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

Despite 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. A biphasic sipper model developed by Hank Samson's laboratory addressed 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 this methodology which investigated the behavioral and neurobiological mechanisms underlying alcohol use. We emphasize how over two decades of research employing this approach have demonstrated that ethanol-directed behaviors are dynamic processes, shaped by internal states, environmental cues, and prior experience. Finally, we introduce an open-source analytical framework in the R programming language designed to standardize the analysis of high-resolution temporal data generated by the biphasic sipper paradigm. 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.

Background: Despite potentially harmful consequences, people routinely encounter alcohol adverts designed to increase consumption of alcohol in preference to safer alternatives. However, individuals differ in the degree to which such adverts elicit preferential alcohol consumption. This study builds upon and extends prior research by testing hypotheses concerning the impact of biased processing during advert viewing on subsequent alcohol craving and consumption.

Method: Sixty-eight undergraduate students viewed beer and soft drink adverts. In some viewing blocks, beer and soft drink adverts played simultaneously to assess participants' attentional bias to beer adverts. In others, participants were asked to choose which type of advert to view, which assessed bias in volitional viewing choice. Participants subsequently rated their craving for beer before completing a taste test designed to yield a behavioral measure of preferential beer consumption.

Results: Attentional bias to alcohol adverts predicted beer craving and preferential beer consumption. The association between attentional bias and preferential beer consumption was mediated by beer craving. An equivalent pattern of prediction was observed when using the viewing choice bias measure as the predictor. Importantly, when variation in either bias measure was statistically controlled for, the other continued to predict preferential beer consumption in a manner that was mediated by beer craving.

Conclusions: Two types of processing bias during advert viewing-viewing preference and attentional bias-were independently associated with subsequent preferential alcohol consumption. In both cases, these associations were accounted for by alcohol craving. The theoretical and applied implications of this are discussed.

Background: Alcohol use disorder (AUD) lacks objective clinical tests; current screening (AUDIT) relies on self-report and can miss risk. Building on our recent whole-blood analysis, where immune dysregulation, particularly IL-1β, predicted AUD risk, we tested whether Toll-like receptor (TLR) stimulation would further unmask risk-related immune signatures.

Methods: Whole blood from 28 young adults (Low-risk: AUDIT <6; High-risk: AUDIT ≥6) was stimulated in culture with lipopolysaccharide (LPS, TLR4) or imiquimod (IMQ, TLR7). Fourteen immune mediators were quantified using Luminex multiplex assays. Group and stimulus effects were tested with aligned rank transform (ART) factorial models; principal component analysis (PCA) summarized the multivariate structure. Predictive associations with AUDIT were assessed via linear regression and Random Forest analyses.

Results: IL-1β, IL-3, IL-6, IL-7, IL-8, IL-18, CCL11, MCP-1, and MIP-1β were elevated in the high-risk group following stimulation. LPS evoked stronger responses than IMQ for IL-1β, IL-6, IL-8, and MIP-1β, whereas MCP-1 was higher with IMQ. PCA distinguished high- from low-risk groups, driven by CCL11, MCP-1, IL-7, IL-3, IL-6, IL-18, MIP-1β, and IL-1β. LPS-evoked IL-1β, IL-3, and CCL11 predicted AUDIT scores (adjusted R² = 0.22-0.37). IMQ-evoked CCL11, IL-18, MIP-1β, IL-1β, and IL-6 were also significant predictors (adjusted R² = 0.16-0.29). After outlier filtering, LPS associations persist, and IMQ-evoked CCL11 and IL-18 remain. Random Forests predicted AUDIT with R² = 0.33 (LPS) and R² = 0.27 (IMQ), with top features IL-3, IL-18, IL-1β, CCL11 (LPS) and IL-6, IL-18, CCL11, IL-1β (IMQ).

Conclusions: LPS and IMQ stimulations unmasked immune response patterns that separated high- from low-risk individuals, with exaggerated pro-inflammatory responses in the high-risk group. IL-1β, IL-3, IL-18, and CCL11 repeatedly predicted AUDIT scores, with IL-1β and IL-3 LPS-dominant and CCL11 and IL-18 LPS/IMQ stimulus-shared. Stimulation-evoked mediator profiling may complement self-report screening and improve risk stratification in drinkers. Further studies are needed to address the exploratory nature of the results.