Trend estimates from national surveys over the last 20 years have suggested converging rates of alcohol use over time between adult men and women. However, limited research has utilized an intersectional lens to examine how sociodemographic characteristics influence gender differences in these trends.

The high mobility group box 1 (HMGB1) pathway plays a pivotal role in the development of alcohol-induced brain injury. Glycyrrhizinic acid (GlyA) is widely regarded as an inhibitor of HMGB1. The objective is to investigate the impact on gene expression in the prefrontal cortex,we sequenced the transcriptome in control, alcohol-exposed, and HMGB1-inhibited groups of mice. We verified our findings by real-time quantitative PCR (qRT-PCR).

Attention-deficit/hyperactivity disorder (ADHD) commonly affects individuals with alcohol use disorder (AUD). However, despite the negative outcomes associated with this comorbidity, ADHD is underdiagnosed in this population. We aim to identify clinical parameters and propose cutoff scores enabling the detection of ADHD among patients with AUD. We retrospectively analyzed data from 199 patients, out of a global sample of 412 who were consecutively admitted to a day hospital for alcohol-related problems between 2009 and 2022. We found that lower level of self-directedness, higher levels of novelty seeking, self-transcendence, harm avoidance and craving, and earlier first alcohol consumption could accurately predict the presence of ADHD in AUD (AUC=0.926). Self-directedness and novelty seeking had the best predictive abilities: a self-directedness score below 52 was associated with an accuracy of 82% and, combined with a novelty seeking score over 53, the accuracy reached 85%. Such findings could be useful to help clinicians detect ADHD in patients with AUD so that they can receive the adequate care.

This study evaluated protective effects of clove (SEO), thyme white (TEO), oregano (OEO), and caraway (CEO) essential oils (EOs), and their binary mixtures, in a zebrafish fetal alcohol spectrum disorder model. Furthermore, folic acid (FA) was used for comparison as it had previously shown protection against ethanol (EtOH)-induced defects. The co-exposure of zebrafish embryos to EtOH (150 mM) and FA (75 μM) or EOs and their binary mixtures (0.5-1 mg/L) was carried out during 6 or 22 hours postfertilization (hpf). Different developmental endpoints (epiboly measurement, survival rate at 24 hpf, embryonic developmental progression measurement at 24 hpf, larval development at 48-96 hpf, and hatching rate at 72-96 hpf) were evaluated at 8-96 hpf. EtOH exposure reduced epiboly. Only FA and the SEO + TEO binary mixture protected against these defects, and SEO and TEO single exposure showed partial protection. Therefore, these groups were chosen for subsequent experiments. At 24 hpf, EtOH showed developmental delay and hatching rate was delayed at 72 hpf. FA, SEO, TEO, and SEO + TEO partially protected against these defects. This study supports the conclusion that FA partially protects against EtOH-induced defects. SEO and TEO single exposure partially protect against EtOH-induced defects. However, the binary mixture of SEO + TEO was more effective, showing similar efficacy as FA.

To combat high-risk alcohol consumption, we introduced a 30-day alcohol abstinence challenge targeted at heavy drinkers with and without chronic pain. Our study aimed to assess the challenge's feasibility and safety and to explore its perceived benefits. Our exploratory aim was to identify participants' coping strategies during the challenge.

Alcohol Use Disorder (AUD) is a chronic brain disorder associated with a high risk of relapse and a limited treatment efficacy. Relapses may occur even after long periods of abstinence and are often triggered by stress or cue induced alcohol craving. C-tactile afferents (CT) are cutaneous nerve fibers postulated to encode pleasant affective touch and known to modulate physiological stress responses. However, their translational potential has not yet been explored extensively in controlled clinical trials. This randomized controlled study aimed to investigate the potential of CT stimulation in modulating relapse predicting biomarkers, physiological cue-reactivity, and subjective alcohol craving in AUD patients in early abstinence. Twenty-one participants meeting DSM-5 criteria for mild to moderate AUD received CT-optimal touch or a non-CT-optimal control treatment while exposed to neutral, stress-inducing, and alcohol-related visual stimuli. The tactile treatment was provided with a robotic device, eliminating the social elements of touch. Heart rate variability (HRV), salivary cortisol, and subjective craving were assessed at the baseline, during and after the treatment and stimuli exposure. The results showed that CT-optimal touch significantly reduced alcohol-cue-elicited standard deviation of normal-to-normal intervals (SDNN) HRV compared to the control group, shifting the HRV reactivity to the direction known to indicate lower relapse susceptibility. Cortisol levels showed no significant differences between the groups, and subjective alcohol craving increased after alcohol cue exposure in both groups. This study found that CT-optimal touch modulates autonomic cue-reactivity in AUD patients, encouraging further research on the therapeutic potential of affective touch. Future research should explore the long-term effects and real-world clinical relevance of CT-optimal touch in alcohol relapse prevention.

Previously, we developed a procedure which showed that longer histories of reinforced alternative behavior decrease the risk of relapse caused by a range of stimuli which had previously occasioned drinking. The decrease in relapse risk was likely due to a decrease in attention to the stimuli over the course of repeated engagement in the alternative behavior. However, this previous procedure was time consuming and did not mirror the procedure we used to observe changes in relapse risk. This study aimed at replicating the previous relationship between the duration of engaging in an alternative behavior and shift in stimulus generalization for drinking using a procedure that allows longitudinal analysis over time and is consistent with other procedures we have developed. Rats were trained to respond for ethanol in the presence of one stimulus (16 kHz tone; food Fixed Ratio (FR)150 and ethanol FR5), and for food in the under another stimulus (8 kHz tone; food and ethanol FR5). Then, recovery-like sessions with food predominant responding occurred in the presence of only the low-cost food stimulus. During these sessions, rats were exposed to non-reinforced graded stimuli alternation from 8 to 16 kHz alternating with the reinforced low-cost food stimulus. The number of responses on each (food and ethanol) lever before completing 5 responses on either lever was the main measure. Consistent with the earlier procedure, the current procedure showed that graded variation of tone from 8 to 16 kHz produced a graded increase in responding for ethanol compared to responding for food. In addition, longer periods of engaging in recovery-like responding shift the generalization function downwards. This procedure confirms the earlier pattern of stimulus generalization over longer periods of behavior consistent with recovery. This strengthens our hypothesis that shifts in attention to alcohol-related stimuli are important to the development of relapse resistance during recovery.

Ethanol withdrawal sensitivity is a risk factor for the development of alcohol use disorder. Heavy episodic drinking during adolescence often encompasses repeated periods of withdrawal. Adolescent intermittent ethanol exposure of laboratory rodents produces several neurobiological deficits that differ between sexes, but the sensitivity to withdrawal as a contributor to the observed sex differences is not clear. The current study assessed the impact of acute withdrawal from a single- and repeated binge ethanol episodes during adolescence as well as protracted abstinence from repeated binge episodes on social anxiety-like behavior (indexed via significant decreases of social investigation) as well as oxytocin (OXT) and vasopressin (AVP) system gene expression in the hypothalamus (HYP) and central amygdala (CeA) in male and female Sprague Dawley rats. Females displayed social anxiety-like behavior during withdrawal from a single binge episode, whereas both sexes showed social anxiety-like changes following acute withdrawal from repeated binge episodes. After a period of protracted abstinence, only males still displayed ethanol-associated social alterations. Analysis of gene expression in separate, non-socially tested subjects revealed that withdrawal from repeated binge episodes during adolescence increased AVP gene expression in the HYP of males and decreased it in females. Males also displayed increased AVP and OXTR gene expression during acute withdrawal from repeated binge episodes in the CeA, with these changes persisting into adulthood. Together, these findings suggest that adolescent females are sensitive to withdrawal from both acute and repeated ethanol exposures, whereas males are sensitive to withdrawal from repeated ethanol exposures, with affective and transcriptional changes persisting into adulthood.

Alcohol and opioid polysubstance use (PSU) is common and often accompanied by higher trait anxiety. Oxytocin decreases anxiety, alcohol- and opioid-seeking and -taking but has not been assessed in the context of PSU. Here we developed a rat model of sequential oxycodone and alcohol PSU to examine the relationship between anxiety, alcohol and oxycodone intake, and the efficacy of systemic oxytocin to attenuate alcohol intake. Male and female Sprague-Dawley rats were assessed for baseline anxiety-like behavior using acoustic startle and the elevated plus maze (EPM). Rats were then given 2-bottle choice access to oxycodone and/or water for 6-hr/day for 7 days, followed by 2-bottle choice access to alcohol (20% v/v) and/or water for five 24-hr sessions across 10 days. Next, monosubstance (oxycodone- or alcohol-alone) rats continued to have access to only one substance/day while PSU rats had access to oxycodone and water for 3-hr, followed by alcohol and water for 6-hr. After 12 days, rats were tested in the EPM 20 hours after alcohol access to examine withdrawal-related anxiety. Next, oxytocin (0, 0.3 or 1.0 mg/kg IP) was administered following the oxycodone/water session, 30 minutes prior to alcohol access. Rats received intragastric oxycodone (2 mg/kg) or water followed by intragastric alcohol (2 g/kg) and blood was collected to determine blood alcohol levels. Elevated baseline anxiety-like behavior was accompanied by reduced alcohol intake. Consumption of oxycodone did not alter alcohol intake but resulted in less anxiety-like behavior during withdrawal and prevented oxytocin from attenuating alcohol intake. Oxytocin (1 mg/kg) reduced alcohol intake in the alcohol-only condition, an effect that persisted for days after a single oxytocin administration. Rats that received oxycodone prior to non-contingent alcohol displayed higher blood alcohol levels than those that did not. These results support the necessity for the testing of medications for substance use in rodent models of PSU.

The unclear mechanisms of ethanol metabolism in the brain highlight the need for a deeper understanding of its metabolic pathways. This study used in vivo microdialysis to simultaneously sample ethanol and its metabolites, acetaldehyde and acetate, in the rat striatum following self-administration of ethanol, emphasizing the natural oral exposure route. To enhance the self-administration, rats underwent two-bottle-choice and limited access training. Dialysate samples, collected every 10 minutes for 2.5 hours, were analyzed using gas chromatography with flame ionization detection (GC-FID). The measured time courses of dialysate concentrations of ethanol, acetaldehyde, and acetate provided insights into dynamics of ethanol metabolism. Notably, in a subject with low ethanol consumption (0.29 g/kg), the concentration of acetaldehyde remained below the limit of detection throughout the experiment. However, the acetate concentration was clearly increased after ethanol consumption in this subject and was comparable to that of other rats with higher ethanol consumption. Compared with focusing only on peak values in the time-courses of concentrations of ethanol and its metabolites, calculating areas under curves provided better models of the relationships between ethanol intake and individual ethanol metabolites, as indicated by the r-square values for the linear regressions. This approach of using the area under the curve accounts for both the amplitude and duration of the concentration profiles, reducing the impact of variations in individual drinking patterns. In vivo microdialysis enables concurrent sampling of brain metabolites during oral ethanol administration, contributing insights into metabolite dynamics. To our knowledge, this paper is the first to report measurement of all three analytes in the brain following self-administration of ethanol. Future studies will explore regional variations and dynamics post-ethanol dependence, further advancing our understanding of ethanol metabolism in the brain.

Early developmental exposure to alcohol has been implicated in adverse effects on the brain, often associated with the onset of neurodevelopmental disorders. Moreover, maternal alcohol consumption during pregnancy has been linked to the manifestation of mental health disorders, such as depression and anxiety, in subsequent generations. These mood disturbances may be attributed to alterations in protein expressions related to depression and anxiety within the hippocampus. While the precise mechanisms remain elusive, it is likely that pre- and postnatal exposure to alcohol induces changes in hippocampus, potentially through epigenetic modifications. The FKBP5 gene, known to modulate the stress response, is particularly relevant in this context. We postulate that alcohol-induced methylation of the FKBP5 gene disrupts HPA axis function, thereby prompting individuals to anxiety-like and depressive-like behaviors. To investigate this hypothesis, female C57BL/6 pups were subjected to early alcohol exposure via intubation with ethanol mixed in artificial milk from Postnatal Day 3 to Day 20. The intubation control pups were subjected to the same procedures without ethanol or milk, and a non-intubated control group included. Anxiety-like and depressive-like behaviors were assessed using the open field test, plus maze test, forced swim test, and tail suspension test when the pups reached 3 months of age. For epigenetic analysis of the FKBP5 gene, genomic DNA was isolated from hippocampal tissues and subjected to bisulfite conversion to distinguish methylated and unmethylated cytosines. Then, methylation-specific PCR was performed to assess methylation levels. Pups exposed to early postnatal alcohol exhibited increased levels of depression-like behavior and susceptibility to anxiety-like behavior during adolescence, as verified by behavioral assessments. Methylation profiling revealed higher rates of methylation within the stress-associated gene FKBP5 in both the early postnatal alcohol-exposed cohort (13.82%) and the intubation control group (3.93%), in contrast to the control cohort devoid of stress or alcohol exposure. These findings suggest a potential epigenetic mechanism underlying the observed behavioral alterations, implicating FKBP5 methylation as a candidate mediator of the increased vulnerability to mood disorders following early postnatal alcohol exposure.

Alcohol use disorder (AUD) affects 5% of the global population. Despite its high prevalence, the pathophysiology of AUD remains enigmatic, hindering the development of novel therapeutics. Interestingly, the liver hormone fibroblast growth factor 21 (FGF21), which is currently in late-stage clinical trials for the treatment of non-alcoholic steatohepatitis, has been implicated by recent genome-wide association studies as a regulator of alcohol consumption.

Moderate prenatal alcohol exposure (mPAE) results in structural alterations to the hippocampus. Previous studies have reported impairments in hippocampal-sensitive tasks, but have not compared performance between male and female animals. In the present study, performance in hippocampal-sensitive spatial memory and anxiety behavior tests were compared across adult male and female saccharin (SACC) control mPAE Long-Evans rat offspring. Two tests of spatial memory were conducted that were aimed at assessing memory for recently acquired spatial information: A delayed spatial alternation task using an M-shaped maze and a delayed match-to-place task in the Morris water task. In both tasks, rats in SACC and mPAE groups showed similar learning and retention of a spatial location even after a 2-h interval between encoding and retention. A separate group of adult male and female SACC and mPAE rat offspring were tested for anxiety-like behaviors in the elevated plus-maze paradigm. In this test, both male and female mPAE rats exhibited a significantly greater amount of time and a greater number of head dips in the open arms, while locomotion and open arm entries did not differ between groups. The results suggest that mPAE produces a reduction in anxiety-like behaviors in both male and female rats in the elevated plus-maze.

Although alcohol and nicotine are two of the most commonly co-used drugs with upwards of 90% of adults with an alcohol use disorder (AUD) in the US also smoking, we don't tend to study alcohol and nicotine use this way. The current studies sought to develop and assess a novel alcohol + nicotine co-access self-administration (SA) model in adult male and female Long-Evans rats. Further, both drugs are implicated in neuroimmune function, albeit in largely opposing ways. Chronic alcohol use increases neuroinflammation via toll-like receptors (TLRs) which in turn increases alcohol intake. By contrast, nicotine produces anti-inflammatory effects, in part, through the monomeric alpha7 receptor (ChRNa7). Following long-term co-access (6 months), rats reliably administered both drugs during daily sessions, however males generally responded for more alcohol and females for nicotine. This was reflected in plasma analysis with translationally relevant intake levels of both alcohol and nicotine, making it invaluable in studying the effects of co-use on behavior and CNS function. Moreover, male rats show sensitivity to alterations in alcohol concentration whereas females show sensitivity to alterations in nicotine concentration. Rats trained on this procedure also developed an anxiogenic phenotype. Finally, we assessed alterations in neuroimmune-related gene expression in the medial prefrontal cortex - prelimbic, (mPFC-PL), nucleus accumbens core (AcbC), and ventral tegmental area (VTA). In the AcbC, where α7 expression was increased and β2 was decreased, markers of pro-inflammatory activity were decreased, despite increases in TLR gene expression suggesting that co-use with nicotine modulates inflammatory state downstream from the receptor level. By contrast, in mPFC-PL where α7 was not increased, both TLRs and downstream proinflammatory markers were increased. Taken together, these findings support that there are brain regional and sex differences with co-use of alcohol + nicotine SA and suggest that targeting nicotinic α7 may represent a novel strategy for treating alcohol + nicotine co-dependence.

Alcohol related liver disease (ALD) affects diverse communities with individual and social characteristics that can impact outcomes. The social vulnerability index (SVI) assigns a score between 0 and 1, where higher scores represent an increased risk of social vulnerability. We sought to assess the impact of SVI on outcomes of patients hospitalized with ALD with access to social support services.

Understanding sex differences in disease prevalence is critical to public health, particularly in the context of alcohol use disorder (AUD). The goal of this study was to understand sex differences in ethanol drinking behavior and define the precise conditions under which sex differences emerge. Consistent with prior work, C57BL/6J females drank more than males under continuous access two-bottle choice conditions. However, using ethanol self-administration - where an operant response results in access to an ethanol sipper for a fixed time period - we found no sex differences in operant response rates or ethanol consumption (volume per body weight consumed, as well as lick behavior). This remained true across a wide range of parameters including acquisition, when the ethanol sipper access period was manipulated, and when the concentration of the ethanol available was scaled. The only sex differences observed were in total ethanol consumption, which was explained by differences in body weight between males and females, rather than by sex differences in motivation to drink. Using dimensionality reduction approaches, we found that drinking behavior in the operant context did not cluster by sex, but rather clustered by high and low drinking phenotypes. Interestingly, these high and low drinking phenotypes in the operant context showed no correlation with those same categorizations in the home cage context within the same animals. These data underscore the complexity of sex differences in ethanol consumption, highlighting the important role that drinking conditions/context plays in the expression of these differences.

The alcohol hangover is a combination of negative mental and physical symptoms which can be experienced after a single episode of alcohol consumption, starting when blood alcohol concentration (BAC) approaches zero. A popular theory suggests that dehydration is the primary cause of alcohol hangover and that the consumption of water could alleviate hangover symptoms. Here, the current evidence on the relationship between hangover severity, thirst, and water consumption is summarized. The positive correlations of the amount of water consumed with both hangover severity and thirst suggest that both dehydration and the hangover are co-occurring after-effects of alcohol consumption. While hangovers were typically relatively enduring, dehydration effects were usually mild and short-lasting. Survey data revealed that water consumption during or directly after alcohol consumption had only a modest effect in preventing next-day hangover. Also, the amount of water consumed during hangover was not related to changes of hangover severity and thirst. Thus, water consumption was not effective to alleviate the alcohol hangover. Taken together, these data suggests that alcohol hangover and dehydration are two co-occurring but independent consequences of alcohol consumption.

Epidemiological studies reveal a high prevalence of alcohol use and comorbidity rates with emotional disorders. This study aims to explore the possible mediational effect of stress-coping strategies on the relationship between symptoms of emotional disorders and problematic alcohol use.

Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) are very prevalent and co-occurring. It is unclear how alcohol exacerbates PTSD predicaments owing to less characterized pathophysiological mechanisms. Also, studies on pharmacological agents that can effectively reverse PTSD-AUD comorbidity have, to date, been scarce. Hence, we designed a methodological approach to investigate the pathophysiological mechanisms and pharmacological outcomes of morin, a neuroprotective flavonoid in mice. After 7 days of PTSD following single-prolonged stress (SPS) induction in mice, the PTSD mice were exposed to intermittent binge ethanol administration using ethanol (2g/kg, oral gavage) every other day, alongside daily morin (50 and 100mg/kg) or fluoxetine (10mg/kg) from days 8-21. The consequences of PTSD-AUD behavior, hypothalamic-pituitary-adrenal-axis (HPA-axis) dysfunction, neurochemistry, oxidative/nitrergic stress, and inflammation were evaluated in the prefrontal-cortex (PFC), striatum, and hippocampus of mice. The exacerbated anxiety-like behavior, and spatial/non-spatial memory deficits, with general depressive phenotypes and social stress susceptibility by SPS-ethanol interaction, were alleviated by morin and fluoxetine, evidenced by reduced corticosterone release and adrenal hypertrophy. SPS-ethanol exacerbates dopamine, serotonin, and glutamic acid decarboxylase alterations, and monoamine oxidase-B and acetylcholinesterase hyperactivities in the striatum, PFC, and hippocampus, respectively, which were prevented by morin. Compared to SPS-ethanol aggravation, morin prevented TNF-α, and IL-6 release, malondialdehyde and nitrite levels, with improved antioxidant (glutathione, superoxide-dismutase, catalase) levels in the hippocampus, PFC, and striatum. Overall, these findings suggest that AUD exacerbated PTSD might be primarily connected, among other mechanisms, with aggravated HPA-axis dysfunction, upregulated neurochemical degradative enzymes, enhancement of oxidative/nitrergic stress and neuroinflammation, stereo-selectively in the mice brains, which morin abated via the preventive mechanisms.

In human adolescents, females often report drinking for coping reasons to avoid negative affective states. We have shown previously that adolescent female rats with elevated levels of anxiety-like behavior under social test circumstances, indexed via low social preference are sensitive to anxiolytic effects of ethanol given intraperitoneally (ip) in a low-to-moderate dose range. This study was designed to test the hypothesis that patterns of neuronal activation across brain regions implicated in social activity and social preference (used as an index of low versus high anxiety-like social responding) would be affected by acute ethanol differently in adolescent females with high and low social preference, with initial levels of social preference also predicting ethanol-induced changes in social behavior. Adolescent female Fos-LacZ rats were given social interaction tests on postnatal day (P)33 for determination of baseline levels of responding to an unfamiliar social partner and on P35 following administration of 0 or 0.75 g/kg ethanol. Brain tissue was collected, and expression of β-galactoside (β-gal) was used as an index of neuronal activation. Baseline levels of social preference did not predict social responsiveness to an acute ethanol challenge, whereas significant decreases in this social measure that reflects anxiety-like behavioral alterations were evident in adolescent females challenged with ethanol relative to saline-injected controls, suggesting high sensitivity to the anxiogenic effects of ethanol. Ethanol precipitated negative relationships between social preference and prefrontal cortical activation, decreased neuronal activation of the anterior cingulate cortex, but substantially increased β-gal expression in the central amygdala. These results suggest high sensitivity of the prefrontal cortical regions and central amygdala to ethanol-induced alterations in adolescent Fos-LacZ females and provide a background for further phenotyping of neurons activated by ethanol under social test circumstances.

Ethanol consumption is increasingly prevalent in communities and has several side effects for humans. Chronic alcohol consumption is often associated with decreased libido and infertility. This study aimed to evaluate the impact of beer on spermatogenesis and proteins and gene expression of P21 and cyclin D1 in testicular tissue.