AlcoholPub Date : 2025-10-04DOI: 10.1016/j.alcohol.2025.10.001
Rachel Schorn , Maureen Riedl , Laura S. Stone , Anna M. Lee , Lucy Vulchanova
{"title":"Chronic alcohol drinking delays recovery from capsaicin- and nerve injury-induced hypersensitivity in mice","authors":"Rachel Schorn , Maureen Riedl , Laura S. Stone , Anna M. Lee , Lucy Vulchanova","doi":"10.1016/j.alcohol.2025.10.001","DOIUrl":"10.1016/j.alcohol.2025.10.001","url":null,"abstract":"<div><div>Chronic pain and alcohol use disorder (AUD) are major health concerns that significantly impair quality of life. Persistent pain is common in individuals with alcohol dependence, and alcohol is commonly used by chronic pain patients for self-medication. The neural mechanisms linking these conditions remain unclear. We hypothesized that chronic alcohol exposure induces hypersensitivity in multiple modalities and increases the duration of recovery in acute and persistent pain models. Using the two-bottle free-choice alcohol consumption paradigm in adult mice, alcohol-induced hypersensitivity (AIH), indicated by reduced mechanical withdrawal thresholds, developed after 4–6 weeks of alcohol consumption compared to age- and sex-matched water-consuming controls. Alcohol-consuming female mice, but not male mice, developed cold hypersensitivity after AIH emerged. To assess the impact of chronic alcohol consumption on acute and persistent pain, we used intraplantar capsaicin and sciatic nerve crush models, respectively. In the capsaicin model, water-treated, but not alcohol-treated, mice recovered from hypersensitivity by 24 h post-injection. In the sciatic nerve crush model, alcohol-consuming mice exhibited slower recovery of mechanical withdrawal thresholds compared to water-consuming controls. While mechanical hypersensitivity in water-consuming mice returned to pre-surgical thresholds by 3–4 weeks post-surgery, recovery in alcohol-consuming mice was both delayed and partial. Surgical intervention did not impact alcohol intake. Overall, our results suggest that chronic voluntary alcohol consumption facilitates the transition to chronic pain by prolonging hypersensitivity and delaying recovery from injuries.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"129 ","pages":"Pages 123-133"},"PeriodicalIF":2.9,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
AlcoholPub Date : 2025-10-03DOI: 10.1016/j.alcohol.2025.10.002
Gleice Kelli Silva-Cardoso, Prosper N'Gouemo
{"title":"Intermittent short- and long-term alcohol exposures influence alcohol consumption, anxiety-like behaviors, and seizure onset in genetically epilepsy-prone rats","authors":"Gleice Kelli Silva-Cardoso, Prosper N'Gouemo","doi":"10.1016/j.alcohol.2025.10.002","DOIUrl":"10.1016/j.alcohol.2025.10.002","url":null,"abstract":"<div><div>The genetically epilepsy-prone rats (GEPR-3s) are known for their hereditary susceptibility to seizures and anxiety. This study investigates the impact of short-term (1 week) and long-term (4 weeks) intermittent alcohol exposure through a two-bottle choice paradigm on voluntary alcohol intake, anxiety-like behaviors, and acoustically evoked seizure susceptibility in the GEPR-3s. Anxiety behaviors were assessed 24 h post alcohol exposure using the light-dark box (LDB), open field (OFT), and elevated plus maze (EPM), alongside evaluations of seizure susceptibility. The results indicated that after 1 week of alcohol exposure, female GEPR-3s had higher alcohol intake and preference than males, while males increased their intake and preference after 4 weeks. Furthermore, females GEPR-3s exhibited anxiolytic effects in all anxiety tests after short-term alcohol exposure. In contrast, males displayed mixed responses, exhibiting anxiogenic effects in both LDB and OFT tests, and increased time in open arms but decreased exploration in the EPM test. Further, short-term alcohol exposure delayed seizure onset across both sexes, suggesting potential anticonvulsant effects. After 4 weeks of alcohol exposure, male GEPR-3s exhibited anxiogenic effects in both LDB and OFT tests, and reduced locomotion in the EPM test. In contrast, female GEPR-3ss showed anxiogenic effects in the LDB test, but anxiolytic effects in the OFT test, with decreased locomotion in the EPM test. Additionally, long-term alcohol exposure decreased seizure latency, indicating proconvulsant effects. These findings highlight the complex, bidirectional, and temporal dynamics between alcohol consumption, anxiety, and inherited predisposition to epilepsy.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"129 ","pages":"Pages 115-122"},"PeriodicalIF":2.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
AlcoholPub Date : 2025-09-25DOI: 10.1016/j.alcohol.2025.09.006
Nabiha Mahmood , Marian L. Logrip
{"title":"Sex differences in the impact of trauma on alcohol self-administration","authors":"Nabiha Mahmood , Marian L. Logrip","doi":"10.1016/j.alcohol.2025.09.006","DOIUrl":"10.1016/j.alcohol.2025.09.006","url":null,"abstract":"<div><div>Challenging encounters can lead to escalated alcohol consumption, as evidenced by individuals grappling with posttraumatic stress disorder (PTSD). However, the precise influence of prior stress experiences, as opposed to acute stressors, on alcohol intake remains incompletely understood. This study sought to simulate the enduring repercussions of trauma using a stress paradigm involving foot shocks presented in an odor-enriched environment. The presence of a scent throughout contextual fear conditioning is more likely to cause stress effects to generalize across various environments, and this paradigm previously reduced working memory performance, one hallmark of PTSD. Male and female Wistar rats were exposed to the stress or control condition (no foot shock), then trained to perform lever presses to obtain alcohol reinforcement. The findings revealed intriguing disparities between the sexes in past stress effects on the acquisition of alcohol self-administration. Specifically, female rats exhibited divergent patterns of alcohol acquisition across days, with the control group showing a swifter acquisition compared to their previously stressed counterparts. This pattern was not observed in males, nor did either sex show differences in relapse-like self-administration after a 5-week abstinence period. Unexpectedly, presentation of the stress session odor cue did not alter alcohol self-administration behavior. Together, these data support heightened sensitivity of females to a trauma-like stressor, although in rats this decreased self-administration, contrary to human data.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"129 ","pages":"Pages 106-114"},"PeriodicalIF":2.9,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
AlcoholPub Date : 2025-09-20DOI: 10.1016/j.alcohol.2025.09.005
Roman A. Zegarelli, Anna K. Radke
{"title":"Contributions of testosterone to excessive alcohol drinking in males: Potential role for interactions with the HPA axis","authors":"Roman A. Zegarelli, Anna K. Radke","doi":"10.1016/j.alcohol.2025.09.005","DOIUrl":"10.1016/j.alcohol.2025.09.005","url":null,"abstract":"<div><div>Excessive alcohol drinking and alcohol use disorders (AUDs) are a significant and increasing public health concern in the United States and worldwide, with men historically having higher rates of alcohol consumption and AUD diagnoses. Despite this, the biological mechanisms underlying sex differences in these outcomes are not fully understood. Endocrine systems are critical regulators of behavior and testosterone has a bidirectional relationship with alcohol in males. Baseline levels of testosterone (T) may bias males toward approach behaviors that increase the tendency to engage in risky drinking behaviors in adolescent and adult men. At the same time, T appears to protect males (particularly rodents) against elevated levels of initial alcohol consumption. T levels also change with alcohol exposure, decreasing with acute and chronic use. This review synthesizes findings from both human and animal studies, highlighting how interactions between the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes may underlie male-specific patterns of alcohol use and risk for AUD. Understanding these mechanisms is essential for preclinical and clinical researchers conducting research in males and for the development of more effective interventions for AUD in men.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"129 ","pages":"Pages 92-105"},"PeriodicalIF":2.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Molecular mechanism underlying alcohol's residual effects: The role of acetaldehyde in mitochondrial dysfunction at synapses in mouse brain cortex","authors":"Analía G. Karadayian , Lautaro Carrere , Analia Czerniczyniec , Silvia Lores-Arnaiz","doi":"10.1016/j.alcohol.2025.09.004","DOIUrl":"10.1016/j.alcohol.2025.09.004","url":null,"abstract":"<div><div>Alcohol residual effects impose significant physiological and cognitive burdens due to acute ethanol exposure; however, its underlying mechanisms remain poorly understood. This study investigates the role of acetaldehyde, the main ethanol metabolite, in driving mitochondrial dysfunction and synaptic impairment during hangover onset. Using a mice model, we evaluated the effects of ethanol (3.8 g/kg) and the alcohol dehydrogenase inhibitor 4-methylpyrazole (4-MP) on brain cortex synaptosomes.</div><div>Ethanol exposure significantly elevated serum acetaldehyde compared with control (p < 0.05), and induced mitochondrial dysfunction, as evidenced by impaired respiration (30 % decrease in basal O<sub>2</sub> uptake vs. control), mitochondrial membrane depolarization and reduced ATP production (50 % decrease vs. control). These effects were mitigated by pre-treatment with 4-MP, which normalized acetaldehyde levels and partially restored mitochondrial function. Notably, ethanol downregulated synaptic proteins (nNOS, GluN2B, PSD-95; p < 0.05), but 4-MP failed to prevent this reduction, suggesting that acetaldehyde would not be involved in synaptic proteins alterations. Further, ethanol disrupted calcium homeostasis and nitric oxide (NO) content. Interestingly, 4-MP alone also reduced calcium uptake and NO content (p < 0.05), indicating potential off-target effects on neuronal signaling.</div><div>While the reduction in acetaldehyde levels preserved mitochondrial integrity, its inability to rescue synaptic protein loss highlights the complexity of hangover pathology, involving both acetaldehyde-dependent and -independent mechanisms. Our findings underscore acetaldehyde's pivotal role in hangover-associated mitochondrial dysfunction but reveal divergent pathways in synaptic impairment. These insights advance the search for targeted hangover therapies by delineating acetaldehyde-dependent toxicity.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"129 ","pages":"Pages 79-91"},"PeriodicalIF":2.9,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
AlcoholPub Date : 2025-09-17DOI: 10.1016/j.alcohol.2025.09.003
Mitchell A. Nothem, Christine M. Side, Simon C. Tran, Anaahat Brar, Lauren A. Buck, Jacqueline M. Barker
{"title":"Chronic pain increases sensitivity to pain-induced reinstatement of ethanol seeking in male mice","authors":"Mitchell A. Nothem, Christine M. Side, Simon C. Tran, Anaahat Brar, Lauren A. Buck, Jacqueline M. Barker","doi":"10.1016/j.alcohol.2025.09.003","DOIUrl":"10.1016/j.alcohol.2025.09.003","url":null,"abstract":"<div><div>Alcohol use disorder (AUD) and chronic pain are complex and debilitating conditions that are highly comorbid. Greater than 50 % of individuals with AUD have chronic pain. Clinical data suggest that people with chronic pain are more likely to report using alcohol to manage chronic pain, and that magnitude of pain is correlated with relapse probability after a period of abstinence. These data led to the hypothesis that pain can drive ethanol seeking and reinstatement in a rodent model of chronic neuropathic pain. A conditioned place preference (CPP) paradigm was used to model ethanol seeking in male C57BL6J mice with a spared nerve injury (SNI). Mice were conditioned with doses of ethanol previously found to reverse pain behavior (0.5 g/kg). Mice with and without SNI showed similar magnitudes of ethanol CPP and rates of extinction. To investigate pain-induced relapse-related behavior, mice underwent reinstatement testing following painful mechanical stimulation which was delivered at either a “moderate” or “high” intensity immediately prior to return to the CPP apparatus. “Moderate” painful hindpaw stimulation reinstated ethanol seeking behavior in SNI-injured, but not sham, mice, while “high” intensity stimulation reinstated ethanol seeking in mice regardless of injury status. These data suggest that males in chronic pain are more susceptible reinstatement of ethanol seeking following a painful experience.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"129 ","pages":"Pages 69-78"},"PeriodicalIF":2.9,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
AlcoholPub Date : 2025-09-10DOI: 10.1016/j.alcohol.2025.09.001
Alexander James Feller , Louis John Kolling , Tien Tran , Shafa Ismail , Jessica Marie Hunter Alberhasky , Samuel Cole Luciano , Catherine Anne Marcinkiewcz
{"title":"Impact of adolescent ethanol binge on serotonin signaling and pain sensitivity post-withdrawal","authors":"Alexander James Feller , Louis John Kolling , Tien Tran , Shafa Ismail , Jessica Marie Hunter Alberhasky , Samuel Cole Luciano , Catherine Anne Marcinkiewcz","doi":"10.1016/j.alcohol.2025.09.001","DOIUrl":"10.1016/j.alcohol.2025.09.001","url":null,"abstract":"<div><div>Adolescence is a critical neurodevelopmental period characterized by heightened neuroplasticity. While the acute effects of binge ethanol (EtOH) consumption are documented, its long-term impact on both pain sensitivity and microglial activation during adolescence remains unclear. Given serotonin's (5-HT) known involvement in pain processing and sensitivity to EtOH, this study examined the effects of adolescent EtOH binge on microglia-induced neuroinflammation in serotonergic nuclei, downstream 5-HT signaling, and pain sensitivity at different time points after EtOH withdrawal. Adolescent male C57BL/6J mice received triweekly oral gavage of 20 % EtOH or water for 4 weeks and were assessed after 24 h and 3 weeks post-withdrawal. We used immunohistochemistry to assess neuroinflammation in the dorsal raphe, median raphe, and raphe magnus by labeling 5-HT, CD68, and P2Y12. Further analyses examined downstream signaling via 5-HT and serotonin transporter (SERT) expression in the nucleus accumbens, anterior cingulate cortex, thalamus, amygdala, hypothalamus, and raphe magnus. Pain sensitivity was then assessed using the Hargreaves test. EtOH exposure led to widespread serotonergic and neuroinflammatory changes. Significant increases in microglia-induced neuroinflammation were observed in the dorsal raphe nucleus, median raphe nucleus, and raphe magnus nucleus after both 24 h and 3 weeks post-withdrawal, along with significant deficits in 5-HT. Similar 5-HT deficits were observed in downstream regions—notably in the anterior cingulate cortex, thalamus, amygdala, and hypothalamus—at varying time points post-withdrawal. EtOH-exposed mice also showed lasting hyperalgesia at both 24 h and 3 weeks post-withdrawal that persisted for up to 9 weeks. These results suggest that persistent hyperalgesia following adolescent EtOH binge may be driven by changes in serotonergic function and microglial activation.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"129 ","pages":"Pages 58-68"},"PeriodicalIF":2.9,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
AlcoholPub Date : 2025-09-04DOI: 10.1016/j.alcohol.2025.09.002
Emma J. Tussey, Maria M. Wong
{"title":"Bidirectional relationships between daily sleep and alcohol use","authors":"Emma J. Tussey, Maria M. Wong","doi":"10.1016/j.alcohol.2025.09.002","DOIUrl":"10.1016/j.alcohol.2025.09.002","url":null,"abstract":"<div><h3>Background</h3><div>Prior longitudinal studies demonstrate that sleep disturbance is a risk factor for alcohol misuse. Experimental research also shows that alcohol intake negatively impacts sleep. The present study evaluated temporal bidirectional relationships between sleep and alcohol intake using intensive longitudinal methods.</div></div><div><h3>Methods</h3><div>57 college students (71 % female, Mage 24.1) participated in a two-week study assessing their daily sleep and alcohol use. Participants wore an actiwatch and completed daily diaries about their sleep and alcohol intake. Multi-level zero-inflated negative binomial models assessed whether prior sleep predicted next-day alcohol use. Linear multi-level models assessed whether alcohol use predicted daily sleep. All models assessed both within- (daily) and between-subject (average) effects because daily variations in sleep could influence alcohol use separately from average patterns and vice versa. Race, age, and sex were controlled in the analyses.</div></div><div><h3>Results</h3><div>Greater average wake after sleep onset (WASO) and sleep onset latency (SOL) and shorter daily total sleep time (TST) predicted greater next-day alcohol intake (WASO IR: 1.009; SOL IR: 1.011; TST IR: 0.998; p < .05). Higher average alcohol intake predicted increased daily WASO (B = 8.944, SE = 4.551, p < .05), TST (B = 12.717, SE = 5.877, p < .05), and decreased daily restedness (B = −0.158, SE = 0.064, p < .05).</div></div><div><h3>Conclusions</h3><div>These results highlight a dynamic bidirectional relationship between sleep and alcohol use. Findings suggest that average sleep and alcohol use patterns may be more meaningful to target than a single instance of poor sleep or excessive alcohol use.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"129 ","pages":"Pages 50-57"},"PeriodicalIF":2.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
AlcoholPub Date : 2025-09-02DOI: 10.1016/j.alcohol.2025.08.005
Yuyang Dong, Matthew W. Buczynski, Ann M. Gregus
{"title":"Alcohol use disorder-associated pain: clinical and preclinical evidence","authors":"Yuyang Dong, Matthew W. Buczynski, Ann M. Gregus","doi":"10.1016/j.alcohol.2025.08.005","DOIUrl":"10.1016/j.alcohol.2025.08.005","url":null,"abstract":"<div><div>Alcohol Use Disorder (AUD) affects millions of people globally and is characterized by cycles of intoxication, withdrawal, and relapse. Convergent clinical and preclinical evidence strongly support the conclusion that AUD precipitates chronic pain marked by mechanical and thermal hypersensitivity, yet currently available FDA-approved therapeutics do not effectively manage AUD-associated pain. This review synthesizes clinical and preclinical evidence on AUD-associated pain, highlighting known phenomena of allodynia and hyperalgesia as well as small and/or large fiber neuropathy in patient subpopulations along with preclinical acute and chronic alcohol exposure paradigm-specific nociceptive phenotypes in rodents. Herein, we provide detailed descriptions and interpretations of outcome measures for different sensory modalities typically utilized in clinical and/or preclinical studies of nociception. We examine how these endpoints vary in rodent models according to the type of alcohol exposure paradigm with regard to route of administration, chronicity, and contingency (forced, voluntary, or combined). Finally, we summarize the prominent molecular mechanisms that have been proposed to mediate alcohol withdrawal-induced pain-like behaviors. While major advances have been made in treatment of AUD, critical gaps in understanding of human pain phenotypes due to lack of quantitative endpoints in clinical trials impede further advancement in refining preclinical models to recapitulate these features. Patient phenotype-driven preclinical models will increase cross-species translational potential for interrogating mechanistic underpinnings and thereby inform future drug discovery campaigns for treatment of AUD-associated pain.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"129 ","pages":"Pages 14-40"},"PeriodicalIF":2.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144989833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}