AlcoholPub Date : 2025-04-03DOI: 10.1016/j.alcohol.2025.03.005
Kameron T. Bell , Jason M. Hughes , Wesley A. Borman , Ryan D. Stoffel , Scott G. Canfield
{"title":"Alcohol diminishes barrier integrity in human stem cell-derived brain microvascular endothelial cells: Role of reactive oxygen species","authors":"Kameron T. Bell , Jason M. Hughes , Wesley A. Borman , Ryan D. Stoffel , Scott G. Canfield","doi":"10.1016/j.alcohol.2025.03.005","DOIUrl":"10.1016/j.alcohol.2025.03.005","url":null,"abstract":"<div><div>The World Health Organization has linked alcohol consumption to over 200 diseases including neurodegenerative diseases. A dysfunctional blood–brain barrier (BBB) has been found to be influential in a number of brain disorders. The BBB is critical in maintaining homeostasis between the brain vasculature and parenchyma and a loss in barrier integrity would enable otherwise impermeable immune cells, molecules, and inflammatory mediators to reach the brain parenchyma. A subset of studies demonstrated that alcohol could diminish BBB integrity, but it is unclear if this effect translates clinically. In this study, we utilize a human stem cell-derived BBB model with near <em>in vivo</em> properties to investigate the effects of alcohol on critical barrier properties. Barrier forming brain-like microvascular endothelial cells (BMECs) were derived from human induced pluripotent stem cells (iPSCs) and exposed to several alcohol concentrations. Alcohol decreased barrier integrity observed by a loss in trans-endothelial electrical resistance and an increase in sodium fluorescein permeability. Alcohol decreased expression and junctional localization of tight junction proteins, a critical component to barrier integrity. Additionally, alcohol did not affect efflux transporter activity or cell viability in BMECs. The detrimental effects of alcohol on BBB properties were due to in part elevated reactive oxygen species (ROS); as scavenging ROS improved barrier properties, including the restoration of tight junction expression and localization. These data suggest that excessive alcohol consumption could diminish the BBB and contribute to the development or exacerbation of brain disorders.</div></div><div><h3>Clinical trial number and registry URL</h3><div>Not applicable.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"125 ","pages":"Pages 55-66"},"PeriodicalIF":2.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788980","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 : 2025-03-21DOI: 10.1016/j.alcohol.2025.03.001
Tang Yujin , Dai Dandan , Zhong Qian , Pan Wenhao , Di Xingwei
{"title":"Epidemiological and demographic drivers of alcohol-attributable pancreatitis from 1990 to 2021: Findings from the 2021 Global Burden of Disease study","authors":"Tang Yujin , Dai Dandan , Zhong Qian , Pan Wenhao , Di Xingwei","doi":"10.1016/j.alcohol.2025.03.001","DOIUrl":"10.1016/j.alcohol.2025.03.001","url":null,"abstract":"<div><h3>Background</h3><div>Alcohol significantly contributes to pancreatitis, causing high global mortality and health burden. This study examines trends in alcohol-attributable pancreatitis (AAP) from 1990 to 2021 using Global Burden of Disease (GBD) 2021 data, focusing on demographic, temporal, and regional variations to inform policymaking.</div></div><div><h3>Methods</h3><div>AAP-related deaths and disability-adjusted life years (DALYs) were analyzed across 204 countries from 1990 to 2021, stratified by Sociodemographic Index (SDI), gender, and age groups. An age-period-cohort model assessed age-standardized DALY rates (ASDR), and decomposition analysis quantified impacts of population growth, aging, and epidemiological changes.</div></div><div><h3>Results</h3><div>AAP-related DALYs rose from 401,700 in 1990 to 699,300 in 2021, though ASDR and ASMR showed declines globally. Burden increased notably in low and lower-middle SDI regions, especially among those under 40, while high SDI regions achieved better control. Males faced a disproportionately high burden due to alcohol consumption patterns, although some regions saw rising female burdens. Low-SDI areas suffered from limited healthcare, increasing alcohol use, and weak policies, with younger populations contributing significantly to rising burdens. Projections estimate 1.146 million DALYs annually by 2050, with males comprising over 90%. A GBD-AAP visualization platform was developed to present burden data and trends.</div></div><div><h3>Conclusions</h3><div>AAP exhibits significant regional and gender disparities. Targeted measures, including alcohol regulation, resource allocation, and public health education, are critical in low-SDI regions and among young males to mitigate AAP burden. The GBD-AAP platform offers valuable tool for targeted interventions.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"125 ","pages":"Pages 67-78"},"PeriodicalIF":2.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694744","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 : 2025-03-17DOI: 10.1016/j.alcohol.2025.03.003
Maya N. Bluitt , Ana C. Muñoz , Joyce Besheer
{"title":"Individual differences in punished alcohol self-administration are unaltered by alcohol vapor exposure","authors":"Maya N. Bluitt , Ana C. Muñoz , Joyce Besheer","doi":"10.1016/j.alcohol.2025.03.003","DOIUrl":"10.1016/j.alcohol.2025.03.003","url":null,"abstract":"<div><div>Continued alcohol use despite negative consequences is a defining feature of alcohol use disorder (AUD). It remains poorly understood whether individual variability in drinking despite negative consequences is due to inherent differences or emerges after prolonged alcohol use. The goal of the present study was to use a rat model of drinking despite negative consequences to assess individual differences in foot shock-punished alcohol self-administration prior to and following alcohol vapor exposure in male Wistar rats. After baseline operant self-administration was established, rats underwent additional self-administration sessions in which random, response-contingent foot shock punishment was introduced. Average percent change from baseline was calculated for each rat during punished sessions and rats were classified into shock-sensitive (SS) and shock-resistant (SR) subgroups using the top and bottom thirds. Rats then underwent 3 cycles of air or alcohol vapor exposure every other week, with unpunished self-administration sessions occurring during the intervening weeks. Following the last vapor cycle, rats were re-assessed for resistance to foot shock during punished self-administration sessions. Alcohol vapor exposure had no effect on punished self-administration overall, nor by subgroup. Examination of individual differences showed that rats classified as SR showed increased unpunished self-administration relative to baseline regardless of air vs. vapor condition. These data suggest that alcohol history has a minimal effect on individual differences in foot shock-punished self-administration.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"125 ","pages":"Pages 43-52"},"PeriodicalIF":2.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665496","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 : 2025-03-15DOI: 10.1016/j.alcohol.2025.03.002
Ming-Chyi Huang , Kevin Tsai , Yu-Hsuan Joni Shao
{"title":"The use of baclofen to reduce alcohol-attributable hospitalizations and emergency department admissions","authors":"Ming-Chyi Huang , Kevin Tsai , Yu-Hsuan Joni Shao","doi":"10.1016/j.alcohol.2025.03.002","DOIUrl":"10.1016/j.alcohol.2025.03.002","url":null,"abstract":"<div><h3>Aims</h3><div>The potential benefit of baclofen in reducing hospitalizations and emergency department (ED) admissions attributed to alcohol-related diagnoses has not been conclusively established. This study aimed to examine the relationship between baclofen use and the incidence of alcohol-attributable hospitalizations and ED admissions in the general population.</div></div><div><h3>Methods</h3><div>We conducted a self-controlled case series study (SCCS) using data from the Taiwan National Health Insurance Research Database. 2904 patients who had at least one alcohol-attributable hospitalization or emergency department admission and were prescribed 28 or more days of baclofen unrelated to alcohol were included. Conditional Poisson regression was used to estimate the incidence rate ratio (IRR) and 95% confidence interval (CI) for the risk of alcohol-attributable hospitalizations and ED admissions during exposure to baclofen, as well as the pre- and post-exposure periods, relative to the baseline period. The contribution of concomitant psychotropic medication use was also assessed.</div></div><div><h3>Results</h3><div>Baclofen was associated with a reduced incidence of alcohol-attributable hospitalizations (IRR = 0.64; 95% CI: 0.53∼0.77) and ED admissions (IRR = 0.56; 95% CI: 0.49∼0.65) in multivariate models. No statistically significant reduction was observed in any admission method in either the pre- or post-exposure period. A dose-dependent response in ED admissions was observed with baclofen, i.e. >60 mg/day associated with a greater decrease in the IRR (0.25, 95% CI: 0.10∼0.62) relative to doses of <30 (0.63, 95% CI: 0.53∼0.75) and 30–60 mg/day (IRR = 0.50, 95% CI: 0.40∼0.63).</div></div><div><h3>Conclusions</h3><div>These findings suggest a possible beneficial effect of baclofen in reducing the incidence of alcohol-attributable hospitalizations and ED admissions.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"125 ","pages":"Pages 35-41"},"PeriodicalIF":2.5,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652640","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 : 2025-02-25DOI: 10.1016/j.alcohol.2025.02.003
Callon M. Williams , Nadine R. Mastroleo , Mark F. Lenzenweger , Emily L. Zale
{"title":"Pain predicts past-month co-use of alcohol and cannabis among emerging adults: Results from the Population Assessment of Tobacco and Health (PATH) Study","authors":"Callon M. Williams , Nadine R. Mastroleo , Mark F. Lenzenweger , Emily L. Zale","doi":"10.1016/j.alcohol.2025.02.003","DOIUrl":"10.1016/j.alcohol.2025.02.003","url":null,"abstract":"<div><div>Alcohol use, cannabis use, and pain are public health concerns among emerging adults (18–24 years old). Co-use of alcohol and cannabis is of particular concern since individuals who co-use alcohol and cannabis use more of each substance and experience greater substance-related harm. Pain and substance use frequently co-occur, and a growing body of literature indicates pain is unique risk factor for substance use. The goal of the current study was to examine moderate/severe pain (vs. no/low pain) as a prospective predictor of engaging in co-use of alcohol and cannabis among emerging adults, and to test sex as a moderator of this hypothesized relationship. Data were drawn from Waves 1–5 of the Population Assessment of Tobacco and Health Study (<em>n</em> = 3544). Unadjusted logistic regression revealed that those with moderate/severe pain at baseline were 1.4 times more likely to engage in past-month co-use of alcohol and cannabis over the next four years (<em>p</em> = .046). The effects of pain on co-use were no longer significant after inclusion of covariates and a pain∗sex interaction term, which was also nonsignificant (<em>ps</em> > .05). These findings provide initial support for pain as a risk factor for engaging in co-use of alcohol and cannabis during emerging adulthood. Future research should continue investigating how pain may motivate co-use of alcohol and cannabis, exploring how pain is associated with other measures of co-use, and determining how providers can incorporate pain-substance use psychoeducation for emerging adults in clinical settings.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"124 ","pages":"Pages 111-119"},"PeriodicalIF":2.5,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525493","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 : 2025-02-11DOI: 10.1016/j.alcohol.2025.02.002
David L. Haggerty , Sara E.M.M.F. Badaro , Eva Nadpara , Carly B. Fabian , Karina P. Abrahao , David M. Lovinger , Max E. Joffe
{"title":"Impact of plastic sipper devices on alcohol self-administration in rodents: Limitations for long-term access paradigms","authors":"David L. Haggerty , Sara E.M.M.F. Badaro , Eva Nadpara , Carly B. Fabian , Karina P. Abrahao , David M. Lovinger , Max E. Joffe","doi":"10.1016/j.alcohol.2025.02.002","DOIUrl":"10.1016/j.alcohol.2025.02.002","url":null,"abstract":"<div><div>Open source devices are becoming widely used in behavioral neuroscience. Despite their advantages in cost effectiveness, modularity, and customization, measurements obtained using newly developed devices may not always recapitulate measurements from existing and validated equipment, potentially due to the materials used in manufacture. In this study, we evaluated a commonly used open-source optical lickometer that delivers fluid via a Hydropac® plastic valve in a multi-site intermittent access two-bottle choice (IA2BC) paradigm for alcohol consumption. Mice were tested with both traditional metal sippers and plastic sippers equipped with Hydropac® valves to assess differences in alcohol intake, preference, and total fluid consumption. Our findings revealed that mice displayed reduced intake and preference for alcohol (10–20% v/v) delivered via the Hydropac® containing plastic sippers. Notably, the effect was observed at both testing sites, suggesting a generalizable phenomenon. The decreased intake was also specific to alcohol, as water, quinine, and sucrose consumption were unaffected by sipper type. To investigate the underlying cause of the reduced alcohol consumption, we pre-incubated Hydropac® valves in 20% alcohol and found that the pre-treated alcohol reduced intake even when delivered via metal sippers. This suggests that prolonged interaction between alcohol and the components of the Hydropac® valves alter the fluid, likely by generating unpalatable contaminants. These results highlight a limitation of using plastic sippers in long-term alcohol self-administration studies. While these devices may remain suitable for limited access paradigms their use in extended access protocols may compromise data integrity. Our study underscores the need for rigorous validation of open-source hardware in each research project.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"125 ","pages":"Pages 17-24"},"PeriodicalIF":2.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
AlcoholPub Date : 2025-02-10DOI: 10.1016/j.alcohol.2025.02.001
Amine Bahi
{"title":"Hippocampal overexpression of tissue-type plasminogen activator “tPA” attenuates social defeat-induced depression and ethanol related behavior in mice","authors":"Amine Bahi","doi":"10.1016/j.alcohol.2025.02.001","DOIUrl":"10.1016/j.alcohol.2025.02.001","url":null,"abstract":"<div><div>Depression and anxiety disorders are often exacerbated by social stress, necessitating the exploration of molecular mechanisms underlying stress resilience. Tissue plasminogen activator (tPA), a serine protease with pleiotropic effects in the brain, plays a critical role in modulating neuroplasticity and stress responses. This study investigates the behavioral and molecular effects of tPA gain-of-function in a social stress paradigm in male C57BL/6 mice using lentiviral vectors. Behaviorally, hippocampal tPA gain-of-function mitigated depression-like responses in the novelty-suppressed feeding, sucrose splash, tail suspension, and forced swim tests following exposure to chronic social stress. Additionally, in a two-bottle choice drinking paradigm, tPA overexpression reduced social stress-induced ethanol intake and preference, suggesting a role in dampening maladaptive coping behaviors. However, analysis of tastants’ intake and preference revealed no significant effects of tPA overexpression, indicating that it does not influence hedonic responses under stress conditions. Molecularly, tPA overexpression preserved hippocampal tPA mRNA expression and maintained levels of mature brain-derived neurotrophic factor in the hippocampus despite chronic stress exposure. These findings highlight the potential neuroprotective effects of tPA in maintaining hippocampal plasticity and mitigating stress-induced dysregulation of critical neurotrophic pathways. Collectively, this study underscores the potential of tPA as a therapeutic target for stress-induced mood and substance use disorders by modulating behavioral and neurobiological responses to chronic social stress.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"125 ","pages":"Pages 1-15"},"PeriodicalIF":2.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412090","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":"Impact of parental ethanol exposure on offspring memory: Sex differences in spatial and passive avoidance tasks","authors":"Amirhossein Heidari , Arman Hajikarim-Hamedani , MohammadBasir Asefi , Haniyeh Soltani , Mohammad Saber Zamani , Yekta Ghane , Setareh Rassa , Mitra Sadat-Shirazi , Mohammad-Reza Zarrindast","doi":"10.1016/j.alcohol.2025.01.009","DOIUrl":"10.1016/j.alcohol.2025.01.009","url":null,"abstract":"<div><div>The impact of parental alcohol exposure on subsequent generations recently gained significant attention. Ethanol, widely consumed by humans, is known for its anxiolytic effects upon initial use. However, repeated ethanol consumption leads to cognitive dysfunction, dependence, and other physical abnormalities. In line with recent publications from our group, this study investigated the role of parental ethanol exposure—10 days prior to gestation—on learning and memory, which are critical cognitive abilities, in male and female offspring.</div><div>Adult male and female Wistar rats (n = 12) were exposed to ethanol (in drinking water) for 30 days, followed by a 10-day ethanol-free period. Each rat was then paired to mate with either an ethanol-naïve (control, n = 12) or ethanol-exposed rat, resulting in four distinct groups: (1) control male and female, (2) ethanol-exposed male and control female (P.EE), (3) ethanol-exposed female and control male (M.EE), and (4) ethanol-exposed male and female (P + M.EE). Adult male and female offspring were tested for spatial learning and memory (Morris Water Maze) and passive avoidance memory. Additionally, brain-derived neurotrophic factor (BDNF) levels in the cerebrospinal fluid were evaluated.</div><div>Results showed that spatial memory was negatively affected by parental ethanol consumption in both male and female offspring, while spatial learning was impaired only in female offspring of ethanol-exposed dams. In the passive avoidance paradigm, memory retrieval was impaired in ethanol-exposed male offspring, whereas in females, only the P + M.EE group showed a deficit in memory retention. While BDNF levels decreased in male offspring, an enhancement in BDNF was observed in female offspring of the P. EE group.</div><div>In conclusion, our findings suggest that parental ethanol exposure before conception has differential impacts on learning and memory, depending on the offspring's sex and the type of memory tested. Spatial memory was affected in both sexes (except for females in the P. EE group), while memory retrieval in the passive avoidance task remained unaffected in female offspring of the P. EE and M. EE groups. Conversely, male offspring of ethanol-exposed sires and dams exhibited deficits in passive avoidance memory. This may suggest that in memory tasks involving inhibitory cues, such as passive avoidance, female offspring of ethanol-exposed dams or sires are more resilient to memory deficits compared to male offspring. This resilience could possibly be attributed to their higher anxiety levels relative to males.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"124 ","pages":"Pages 13-21"},"PeriodicalIF":2.5,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191604","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 : 2025-02-01DOI: 10.1016/j.alcohol.2024.12.001
Suthat Liangpunsakul , Lorenzo Leggio
{"title":"FGF21 responses to alcohol, an insight from a comparative study in individuals with alcohol use disorder","authors":"Suthat Liangpunsakul , Lorenzo Leggio","doi":"10.1016/j.alcohol.2024.12.001","DOIUrl":"10.1016/j.alcohol.2024.12.001","url":null,"abstract":"","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"122 ","pages":"Pages 11-13"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866587","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 : 2025-02-01DOI: 10.1016/j.alcohol.2024.12.004
Vernon Garcia-Rivas , Alexa R. Soares , Merrilee A. Thomas , Jessica J. Na , Asia Smith , Marina R. Picciotto , Yann S. Mineur
{"title":"Alcohol drinking is attenuated by PDE4 inhibition but partial microglia depletion is not sufficient to block stress-induced escalation of alcohol intake in female mice","authors":"Vernon Garcia-Rivas , Alexa R. Soares , Merrilee A. Thomas , Jessica J. Na , Asia Smith , Marina R. Picciotto , Yann S. Mineur","doi":"10.1016/j.alcohol.2024.12.004","DOIUrl":"10.1016/j.alcohol.2024.12.004","url":null,"abstract":"<div><div>Stress is a major contributing factor to binge drinking and development of alcohol use disorders (AUD), particularly in women. Both stress and chronic ethanol can enhance neuroinflammatory processes, which may dysregulate limbic circuits involved in ethanol reinforcement. Clinical and preclinical studies have identified sex differences in alcohol intake in response to neuroinflammatory triggers. Since both cyclic AMP (cAMP) signaling and microglial activation contribute to neuroinflammation, we explored their contribution to stress-induced ethanol drinking in mice. To this end, we first trained C57BL/6J male and female mice to volitionally drink ethanol through a modified version of the “Drinking-in-the-Dark” paradigm. We then assessed whether exposure to foot shock stress followed by repeated exposure to the previously stress-paired context might alter volitional ethanol drinking. We observed that stress exposure resulted in a delayed increase in ethanol intake, but only in female mice. The anti-inflammatory drug Apremilast, an inhibitor of phosphodiesterase type 4 (PDE4; the primary enzyme for cAMP degradation in the brain), reduced ethanol intake and decreased preference for ethanol regardless of stress exposure in females. In contrast, a partial pharmacological depletion of microglia via PLX3397 treatment did not significantly alter baseline ethanol drinking or stress-induced ethanol drinking in female mice. This study shows that female mice are more susceptible to stress-induced ethanol drinking than males, and that this occurs even after partial microglial depletion. In addition, modulation of cAMP signaling by Apremilast administration reduced ethanol drinking regardless of stress exposure, supporting the idea that it might be useful for treatment of AUD.</div></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":"122 ","pages":"Pages 31-42"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900636","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}