Chronic Alcohol Use Research Articles

ADVANCEMENTS IN UNDERSTANDING AND MANAGING ALCOHOL WITHDRAWAL SYNDROME: A COMPREHENSIVE REVIEW

Alcohol withdrawal syndrome (AWS) is a clinically significant condition that can arise upon abrupt cessation or reduction of alcohol consumption in individuals with alcohol dependence. This review article provides a comprehensive overview of AWS, encompassing its epidemiology, pathophysiology, clinical manifestations, assessment tools, and management strategies. We discuss the neurobiological mechanisms underlying AWS, including the role of neurotransmitter systems such as gamma-aminobutyric acid (GABA) and glutamate, as well as neuroadaptive changes that occur with chronic alcohol use. Furthermore, we explore the spectrum of clinical manifestations associated with AWS, ranging from mild withdrawal symptoms to severe complications such as delirium tremens and seizures. Diagnostic tools and scoring systems commonly used for assessing AWS severity are examined, along with evidence-based approaches for pharmacological and non-pharmacological management of AWS. Additionally, we highlight emerging research areas and future directions in the field of AWS, including novel treatment modalities and potential biomarkers for predicting withdrawal severity and treatment response. This comprehensive review aims to provide clinicians, researchers, and healthcare professionals with a thorough understanding of AWS to facilitate early recognition, appropriate management, and improved outcomes for individuals affected by this condition.

Reciprocal relations between acute interpersonal negative life events and acute alcohol use: An examination of the 24 h preceding suicide attempts among hospitalized patients

ObjectiveTo examine the within-person relations between acute alcohol use and interpersonal negative life events (INLEs) in the 24 h preceding suicide attempts. MethodParticipants were 151 adult patients (67.55 % female; M age = 36.00) who were hospitalized within 24 h of a suicide attempt. Participants completed the Timeline Follow-back for Suicide Attempts interview to gather information about hourly events for the 24 h preceding their suicide attempt. Hierarchical logistic models were estimated to examine the influence of acute INLEs on next-hour alcohol use and acute alcohol use on next-hour INLEs. Biological sex and chronic alcohol use (past year) were evaluated as potential moderators. ResultsOverall, acute alcohol use was associated with increased odds of next-hour INLEs and acute INLEs were associated with increased odds of next-hour alcohol use. Moderator analyses indicated that the influence of alcohol use on INLEs increased as participants' level of chronic alcohol use decreased, and relations did not vary by biological sex. ConclusionsThere is a bidirectional relation between INLEs and alcohol use in the hours preceding suicide attempts. Understanding that these within-person interrelations may differ in strength depending on one's level of chronic alcohol use has practical utility for providers tasked with clinical decision making.

Revisiting the Alcohol-Aggression Link: The Impact of Alcohol Consumption Patterns

Laboratory studies have repeatedly reported a link between alcohol and aggression, yet many rely on single-dose administration methods and overlook variations in alcohol consumption patterns. The present study investigates the effects of alcohol on aggressive behavior using a double-blind, placebo-controlled cumulative drinking administration approach that mirrors the natural drinking behaviors often observed in pubs within a laboratory setting. This study also pioneers the examination of how alcohol consumption patterns (light or heavy) moderate the relationship between precise Breath Alcohol Concentration (BrAC) levels and extreme aggressive behavior. Seventy-five light (N=38) and heavy (N=37) alcohol drinkers were randomly assigned to alcohol (N=33) or placebo (N=42) conditions. Participants drank four drinks successively. Taylor's aggression paradigm was completed twenty minutes after each drink. Multilevel modeling was applied to analyze the effects of precise BrAC and account for within-person variability. Alcohol showed a dose-dependent effect on aggression; as alcohol levels rose, so did aggression (p<.001). Alcohol consumption pattern moderated the effect of cumulative BrAC on aggression, such that the effect was more substantial for light as compared with individuals who drink heavily (p=.03). The current study highlights the moderating role of alcohol consumption pattern in the association between precise BrAC levels and extreme aggression, offering insights into individual differences in susceptibility to alcohol-induced aggression, and supporting the I3 meta-theory (Finkel, 2014). The Findings underscore the importance of investigating the interplay between acute and chronic alcohol use on behavior, challenging conventional thresholds for hazardous drinking classification. Implications for future studies, legislators, and policymakers are discussed.

Central Pontine Myelinolysis Induced by Rapid Correction of Hyponatremia in a Patient With Chronic Alcohol Use Disorder: A Case Report

Central Pontine Myelinolysis Induced by Rapid Correction of Hyponatremia in a Patient With Chronic Alcohol Use Disorder: A Case Report

Reduced GABA Levels in the ACC of Actively Drinking High Risk Individuals Compared to Recently Detoxified Alcohol-Dependent Patients.

Acute gamma-aminobutyric acid (GABAergic) effects of alcohol consumption are well-known, whereas prior research has yielded inconsistent findings regarding on adaptations of the GABAergic neurotransmitter system to chronic alcohol use. Previous studies indicate either elevated or reduced GABA levels in cortical regions such as the anterior cingulate cortex (ACC) in persons with alcohol use disorder (AUD). We tested the hypothesis that active alcohol consumption compared to abstinence contributes to GABA levels as observed in prior research on chronic alcohol use. We investigated GABA levels in the ACC of 31 healthy controls (low risk, LR), 38 high risk individuals providing an active drinking pattern (high risk, HR) and 27 recently detoxified alcohol-dependent (AD) subjects via proton magnetic resonance spectroscopy (1H-MRS). GABA levels in the ACC were significantly lower in HR compared with AD, but did neither differ between LR and AD nor between LR and HR. Also, we observed a quadratic effect indicating a distribution of GABA levels in the ACC as follows: LR > HR < AD. GABA levels were not associated with abstinence duration in AD. This study suggests that the GABAergic neurotransmitter system is blunted in AUD. More precisely GABA levels in the ACC seem to be higher in recently detoxified AD patients than in individuals at high risk which might suggest that GABA levels may increase after abstinence. No correlation was found between GABA levels and abstinence duration. Longitudinal studies are required to investigate alterations in the GABAergic system throughout the development and maintenance of AUD. No: NCT02094196. Registered 20 March 2014, https://clinicaltrials.gov/study/NCT02094196.

The Role of Lymph-Adipose Crosstalk in Alcohol-Induced Perilymphatic Adipose Tissue Dysfunction.

Chronic alcohol use leads to metabolic dysfunction in adipose tissue. The underlying mechanisms and the contribution of alcohol-induced adipose tissue dysfunction to systemic metabolic dysregulation are not well understood. In our previous studies, we found that chronic alcohol feeding induces mesenteric lymphatic leakage, perilymphatic adipose tissue (PLAT) inflammation, and local insulin resistance in rats. The goal of this study was to further explore the link between alcohol-induced lymphatic leakage and PLAT immunometabolic dysregulation, locally and systemically, using in vivo and ex vivo approaches. Male rats received a Lieber-DeCarli liquid diet, of which 36% of the calories were from alcohol, for 10 weeks. Time-matched control animals were pair-fed. Adipokine levels were measured in PLAT, subcutaneous fat, plasma, and mesenteric lymph samples. Glucose tolerance was assessed after 10 weeks. Further, we used a novel ex vivo lymph-stimulated naïve PLAT explant approach to modeling lymph leakage to assess changes in adipokine secretion and expression of proinflammatory markers after stimulation with lymph from alcohol- or pair-fed animals. Our data show that chronic alcohol-fed rats presented PLAT-specific decreases in adiponectin and leptin levels, alterations in the expression of genes involved in lipid metabolic pathways, and associated impaired whole-body glucose homeostasis. Further, we found that direct naïve PLAT stimulation with lymph contents from alcohol-fed animals increased IL-6 expression in demonstrating the ability of lymph contents to differentially impact naïve adipose tissue. Overall, chronic alcohol feeding leads to depot-specific alterations in metabolic profile, impaired systemic glucose tolerance, and lymph-induced adipose tissue inflammation. The specific lymph components leading to PLAT immunometabolic dysregulation remain to be determined.

Successful Aging and Self-Neglect Among Community-Dwelling Older People.

It was aimed to explore the relationship between successful aging and self-neglect and factors affecting successful aging among community-dwelling older people. This cross-sectional study was conducted with 316 participants aged 60 years and older in a Family Health Center (FHC). The data were collected by using the questionnaire form, Successful Aging Scale and Self-Neglect Scale. The questionnaire form includes sociodemographic characteristics, independence (Katz Daily Life Activities Scale) and well-being status (WHO-5 Well-Being Index), psychosocial support (Multidimensional Perceived Social Support Scale), and depressive symptoms (two questions-complaints such as feeling depressed or hopeless and loss of interest and inability to enjoy life). Participants had a mean age of 67.5 (SD: 6.5) years, 55.4% were female. A strong positive correlation was determined between successful aging score and self-neglect score (r = 0.741, p < 0.001). Factors affecting successful aging were age, working status, education level, body mass index, physical activity, subjective health perception, health screening status, self-neglect level, depressive symptoms, independence in activities, well-being status, and psychosocial support. Gender, income status, chronic disease presence, cigarette and alcohol use, living alone, and family type did not affect it. According to multivariate linear regression, the factors affecting successful aging were age, psychosocial support presence, and self-neglect level (p < 0.05). Older people have low successful aging and self-neglect scores. Successful aging is better at a young age, in the presence of psychosocial support and a low level of self-neglect. It is recommended to increase the existence of psychosocial support for them and to plan interventions to reduce self-neglect.

Role of Imaging in Screening for Hepatocellular Carcinoma.

Primary liver cancer is among the most common cancers globally. It is the sixth-most common malignancy encountered and the third-most common cause of cancer-related death. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, accounting for about 90% of primary liver cancers. The majority of HCCs occur in patients with underlying cirrhosis, which results from chronic liver diseases such as fatty liver, hepatitis B and hepatitis C infections, and chronic alcohol use, which are the leading causes. The obesity pandemic has led to an increased prevalence of nonalcoholic fatty liver disease (NAFLD), which leads to nonalcoholic steatohepatitis and could progress to cirrhosis. As HCC is among the most common cancers and occurs in the setting of chronic liver disease in most patients, screening the population at risk could help in early diagnosis and management, leading to improved survival. Screening for HCC is performed using biochemical marker testing such as α-fetoprotein (AFP) and cross-sectional imaging. It is critical to emphasize that HCC could potentially occur in patients without cirrhosis (non-cirrhotic HCC), which can account for almost 20% of all HCCs. The lack of cirrhosis can cause a delay in surveillance, which could potentially lead to diagnosis at a later stage, worsening the prognosis for such patients. In this article, we discuss the diagnosis of cirrhosis in at-risk populations with details on the different modalities available for screening HCC in patients with cirrhosis, emphasizing the role of abdominal ultrasounds, the primary imaging modality in HCC screening.

Transgenic expression of human cytochrome P450 2E1 in C. elegans and rat PC-12 cells sensitizes to ethanol-induced locomotor and mitochondrial effects

Chronic alcohol (ethanol) use is increasing in the United States and has been linked to numerous health issues in multiple organ systems including neurological dysfunction and diseases. Ethanol toxicity is mainly driven by the metabolite acetaldehyde, which is generated through three pathways: alcohol dehydrogenase (ADH2), catalase (CAT), and cytochrome P450 2E1 (CYP2E1). ADH2, while the main ethanol clearance pathway in the liver, is not expressed in the mammalian brain, resulting in CAT and CYP2E1 driving local metabolism of ethanol in the central nervous system. CYP2E1 is known to generate reactive metabolites and reactive oxygen species and localizes to the mitochondria (mtCYP2E1) and endoplasmic reticulum (erCYP2E1). We sought to understand the consequences of mtCYP2E1 and erCYP2E1 in the nervous system during acute ethanol exposure. To answer this question, we generated transgenic Caenorhabditis elegans roundworms expressing human CYP2E1 in the mitochondria, endoplasmic reticulum, or both and exposed them to ethanol. We found that at lower concentrations, wild-type and mtCYP2E1-expressing worms had a small but significant inhibition of locomotion, whereas the erCYP2E1-expressing worms showed protection from this inhibition. At higher doses, all strains had reduced locomotion, but the erCYP2E1-expressing worms recovered faster than wild-type controls. CYP2E1 expression, regardless of organellar targeting, reduced mitochondrial respiration in response to ethanol. Similarly, transgenic expression of CYP2E1 in either organelle in PC-12 rat neuronal cell lines sensitized them to ethanol-induced cell death. Together, these findings suggest that subcellular localization of CYP2E1 impacts behavioral effects of ethanol and should be further studied in the mammalian central nervous system.

Sexual Dysfunction, Marital Adjustment, and Quality of Life Among Male Persons with Alcohol Dependence Syndrome Attending Tertiary Healthcare Institution in Northeast India: A Cross-Sectional Study

Background: Sexual dysfunction is one of the major problems associated with the chronic use of alcohol. Sexual dysfunction is also significantly associated with marital adjustment and quality of life. Aim and objectives: To determine the prevalence of sexual dysfunction and its association with marital adjustment and quality of life among persons with alcohol dependence syndrome (ADS) and to compare with the healthy control group. Materials and methods: The present study used a cross-sectional, comparative, and descriptive research design. A purposive sampling technique was used to select the sample of 128 (64 patients with ADS and 64 healthy control persons) between the ages of 21 and 50, from the Department of Addiction Medicine, LGB Regional Institute of Mental Health (LGBRIMH), Tezpur, Assam. Sociodemographic and clinical data sheet, the Arizona Sexual Experience Scale (ASEX), the Severity of Alcohol Dependence Questionnaire (SDAQ), the Alcohol Use Disorders Identification Test (AUDIT), the International Index of Erectile Dysfunction (IIED), and The Drug Abuse Screening Test scales (DAST) were used. Results: The study revealed a higher prevalence of sexual dysfunction in the ADS group (64%) compared to the healthy control group (35.9%) (Chi-square = 46.916; p &lt; .001). Marital satisfaction was significantly lower in the ADS group than in the healthy control group (Fisher’s exact test = 76.932; p &lt; .001). Quality of life was also diminished in the ADS group, particularly in the physical ( t = −5.310; p &lt;.001), social ( t = −4.481; p &lt; .001), and environmental domains ( t = −4.250; p &lt; .001). Furthermore, sexual dysfunction exhibited a significant negative correlation with marital adjustment ( r = −0.676; p &lt; .01) and all domains of quality of life [physical domain ( r = −0.235; p &lt; .001), social domain ( r = −0.383; p &lt; .001), and environmental domain ( r = −0.383; p &lt; .001)]. Conclusion: The prevalence of sexual dysfunction and erectile dysfunction was high in persons with alcohol dependence syndrome as compared to the healthy control group and it has a relationship with marital adjustment and quality of life. The findings highlight the importance of screening and evaluating sexual dysfunction in individuals with alcohol dependence. Comprehensive pharmacological and nonpharmacological services are warranted to address the unique needs of this population, promoting both recovery from alcohol dependence and improvement in overall quality of life.

A - 103 Exploring the Diagnostic Criteria for Alcohol-Related Dementia: a Case Study

Abstract Objective Excessive and chronic alcohol use can cause structural/functional abnormalities in the brain, including cognitive impairment (CI) (Harper, 2009). Despite these established risks, alcohol-related dementia (ARD) has received little recognition, mainly due to lack of a distinct pathophysiological profile. Through a case differential approach (concussion vs. ARD), the authors aim to clarify diagnostic criteria for ARD. Methods A 56-year-old right-handed male presented to the emergency room after fall with head strike (no loss of consciousness) with alcohol withdrawal delirium. Symptoms of cerebellar ataxia and CI of 6-month duration were noted. Past medical history was significant for alcohol use (four standard units per day), hyperlipidemia, tobacco use, and depression/anxiety. Neuroimaging revealed cerebral atrophy and chronic small vessel ischemic disease. A neuropsychological evaluation (NPE) was conducted 18 days post-fall. Results NPE revealed relative weaknesses in working memory, complex attention, and visual abstraction. Impairments were noted in visuospatial organization/planning, processing speed, basic attention, verbal fluency, and verbal memory. Motor examination was evident for intention tremor. Conclusion Brain changes associated with ARD include volume loss, altered glucose metabolism, reduced neuronal density, changes in frontal lobe function, and white matter loss. In contrast, individuals affected by concussions may encounter challenges with attention/concentration, processing speed, and working memory. Distinguishing a clear diagnostic profile for ARD is difficult due to high rates of concomitant concussion in this population. The patient’s deficits exceed those expected due to concussion alone, with an anticipated cognitive recovery timeframe of 7–14 days (Iverson, 2006). Furthermore, neuroimaging and NPE results support the diagnostic hypothesis of ARD.

Network meta-analysis on the mechanisms underlying alcohol augmentation of acute pancreatitis and diabetes type II.

Pancreatitis is a severe inflammatory pathology that occurs from pancreatic duct and exocrine acinar injury, leading to improper secretion of digestive enzymes, auto-digestion of the pancreas, and subsequent inflammation. Clinical reports show that 60%-90% of pancreatitis patients have a history of chronic alcohol use. More recent studies reveal that exocrine pancreas disorders like acute pancreatitis can precede diabetes type II onset, though mechanisms are not yet fully known. This study identified molecules and key signaling pathways underlying alcohol-induced acute pancreatitis and their effects on diabetes type II onset. Data on human peripheral blood samples with or without acute pancreatitis were retrieved from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (accession number GSE194331). Acute pancreatitis-mediated differentially expressed genes (DEGs) were generated from GSE194331 using CLC Genomics Workbench 12. Molecules associated with ethanol (EtOH), acute pancreatitis, and diabetes type II were collected from QIAGEN Knowledge Base (QKB). The relationship between the molecules and signaling pathways associated with EtOH, acute pancreatitis, or diabetes type II was examined using various Ingenuity Pathway Analysis (IPA) tools. Our investigation showed that acute pancreatitis-mediated DEGs were closely associated with EtOH by revealing that EtOH-induced acute pancreatitis appears to lead to the onset of diabetes type II. We found that diabetes type II onset was mediated by pro-inflammatory and metabolic mechanisms underlying EtOH-induced acute pancreatitis, involving increased expression of cytokines including macrophage migration inhibitory factor (MIF), and decreased expression of hormones such as insulin. Exposure to alcohol may promote diabetes type II by affecting the activity of key inflammatory and metabolic mediators involved in acute pancreatitis. These findings call for further investigation into the role of pro-inflammatory and metabolic mediators like resistin, IL-6, and insulin in EtOH-induced diabetes type II associated with acute pancreatitis pathologies.

Neurocognitive function and medical care utilization in Veterans treated for substance use disorder

BackgroundVeterans with substance use disorder (SUD) are at high risk for cognitive problems due to neurotoxic effects of chronic drug and alcohol use coupled in many cases with histories of traumatic brain injury (TBI). These problems may in turn result in proneness to SUD relapse and reduced adherence to medical self-care regimens and therefore reliance on health care systems. However, the direct relationship between cognitive function and utilization of Veterans Health Administration (VHA) SUD and other VHA health care services has not been evaluated. We sought initial evidence as to whether neurocognitive performance relates to repeated health care engagement in Veterans as indexed by estimated VHA care costs.MethodsNeurocognitive performance in 76 Veterans being treated for SUD was assessed using CNS-Vital Signs, a commercial computerized cognitive testing battery, and related to histories of outpatient and inpatient/residential care costs as estimated by the VHA Health Economics Resource Center.ResultsAfter controlling for age, an aggregate metric of overall neurocognitive performance (Neurocognition Index) correlated negatively with total VHA health care costs, particularly with SUD-related outpatient care costs but also with non-mental health-related care costs. Barratt Impulsiveness Scale scores also correlated positively with total VHA care costs.ConclusionsIn Veterans receiving SUD care, higher impulsivity and lower cognitive performance were associated with greater health care utilization within the VHA system. This suggests that veterans with SUD who show lower neurocognitive performance are at greater risk for continued health problems that require healthcare engagement. Cognitive rehabilitation programs developed for brain injury and other neurological conditions could be tried in Veterans with SUD to improve their health outcomes.

Bed nucleus of the stria terminalis network responses to unpredictable threat in early alcohol abstinence.

Anxiety during early alcohol abstinence, likely resulting from neural changes caused by chronic alcohol use, contributes to high relapse rates. Studies in rodents show heightened activation during early abstinence in the bed nucleus of the stria terminalis (BNST)-a neural hub for anxiety-and its extended anxiety-related corticolimbic network. Despite the clinical importance of early abstinence, few studies investigate the underlying neural mechanisms. To address this gap, we investigated brain function in early alcohol abstinence (EA = 20, 9 women) relative to controls (HC = 20, 11 women) using an unpredictable threat task shown to engage the BNST and corticolimbic brain regions involved in anxiety and alcohol use disorder (AUD). Group, anxiety, and sex were predictors used to determine whole-brain activation and BNST functional connectivity. We found widespread interactions of group × anxiety and group × anxiety × sex for both activation and BNST connectivity during unpredictable threat. In the EA group, higher anxiety was correlated with activation in the BNST, rostral anterior cingulate cortex (ACC), insula (men only), and dorsal ACC (men only). In the HC group, higher anxiety was negatively correlated with activation in the BNST, nucleus accumbens, thalamus, and insula (men only). For connectivity, anxiety was positively correlated in EA and negatively correlated in HC, between the BNST and the amygdala, ventromedial prefrontal cortex (PFC), and dorsomedial PFC; EA men showed stronger BNST-vmPFC connectivity than HC men. These novel findings provide preliminary evidence for alterations in the BNST and anxiety-related corticolimbic brain regions in early alcohol abstinence, adding to growing literature in humans supporting the BNST's role in anxiety and sex-dependent effects of chronic alcohol use.

Dangerous Intersection of Alcoholism and Othello Syndrome: A Comprehensive Review of Delusional Jealousy and Treatment Strategies.

The modern pace of life, increased susceptibility to stressors, and easy access to psychoactive substances have contributed to the increase in the number of people addicted to alcohol. Alcoholism has serious and life-threatening consequences, one of which is brain damage causing morbid jealousy, otherwise known as Othello syndrome. The disease, currently classified as a subtype of delusional disorder, manifests itself in groundless and dangerous judgments about a partner's sexual infidelity. People with Othello syndrome constantly believe in their partner's infidelity despite inadequate evidence of it. Patients become aggressive toward their partners as well as themselves, which is why in a fit of anger they can commit murder or suicide. Othello syndrome can occur as a symptom of an underlying mental illness, but it is most often associated with brain damage caused by chronic alcohol use. Antipsychotic drugs and serotonin reuptake inhibitors are used in pharmacotherapy. Targeted treatment using the neuropeptide oxytocin, which modulates the transmitter systems responsible for disease symptoms, is also being considered. The use of oxytocin seems groundbreaking, but it remains at the research stage. The treatment of addictions and primary diseases, as well as long-term cognitive-analytic psychotherapy, also have a huge impact. Othello syndrome is a life-threatening disease with an insidious course and serious consequences. This article aims to review the manifestations of morbid jealousy, including delusional disorder, and the association with alcoholism.

Characteristics of human donor lungs utilized for research.

Many fundamental discoveries have occurred using primary cells from deceased donor lungs. These cells respond differently to injury when there are underlying co-morbidities like diabetes mellitus, hypertension, aging and exposures to cigarette smoke, cocaine and chronic alcohol use. However, the prevalence of these characteristics in donor lungs utilized for research is currently unknown. This retrospective cohort study procured data of lung transplant donors from Mid-America Transplant from January 2017 until July 2023. The donors were characterized based on lung utilization into three groups - lungs used for research, lungs used for transplant, and lungs not recovered from donors for either research or transplantation. The mean age of donors whose lungs were utilized for research was 41±18 years. 25% of them were expanded criteria donors (ECD) while 10% of the donors in the transplant cohort were ECD. 14% of the donors whose lungs were utilized for research had history of diabetes compared to 8% of donors whose lungs were transplanted. A quarter of the research donor population had positive history of cigarette use within the preceding 20 years. At least 40% of donors had a positive history of non-intravenous drug use, of whom a majority had a history of continued non-intravenous drug use. No strict selection criteria or protocols exist when human donor lungs are obtained for ex-vivo research. There is a high prevalence of diabetes mellitus, history of smoking and non-intravenous drug use along with older age distribution in donors whose lungs used are for research.

Examining the moderating role of cannabis use on the relationship between alcohol consumption and inflammation in individuals with alcohol use disorder.

Inflammation appears to be a critical mechanism in the development of alcohol use disorder (AUD) and a consequence of chronic alcohol use. The potential anti-inflammatory properties of cannabis may modulate the proinflammatory effects of alcohol. This study sought to extend previous work investigating the relationship between alcohol consumption, cannabis use and circulating interleukin (IL)-6 levels in a sample with AUD. One hundred and thirty-three individuals with an AUD provided blood samples to assess IL-6 and answered questions regarding alcohol and cannabis use. An ordinary least squares multiple regression analysis was conducted to assess the effect of alcohol and cannabis use on IL-6. A moderation analysis examined cannabis use as a potential moderator of the relationship between alcohol use and circulating IL-6 levels. Alcohol use was predictive of higher log IL-6 levels (standardized β = 0.16, p = 0.03), while cannabis use was not predictive of log IL-6 levels (p = 0.36). Days of cannabis use moderated the relationship between alcohol use and IL-6 levels, such that the relationship between alcohol use and IL-6 levels was only significant in individuals with AUD without recent cannabis use. This study extends previous work to a clinical sample with an AUD and underscores the importance of considering cannabis use in studies on alcohol use and inflammation. This study also indicates the need for in-depth analyses on cannabinoids and inflammation and the interaction between cannabinoids and alcohol use on inflammation.

A novel alcohol+nicotine co-use self-administration procedure reveals sex differences and differential alteration of mesocorticolimbic TLR- and cholinergic-related neuroimmune gene expression in rats

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.

Parental Alcohol Exposures Associate with Lasting Mitochondrial Dysfunction and Accelerated Aging in a Mouse Model.

Although detrimental changes in mitochondrial morphology and function are widely described symptoms of fetal alcohol exposure, no studies have followed these mitochondrial deficits into adult life or determined if they predispose individuals with fetal alcohol spectrum disorders (FASDs) to accelerated biological aging. Here, we used a multiplex preclinical mouse model to compare markers of cellular senescence and age-related outcomes induced by maternal, paternal, and dual-parental alcohol exposures. We find that even in middle life (postnatal day 300), the adult offspring of alcohol-exposed parents exhibited significant increases in markers of stress-induced premature cellular senescence in the brain and liver, including an upregulation of cell cycle inhibitory proteins and increased senescence-associated β-galactosidase activity. Strikingly, in the male offspring, we observe an interaction between maternal and paternal alcohol use, with histological indicators of accelerated age-related liver disease in the dual-parental offspring exceeding those induced by either maternal or paternal alcohol use alone. Our studies indicate that chronic parental alcohol use causes enduring mitochondrial dysfunction in offspring, resulting in a reduced NAD+/NAHD ratio and altered expression of the NAD+-dependent deacetylases SIRT1 and SIRT3. These observations suggest that some aspects of FASDs may be linked to accelerated aging due to programmed changes in the regulation of mitochondrial function and cellular bioenergetics.

Sex and sobriety: Human brain structure and function in AUD abstinence

Women are drinking alcohol as much as men for the first time in history. Women experience more health-related consequences from alcohol use disorder (AUD), like increased prevalence of alcohol-related cancers, faster progression of alcohol-related liver disease, and greater risk for relapse compared to men. Thus, sex differences in chronic alcohol use pose a substantial public health problem. Despite these evident sex differences, our understanding of how these differences present during alcohol abstinence is limited. Investigations of brain structure and function are therefore critical for disentangling factors that lead to sex differences in AUD abstinence. This review will discuss current human neuroimaging data on sex differences in alcohol abstinence, focusing on structural and functional brain measures. Current structural imaging literature reveals that abstinent men have smaller gray and white matter volume and weaker structural connectivity compared to control men. Interestingly, abstinent women do not show differences in brain structure when compared to controls; instead, abstinent women show a relation between alcohol use and decreased measures of brain structure. Current functional brain studies reveal that abstinent men exhibit greater brain activation and stronger task-based functional connectivity to aversive stimuli than control men, while abstinent women exhibit lesser brain activation and weaker task-based functional connectivity than control women. Together, the current literature suggests that sex differences persist well into alcohol abstinence and impact brain structure and function differently. Understanding how men and women differ during alcohol abstinence can improve our understanding of sex-specific effects of alcohol, which will be critical to augment treatment methods to better serve women.