributions to alcohol consumption and problems in the context of childhood maltreatment and lifetime trauma. DesignMain and interaction effects models predicting alcohol consumption and problems were estimated using multiple linear regression. Covariates included age, sex, education, employment status, and ancestral principal components. SettingUSA ParticipantsA sample of 2,114 Black adults (75% female; Mage=39.88, SD=13.92) recruited from the Grady Trauma Hospital in Atlanta, Georgia. MeasurementPolygenic scores (PGS) for trauma-related symptoms (re-experiencing: PGSREEX, avoidance: PGSAVOID, hyperarousal: PGSHYPER, PTSD symptom score: PGSPCL) and alcohol consumption (PGSAUDIT-C) and use disorder (AUD; PGSAUD) were derived using genome-wide association Million Veterans Program summary statistics with PRS-CS. FindingsChildhood maltreatment and lifetime trauma (excluding childhood abuse) were positively associated with alcohol consumption (AUDIT-C) ({beta}childhood-maltreatment=0.17, SE=0.02; {beta}lifetime-trauma=0.28, SE=0.02) and alcohol problems (AUDIT-P) ({beta}childhood-maltreatment=0.25, SE=0.02; {beta}lifetime-trauma=0.27, SE=0.02). None of the PGSs were associated with AUDIT-C, but both the PGSs for re-experiencing ({beta}=0.1, SE=0.03) and avoidance ({beta}=0.08, SE=0.03) were positively associated with AUDIT-P. Experiencing lifetime trauma and being at elevated genetic risk for AUD (interaction-{beta}Trauma_x_PGSAUD=0.17, SE=0.05) and hyperarousal (interaction-{beta}TraumaxPGSHYPER=0.11, SE=0.06) were associated with higher AUDIT-P scores; while more lifetime trauma and higher genetic risk for AUD were associated with higher AUDIT-C scores (interaction-{beta}Trauma_x_PGSAUD=0.12, SE=0.05). ConclusionsIndividuals with elevated genetic risk for AUD are more likely to consume alcohol and to develop worse alcohol problems in the context of lifetime trauma. Interventions focused on also minimizing the effects of trauma-exposure would be particularly beneficial among individuals at risk for AUD.

Alcohol use disorder (AUD) is known to have a significant genetic component, yet there remains a substantial gap between its heritability and findings from genome-wide association studies. One potential factor contributing to this gap may be genetic interactions, or epistasis, a largely unexplored aspect in the context of AUD. The aim of this study was to investigate the role of epistasis in AUD susceptibility and severity among American Indians, a population that exhibits the highest rates of AUD among all ethnic groups in the U.S. We began by identifying genes previously linked to alcohol dependence and AUD, then expanded this gene set through biological networks, ultimately comprising 3,736 genes and regulatory elements. The final gene set was mapped to over 476K variants in an American Indian cohort of 742 individuals. We performed a pairwise genetic interaction association analysis on the variant set, followed by a bi-clustering procedure to group the interacting SNP pairs into interacting intervals. A total of 114 interacting pairs of genes and regulatory elements were identified to be significantly associated with AUD severity. These genes were enriched for immune system, cell adhesion, neuronal, and disease pathways. Their expressions were particularly enriched in midbrain GABAergic neurons. Our study represents the first large-scale genetic interaction study of AUD in any population. Our findings suggest that epistasis may significantly contribute to the development and progression of AUD.