Alcohol use disorder (AUD) is a leading contributor to global morbidity and mortality, yet current treatments remain underutilized and only partially effective. Although AUD has traditionally been conceptualized as a brain-centered disorder, emerging evidence supports an integrative framework in which peripheral physiological signals influence central neural circuits that regulate motivation, affect, and reinforcement. This review examines the effects of alcohol on the gut-vagal-brain axis and evaluates the role of vagal signaling in the development and maintenance of AUD. Chronic alcohol exposure disrupts intestinal barrier integrity, alters microbiome composition, and promotes systemic inflammation, generating inflammatory and metabolic signals that can engage vagal sensory pathways. However, the direct effects of these alcohol-associated peripheral adaptations on vagal signaling and downstream CNS circuits in AUD remain incompletely defined. Preclinical studies demonstrate that surgical and pharmacological manipulation of vagal signaling alters alcohol intake, relapse-like behavior, and stress responsivity, supporting a functional role for vagal pathways in alcohol-related behaviors. Clinical studies similarly report reduced vagal tone and autonomic imbalance in individuals with AUD, suggesting translational relevance. Emerging neuromodulatory approaches, including invasive and transcutaneous vagus nerve stimulation (VNS), show promise for reducing craving and improving affective symptoms; however, current evidence remains limited. In this review, we synthesize current evidence examining how chronic alcohol exposure may disrupt gut-vagal-brain communication and discuss the potential contribution of these changes to alcohol use disorder. We identify potential mechanistic pathways and knowledge gaps, and highlight the need for more circuit-specific and longitudinal studies to evaluate vagal pathways as therapeutic targets for AUD.

Protein kinase A (PKA) phosphorylation of GABAA receptor β3 subunits is a mechanism by which the PDE4 inhibitor apremilast prolongs recovery from ethanol intoxication, prevents acute tolerance, and reduces drinking in mice. In contrast, PKA phosphorylation of GABAA β1 subunits is not required for apremilast's effects on tolerance and drinking. Based on these findings, we hypothesized that directly activating β3-containing GABAA receptors would produce ethanol phenotypes similar to apremilast treatment. While no known compounds selectively activate β3-containing GABAA receptors, positive allosteric modulators selective for β2/β3-over β1-subunit containing receptors do exist. We tested four such modulators (loreclezole, etifoxine, topiramate, and compound 2-261) on voluntary ethanol drinking and related behaviors in mice. Like apremilast, all four compounds dose-dependently prolonged recovery from ethanol-induced ataxia, prevented the development of acute tolerance, and reduced two-bottle choice ethanol consumption without altering blood ethanol clearance. Thus, both indirect activation of β3-containing GABAA receptors by apremilast and direct activation by positive allosteric modulators with selectivity for β2/β3-containing receptors reduce ethanol drinking while preventing acute tolerance.

Prenatal ethanol exposure (PEE) alters neurobehavioral function, yet the factors associated with these effects, particularly in interaction with stress, remain poorly understood. We examined whether combined exposure to PEE and adolescent restraint stress altered compulsive-like behavior and, in the sex showing the clearest combined effects, assessed gut microbiota composition and neuroimmune-related gene expression. Male and female Wistar rats exposed to ethanol on gestational days 17-20 were subjected to restraint stress (RES) or control conditions during adolescence. Behavioral assessments included the open field, light-dark box, marble burying, and perseverance tasks. Gut microbiota composition was analyzed using 16S rRNA sequencing, and central gene expression of inflammatory and neuromodulatory markers was measured. Behavioral effects were sex-dependent. In males, the combined PEE+RES condition produced a compulsive-perseverative phenotype, reflected by increased marble burying and reduced return latency to a specific object. In females, increased marble burying was observed after PEE alone. Microbiota analyses, conducted in males only due to them exhibiting the greatest joint effects of the PEE+RES exposure, revealed no significant differences in overall beta diversity, but identified several taxon-specific reductions. These reductions, which were most pronounced under combined PEE+RES exposure, involved members of the Lactobacillaceae, Muribaculaceae, Christensenellaceae, and Lachnospiraceae families, as well as the genera Butyricicoccus and Intestinimonas. PEE and RES were associated with region- and marker-specific alterations in Tnf and Oxtr gene expression. The findings suggest the involvement of the microbiota-gut-brain axis in the effects of PEE, with RES potentially exacerbating this vulnerability.

Alcohol use occurs in both men and women, yet preclinical alcohol research has historically focused on male rodents. Adolescent stress is a known risk factor for later alcohol misuse, but how stress history interacts with sex to influence intake remains unclear. To address this, we examined whether repeated adolescent restraint stress alters voluntary ethanol consumption in male and female BALB/cJ and C57BL/6J mice. Mice underwent 14 days of 2-h daily restraint beginning on postnatal day (PND) 37, followed by 4 weeks of binge-like ethanol drinking using the Drinking-in-the-Dark protocol starting on PND 53. Body weight and fecal corticosterone were measured to assess physiological adaptation and hypothalamic-pituitary-adrenal axis activity. Adolescent stress increased ethanol consumption in both strains, but with distinct temporal patterns. C57BL/6J mice showed a transient increase during the second week of drinking, whereas male BALB/cJ mice showed increased consumption during the fourth week. Stress delayed body weight gain in both strains, but recovery differed by strain and sex. Female C57BL/6J mice recovered by the final days of stress, whereas male and female BALB/cJ mice recovered within 2 weeks after stress ended. In contrast, male C57BL/6J mice did not recover. One week after stress cessation, fecal corticosterone remained elevated in stressed BALB/cJ mice, but not in C57BL/6J mice. These findings demonstrate that sex and genetic background shape physiological recovery from adolescent stress and subsequent ethanol consumption.

Literature suggests that there may be overlap between proneness to overeating-induced obesity and excessive alcohol drinking, and that this may occur in part via the endogenous opioid system in the nucleus accumbens (NAc). To investigate this, we used rats selectively bred for their susceptibility or resistance to diet-induced obesity (obesity-prone, OP, and obesity-resistant, OR), and examined their (1) ethanol drinking under the intermittent access two-bottle-choice procedure, (2) sucrose drinking under the intermittent access two-bottle-choice procedure, and (3) enkephalin, dynorphin, and opioid receptor mRNA in the NAc core and NAc shell. While we found no major differences in measures of sucrose drinking, male OP compared to OR rats had higher levels of 24-h ethanol drinking and preference, while female OP compared to OR rats had higher levels of binge-like (30-min) ethanol drinking and corresponding blood ethanol concentrations. In parallel, both male and female OP compared to OR rats had higher expression of enkephalin but not dynorphin mRNA in the NAc core, and males had higher expression of mRNAs encoding mu, delta, and kappa opioid receptors in the NAc core. Together, these results show that proneness to obesity is associated with excessive ethanol drinking prior to the onset of obesity. Further, they suggest that this could be driven in part through differences in the NAc endogenous opioid system, particularly for males and via the NAc core. This supports the idea that proneness to excessive alcohol drinking may share neurobehavioral mechanisms with susceptibility to diet-induced obesity.

Chronic ethanol exposure, a key feature of alcohol use disorder (AUD), can affect the nervous system, but its molecular impact on the olfactory bulb remains unclear. In this study, an intermittent two-bottle voluntary drinking model was established in male mice, and transcriptome sequencing was performed on olfactory bulb tissues. DESeq2 analysis identified 188 differentially expressed genes, including 68 upregulated and 120 downregulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathway database (Reactome) analyses indicated that ethanol-responsive genes were predominantly enriched in receptor-mediated signaling pathways, particularly those linked to G protein-coupled receptor (GPCR) signaling. Protein-protein interaction analysis further identified eight core GPCR-related genes. Quantitative real-time PCR (qRT-PCR) validation revealed that Cxcl10, Grp, Pcp2, and Pdyn were markedly downregulated in the ethanol group. These results suggest that chronic ethanol exposure is associated with transcriptional alterations in the male mouse olfactory bulb and may selectively affect several GPCR-related signaling components. This study provides candidate molecular evidence for further investigation of ethanol-associated olfactory dysfunction.

Rodent models of prenatal alcohol exposure are a powerful tool for studying causal factors of prenatal exposure effects. Under the New Mexico Alcohol Research Center, we combined a voluntary drinking-in-the-dark (DID) paradigm with a Volumetric Drinking Monitor (VDM) system to quantify maternal ethanol (EtOH) intake, drinking duration, and drinking patterns throughout gestation and determined whether these variables altered breeding success or early offspring development. Female C57BL/6J mice received daily 2-h access to either 20% EtOH or water using the VDM system. Following a two-week acclimation period, breeding was initiated while daily drinking continued throughout gestation until parturition. Breeding success, litter characteristics, and early growth were evaluated from 176 dam-sire pairings across three breeding cohorts, yielding over 800 offspring for demographic analyses. Maternal EtOH exposure did not affect pregnancy success, litter loss, litter size, pup weight at postnatal day 10, offspring sex distribution, or weaning weight. Average daily gestational EtOH consumption and duration of preconception EtOH exposure did not predict offspring outcomes. Although EtOH-exposed dams consistently exhibited front-loading behavior, neither front-loading status nor front-loading intensity was associated with litter characteristics or early offspring growth. Moderate voluntary maternal EtOH consumption, duration of exposure, or drinking pattern did not drive litter characteristics that may affect the early-life environment (pup number and sex) or early growth markers (P10 and weaning weight). These data indicate that differences in the early postnatal environment are not likely to be responsible for long-term behavioral and neurobiological phenotypes reported in offspring produced using this paradigm.

This study examined the relationships among emotional states (positive and negative), alcohol expectancies, alcohol consumption, and students' subjectively perceived positive drinking experiences as well as subjectively perceived negative alcohol-related consequences among junior college students in Mainland China using a three-wave longitudinal design. Emotional states and alcohol expectancies were assessed at Time 1, alcohol consumption at Time 2, and alcohol-related consequences at Time 3, thereby reducing common method bias and improving temporal inference. The final analytic sample included 4439 participants. Results showed that both positive and negative emotional states, as well as positive alcohol expectancies, were significantly associated with alcohol consumption. Alcohol consumption was also positively related to both perceived short-term positive drinking experiences and harmful alcohol-related outcomes. Structural equation modeling indicated that emotional states and alcohol expectancies significantly predicted alcohol-related outcomes indirectly through alcohol consumption. Importantly, mediation analyses revealed a full mediation pattern, suggesting that psychological factors did not directly influence alcohol-related consequences once drinking behavior was included in the model. Notably, all perceived positive drinking outcomes reported by young student participants are only transient subjective feelings rather than objective benefits of alcohol; interpretations of such perceived rewards among adolescents should be treated with extreme caution, as youth episodic drinking frequently accompanies heightened risks of anxiety, depression and other behavioral problems. These findings indicate that alcohol consumption serves as a key proximal mechanism linking distal psychological antecedents to both subjectively perceived favorable harmful drinking outcomes. The results extend Self-Medication Theory and provide empirical evidence for a self-medication pathway of alcohol use, demonstrating that emotional and cognitive factors operate primarily through drinking behavior rather than exerting direct effects on alcohol-related consequences. Overall, the study highlights the importance of targeting both emotional regulation and alcohol consumption in prevention and intervention efforts among young junior college student populations in China.

In the central nervous system (CNS), microglial cells regulate the immune response by mediating neuroinflammation. Alcohol abuse leads to neuroinflammation and neurodegeneration in CNS. In the context of COVID-19, neuroinflammation and glial reactivity are mediated by the infection of human glial cells by SARS-CoV-2, which recognizes the angiotensin-converting enzyme 2 (ACE2) and other proteins, such as transmembrane serine protease 2 (TMPRSS2), through its surface Spike-1 protein. Although several risk factors for COVID-19 progression have been described, it remains unknown how alcohol consumption affects SARS-CoV-2 Spike protein-induced microglial reactivity. In this study, murine microglial cultures (BV-2) were exposed to ethanol alone and subsequently challenged with the Spike protein. Immunofluorescence analysis revealed that ethanol treatment (1%) did not affect the levels of the reactivity-related proteins C3 and CD86 or the phagocytic potential of microglial cells, although it reduced the number of cells exhibiting an amoeboid morphology. However, ethanol treatment prevented the Spike protein-induced increase in C3 levels, amoeboid cell numbers, and phagocytic activity. Furthermore, chronic in vivo exposure to ethanol decreased ACE2 and TMPRSS2 levels in the cerebral cortex of mice, whereas treatment with higher ethanol concentrations in vitro decreased only TMPRSS2 levels. These data suggest that ethanol exposure suppresses the ability of microglia to respond to the pro-inflammatory effects induced by the Spike protein. This impairment may contribute to the loss of microglial function in regulating the immune response and neuroinflammation in the CNS in the context of COVID-19.

Alcohol intake is known to influence serum high-density lipoprotein cholesterol (HDL-C), yet how drinking patterns shape this association is less researched. We examined whether frequency of drinking versus amount per occasion was differently related to HDL-C in a large population sample. Data were taken from a cross-sectional study of 18,614 respondents aged 40-79 years in the Tromsø general population health study. Alcohol use was assessed by self-report. Fasting HDL-C was measured using standardized laboratory protocols. Mean alcohol intake was 6.7 g/day and mean HDL-C 1.57 mmol/L. Total alcohol consumption correlated positively with HDL-C (r = 0.075; p < 0.001). In regression models, each additional gram/day was associated with an increase of 0.005 mmol/L HDL-C (95% CI 0.004-0.005; p < 0.001). Drinking frequency showed a positive correlation to HDL-C (r = 0.183; p < 0.001), whereas amount per occasion was inversely related to HDL-C (r = -0.128; p < 0.001). A significant frequency × amount interaction indicated that higher amounts per occasion were linked to lower HDL-C primarily among the infrequent drinkers (p < 0.001). The results indicate that the alcohol-HDL-C association was driven by how often alcohol was consumed rather than how much was consumed per occasion. Frequent, lower-dose drinking related to higher HDL-C, whereas infrequent, higher-dose occasions related to lower HDL-C. These findings underscore the need to consider drinking patterns, beyond average intake, when interpreting HDL-C and appraising alcohol-related cardiovascular risk.