Chronic Drinking Research Articles

Effects of voluntary chronic intermittent access to ethanol on the behavioral performance in adult C57BL/6 J mice

BackgroundChronic alcohol drinking increases the risk of alcohol use disorders, causing various neurological disorders. However, the impact of different ethanol levels on a spectrum of behaviors during chronic drinking remains unclear. In this study, we established an intermittent access to ethanol in a two-bottle choice (IA2BC) procedure to explore the dose-dependent effects of ethanol on the behavioral performance of C57BL/6 J mice. MethodsAdult male C57BL/6 J mice were provided voluntary access to different ethanol concentrations (0 %, 5 %, 10 %, and 20 % ethanol) under a 12-week IA2BC paradigm. A battery of behavioral tests was administered to assess alterations in pain threshold, anxiety-like behaviors, locomotor activity, motor coordination, and cognition. Ethanol consumption and preference were monitored during each session. Moreover, the liver, heart, and lung tissues were examined using pathological microscopy. ResultsThe average (standard deviation) ethanol consumption of mice under the IA2BC paradigm increased dose-dependently to 5.1 (0.2), 8.7 (0.7), and 15.9 (0.8) g/kg/24 h with 5 %, 10 %, and 20 % ethanol, respectively. However, there is no significant difference in ethanol preference among all the ethanol groups. Chronic ethanol drinking caused hyperalgesia, cognitive impairment, and motor incoordination, but caused no changes in body temperature, locomotor activity, or anxiety-like behaviors. Minor histopathological alterations in the liver were detected; however, no major abnormal pathology was observed in the heart or lungs. ConclusionThese findings clarify the link between ethanol dosage and behavioral changes in mice over a 12-week IA2BC paradigm, thereby bridging the knowledge gap regarding the effects of chronic ethanol drinking on neurological disorders.

Abstract Mo129: Elevation in male sex hormone metabolites with increased risk factors for inflammation and clotting in female kidneys following chronic binge drinking

Background: Binge drinking is a major systemic health concern. Binge drinking could alter renal metabolome and induce markers of injury as per our previously published work. Further investigation into the top regulated pathways revealed alterations sex hormone biosynthesis pathway was altered in a sex specific manner following 6 weeks of binge drinking. Our goal is to unveil individual metabolite mediators belonging to sex hormone biosynthesis pathway and to investigate the connecting link to cardiorenal health in both sexes following chronic binge drinking. Materials and Methods: For this work, n=3 male and female mice belonging to either control (water fed) or ethanol (20% fed in water) treatment groups were included. At the age of 8- 10 weeks, mice underwent water or binge (20% ethanol) drinking from Monday to Thursday for 4 hours, in dark cycle. This cycle was repeated for 6 weeks. Renal tissues from our experimental groups were collected at the end of 6 weeks and subjected to untargeted metabolomics. In brief, Ultra Performance Liquid Chromatography (UPLC) with Time-of-flight Mass Spectrometry (ESI-TOF-MS) followed by Mass spectrometry based separation was used to identify significantly altered metabolites. Results: Steroid hormone biosynthesis was the one among the top regulated pathways. Metabolites belonging to male hormone biosynthesis were the significantly altered one but specifically in females. Dehydroepiandrosterone, and it’s downstream 11-hydroxytestosterone were upregulated only in females and not in males. Female binge drinking group demonstrated an increase of 4.24 (fold) and 2.21 (fold) for dehydroepiandrosterone, and 11-hydroxytestosterone respectively as per the Log 2 Fold change values with a statistical significance of P<0.05 . Interestingly, this increase in male hormone metabolites we observed in females were also accompanied by an increase in metabolites of proinflammatory and prothrombotic mediators, thromboxane B3 and 5- Oxo- 12 HETE, of 2.3 (fold) and over 1.6 (fold) respectively as per Log 2 Fold change values and with a statistical difference of P<0.05 . Conclusion: Our data clearly demonstrate a sex specific effect following chronic binge drinking, where females have an increase in male hormones accompanied by an increase in prothrombotic and proinflammatory factors.

Dynamic regulation of CeA gene expression during acute and protracted abstinence from chronic binge drinking of male and female C57BL/6J mice

While there are numerous brain regions that have been shown to play a role in this AUD in humans and animal models, the central nucleus of the amygdala (CeA) has emerged as a critically important locus mediating binge alcohol consumption. In this study, we sought to understand how relative gene expression of key signaling molecules in the CeA changes during different periods of abstinence following bouts of binge drinking. To test this, we performed drinking in the dark (DID) on two separate cohorts of C57BL/6J mice and collected CeA brain tissue at 1 day (acute) and 7 days (protracted) abstinence after DID. We used qRTPCR to evaluate relative gene expression changes of 25 distinct genes of interest related to G protein-coupled receptors (GPCRs), neuropeptides, ion channel subunits, and enzymes that have been previously implicated in AUD. Our findings show that during acute abstinence CeA punches collected from female mice had upregulated relative mRNA expression of the gamma-aminobutyric acid receptor subunit alpha 2 (Gabra2), and the peptidase, angiotensinase c (Prcp). CeA punches from male mice at the same time point in abstinence had upregulated relative mRNA encoding for neuropeptide-related molecules, neuropeptide Y (Npy) and somatostatin (Sst), as well as the neuropeptide Y receptor Y2 (Npyr2), but downregulated Glutamate ionotropic receptor NMDA type subunit 1 (Grin1). After protracted abstinence, CeA punches collected from female mice had increased mRNA expression of corticotropin releasing hormone (Crh) and Npy. CeA punches collected from male mice at the same timepoint had upregulated relative mRNA expression of Npy2r, Npy, and Sst. Our findings support that there are differences in how the CeA of male and female mice respond to binge-alcohol exposure, highlighting the need to understand the implications of such differences in the context of AUD and binge drinking behavior.

Hepatic LRP-1 plays an important role in amyloidosis in Alzheimer's disease mice: Potential role in chronic heavy alcohol feeding

BackgroundHepatic lipoprotein receptor-related protein 1 (LRP-1) plays a central role in peripheral amyloid beta (Aβ) clearance, but its importance in Alzheimer's disease (AD) pathology is understudied. Our previous work showed that intragastric alcohol feeding to C57BL/6 J mice reduced hepatic LRP-1 expression which correlated with significant AD-relevant brain changes. Herein, we examined the role of hepatic LRP-1 in AD pathogenesis in APP/PS1 AD mice using two approaches to modulate hepatic LRP-1, intragastric alcohol feeding to model chronic heavy drinking shown by us to reduce hepatic LRP-1, and hepato-specific LRP-1 silencing. MethodsEight-month-old male APP/PS1 mice were fed ethanol or control diet intragastrically for 5 weeks (n = 7–11/group). Brain and liver Aβ were assessed using immunoassays. Three important mechanisms of brain amyloidosis were investigated: hepatic LRP-1 (major peripheral Aβ regulator), blood-brain barrier (BBB) function (vascular Aβ regulator), and microglia (major brain Aβ regulator) using immunoassays. Spatial LRP-1 gene expression in the periportal versus pericentral hepatic regions was confirmed using NanoString GeoMx Digital Spatial Profiler. Further, hepatic LRP-1 was silenced by injecting LRP-1 microRNA delivered by the adeno-associated virus 8 (AAV8) and the hepato-specific thyroxine-binding globulin (TBG) promoter to 4-month-old male APP/PS1 mice (n = 6). Control male APP/PS1 mice received control AAV8 (n = 6). Spatial memory and locomotion were assessed 12 weeks after LRP-1 silencing using Y-maze and open-field test, respectively, and brain and liver Aβ were measured. ResultsAlcohol feeding reduced plaque-associated microglia in APP/PS1 mice brains and increased aggregated Aβ (p < 0.05) by ELISA and 6E10-positive Aβ load by immunostaining (p < 0.05). Increased brain Aβ corresponded with a significant downregulation of hepatic LRP-1 (p < 0.01) at the protein and transcript level, primarily in pericentral hepatocytes (zone 3) where alcohol-induced injury occurs. Hepato-specific LRP-1 silencing significantly increased brain Aβ and locomotion hyperactivity (p < 0.05) in APP/PS1 mice. ConclusionChronic heavy alcohol intake reduced hepatic LRP-1 expression and increased brain Aβ. The hepato-specific LRP-1 silencing similarly increased brain Aβ which was associated with behavioral deficits in APP/PS1 mice. Collectively, our results suggest that hepatic LRP-1 is a key regulator of brain amyloidosis in alcohol-dependent AD.

Sex differences in basal motivated behavior, chronic ethanol drinking, and amygdala activity in female and male mice

Alcohol use disorder (AUD) is a major public health concern that despite its prevalence, lacks a widely-effective treatment due to the complexity of AUD pathology. AUD is highly comorbid with other psychiatric conditions including anxiety and mood disorders, however it is unclear how these disorders influence each other. The underlying etiology of these comorbidities is difficult to decipher and factors including sex, stress, and the environment further complicate both diagnosis and treatment strategies. To understand more about this bidirectional relationship between AUD and comorbid psychiatric disorders, we ran male and female C57Bl/6j mice through baseline behavioral testing followed by intermittent access-two bottle choice (IA-2BC) drinking. We found no sex differences in basal anxiety-like or depressive-like behavior, however females displayed enhanced motivated feeding behavior. Females consumed more ethanol than males, at both 1hr and 24hr timepoints. Basal affective state did not predict subsequent ethanol intake in either sex, however exploratory behavior was positively correlated with drinking in males but not females. We then re-assessed negative affect behavior following chronic ethanol drinking to determine if drinking impacted subsequent affective behavior and found no relationship between ethanol intake and affective state in males or females. We also examined how chronic ethanol drinking affected central amygdala (CeA) and basolateral amygdala (BLA) neuronal activity in males and females. Ethanol-drinking females had a decrease in CeA neuronal activity, driven by reduced activity in the lateral (CeAl) sub-region, while in males there was no significant difference in CeA activity compared to water controls. Neither males or females had a significant change in BLA neuronal activity following chronic ethanol drinking. Collectively, these results demonstrate sex differences in basal motivated behavior, drinking behavior, and subregion-specific amygdala neuronal activity following chronic ethanol drinking which may inform the sex differences seen in patients diagnosed with AUD and comorbid conditions.

Differential regulation of G protein-coupled receptor-associated proteins in the caudate and the putamen of cynomolgus macaques following chronic ethanol drinking.

The dorsal striatum is composed of the caudate nucleus and the putamen in human and non-human primates. These two regions receive different cortical projections and are functionally distinct. The caudate is involved in the control of goal-directed behaviors, while the putamen is implicated in habit learning and formation. Previous reports indicate that ethanol differentially influences neurotransmission in these two regions. Because neurotransmitters primarily signal through G protein-coupled receptors (GPCRs) to modulate neuronal activity, the present study aimed to determine whether ethanol had a region-dependent impact on the expression of proteins that are involved in the trafficking and function of GPCRs, including G protein subunits and their effectors, protein kinases, and elements of the cytoskeleton. Western blotting was performed to examine protein levels in the caudate and the putamen of male cynomolgus macaques that self-administered ethanol for 1 year under free access conditions, along with control animals that self-administered an isocaloric sweetened solution under identical operant conditions. Among the 18 proteins studied, we found that the levels of one protein (PKCβ) were increased, and 13 proteins (Gαi1/3, Gαi2, Gαo, Gβ1γ, PKCα, PKCε, CaMKII, GSK3β, β-actin, cofilin, α-tubulin, and tubulin polymerization promoting protein) were reduced in the caudate of alcohol-drinking macaques. However, ethanol did not alter the expression of any proteins examined in the putamen. These observations underscore the unique vulnerability of the caudate nucleus to changes in protein expression induced by chronic ethanol exposure. Whether these alterations are associated with ethanol-induced dysregulation of GPCR function and neurotransmission warrants future investigation.

Restoring Cardiac Health: Abstinence Leads to Recovery from Alcohol-Induced Cardiomyopathy

Chronic drinking can lead to alcohol-induced cardiomyopathy (ACM), a disease currently without a cure. Using a mouse model of ACM, we observed significant cardiac dysfunction after 30 days. Our study’s goal was to investigate the potential restoration of cardiac function following a period of abstinence. Our hypothesis is that abstinence can lead to an observable recovery in overall cardiac function. C57BL/6J mice were given the Lieber-DeCarli liquid diet with 5% ethanol for 30 days, with two ethanol binges on days 10 and 30 (5 g/kg). After the 30-day ethanol exposure, the mice were transitioned to an ethanol-free diet for an additional 30 days. Left ventricular catheterization and echocardiography were conducted at the 30- and 60-day timepoints. 30 days of ethanol consumption led to significant decreases in both systolic and diastolic function. However, following a period of alcohol abstinence, there was a marked improvement. Specifically, the 30-day ethanol mice exhibited increases in stroke work and dP/dt max after 30 days of abstinence; stroke work increased from 1119 ± 89 mmHg*μL to 2032 ± 139 mmHg*μL (p &lt; 0.0001), and dP/dt max increased from 8054 ± 664 mmHg/s to 11967 ± 449 mmHg/s (p &lt; 0.001). Diastolic function also improved; dP/dt min from -7711 ± 561 mmHg/s to -10202 ± 594 (p &lt; 0.01). We also found a significant increase in load-independent cardiac contractility, i.e. the slope of end systolic pressure volume relation: 6.89 ± 0.6 mmHg/μL to 10.59 ± 1.57 mmHg/μL (p &lt; 0.05). In conclusion, abstinence after chronic ethanol exposure can lead to a restoration of cardiac function in C57BL/6J mice. This model parallels limited clinical data on abstinence and will allow us to study the underlying mechanisms responsible for the restoration of function. R21AA029747 (JG, CB), F30AA030472 (JE). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A Brief Review on Korsakoff Syndrome

Korsakoff Syndrome (KS) is a residual syndrome which is characterized with neuropsychological conditions affecting the daily life of chronic drinkers of alcohol. Sergei Korsakoff is a Russian neuropsychiatrist, in the year 1887 given a note on the Korsakoff syndrome which is characterized by an extraordinary peculiar amnesia which has been associated with peripheral inflammation of the nerves. This syndrome can be chronic in onset and remains permanent. The person suffering with KS can be observed with cognitive and behavioral dysfunction. The symptoms of amnesia, executive dysfunction, confabulation, apathy and social-cognitive impairments can be observed in these affected patients. In the aspect of the pharmacological treatment of KS sufficient concentration of thiamine should be administered parenterally. In alcoholic patients, the doses of thiamine can be administered approximately 500mg or above but the evidence in this aspect is less available. Compared to the pharmacological therapy, the rehabilitation programme can be more helpful to the patients with KS. Among six studies, evidence was produced that some of the techniques which can be helpful for the compensation of memory can include use of agendas, memory cards, gadgets like mobiles and smart watches can be helpful in the patients with KS. For the better improvement of the cognition, interventions associated with errorless learning can be possible theoretically. In this learning process the patients are not permitted to make any errors. This may also support the semantic learning process.

Hemorrhagic Strokes Attributable to Chronic Alcohol Consumption and Heavy Episodic Drinking in France.

To estimate the number of cases and deaths related to hemorrhagic stroke (HS) attributable to a chronic alcohol consumption and to heavy episodic drinking (HED) in France. A population-attributable fraction (PAF) estimation approach was used. Relative risks for HS with alcohol consumption were extracted from the INTERSTROKE study. Levels of alcohol consumption in the French population were collected from the 2017 Health Barometer. Data on HS morbidity and mortality were extracted from the French National Health Data System (SNDS). We estimated that 7.2% (n = 2,100) and 6.6% (n = 1,900) of cases with HS were attributable to chronic alcohol consumption and HED, respectively. PAFs were higher in men than in women with 11.5% vs 2.6% for a chronic consumption and 10.7% vs 2.1% for HED, respectively. We estimated that 7.0% of HS deaths (n = 1,100) were attributable to chronic alcohol consumption and 5.1% attributable to HED (n = 800). Finally, 16.3% of patients with HS (n = 4,700) and 14.1% of HS deaths (n = 2,300) were attributable to overall chronic alcohol consumption or to monthly HED. These results remind the importance of alcohol consumption in the occurrence of HS and the importance of implementing primary and secondary prevention measures, particularly among young people, where HED is most common.

Estrogen signaling in the dorsal raphe regulates binge-like drinking in mice

Estrogens promote binge alcohol drinking and contribute to sex differences in alcohol use disorder. However, the mechanisms are largely unknown. This study aims to test if estrogens act on 5-hydroxytryptamine neurons in the dorsal raphe nucleus (5-HTDRN) to promote binge drinking. We found that female mice drank more alcohol than male mice in chronic drinking in the dark (DID) tests. This sex difference was associated with distinct alterations in mRNA expression of estrogen receptor α (ERα) and 5-HT-related genes in the DRN, suggesting a potential role of estrogen/ERs/5-HT signaling. In supporting this view, 5-HTDRN neurons from naïve male mice had lower baseline firing activity but higher sensitivity to alcohol-induced excitation compared to 5-HTDRN neurons from naïve female mice. Notably, this higher sensitivity was blunted by 17β-estradiol treatment in males, indicating an estrogen-dependent mechanism. We further showed that both ERα and ERβ are expressed in 5-HTDRN neurons, whereas ERα agonist depolarizes and ERβ agonist hyperpolarizes 5-HTDRN neurons. Notably, both treatments blocked the stimulatory effects of alcohol on 5-HTDRN neurons in males, even though they have antagonistic effects on the activity dynamics. These results suggest that ERs’ inhibitory effects on ethanol-induced burst firing of 5-HTDRN neurons may contribute to higher levels of binge drinking in females. Consistently, chemogenetic activation of ERα- or ERβ-expressing neurons in the DRN reduced binge alcohol drinking. These results support a model in which estrogens act on ERα/β to prevent alcohol-induced activation of 5-HTDRN neurons, which in return leads to higher binge alcohol drinking.

Histone deacetylase inhibitor decreases hyperalgesia in a mouse model of alcohol withdrawal-induced hyperalgesia.

Alcohol withdrawal-induced hyperalgesia (AWH) is characterized as an increased pain sensitivity observed after cessation of chronic alcohol use. Alcohol withdrawal-induced hyperalgesia can contribute to the negative affective state associated with abstinence and can increase susceptibility to relapse. We aimed to characterize pain sensitivity in mice during withdrawal from two different models of alcohol exposure: chronic drinking in the dark (DID) and the Lieber-DeCarli liquid diet. We also investigated whether treatment with a histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), could ameliorate AWH in mice treated with the Lieber-DeCarli diet. Male and female C57BL/6J mice were used for these studies. In the DID model, mice received bottles of 20% ethanol or water during the dark cycle for 4 h per day on four consecutive days per week for 6 weeks. Peripheral mechanical sensitivity was measured weekly the morning of Day 5 using von Frey filaments. In the Lieber-DeCarli model, mice received ethanol (5% v/v) or control liquid diet for 10 days, along with a single binge ethanol gavage (5 g/kg) or control gavage, respectively, on Day 10. Peripheral mechanical sensitivity was measured during the liquid diet administration and at 24 and 72 h into ethanol withdrawal. An independent group of mice that received the Lieber-DeCarli diet were administered SAHA (50 mg/kg, i.p.) during withdrawal. Male mice exhibited mechanical hypersensitivity after consuming ethanol for 5 weeks in the DID procedure. In the Lieber-DeCarli model, ethanol withdrawal led to hyperalgesia in both sexes. Suberoylanilide hydroxamic acid treatment during withdrawal from the ethanol liquid diet alleviated AWH. These results demonstrate AWH in mice after chronic binge drinking in males and after Lieber-DeCarli liquid diet administration in both sexes. Like previous findings in rats, HDAC inhibition reduced AWH in mice, suggesting that epigenetic mechanisms are involved in AWH.

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.

Sex differences in binge alcohol drinking and the behavioral consequences of protracted abstinence in C57BL/6J mice.

Binge alcohol drinking is a risk factor linked to numerous disease states including alcohol use disorder (AUD). While men binge drink more alcohol than women, this demographic gap is quickly shrinking, and preclinical studies demonstrate that females consistently consume more alcohol than males. Further, women are at increased risk for the co-expression of AUD with neuropsychiatric diseases such as anxiety and mood disorders. However, little is understood about chronic voluntary alcohol drinking and its long-term effects on behavior. Here, we sought to characterize sex differences in chronic binge drinking and the effects of protracted alcohol abstinence on anxiety- and affective-related behaviors in males and females. We assessed binge alcohol drinking patterns in male and female C57BL/6J mice using a modified Drinking in the Dark (DID) paradigm in which mice received home cage access to one bottle of 10% or 20% alcohol (EtOH) or water for 2h per day on Days 1-3 and to two bottles (EtOH/H2O + H2O) for 24h on Day 4 for 8 weekly cycles. Mice were then tested for the effects of protracted abstinence on avoidance, affective, and compulsive behaviors. Female mice consumed more alcohol than males consistently across cycles of DID and at 2, 4, and 24-h timepoints within the day, with a more robust sex difference for 20% than 10% EtOH. Females also consumed more water than males, an effect that emerged at the later time points; this water consumption bias diminished when alcohol was available. Further, while increased alcohol consumption was correlated with decreased water consumption in males, there was no relationship between these two measures in females. Alcohol preference was higher in 10% vs. 20% EtOH for both sexes. During protracted abstinence following chronic binge drinking, mice displayed decreased avoidance behavior (elevated plus maze, open field, novelty suppressed feeding) and increased compulsive behavior (marble burying) that was especially robust in females. There was no effect of alcohol history on stress coping and negative affective behaviors (sucrose preference, forced swim test, tail suspension) in either sex. Female mice engaged in higher volume binge drinking than their male counterparts. Although females also consumed more water than males, their higher alcohol consumption was not driven by increased total fluid intake. Further, the effects of protracted abstinence following chronic binge drinking was driven by behavioral disinhibition that was more pronounced in females. Given the reciprocal relationship between risk-taking and alcohol use in neuropsychiatric disease states, these results have implications for sex-dependent alcohol drinking patterns and their long-term negative neuropsychiatric/physiological health outcomes in humans.

Analytical description of adolescent binge drinking patients

BackgroundBinge drinking is a widespread health compromising behavior among adolescents and young adults, leading to significant health problems, injuries and mortality. However, data on alcohol consumption is often unreliable, as it is mainly based on self-reporting surveys. In this five-year study (2014–2019) at the University Children’s Hospital Zurich, we analyzed blood samples from adolescent binge drinking patients to investigate blood alcohol concentrations (BACs), co-ingestion of drugs, assess compliance between self-reported and measured substance use, and test for genetic components of innate alcohol tolerance. Furthermore, hair analysis was performed to retrospectively access drug exposure and to evaluate the potential of hair analysis to assess binge drinking.MethodsIn a prospective, single-center study, patients with alcohol intoxications aged 16 years and younger were included. Blood and hair samples were analyzed by sensitive liquid chromatography – tandem mass spectrometry drug analysis. HTTLPR genotyping was performed with PCR and fragment analysis.ResultsAmong 72 cases, 72 blood and 13 hair samples were analyzed. BACs ranged from 0.08–3.20‰ (mean 1.63‰, median 1.60‰), while a mean concentration of 3.64 pg/mg hair (median 3.0 pg/mg) of the alcohol marker ethyl glucuronide (EtG) was detected in eleven hair samples, providing no evidence of chronic excessive drinking. In 47% of the cases, co-ingested drugs were qualitatively detected next to ethanol, but only 9% of the detected drugs had blood concentrations classified as pharmacologically active. Cannabis consumption (22%) and stimulant intake (16%) were the most frequently observed drugs. Compliance between patients’ statements and measured substances matched well. Although we investigated the genetic contribution to innate alcohol tolerance via the 5-HTTLPR polymorphism, the diverse genetic background of the cohort and small sample size did not allow any conclusions to be drawn.ConclusionAlmost half of our binge drinking patients tested positive for other substances, primarily cannabis. We anticipate that our study enhances understanding of consumption behavior of young people and encourage continued efforts to address the harmful effects of binge drinking and co-occurring substance use.

Marchiafava–Bignami disease after the white matter lesions: A case report

AbstractMarchiafava–Bignami disease (MBD) is an uncommon alcoholism‐related neuropsychiatric disorder, featured with symmetrical demyelination of part or whole corpus callosum (CC). Previous studies reported follow‐up neuroimaging changes with necrosis, cystic degeneration, and atrophy of the CC after the diagnosis of MBD, but it is unclear whether the white matter is damaged before MBD. We report a case of alcoholic MBD whose magnetic resonance imaging revealed structural lesions in the white matter before the typical demyelination of CC during MBD, which support the prior hypothesis that chronic hazardous drinking may initially lead to microstructure abnormalities of the white matter and CC through some possible mechanisms, then microstructure lesions in the CC, and white matter deterioration into extensive demyelination, that is MBD. In future clinical practice, when patients with chronic alcoholism seek treatment for neuropsychiatric disorders, they may need to undergo repeated MRI scans to reveal progressive neuroimaging features before and after MBD.

SAT160 Alcoholic Ketoacidosis : An Endocrine Emergency

Abstract Disclosure: L.E. Tiu: None. T.D. Crisostomo: None. Background: Alcoholic Ketoacidosis is a complex metabolic condition frequently confused with Diabetic Ketoacidosis. Currently, there remains an undefined consensus guideline in the diagnosis and management of this disorder that leads to unreported cases. Clinical Case: A 47-year-old male presented with 2-day history of poor dietary intake due to abdominal pain and vomiting after an alcoholic binge drinking. He is a chronic alcoholic beverage drinker (2 liters of beer per day for 10 years). He has family history of Type 2 Diabetes Mellitus but has no known co-morbidities. Upon admission, vital signs were normal, but he was drowsy and incoherent with signs of dehydration and epigastric tenderness. Initial capillary blood glucose was 52 mg/dL. D50W 50ml intravenously was given with repeat CBG of 222 mg/dL. Arterial blood gas (ABG) showed high anion gap metabolic acidosis (pH 7.0 and anion gap of 42) with undetectable bicarbonate and elevated lactate at 17mmol/L. Serum ketones were elevated at 6mmol/L but Hba1c was normal at 4.6 %. Thus, Alcoholic Ketoacidosis was highly considered. Intravenous hydration with saline solution was instituted then shifted to D10W 125mL/hour to allow insulin infusion therapy at initial rate of 2units/hour. Sodium bicarbonate 100 mEqs was given intravenously with recovery of sensorium thereafter. Oral Vitamin B supplement was started, and two doses of Thiamine 100 mg/IV were given. Other tests showed hyperkalemia (5.28meq/L), hypochloridemia (89.7meq/L), hyperuricemia (12.74mg/dL), and hyperphosphatemia (5.8mg/dL). Serial monitoring and correction of electrolytes were done. Moreover, management integrated simultaneous referrals to other subspecialties to rule out other causes of encephalopathy, to evaluate and manage Hypertriglyceridemic Pancreatitis and Alcoholic Liver Disease, and to facilitate nutritional, psychosocial support and rehabilitation. On 2nd hour, repeat ABG showed improvement of pH to 7.3 and HCO3 to 9.80mmol/L. Lactate decreased to 12.70mmol/L. On the 17th hour, ABG showed metabolic alkalosis with resolution of ketosis hence insulin was discontinued. CBG levels for the next 24-48 hours were within normal limits. Oral feeding was supplemented with parenteral nutrition due to decreased appetite. On 48th hour, he displayed combative behavior with visual hallucinations, but there was no consent for psychiatric referral. On 72nd hour, there was spontaneous marked improvement in his behavior. He was discharged clinically stable. Conclusion: Early recognition of Alcoholic Ketoacidosis is imperative. This is an unrecognized endocrine emergency that portends good outcome with timely diagnosis and management. Treatment includes 1. adequate fluid resuscitation 2. thiamine 3. judicious use of insulin and bicarbonate 4. correction of electrolytes 5. multidisciplinary team management. Presentation: Saturday, June 17, 2023

Chronic alcohol consumption dysregulates innate immune response to SARS-CoV-2 in the lung

Alcohol consumption is widespread with over half of the individuals over 18 years of age in the U.S. reporting alcohol use in the last 30 days. Moreover, 9 million Americans engaged in binge or chronic heavy drinking (CHD) in 2019. CHD negatively impacts pathogen clearance and tissue repair, including in the respiratory tract, thereby increasing susceptibility to infection. Although, it has been hypothesized that chronic alcohol consumption negatively impacts COVID-19 outcomes; the interplay between chronic alcohol use and SARS-CoV-2 infection outcomes has yet to be elucidated. In this study we employed luminex, scRNA sequencing, and flow cytometry to investigate the impact of chronic alcohol consumption on SARS-CoV-2 anti-viral responses in bronchoalveolar lavage cell samples from humans with alcohol use disorder and rhesus macaques that engaged in chronic drinking. Our data show that in both humans (n=6) and macaques (n=11), the induction of key antiviral cytokines and growth factors was decreased with chronic ethanol consumption. Moreover, in macaques fewer differentially expressed genes mapped to Gene Ontology terms associated with antiviral immunity following 6 month of ethanol consumption while TLR signaling pathways were upregulated. These data are indicative of aberrant inflammation and reduced antiviral responses in the lung with chronic alcohol drinking. This study was supported by NIH 1R01AA028735-04 (Messaoudi), U01AA013510-20 (Grant), R24AA019431-14 (Grant), R24AA019661 (Burnham), P-51OD011092 (ONPRC core grant support). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

알코올 사용장애와 알츠하이머 병 환자의 인지기능 평가 차이에 관한 비교 연구

Objectives: There are a few studies on how much and which cognitive function is specifically damaged by chronic alcohol drinking. By comparing neurocognitive function test results between patients with alcohol use disorder and those with Alzheimer’s disease, we aimed to find out which neurocognitive function is damaged by chronic alcohol drinking. In addition, we investigated whether the structural changes in the brain were related to cognitive function decline.&#x0D; Methods: Korean Wechsler Adult Intelligence Scale-IV and Seoul Neuropsychological Screening Battery-II were performed among patients who were diagnosed with Alzheimer’s disease and those who were diagnosed with alcohol use disorder at the department of psychiatry in Pusan National University Yangsan Hospital from November 2008 to May 2022. Among the neurocognitive domains, intelligence quotient, memory quotient, executive intelligence quotient, auditory attention and visual attention were compared. Among those who underwent cognitive function tests, the reading results for brain CT or MRI were compared.&#x0D; Results: There was no significant difference between the two groups in visual attention (p=0.219). Meanwhile, structural changes in the brain were less in the alcohol use disorder group compared to the Alzheimer’s disease group.&#x0D; Conclusion: Chronic drinking, impaired especially, visual attention to the level of Alzheimer’s disease at a relatively early age. Additional research on cognitive function impairment in alcohol use disorders is needed, referring to the results of this study.

Metadehumanization, fundamental needs and coping strategies: A comparison of drinkers at low versus high risk of alcohol use disorder

The interpersonal difficulties documented in chronic excessive drinking might foster the progression toward severe alcohol use disorder (SAUD). Characterizing these interpersonal difficulties and their commonalities with patients already presenting a diagnosed SAUD is needed to develop targeted prophylactic interventions. Patients with SAUD present metadehumanization (i.e., the perception of being considered as less than human by others), which is associated with deleterious consequences (e.g., reduced fundamental needs satisfaction, increased negative emotions, reduced self-esteem, disrupted coping strategies) involved in the persistence of this disorder. No study has investigated metadehumanization among individuals not diagnosed with SAUD but at high risk of alcohol use disorder. We measured metadehumanization, emotions, self-esteem, coping strategies, and fundamental needs threat among such high-risk drinkers (N = 86; AUDIT score higher than 15), and matched low-risk drinkers (N = 100, AUDIT score <8). Compared to low-risk drinkers, high-risk drinkers felt more dehumanized and reported increased fundamental needs threat, negative emotions, anxiety, depression, and more frequent use of both adaptive and maladaptive coping strategies, including alcohol use. Mediation analyses controlling for anxiety/depression revealed that the differences in emotions and coping strategies were explained by metadehumanization and fundamental needs threat. Despite not being diagnosed with SAUD and being untreated, high-risk drinkers are more similar to patients with SAUD than to low-risk drinkers. In view of its links with factors favoring SAUD, metadehumanization should be considered in experimental studies among high-risk drinkers and treated by specific interventions.

Significance of Selected Environmental and Biological Factors on the Risk of FASD in Women Who Drink Alcohol during Pregnancy.

Prenatal alcohol exposure (PAE), which refers to alcohol consumption by pregnant women, is associated with the risk of numerous severe complications during fetal development. The State Agency for Alcohol Problem Solving reports that the incidence of fetal alcohol spectrum disorder (FASD) in Poland's general population is over 1.7%, and the incidence of fetal alcohol syndrome (FAS) is estimated at more than 0.5%. This study aimed to evaluate the significance of alcohol exposure and focused on the pattern of alcohol intoxication exhibited by the mother during pregnancy and other environmental factors of the maternal environment contributing to the development of FASD. The study covered 554 subjects, including 251 mothers and 303 children (213 girls and 90 boys). The mother's drinking problem was determined based on the information obtained from the case history. All children qualified for the study fulfilled the h-PAE (high alcohol exposure) criteria during their fetal life. The clinical diagnosis of FAS and pFAS (occurrence of morphological symptoms of fetal alcohol syndrome) was made using a four-digit diagnostic questionnaire validated in the Polish version of the Washington Questionnaire for the assessment of the spectrum of alcohol-related neurodevelopmental disorders or alcohol-related cognitive impairment (ARND/C). Statistical analysis of the obtained research results was developed using statistical software-STATISTICA PL, version 13.1 (StatSoft, Inc., Szczecin, Poland 2016, STATISTICA-data analysis software system, version 13.1). The most destructive drinking behaviors are compulsive intoxication (BD, binge drinking) during the first 6 weeks of pregnancy and chronic addiction throughout its duration (CHD, chronic drinking). Chronic alcohol intoxication (CHD) leads to a poorer nutritional status in mothers, which is reflected in a lower body mass index (BMI) (<18 kg/m2).