Development Of Alcohol Use Disorders Research Articles

Binge drinking trajectories across adolescence and early adulthood: Associations with genetic influences for dual-systems impulsive personality traits, alcohol consumption, and alcohol use disorder.

Binge drinking is a relatively common pattern of alcohol use among youth with normative frequency trajectories peaking in emerging and early adulthood. Frequent binge drinking is a critical risk factor for not only the development of alcohol use disorders (AUDs) but also increased odds of alcohol-related injury and death, and thus constitutes a significant public health concern. Changes in binge drinking across development are strongly associated with changes in impulsive personality traits (IPTs) which have been hypothesized as intermediate phenotypes associated with genetic risk for heavy alcohol use and AUD. The current study sought to examine the extent to which longitudinal changes in binge drinking and intoxication frequency across adolescence and early adulthood are associated with genetic influences underlying dual-systems IPTs (i.e., top-down [lack of self-control] and bottom-up [sensation seeking and urgency] constructs) alongside genetic risk for alcohol consumption and AUD. Associations were tested using conditional latent growth curve polygenic score (PGS) models in three independent longitudinal samples ( N =10,554). Results suggested consistent significant and independent associations across all samples between sensation seeking PGSs and model intercepts (i.e., higher frequency of binge drinking at first measurement occasion) and alcohol consumption PGSs and model slopes (i.e., steeper increases toward peak binge drinking frequency). Urgency PGSs were not significantly associated with changes in binge drinking or intoxication frequency. Collectively, these findings highlight the role of unique but correlated IPT and alcohol-specific genetic factors in the emergence and escalation of binge drinking during adolescence and early adulthood.

Sex-dependent effects of ethanol withdrawal from a single- and repeated binge episode exposures on social anxiety-like behavior and neuropeptide gene expression in adolescent rats

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.

BNST CRF receptor type 1 modulates mechanical hypersensitivity induced by adolescent alcohol exposure in adult female mice.

Alcohol exposure during adolescence has been linked to long-lasting behavioral consequences, contributing to the development of alcohol use disorder. Negative affect and chronic pain during alcohol withdrawal are critical factors influencing problematic alcohol use and relapse. Our previous research demonstrated that adolescent intermittent ethanol (AIE) vapor exposure elicits sex-specific negative affect-like behavior in adult mice following stress exposure. Additionally, AIE induces persistent mechanical hypersensitivity, which is accompanied by increased activation of corticotropin-releasing factor receptor type 1 (CRFR1) neurons in the dorsolateral bed nucleus of the stria terminalis (dlBNST). This study extends previous work by investigating plasma corticosterone levels and CRFR1 protein expression in the dlBNST following restraint stress exposure in adult mice with an AIE history. We also aim to explore the role of dlBNST CRFR1 signaling in mediating negative affect-like behavior and mechanical hypersensitivity. Female mice exhibited elevated plasma corticosterone levels compared to males following restraint stress. Moreover, females with AIE history showed higher expression of CRFR1 protein in the dlBNST compared to air controls. Antagonism of CRFR1 in the dlBNST blocked AIE-induced mechanical hypersensitivity in adult females but did not affect stress-induced negative affect-like behavior. In alcohol-naïve females, intra-dlBNST administration of a CRFR1 agonist induced mechanical hypersensitivity. These findings provide new insights into the neurobiological mechanisms underlying stress-induced negative affect and pain-related behavior, both influenced by a history of adolescent alcohol exposure. The results suggest that CRFR1 antagonists warrant further investigation for their potential in addressing alcohol-related chronic pain.

The combination of donepezil and cognitive training for improving treatment outcomes for alcohol use disorder: Design of a randomized controlled trial

BackgroundThe development of alcohol use disorder (AUD) is a major concern in public health, and cognitive impairments caused by alcohol are involved in this process. Emerging neurobiological evidence suggests that donepezil, an anticholinesterase agent, may improve AUD treatment outcomes by enhancing neurocognitive functioning. Previous research has also suggested that cognitive remediation therapy (CRT) could potentially improve cognitive function and AUD treatment outcomes. We present the rationale and design of a trial to evaluate the combination of donepezil and cognitive remediation therapy (donepezil + CRT) as an intervention for AUD. MethodsWe propose a 13-week, randomized, double-blind, placebo-controlled, between-subjects trial comparing 4 groups (donepezil + CRT vs. donepezil alone vs. CRT alone vs. placebos) as an intervention for AUD. The main goal of the study is to evaluate if donepezil + CRT is superior to placebo in reducing heavy drinking days and improving neurocognitive functioning. A total of 160 patients (4 groups, 40 per each group) with AUD between the ages of 18–80 years will be recruited at Yale University and the VA Connecticut Healthcare System. Primary outcome measures include 1) heavy drinking by Timeline Follow Back (TLFB) over 13 weeks and 2) global neurocognitive functioning by a global index of neurocognitive function score at 7 and 13 weeks. DiscussionThis protocol paper describes the rationale and proposed methods for the randomized controlled trial for improving AUD treatment outcomes. This project has significant clinical potential to help patients suffering from AUD by improving their cognition and reducing alcohol consumption.Trial Registration:NCT05042102

Age- and sex-driven alterations in alcohol consumption patterns: Role of brain ethanol metabolism and the opioidergic system in the nucleus accumbens

Alcohol consumption leads to significant neurochemical and neurobiological changes, contributing to the development of alcohol use disorders (AUDs), which exhibit sex- and age-dependent variations according to clinical data. However, preclinical studies often neglect these factors when investigating alcohol consumption patterns. In this study, we present data on male and female rats continuously exposed to a 20 % ethanol solution for one month. The animals were divided into two groups based on their age at the onset of drinking (8 and 12 weeks old). Interestingly, 12-week-old males consumed significantly less alcohol than both 12-week-old females and 8-week-old animals, indicating that alcohol consumption patterns vary with sex and age in our model. Additionally, to advance in the study of the neurobiological alterations induced by ethanol intake in the mesocorticolimbic system (MCLS) that may participate in its reinforcing properties and the maintenance of alcohol drinking behavior, we measured catalase activity—an enzyme involved in alcohol metabolism and related to ethanol reinforcement—in the nucleus accumbens (NAc) of these animals. Furthermore, we measured the levels of mu (MOR), kappa (KOR), delta (DOR), and nociceptin (NOP) opioid receptors in the NAc, as the endogenous opioidergic system plays a pivotal role in regulating the MCLS and alcohol reinforcement. MOR levels were lower in high alcohol-consuming groups (8-week-old males and all females). Both DOR and NOP levels decreased with age, whereas KOR levels remained unchanged. Our findings suggest that the age at onset of alcohol consumption critically influences alcohol intake, particularly in males. Additionally, females consistently showed higher alcohol intake regardless of age, highlighting inherent sex-specific differences. The dynamic changes in catalase activity and opioid receptor expression suggest the involvement of these factors in modulating alcohol consumption.

The key role of specific DSM-5 diagnostic criteria in the early development of alcohol use disorder: Findings from the RADAR prospective cohort study.

Prevention and early intervention of alcohol use disorder (AUD) is a public health priority, yet there are gaps in our understanding of how AUD emerges, which symptoms of AUD come first, and whether there are modifiable risk factors that forecast the development of the disorder. This study investigated potential early-warning-sign symptoms for the development of AUD. Data were from the RADAR study, a prospective cohort study of contemporary emerging adults across Australia (n = 565, mean age = 18.9, range = 18-21 at baseline, 48% female). Participants were interviewed five times across a 2.5-year period. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) AUD criteria and diagnoses were assessed by clinical psychologists using the Structured Clinical Interview for DSM-IV (SCID-IV), modified to cover DSM-5 criteria. Hazard analyses modeled the time from first alcoholic drink to the emergence of any AUD criteria and determined which first-emergent AUD criteria were associated with a faster transition to disorder. By the final time point, 54.8% of the sample had experienced at least one DSM-5 AUD criterion and 26.1% met criteria for DSM-5 AUD. The median time from first AUD criterion to a diagnosis of AUD was 4 years. Social problems from drinking (hazard ratio [HR] = 3.24, CI95 = 2.14, 4.92, p < 0.001), major role (HR = 2.53, CI95 = 1.58, 4.06, p < 0.001), and drinking larger amounts/for longer than intended (HR = 2.04, CI95 = 1.20, 3.46, p = 0.008) were first-onset criteria associated with a faster transition to AUD. In the context of a prospective general population cohort study of the temporal development of AUD, alcohol-related social problems, major role problems, and using more or for longer than intended are key risk factors that may be targeted for early intervention.

Characterization in the rat of the individual tendency to rely on alcohol to cope with distress and the ensuing vulnerability to drink compulsively.

Only some vulnerable individuals who recreationally drink alcohol eventually develop the compulsive drinking pattern that characterizes alcohol use disorder. A new frontier in biomedical research lies in understanding the neurobehavioural mechanisms of this individual vulnerability, a necessary step towards developing novel effective therapeutic strategies. Translational research has been hindered by the lack of valid, reliable and robust approaches that enable the study of the influence of the reliance on alcohol to cope with stress or self-medicate negative emotional states on the subsequent transition to alcohol use disorder. We have therefore developed a behavioural task in the rat that enables the investigation of the neural and cellular basis of the exacerbation of the vulnerability to develop compulsive alcohol drinking by the use of alcohol to develop an adjunctive, anxiolytic, polydipsic drinking behaviour in a schedule-induced polydipsia procedure. Hence, in our task, alcohol is introduced in the schedule-induced polydipsia context after several weeks of training with water so that rats are exposed to alcohol for the first time in a distressing context and learn to drink alcohol as a coping strategy. Capitalizing on this protocol, we have consistently been able to identify a subpopulation of rats that were unable to learn to cope with negative states by drinking water and relied on alcohol to do so. This maladaptive reliance on alcohol drinking to cope with distress has been shown to be associated with an exacerbation of the subsequent transition to compulsive drinking. Furthermore, these vulnerable rats reached blood alcohol levels comparable to that of intoxication in humans, thereby developing two key features of alcohol use disorder, namely excessive alcohol intake and compulsive drinking. Altogether, this behavioural task provides a novel and unique tool for the investigation of the neurobehavioural mechanisms underlying the exacerbation of the individual vulnerability to developing compulsive alcohol drinking by the use of alcohol as a strategy to cope with distress, and for the evaluation of the efficacy of potential therapeutic strategies in a personalized medicine approach. This procedure, which focuses on an understudied but key factor of the development of alcohol use disorder, may become widely used as it benefits the fields of alcohol, emotion regulation and stress, the interest in which has substantially increased since the evidence of a profound exacerbation of alcohol use and alcohol-related negative consequences by the distress and social isolation engendered by the various measures implemented worldwide in response to the COVID-19 pandemic.

Brain correlates and functional connectivity linking stress, autonomic dysregulation, and alcohol motivation

High stress is a key risk factor for alcohol use disorder (AUD) and often accompanied by physiological dysregulation including autonomic nervous system (ANS) disruptions. However, neural mechanisms underlying drinking behaviors associated with stress and ANS disruptions remain unclear. The current study aims to understand neural correlates of stress, ANS disruptions, and subsequent alcohol intake in social drinkers with risky drinking. Using functional magnetic resonance imaging (fMRI), we investigated brain and heart rate (HR) autonomic responses during brief exposure to stress, alcohol, and neutral cues utilizing a well-validated, individualized imagery paradigm in 48 social drinkers of which 26 reported high-risk drinking (HD) while 22 reported low-risk drinking (LD) patterns. Results indicated that HD individuals showed stress and ANS disruptions with increased basal HR, stress-induced craving, and decreased brain response to stress exposure in frontal-striatal regions including the ventromedial prefrontal cortex (VmPFC), anterior cingulate cortex, striatum, insula, and temporal gyrus. Furthermore, whole-brain correlation analysis indicated that greater basal HR was associated with hypoactive VmPFC, but hyperactive medulla oblongata (MOb) responses during stress, with an inverse association between activity in the VmPFC and Mob (whole-brain corrected (WBC), p < 0.05). Functional connectivity with the MOb as a seed to the whole brain indicated that HD versus LD had decreased functional connectivity between the VmPFC and MOb during stress (WBC, p < 0.05). In addition, those with more compromised functional connectivity between the VmPFC and MOb during stress consumed greater amount of alcohol beverage during an experimental alcohol taste test conducted on a separate day, as well as in their self-reported weekly alcohol intake. Together, these results indicate that stress-related, dysfunctional VmPFC control over brain regions of autonomic arousal contributes to greater alcohol motivation and may be a significant risk factor for hazardous alcohol use in non-dependent social drinkers. Findings also suggest that restoring VmPFC integrity in modulating autonomic arousal during stress may be critical for preventing the development of AUD.

Alcohol withdrawal seizures, epilepsy and brain trauma

IntroductionAlcohol addiction can lead to withdrawal seizures, but most patients do not develop epilesy. In some cases a permanent complication occurs - symptomatic epilepsy. In other cases epilepsy precedes alcohol addiction. Comorbidity may pose serious chalenges to treating clinicians. There are conflicting data regarding relationship between alcohol use, seizures and epilepsy (Scorza CA et al.,CLINICS 2020;75:e1770). Other factors like brain trauma may have impact in genesis of epileptic states as well.ObjectivesEvaluation of interplay between seizures, epilepsy and brain trauma in patients with alcohol use disorder.MethodsAnalysis of a case series in a hospital setting and review of relevant literature.ResultsIn our series of cases the number of patients who have suffered epilepsy before the onset of alcohol use is small. In most of the hospitalized patients epilepsy occurred after the development of alcohol use disorder. In this group we observed that head and brain trauma play role in genesis of seizures and epilepsy and in some instances the reverse happens.ConclusionsOur data indicate the potential role of brain trauma as predisposing and complicating factor in patients who developed seisures and epilepsy. Seizures sometimes increase the risk of brain trauma. Seizures and trauma are important factors in typology of Lesch (Lesch et al. 2011) and a serious evaluation in this direction is improtant, because its diagnostic, therapeutic and prognostic implications. Further clarification in this field is necessary.Disclosure of InterestNone Declared

Different measures of alcohol use as predictors of DSM-5 alcohol use disorder among adolescents – A cohort study from Sweden

Background and aimsThis study addresses a significant gap in existing research by investigating the longitudinal relationship between various measures of alcohol use and the development of alcohol use disorders (AUDs) in a cohort of Swedish adolescents. MethodsA prospective longitudinal survey was conducted on 3999 adolescents in Sweden who were in 9th grade in 2017 and were followed up in 2019. Baseline assessments included lifetime alcohol use, recent use (past 30 days), risky drinking (AUDIT-C), and heavy episodic drinking (HED). Follow-up assessments comprised eleven items measuring DSM-5 AUD criteria. The study explores prospective associations between these diverse alcohol use measures and the occurrence of AUD, while also calculating population attributable fractions (PAF). FindingsThe proportion of alcohol consumers who met the criteria for AUD at follow-up was 31.8%. All baseline measures of alcohol use exhibited associations with subsequent AUD. Notably, the HED group demonstrated the highest prevalence of AUD at 51.4% (p<.001). However, when calculating PAFs, any lifetime alcohol use emerged as the most substantial contributor, accounting for 10.8% of all subsequent AUD cases. ConclusionsThis study underscores that alcohol use during mid-adolescence heightens the risk of developing AUD in late adolescence. Among the various measures, heavy episodic drinking presents the highest risk for later AUD. From a public health perspective, preventing any alcohol use emerges as the most effective strategy to mitigate the population-level burden of disease of AUD.

Adolescent alcohol exposure modifies adult anxiety-like behavior and amygdala sensitivity to alcohol in rats: Increased c-Fos activity and sex-dependent microRNA-182 expression

Adolescent binge alcohol drinking is a serious health concern contributing to adult alcohol abuse often associated with anxiety disorders. We have used adolescent intermittent ethanol (AIE) administration as a model of binge drinking in rats in order to explore its long-term effect on the basolateral amygdala (BLA) responsiveness to alcohol and anxiety-like behavior. AIE increased the number of BLA c-Fos positive cells in adult Wistar rats and anxiety-like behavior assessed by the open field test (OFT). Additionally, in adult female rats receiving AIE BLA over expression of miR-182 was found. Therefore, our results indicate that alcohol consumption during adolescence can lead to enduring changes in anxiety-like behavior and BLA susceptibility to alcohol that may be mediated by sex-dependent epigenetic changes. These results contribute to understanding the mechanisms involved in the development of alcohol use disorders (AUD) and anxiety-related disorders.

Line- and sex-dependent effects of juvenile stress on contextual fear- and anxiety-related behavior in high- and low-alcohol-preferring mouse lines

Juvenile stress (JS) is a known risk factor for the development of alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD), both of which are frequently co-morbid. Data suggest there may be common, genetically-influenced biological responses to stress that contribute to the development of both AUD and PTSD. The present study investigated the impact of JS on contextual fear learning and extinction, as well as corticosterone (CORT) responses before and after JS, before and after contextual fear conditioning (CFC), and after fear extinction in male and female high-alcohol-preferring (HAP2) and low-alcohol-preferring (LAP2) mouse lines. We also measured unconditioned anxiety-related behavior in the light-dark-transition test before CFC. HAP2 and LAP2 mice did not differ in fear acquisition, but HAP2 mice showed faster fear extinction compared to LAP2 mice. No effects of JS were seen in HAP2 mice, whereas in LAP2 mice, JS reduced fear acquisition in males and facilitated fear extinction in females. Females showed greater fear-related behavior relative to males, regardless of subgroup. HAP2 males demonstrated more anxiolytic-like responses than LAP2 males and LAP2 females demonstrated more anxiolytic-like responses than LAP2 males in the light-dark transition test. HAP2 and LAP2 mice did not differ in CORT during the juvenile stage; however, adult LAP2 mice showed greater CORT levels than HAP2 mice at baseline and after CFC and extinction testing. These findings build upon prior work in these unique mouse lines that differ in genetic propensity toward alcohol preference and provide new information regarding contextual fear learning and extinction mechanisms theorized to contribute to co-morbid AUD and PTSD.

Adolescent intermittent ethanol (AIE) produces lasting, sex-specific changes in rat body fat independent of changes in white blood cell composition.

Early initiation of alcohol use during adolescence, and adolescent binge drinking are risk factors for the development of alcohol use disorder later in life. Adolescence is a time of rapid sex-dependent neural, physiological, and behavioral changes as well as a period of heightened vulnerability to many effects of alcohol. The goal of the present studies was to determine age-related changes in blood (leukocyte populations) and body composition across adolescence and early adulthood, and to investigate whether adolescent intermittent ethanol (AIE) exposure would alter the trajectory of adolescent development on these broad physiological parameters. We observed significant ontogenetic changes in leukocyte populations that were mirrored by an age-related increase in cytokine expression among mixed populations of circulating leukocytes. Despite these developmental changes, AIE did not significantly alter overall leukocyte numbers or cytokine gene expression. However, AIE led to sex-specific changes in body fat mass and fat percentage, with AIE-exposed male rats showing significantly decreased fat levels and female rats showing significantly increased fat levels relative to controls. These changes suggest that while AIE may not alter overall leukocyte levels, more complex phenotypic changes in leukocyte populations could underlie previously reported differences in cytokine expression. Coupled with long-term shifts in adipocyte levels, this could have long-lasting effects on innate immunity and the capacity of individuals to respond to later immunological and physiological threats.

Sex-specific negative affect-like behaviour and parabrachial nucleus activation induced by BNST stimulation in adult mice with adolescent alcohol history.

Adolescent alcohol use is a strong predictor for the subsequent development of alcohol use disorders later in life. Additionally, adolescence is a critical period for the onset of affective disorders, which can contribute to problematic drinking behaviours and relapse, particularly in females. Previous studies from our laboratory have shown that exposure to adolescent intermittent ethanol (AIE) vapour alters glutamatergic transmission in the bed nucleus of the stria terminalis (BNST) and, when combined with adult stress, elicits sex-specific changes in glutamatergic plasticity and negative affect-like behaviours in mice. Building on these findings, the current work investigated whether BNST stimulation could substitute for stress exposure to increase the latency to consume a palatable food in a novel context (hyponeophagia) and promote social avoidance in adult mice with AIE history. Given the dense connections between the BNST and the parabrachial nucleus (PBN), a region involved in mediating threat assessment and feeding behaviours, we hypothesized that increased negative affect-like behaviours would be associated with PBN activation. Our results revealed that the chemogenetic stimulation of the dorsolateral BNST induced hyponeophagia in females with AIE history, but not in female controls or males of either group. Social interaction remained unaffected in both sexes. Notably, this behavioural phenotype was associated with higher activation of calcitonin gene-related peptide and dynorphin cells in the PBN. These findings provide new insights into the neurobiological mechanisms underlying the development of negative affect in females and highlight the potential involvement of the BNST-PBN circuitry in regulating emotional responses to alcohol-related stimuli.

Ninein, a candidate gene for ethanol anxiolysis, shows complex exon-specific expression and alternative splicing differences between C57BL/6J and DBA/2J mice.

Ethanol's anxiolytic actions contribute to increased consumption and the development of Alcohol Use Disorder (AUD). Our laboratory previously identified genetic loci contributing to the anxiolytic-like properties of ethanol in BXD recombinant inbred mice, derived from C57BL/6J (B6) and DBA/2J (D2) progenitor strains. That work identified Ninein (Nin) as a candidate gene underlying ethanol's acute anxiolytic-like properties in BXD mice. Nin has a complex exonic content with known alternative splicing events that alter cellular distribution of the NIN protein. We hypothesize that strain-specific differences in Nin alternative splicing contribute to changes in Nin gene expression and B6/D2 strain differences in ethanol anxiolysis. Using quantitative reverse-transcriptase PCR to target specific Nin splice variants, we identified isoform-specific exon expression differences between B6 and D2 mice in prefrontal cortex, nucleus accumbens and amygdala. We extended this analysis using deep RNA sequencing in B6 and D2 nucleus accumbens samples and found that total Nin expression was significantly higher in D2 mice. Furthermore, exon utilization and alternative splicing analyses identified eight differentially utilized exons and significant exon-skipping events between the strains, including three novel splicing events in the 3' end of the Nin gene that were specific to the D2 strain. Additionally, we document multiple single nucleotide polymorphisms in D2 Nin exons that are predicted to have deleterious effects on protein function. Our studies provide the first in-depth analysis of Nin alternative splicing in brain and identify a potential genetic mechanism altering Nin expression and function between B6 and D2 mice, thus possibly contributing to differences in the anxiolytic-like properties of ethanol between these strains. This work adds novel information to our understanding of genetic differences modulating ethanol actions on anxiety that may contribute to the risk for alcohol use disorder.

Alcohol, HMGB1, and Innate Immune Signaling in the Brain.

Binge drinking (i.e., consuming enough alcohol to achieve a blood ethanol concentration of 80 mg/dL, approximately 4-5 drinks within 2 hours), particularly in early adolescence, can promote progressive increases in alcohol drinking and alcohol-related problems that develop into compulsive use in the chronic relapsing disease, alcohol use disorder (AUD). Over the past decade, neuroimmune signaling has been discovered to contribute to alcohol-induced changes in drinking, mood, and neurodegeneration. This review presents a mechanistic hypothesis supporting high mobility group box protein 1 (HMGB1) and Toll-like receptor (TLR) signaling as key elements of alcohol-induced neuroimmune signaling across glia and neurons, which shifts gene transcription and synapses, altering neuronal networks that contribute to the development of AUD. This hypothesis may help guide further research on prevention and treatment. The authors used the search terms "HMGB1 protein," "alcohol," and "brain" across PubMed, Scopus, and Embase to find articles published between 1991 and 2023. The database search found 54 references in PubMed, 47 in Scopus, and 105 in Embase. A total of about 100 articles were included. In the brain, immune signaling molecules play a role in normal development that differs from their functions in inflammation and the immune response, although cellular receptors and signaling are shared. In adults, pro-inflammatory signals have emerged as contributing to brain adaptation in stress, depression, AUD, and neurodegenerative diseases. HMGB1, a cytokine-like signaling protein released from activated cells, including neurons, is hypothesized to activate pro-inflammatory signals through TLRs that contribute to adaptations to binge and chronic heavy drinking. HMGB1 alone and in heteromers with other molecules activates TLRs and other immune receptors that spread signaling across neurons and glia. Both blood and brain levels of HMGB1 increase with ethanol exposure. In rats, an adolescent intermittent ethanol (AIE) binge drinking model persistently increases brain HMGB1 and its receptors; alters microglia, forebrain cholinergic neurons, and neuronal networks; and increases alcohol drinking and anxiety while disrupting cognition. Studies of human postmortem AUD brain have found elevated levels of HMGB1 and TLRs. These signals reduce cholinergic neurons, whereas microglia, the brain's immune cells, are activated by binge drinking. Microglia regulate synapses through complement proteins that can change networks affected by AIE that increase drinking, contributing to risks for AUD. Anti-inflammatory drugs, exercise, cholinesterase inhibitors, and histone deacetylase epigenetic inhibitors prevent and reverse the AIE-induced pathology. Further, HMGB1 antagonists and other anti-inflammatory treatments may provide new therapies for alcohol misuse and AUD. Collectively, these findings suggest that restoring the innate immune signaling balance is central to recovering from alcohol-related pathology.

Transcriptome changes in the nucleus of the solitary tract induced by repeated stress, alcohol dependence, or stress-induced drinking in dependent mice

Stress increases alcohol consumption in dependent animals and contributes to the development of alcohol use disorder. The nucleus of the solitary tract (NTS) is a critical brainstem region for integrating and relaying central and peripheral signals to regulate stress responses, but it is not known if it plays a role in alcohol dependence- or in stress-induced escalations in alcohol drinking in dependent mice. Here, we used RNA-sequencing and bioinformatics analyses to study molecular adaptations in the NTS of C57BL/6J male mice that underwent an ethanol drinking procedure that uses exposure to chronic intermittent ethanol (CIE) vapor, forced swim stress (FSS), or both conditions (CIE + FSS). Transcriptome profiling was performed at three different times after the last vapor cycle (0-hr, 72-hr, and 168-hr) to identify changes in gene expression associated with different stages of ethanol intoxication and withdrawal. In the CIE and CIE + FSS groups at 0-hr, there was upregulation of genes enriched for cellular response to type I interferon (IFN) and type I IFN- and cytokine-mediated signaling pathways, while the FSS group showed upregulation of neuronal genes. IFN signaling was the top gene network positively correlated with ethanol consumption levels in the CIE and CIE + FSS groups. Results from different analyses (differential gene expression, weighted gene coexpression network analysis, and rank-rank hypergeometric overlap) indicated that activation of type I IFN signaling would be expected to increase ethanol consumption. The CIE and CIE + FSS groups also shared an immune signature in the NTS as has been demonstrated in other brain regions after chronic ethanol exposure. A temporal-based clustering analysis revealed a unique expression pattern in the CIE + FSS group that suggests the interaction of these two stressors produces adaptations in synaptic and glial functions that may drive stress-induced drinking.

The Impact of the COVID-19 Pandemic on the Severity of Alcohol Use Disorder: Significance of Dual Disorders.

The coronavirus disease 2019 (COVID-19) pandemic has been assumed to impact patients diagnosed with alcohol use disorder (AUD). The severity of the influence that the COVID-19 pandemic had on the symptoms of AUD has not yet been revealed in detail. The aim of this study was to examine the impact of the COVID-19 pandemic on patients diagnosed with AUD. This retrospective study was conducted between 11 March 2017 and 31 May 2022 in Hungary. Medical charts (N = 1082) of inpatients with the diagnosis of AUD were reviewed. Based on the dates of admissions, two groups were created: the 'before COVID-19' group (11 March 2017-10 March 2020) and the 'during COVID-19' group (11 March 2020-31 May 2022). Chi-square tests, independent-sample t-tests, and multinomial logistic regressions were performed. The occurrence of delirium tremens (DT) and psychiatric co-morbidities was significantly higher during the pandemic. Our results showed that the occurrence of DT and psychiatric co-morbidities significantly increased during the pandemic. Our results revealed that the pandemic enhanced the severe consequences of AUD, and the development of AUD might have increased in frequency among individuals previously diagnosed with mental illness during the pandemic. These findings indicate the significance of dual disorders in the post-pandemic period.

Diagnostic Criteria for Identifying Individuals at High Risk of Progression From Mild or Moderate to Severe Alcohol Use Disorder

Current Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) diagnoses of substance use disorders rely on criterion count-based approaches, disregarding severity grading indexed by individual criteria. To examine correlates of alcohol use disorder (AUD) across count-based severity groups (ie, mild, moderate, mild-to-moderate, severe), identify specific diagnostic criteria indicative of greater severity, and evaluate whether specific criteria within mild-to-moderate AUD differentiate across relevant correlates and manifest in greater hazards of severe AUD development. This cohort study involved 2 cohorts from the family-based Collaborative Study on the Genetics of Alcoholism (COGA) with 7 sites across the United States: cross-sectional (assessed 1991-2005) and longitudinal (assessed 2004-2019). Statistical analyses were conducted from December 2022 to June 2023. Sociodemographic, alcohol-related, psychiatric comorbidity, brain electroencephalography (EEG), and AUD polygenic score measures as correlates of DSM-5 AUD levels (ie, mild, moderate, severe) and criterion severity-defined mild-to-moderate AUD diagnostic groups (ie, low-risk vs high-risk mild-to-moderate). A total of 13 110 individuals from the cross-sectional COGA cohort (mean [SD] age, 37.8 [14.2] years) and 2818 individuals from the longitudinal COGA cohort (mean baseline [SD] age, 16.1 [3.2] years) were included. Associations with alcohol-related, psychiatric, EEG, and AUD polygenic score measures reinforced the role of increasing criterion counts as indexing severity. Yet within mild-to-moderate AUD (2-5 criteria), the presence of specific high-risk criteria (eg, withdrawal) identified a group reporting heavier drinking and greater psychiatric comorbidity even after accounting for criterion count differences. In longitudinal analyses, prior mild-to-moderate AUD characterized by endorsement of at least 1 high-risk criterion was associated with more accelerated progression to severe AUD (adjusted hazard ratio [aHR], 11.62; 95% CI, 7.54-17.92) compared with prior mild-to-moderate AUD without endorsement of high-risk criteria (aHR, 5.64; 95% CI, 3.28-9.70), independent of criterion count. In this cohort study of a combined 15 928 individuals, findings suggested that simple count-based AUD diagnostic approaches to estimating severe AUD vulnerability, which ignore heterogeneity among criteria, may be improved by emphasizing specific high-risk criteria. Such emphasis may allow better focus on individuals at the greatest risk and improve understanding of the development of AUD.

A preliminary investigation of salivary α-amylase as a novel biomarker of subjective response to alcohol: A brief report.

Alcohol misuse represents a universal public health concern that spans multiple demographics. As such, understanding shared, biological indicators of alcohol-related risk is vital to implementing targeted prevention and intervention efforts. Self-report measures of subjective response to alcohol (SR) capture both psychological and pharmacological effects of alcohol and robustly predict patterns of alcohol use, negative consequences, and the development of alcohol use disorders. Importantly, several biological markers of alcohol's sedating effects, including cortisol, have been identified and complement subjective response assessments. However, biological markers of alcohol's stimulating effects are less understood. Studies have implicated alcohol-induced changes in heart rate as a viable marker, but heart rate measurements are susceptible to measurement error. Salivary α-amylase, a reliable indicator of sympathetic nervous system activation, represents a promising alternative biomarker of alcohol-induced stimulation. Using data from a large, placebo-controlled alcohol administration study (N = 448), the present study examined the extent to which α-amylase is a viable marker of alcohol-induced stimulation. To test this, a measurement model was estimated in which baseline and ascending limb subjective stimulation latent variables were created using two validated measures of subjective response. Ascending self-reports of stimulation and levels of α-amylase were then regressed onto beverage conditions and allowed to correlate with each other. Findings indicated that α-amylase is sensitive to acute alcohol consumption and is positively, but not statistically reliably, related to the ascending limb stimulant SR. Future studies should consider including salivary α-amylase as a noninvasive physiological indicator of alcohol's stimulating effects. (PsycInfo Database Record (c) 2023 APA, all rights reserved).