RESUMEN
Despite a lack of clinical data demonstrating the effectiveness of alcohol swab cleansing prior to vaccinations as a prophylactic measure to prevent skin infections, it is recommended for vaccine administration by the Canadian Immunization Guide. The objective of this study was to evaluate the risk of adverse events after omitting alcohol skin cleansing in long-term care (LTC) residents receiving vaccinations during the COVID-19 pandemic. Two medium-sized LTC homes participated in a cohort study, whereby one LTC used alcohol swab cleansing prior to resident vaccinations and the other did not. All residents received two doses of the BNT162b2 COVID-19 vaccine separated by an average (SD) 29.3 (8.5) days. The electronic chart records of participants were reviewed by researchers blinded to group allocation to assess for the presence of adverse events following immunization (AEFI), including reactogenicity, cellulitis, abscess, or systemic reactions. Log-binomial regression was used to compute risk ratios (with 95% confidence intervals) of an AEFI according to alcohol swab status. 189 residents were included, with a total of 56 AEFI between the two doses. The risk of reactogenicity (adjusted RR 0.54, 95% CI 0.17-1.73) or systemic reactions (adjusted RR 0.75, 95% CI 0.26-2.13) did not differ for the residents that received alcohol skin antisepsis compared to those that did not. There were no cases of cellulitis or abscess. This study did not demonstrate an elevated risk of AEFI in LTC residents receiving two doses of the BNT162b2 mRNA COVID vaccine without alcohol skin antisepsis.
Asunto(s)
Vacuna BNT162 , Vacunas contra la COVID-19 , COVID-19 , Cuidados a Largo Plazo , Vacunación , Humanos , Masculino , Femenino , COVID-19/prevención & control , Anciano , Estudios de Cohortes , Vacuna BNT162/administración & dosificación , Vacuna BNT162/efectos adversos , Vacunación/efectos adversos , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/administración & dosificación , Anciano de 80 o más Años , SARS-CoV-2/inmunología , Canadá , Etanol/efectos adversos , Etanol/administración & dosificaciónRESUMEN
BACKGROUND: Portal hypertension affects hepatic, splanchnic and portosystemic collateral systems. Although alcohol is a well-known risk factor for liver cirrhosis, it also affects vascular contractility. However, the relevant effects on portal hypertension have not been evaluated in non-alcoholic cirrhosis. The present study aimed to investigate the impacts of low-dose alcohol on portal hypertension-related derangements in non-alcoholic cirrhotic rats. METHODS: Sprague-Dawley rats received bile duct ligation to induce cirrhosis or sham operation as controls. The chronic or acute effects of low-dose alcohol (2.4 g/kg/day, oral gavage, approximately 1.3 drinks/day in humans) were evaluated. RESULTS: The chronic administration of low-dose alcohol did not precipitate liver fibrosis in the sham or cirrhotic rats; however, it significantly increased splanchnic blood inflow (P=0.034) and portosystemic collaterals (P=0.001). Mesenteric angiogenesis and pro-angiogenic proteins were up-regulated in the alcohol-treated cirrhotic rats, and poorer collateral vasoresponsiveness to vasoconstrictors (P<0.001) was noted. Consistently, acute alcohol administration reduced splenorenal shunt resistance. Collateral vasoresponsiveness to vasoconstrictors also significantly decreased (P=0.003). CONCLUSIONS: In non-alcoholic cirrhosis rats, a single dose of alcohol adversely affected portosystemic collateral vessels due to vasodilatation. Long-term alcohol use precipitated splanchnic hyperdynamic circulation, in which mesenteric angiogenesis played a role. Further studies are warranted to evaluate the benefits of avoiding low-dose alcohol consumption in patients with non-alcoholic cirrhosis.
Asunto(s)
Etanol , Hipertensión Portal , Cirrosis Hepática , Ratas Sprague-Dawley , Circulación Esplácnica , Animales , Etanol/administración & dosificación , Masculino , Ratas , Circulación Esplácnica/efectos de los fármacos , Cirrosis Hepática/fisiopatología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Hipertensión Portal/fisiopatología , Hipertensión Portal/etiología , Hipertensión Portal/inducido químicamente , Hipertensión Portal/patología , Circulación Colateral/efectos de los fármacos , Vasoconstricción/efectos de los fármacosRESUMEN
BACKGROUND: Methamphetamine is frequently co-consumed with alcohol, yet combined effects on visually guided behaviours have not been experimentally assessed. This study examined whether methamphetamine and alcohol-induced changes in gaze behaviour can be accurately detected and indexed during a simulated driving task to establish characteristic patterns relevant to traffic safety. METHODS: In a randomised, placebo-controlled, cross-over study design, the effects of acute oral methamphetamine (0.42 mg/kg) were assessed with and without low doses of alcohol (target 0.04% blood alcohol content) on gaze behaviour during driving. Twenty healthy adults (mean age 29.5 years (SD ± 4.9), 40% female) completed four, 1-h simulated drives with simultaneous eye monitoring using the SensoMotoric Instruments cap-mounted eye tracker over a 4-week experimental paradigm. Gaze entropy measures were used to quantify visual scanning efficiency, expressed as gaze transition entropy and stationary gaze entropy. Fixations, recorded as duration (milliseconds, ms) and rate (count) per minute, were examined in 10-min bins over the duration of the drive. Driving performance was assessed by the standard deviation of lateral position, standard deviation of speed and steering variability. RESULTS: Methamphetamine increased the rate and duration of fixations and produced a less dispersed but more disorganised pattern of gaze during highway driving while preserving performance. Alcohol alone impaired both oculomotor control and driving performance, even when consumed at levels well below the legal limit stipulated in many international jurisdictions. CONCLUSIONS: Methamphetamine-affected drivers display inefficient exploration in a limited visual range during driving. Eye-tracking metrics thus show potential for indexing intoxication due to psychoactive substance usage.
Asunto(s)
Consumo de Bebidas Alcohólicas , Conducción de Automóvil , Estudios Cruzados , Metanfetamina , Humanos , Femenino , Masculino , Método Doble Ciego , Adulto , Metanfetamina/administración & dosificación , Adulto Joven , Tecnología de Seguimiento Ocular , Movimientos Oculares/efectos de los fármacos , Fijación Ocular/efectos de los fármacos , Fijación Ocular/fisiología , Etanol/farmacología , Etanol/administración & dosificación , Desempeño Psicomotor/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Estimulantes del Sistema Nervioso Central/administración & dosificaciónRESUMEN
The mechanisms contributing to alcohol use disorder (AUD) are complex and the orexigenic peptide ghrelin, which enhances alcohol reward, is implied as a crucial modulator. The major proportion of circulating ghrelin is however the non-octanoylated form of ghrelin, des-acyl ghrelin (DAG), whose role in reward processes is unknown. As recent studies show that DAG decreases food intake, we hypothesize that DAG attenuates alcohol-related responses in animal models. Acute and repeated DAG treatment dose-dependently decreased alcohol drinking in male and female rats. In these alcohol-consuming male rats, repeated DAG treatment causes higher levels of dopamine metabolites in the ventral tegmental area, an area central to reward processing. The role of DAG in reward processing is further supported as DAG prevents alcohol-induced locomotor stimulation, reward in the conditioned place preference paradigm, and dopamine release in the nucleus accumbens in male rodents. On the contrary, DAG does not alter the memory of alcohol reward or affect neurotransmission in the hippocampus, an area central to memory. Further, circulating DAG levels are positively correlated with alcohol drinking in female but not male rats. Studies were conducted in attempts to identify tentative targets of DAG, which currently are unknown. Data from these recombinant cell system revealed that DAG does not bind to either of the monoamine transporters, 5HT2A, CB1, or µ-opioid receptors. Collectively, our data show that DAG attenuates alcohol-related responses in rodents, an effect opposite to that of ghrelin, and contributes towards a deeper insight into behaviors regulated by the ghrelinergic signaling pathway.
Asunto(s)
Consumo de Bebidas Alcohólicas , Dopamina , Ghrelina , Núcleo Accumbens , Recompensa , Área Tegmental Ventral , Animales , Ghrelina/farmacología , Ghrelina/metabolismo , Masculino , Ratas , Femenino , Dopamina/metabolismo , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efectos de los fármacos , Etanol/farmacología , Etanol/administración & dosificación , Humanos , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratas Sprague-DawleyRESUMEN
Oral ulcers present as recurrent and spontaneous lesions, often causing intolerable burning pain that significantly disrupts patients' daily lives and compromises their quality of life. In addressing this clinical challenge, oral dissolving films (ODFs) have emerged as promising pharmaceutical formulations for oral ulcer management due to their rapid onset of action, ease of administration, and portability. In this study, ODFs containing the insoluble drug dexamethasone (Dex) were formulated for the treatment of oral ulcers in rabbits using a solvent casting method with ethanol as the solvent. To optimize the composition of the ODFs, a Box-Behnken Design (BBD) experiment was employed to investigate the effects of varying concentrations of hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), and plasticizer (glycerol) on key parameters, such as disintegration time, tensile strength, and peel-off efficiency of the films. Subsequently, the film properties of the Dex-loaded ODFs (ODF@Dex) were thoroughly assessed, revealing favorable attributes, including homogeneity, mechanical strength, and solubility. Notably, the use of ethanol as the solvent in the ODF preparation facilitated the homogeneous distribution of insoluble drugs within the film matrix, thereby enhancing their solubility and dissolution rate. Leveraging the potent pharmacological activity of Dex, ODF@Dex was further evaluated for its efficacy in promoting ulcer healing and mitigating the expression of inflammatory factors both in vitro and in vivo. The findings demonstrated that the ODF@Dex exerted significant antiulcer effects by modulating the PI3K/Akt signaling pathway, thus contributing to ulcer resolution. In conclusion, our study underscores the potential of HPC-based ODFs formulated with ethanol as a solvent as a promising platform for delivering insoluble drugs, offering a viable strategy for the clinical management of oral ulcers.
Asunto(s)
Celulosa , Dexametasona , Úlceras Bucales , Solubilidad , Dexametasona/química , Dexametasona/administración & dosificación , Celulosa/análogos & derivados , Celulosa/química , Conejos , Animales , Úlceras Bucales/tratamiento farmacológico , Administración Oral , Masculino , Resistencia a la Tracción , Liberación de Fármacos , Etanol/química , Etanol/administración & dosificación , Composición de Medicamentos/métodosRESUMEN
BACKGROUND: Alcohol abuse, a prevalent global health issue, is associated with the onset of cognitive impairment and neurodegeneration. Actin filaments (F-actin) and microtubules (MTs) polymerized from monomeric globular actin (G-actin) and tubulin form the structural basis of the neuronal cytoskeleton. Precise regulation of the assembly and disassembly of these cytoskeletal proteins, and their dynamic balance, play a pivotal role in regulating neuronal morphology and function. Nevertheless, the effect of prolonged alcohol exposure on cytoskeleton dynamics is not fully understood. This study investigates the chronic effects of alcohol on cognitive ability, neuronal morphology and cytoskeleton dynamics in the mouse hippocampus. METHODS: Mice were provided ad libitum access to 5% (v/v) alcohol in drinking water and were intragastrically administered 30% (v/v, 6.0 g/kg/day) alcohol for six weeks during adulthood. Cognitive functions were then evaluated using the Y maze, novel object recognition and Morris water maze tests. Hippocampal histomorphology was assessed through hematoxylin-eosin (HE) and Nissl staining. The polymerized and depolymerized states of actin cytoskeleton and microtubules were separated using two commercial assay kits and quantified by Western blot analysis. RESULTS: Mice chronically exposed to alcohol exhibited significant deficits in spatial and recognition memory as evidenced by behavioral tests. Histological analysis revealed notable hippocampal damage and neuronal loss. Decreased ratios of F-actin/G-actin and MT/tubulin, along with reduced levels of polymerized F-actin and MTs, were found in the hippocampus of alcohol-treated mice. CONCLUSIONS: Our findings suggest that chronic alcohol consumption disrupted the assembly of the actin cytoskeleton and MTs in the hippocampus, potentially contributing to the cognitive deficits and pathological injury induced by chronic alcohol intoxication.
Asunto(s)
Citoesqueleto de Actina , Etanol , Hipocampo , Microtúbulos , Animales , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Citoesqueleto de Actina/efectos de los fármacos , Citoesqueleto de Actina/metabolismo , Masculino , Etanol/farmacología , Etanol/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Depresores del Sistema Nervioso Central/farmacología , Depresores del Sistema Nervioso Central/administración & dosificación , Modelos Animales de Enfermedad , Conducta Animal/efectos de los fármacosRESUMEN
BACKGROUND: One possible reason for the lack of FDA-approved pharmacotherapies to treat cocaine use disorder (CUD) is that, although cocaine is typically used in combination with alcohol, it is studied in isolation in preclinical studies. A better understanding of the cocaine-alcohol interactions that promote polysubstance use (PSU) will improve animal models of CUD and hasten pharmacotherapy development. We used a rhesus monkey model of cocaine-alcohol PSU to investigate one possible mechanism: that alcohol is used to mitigate negative effects associated with termination of cocaine use. METHODS: In 6 adult male rhesus monkeys, the relationship between self-administered cocaine intake and oral ethanol intake 2hours later was examined during self-administration of cocaine (0.0003-0.3mg/kg per injection, i.v.) under a fixed-ratio 30 schedule (FR30) or a progressive-ratio (PR) schedule. Next, ethanol consumption was measured 0-120minutes after experimenter-administered cocaine (0.3-1.7mg/kg, i.v.). RESULTS: Self-administered cocaine intake under both FR30 and PR schedules was unrelated to oral ethanol intakes 2hours later. When cocaine was administered non-contingently, cocaine decreased ethanol intake as well as intake of a non-alcoholic solution in monkeys who never consumed ethanol (n=4) in a time- and dose-dependent manner. CONCLUSIONS: Taken together, the results do not provide evidence for cocaine-induced increases in ethanol consumption. By extension, the results do not support the hypothesis that cocaine users drink alcohol to counteract negative effects that occur after terminating use. This finding implies either that such effects do not exist or that such effects exist but are unaffected by ethanol.
Asunto(s)
Consumo de Bebidas Alcohólicas , Cocaína , Macaca mulatta , Autoadministración , Animales , Masculino , Cocaína/administración & dosificación , Etanol/administración & dosificación , Esquema de Refuerzo , Relación Dosis-Respuesta a Droga , Trastornos Relacionados con CocaínaRESUMEN
Alcoholic liver injury (ALI) stands as a prevalent affliction within the spectrum of complex liver diseases. Prolonged and excessive alcohol consumption can pave the way for liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Recent findings have unveiled the protective role of proline serine-threonine phosphatase interacting protein 2 (PSTPIP2) in combating liver ailments. However, the role of PSTPIP2 in ALI remains mostly unknown. This study aimed to determine the expression profile of PSTPIP2 in ALI and to uncover the mechanism through which PSTPIP2 affects the survival and apoptosis of hepatocytes in ALI, using both ethyl alcohol (EtOH)-fed mice and an EtOH-induced AML-12 cell model. We observed a consistent decrease in PSTPIP2 expression both in vivo and in vitro. Functionally, we assessed the impact of PSTPIP2 overexpression on ALI by administering adeno-associated virus 9 (AAV9)-PSTPIP2 into mice. The results demonstrated that augmenting PSTPIP2 expression significantly shielded against liver parenchymal distortion and curbed caspase-dependent hepatocyte apoptosis in EtOH-induced ALI mice. Furthermore, enforcing PSTPIP2 expression reduced hepatocyte apoptosis in a stable PSTPIP2-overexpressing AML-12 cell line established through lentivirus-PSTPIP2 transfection in vitro. Mechanistically, this study also identified signal transducer and activator of transcription 3 (STAT3) as a direct signaling pathway regulated by PSTPIP2 in ALI. In conclusion, our findings provide compelling evidence that PSTPIP2 has a regulatory role in hepatocyte apoptosis via the STAT3 pathway in ALI, suggesting PSTPIP2 as a promising therapeutic target for ALI.
Asunto(s)
Apoptosis , Factor de Transcripción STAT3 , Animales , Masculino , Ratones , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Apoptosis/efectos de los fármacos , Línea Celular , Etanol/toxicidad , Etanol/administración & dosificación , Hepatocitos/metabolismo , Hepatocitos/patología , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/patología , Hepatopatías Alcohólicas/prevención & control , Ratones Endogámicos C57BL , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genéticaRESUMEN
Ethanol (EtOH) intake and noise exposure are particularly concerning among human adolescents because the potential to harm brain. Unfortunately, putative underlying mechanisms remain to be elucidated. Moreover, implementing non-pharmacological strategies, such as enriched environments (EE), would be pertinent in the field of neuroprotection. This study aims to explore possible underlying triggering mechanism of hippocampus-dependent behaviors in adolescent animals of both sexes following ethanol intake, noise exposure, or a combination of both, as well as the impact of EE. Adolescent Wistar rats of both sexes were subjected to an intermittent voluntary EtOH intake paradigm for one week. A subgroup of animals was exposed to white noise for two hours after the last session of EtOH intake. Some animals of both groups were housed in EE cages. Hippocampal-dependent behavioral assessment and hippocampal oxidative state evaluation were performed. Results show that different hippocampal-dependent behavioral alterations might be induced in animals of both sexes after EtOH intake and sequential noise exposure, that in some cases are sex-specific. Moreover, hippocampal oxidative imbalance seems to be one of the potential underlying mechanisms. Additionally, most behavioral and oxidative alterations were prevented by EE. These findings suggest that two frequently found environmental agents may impact behavior and oxidative pathways in both sexes in an animal model. In addition, EE resulted a partially effective neuroprotective strategy. Therefore, it could be suggested that the implementation of a non-pharmacological approach might also potentially provide neuroprotective advantages against other challenges. Finally, considering its potential for translational human benefit might be worth.
Asunto(s)
Etanol , Hipocampo , Ruido , Ratas Wistar , Animales , Hipocampo/efectos de los fármacos , Masculino , Femenino , Etanol/administración & dosificación , Etanol/toxicidad , Ruido/efectos adversos , Ratas , Consumo de Bebidas Alcohólicas , Caracteres Sexuales , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiologíaRESUMEN
Ethanol consumption is associated with positive, negative, and neutral effects on the skeletal system. Our previous work using a nonhuman primate model of voluntary ethanol consumption showed that chronic ethanol use has an impact on skeletal attributes, most notably on biochemical markers of bone turnover. However, these studies were limited by small sample sizes and resulting lack of statistical power. Here, we applied a machine learning framework to integrate data from 155 monkeys (100 ethanol and 55 controls) to identify the bone features associated with chronic ethanol use. Specifically, we analyzed the influence of ethanol consumption on biomarkers of bone turnover and cancellous and cortical bone architecture in tibia. We hypothesized that chronic ethanol use for 6 months to 2.5 years would result in measurable changes to cancellous features and the biochemical markers compared to control animals. We observed a decrease in bone turnover in monkeys exposed to ethanol; however, we did not find that ethanol consumption resulted in measurable changes in bone architecture.
Asunto(s)
Consumo de Bebidas Alcohólicas , Biomarcadores , Remodelación Ósea , Etanol , Tibia , Animales , Tibia/efectos de los fármacos , Tibia/metabolismo , Tibia/diagnóstico por imagen , Remodelación Ósea/efectos de los fármacos , Biomarcadores/sangre , Etanol/farmacología , Etanol/administración & dosificación , Consumo de Bebidas Alcohólicas/sangre , Consumo de Bebidas Alcohólicas/efectos adversos , Masculino , Femenino , Macaca mulattaRESUMEN
Although previous research has illustrated the effects of the consumption of alcohol and caffeine individually, less research has focused on the popular combination of the two drugs. The increase in alcohol consumption when combined with caffeine has led to the idea that the stimulant effects of caffeine may mask the depressant effects of alcohol, and this may contribute to increased binge drinking as the individual feels more awake and stimulated. Preclinical research has shown various effects of combined alcohol and caffeine where several studies show decreased alcohol consumption and others show increased alcohol consumption and even binge-like drinking. Results from a previous study in our lab indicate that intermittent access (IA) to steady levels of low (0.015 %) but not moderate (0.03 %) caffeine increased alcohol consumption in male C57BL/6J mice. The current studies further investigated the sex and dose differences in adult mice receiving varying concentrations of caffeine on combined alcohol intake. In Experiment 1, adult mice (n = 50, 25 males and 25 females) had IA to one of the following experimental bottles throughout the 4 week period: water, alcohol (10 % v/v), caffeine (0.015 % w/v), or 10 % alcohol +0.015 % caffeine. In Experiment 2, adult mice (n = 70, 35 males and 35 females) were given IA to one of the following experimental bottles: water, alcohol (10 % v/v; steady, maintained throughout the 4 weeks), caffeine (increasing 0.01 % to 0.015 % to 0.02 % to 0.03 % weekly), or 10 % alcohol+increasing caffeine (at the previously mentioned concentrations). When both caffeine and alcohol concentrations remained steady throughout the 4 weeks, there was no change in alcohol consumption. Chronic exposure to IA caffeine led to increased locomotor activity and decreased freezing episodes when tested in the open field test approximately 6 h after removal of the bottles. In Experiment 2, caffeine dose-dependently increased alcohol co-consumption in male mice whereas female mice consumed less alcohol when it was presented in conjunction with caffeine. The results in males are in line with clinical literature suggesting that the combination of alcohol and caffeine may lead to increased stimulation and alcohol drinking. Additionally, these studies provide evidence that the escalation of caffeine is crucial when investigating alcohol and caffeine co-consumption using the IA paradigm.
Asunto(s)
Consumo de Bebidas Alcohólicas , Cafeína , Relación Dosis-Respuesta a Droga , Etanol , Ratones Endogámicos C57BL , Animales , Masculino , Cafeína/farmacología , Cafeína/administración & dosificación , Femenino , Ratones , Etanol/administración & dosificación , Etanol/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Estimulantes del Sistema Nervioso Central/administración & dosificación , Factores Sexuales , Caracteres SexualesRESUMEN
BACKGROUND: Hepatic lipoprotein receptor-related protein 1 (LRP-1) plays a central role in peripheral amyloid beta (Aß) 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. METHODS: Eight-month-old male APP/PS1 mice were fed ethanol or control diet intragastrically for 5 weeks (n = 7-11/group). Brain and liver Aß were assessed using immunoassays. Three important mechanisms of brain amyloidosis were investigated: hepatic LRP-1 (major peripheral Aß regulator), blood-brain barrier (BBB) function (vascular Aß regulator), and microglia (major brain Aß 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 Aß were measured. RESULTS: Alcohol feeding reduced plaque-associated microglia in APP/PS1 mice brains and increased aggregated Aß (p < 0.05) by ELISA and 6E10-positive Aß load by immunostaining (p < 0.05). Increased brain Aß 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 Aß and locomotion hyperactivity (p < 0.05) in APP/PS1 mice. CONCLUSION: Chronic heavy alcohol intake reduced hepatic LRP-1 expression and increased brain Aß. The hepato-specific LRP-1 silencing similarly increased brain Aß 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.
Asunto(s)
Enfermedad de Alzheimer , Hígado , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad , Ratones Endogámicos C57BL , Ratones Transgénicos , Animales , Enfermedad de Alzheimer/metabolismo , Masculino , Ratones , Hígado/metabolismo , Amiloidosis/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Etanol/administración & dosificación , Modelos Animales de Enfermedad , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Chronic ethanol consumption increased extracellular glutamate concentrations in several reward brain regions. Glutamate homeostasis is regulated in majority by astrocytic glutamate transporter 1 (GLT-1) as well as the interactive role of cystine/glutamate antiporter (xCT). In this study, we aimed to determine the attenuating effects of a novel beta-lactam MC-100093, lacking the antibacterial properties, on ethanol consumption and GLT-1 and xCT expression in the subregions of nucleus accumbens (NAc core and NAc shell) and medial prefrontal cortex (Infralimbic, mPFC-IL and Prelimbic, mPFC-PL) in male and female alcohol-preferring (P) rats. Female and male rats were exposed to free access to ethanol (15% v/v) and (30% v/v) and water for five weeks, and on Week 6, rats were administered 100 mg/kg (i.p) of MC-100093 or saline for five days. MC-100093 reduced ethanol consumption in both male and female P rats from Day 1-5. Additionally, MC-100093 upregulated GLT-1 and xCT expression in the mPFC and NAc subregions as compared to ethanol-saline groups in female and male rats. Chronic ethanol intake reduced GLT-1 and xCT expression in the IL and PL in female and male rats, except there was no reduction in GLT-1 expression in the mPFC-PL in female rats. Although, MC-100093 upregulated GLT-1 and xCT expression in the subregions of NAc, we did not observe any reduction in GLT-1 and xCT expression with chronic ethanol intake in female rats. These findings strongly suggest that MC-100093 treatment effectively reduced ethanol intake and upregulated GLT-1 and xCT expression in the mPFC and NAc subregions in male and female P rats.
Asunto(s)
Consumo de Bebidas Alcohólicas , Astrocitos , Etanol , Transportador 2 de Aminoácidos Excitadores , Núcleo Accumbens , Animales , Femenino , Masculino , Consumo de Bebidas Alcohólicas/metabolismo , Ratas , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Transportador 2 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores/biosíntesis , Etanol/administración & dosificación , Etanol/farmacología , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Depresores del Sistema Nervioso Central/farmacología , Depresores del Sistema Nervioso Central/administración & dosificación , Caracteres SexualesAsunto(s)
Ablación por Catéter , Etanol , Taquicardia Ventricular , Humanos , Etanol/administración & dosificación , Taquicardia Ventricular/cirugía , Taquicardia Ventricular/fisiopatología , Taquicardia Ventricular/diagnóstico , Ablación por Catéter/métodos , Resultado del Tratamiento , Ventrículos Cardíacos/cirugía , Ventrículos Cardíacos/fisiopatología , Masculino , Técnicas Electrofisiológicas Cardíacas , Catéteres CardíacosRESUMEN
Alcohol-associated social facilitation together with attenuated sensitivity to adverse alcohol effects play a substantial role in adolescent alcohol use and misuse, with adolescent females being more susceptible to adverse consequences of binge drinking than adolescent males. Adolescent rodents also demonstrate individual and sex differences in sensitivity to ethanol-induced social facilitation and social inhibition, therefore the current study was designed to identify neuronal activation patterns associated with ethanol-induced social facilitation and ethanol-induced social inhibition in male and female adolescent cFos-LacZ rats. Experimental subjects were given social interaction tests on postnatal day (P) 34, 36, and 38 after an acute challenge with 0, 0.5 and 0.75â¯g/kg ethanol, respectively, and ß-galactosidase (ß-gal) expression was assessed in brain tissue of subjects socially facilitated and socially inhibited by 0.75â¯g/kg ethanol. In females, positive correlations were evident between overall social activity and neuronal activation of seven out of 13 ROIs, including the prefrontal cortex and nucleus accumbens, with negative correlations evident in males. Assessments of neuronal activation patterns revealed drastic sex differences between ethanol responding phenotypes. In socially inhibited males, strong correlations were evident among almost all ROIs (90â¯%), with markedly fewer correlations among ROIs (38â¯%) seen in socially facilitated males. In contrast, interconnectivity in females inhibited by ethanol was only 10â¯% compared to nearly 60â¯% in facilitated subjects. However, hub analyses revealed convergence of brain regions in males and females, with the nucleus accumbens being a hub region in socially inhibited subjects. Taken together, these findings demonstrate individual and sex-related differences in responsiveness to acute ethanol in adolescent rats, with sex differences more evident in socially inhibited by ethanol adolescents than their socially facilitated counterparts.
Asunto(s)
Etanol , Caracteres Sexuales , Conducta Social , Animales , Masculino , Femenino , Etanol/farmacología , Etanol/administración & dosificación , Depresores del Sistema Nervioso Central/farmacología , Depresores del Sistema Nervioso Central/administración & dosificación , Ratas , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Interacción Social/efectos de los fármacos , Ratas Transgénicas , Proteínas Proto-Oncogénicas c-fos/metabolismo , Inhibición PsicológicaRESUMEN
Background: Non-medical use of amphetamine and other stimulants prescribed for treatment of attention deficit/hyperactivity disorder (ADHD) is of special concern when combined with alcohol consumption. In a previous study, we modeled chronic ethanol-amphetamine co-use in adolescent Long-Evans (LE) rats and provided evidence that amphetamine attenuates alcohol withdrawal symptoms.Objectives: This project modeled co-use of amphetamine with alcohol in adolescents with ADHD-like symptoms by examining ethanol-amphetamine administration in adolescent Spontaneously Hypertensive Rats (SHR), an experimental model for the study of ADHD. Withdrawal symptoms were compared among SHR and two control rat strains, LE and Wistar Kyoto (WKY).Methods: At postnatal day 32, parallel groups of 12-24 male SHR, WKY and LE rats were administered a liquid diet containing ethanol (3.6%) and/or amphetamine (20 mg/L). Following administration periods up to 26 days, rats were withdrawn from their treatment and tested for overall severity of alcohol withdrawal symptoms, general locomotor activity, and anxiety-like behavior.Results: Overall withdrawal severity was lower for SHR than for LE (p < .001) or WKY (p = .027). Co-consumption of amphetamine decreased withdrawal severity for LE (p = .033) and WKY (p = .011) but not SHR (p = .600). Only WKY showed increased anxiety-like behavior during withdrawal (p = .031), but not after amphetamine co-administration (p = .832).Conclusion: Alcohol withdrawal severity may be attenuated when co-used with amphetamine. However, as a model for ADHD, SHR adolescents appeared resistant to developing significant signs of alcohol withdrawal following alcohol consumption. Whether alcohol withdrawal symptoms are attenuated or absent, potential consequences could include a decreased awareness of an emerging problem with alcohol use.
Asunto(s)
Anfetamina , Trastorno por Déficit de Atención con Hiperactividad , Modelos Animales de Enfermedad , Etanol , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Síndrome de Abstinencia a Sustancias , Animales , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Masculino , Ratas , Anfetamina/administración & dosificación , Etanol/administración & dosificación , Ratas Long-Evans , Actividad Motora/efectos de los fármacos , Ansiedad , Estimulantes del Sistema Nervioso Central/administración & dosificaciónRESUMEN
The timing, rate, and quantity of gestational alcohol consumption, collectively referred to here as Maternal Drinking Patterns (MDPs), are of known importance to fetal developmental outcomes. However, few studies have directly evaluated the impact of MDPs on offspring behavior. To do so, we used specialized equipment to record the precise amount and timing of alcohol consumption in pregnant dams, and then characterized MDPs using Principle Component Analysis (PCA). We next tested offspring on behaviors we have previously identified as impacted by prenatal alcohol exposure, and evaluated them where possible in the context of MDPs. Male alcohol exposed mice exhibited longer latencies to fall on the rotarod compared to their controls, which we attribute to a delayed decrease in body weight-gain. This effect was mediated by MDPs within the first 15 min of alcohol access (i.e. alcohol frontloading), where the highest performing male offspring came from dams exhibiting the highest rate of alcohol frontloading. Female alcohol exposed mice displayed reduced locomotor activity in the open field compared to controls, which was mediated by MDPs encompassing the entire drinking session. Surprisingly, total gestational alcohol exposure alone was not associated with any behavioral outcomes. Finally, we observed allodynia in alcohol exposed mice that developed more quickly in males compared to females, and which was not observed in controls. To our knowledge, this report represents the highest resolution assessment of alcohol drinking throughout gestation in mice, and one of few to have identified relationships between specific alcohol MDPs and neurobehavioral outcomes in offspring.
Asunto(s)
Consumo de Bebidas Alcohólicas , Etanol , Efectos Tardíos de la Exposición Prenatal , Animales , Femenino , Embarazo , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/psicología , Masculino , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Ratones , Etanol/administración & dosificación , Ratones Endogámicos C57BL , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiologíaRESUMEN
BACKGROUND: Binge drinking at adolescence is a risk factor for problematic alcohol (ethanol) consumption later in life, yet the murine studies that modelled this phenomenon via ethanol self-administration have provided mixed findings. Antagonism of the sigma-1 receptor (S1-R) system at adolescence modulates ethanol's motivational effects and intake. It is still unknown, however, whether this antagonism would protect against enhanced ethanol intake at adulthood after adolescent binge ethanol exposure. METHODS: Exp. 1 and 2 tested adults male or female Wistar rats -exposed or not to ethanol self-administration at adolescence (postnatal days 31-49; nine 2-hour sessions of access to 8-10% ethanol)- for ethanol intake using 24-h two-bottle choice test (Exp. 1) or time restricted, single-bottle, tests (Exp. 2). Experiments 2-5 evaluated, in adolescent or adult rats, the effects of the S1-R antagonist S1RA on ethanol intake and on ethanol-induced conditioned taste or place aversion. Ancillary tests (e.g., novel object recognition, ethanol-induced locomotor activity) were also conducted. RESULTS: Adolescent ethanol exposure promoted ethanol consumption at both the restricted, single-bottle, and at the two-bottle choice tests conducted at adulthood. S1RA administration reduced ethanol intake at adulthood and facilitated the development of ethanol-induced taste (but not place) aversion. CONCLUSIONS: S1RA holds promise for lessening ethanol intake after chronic and substantial ethanol exposure in adolescence that results in heightened ethanol exposure at adulthood. This putative protective effect of S1-R antagonism may relate to S1RA exacerbating the aversive effects of this drug.
Asunto(s)
Consumo de Bebidas Alcohólicas , Consumo Excesivo de Bebidas Alcohólicas , Etanol , Ratas Wistar , Receptores sigma , Autoadministración , Animales , Masculino , Ratas , Femenino , Etanol/administración & dosificación , Etanol/farmacología , Consumo Excesivo de Bebidas Alcohólicas/psicología , Receptores sigma/antagonistas & inhibidores , Consumo de Bebidas Alcohólicas/psicología , Receptor Sigma-1 , Factores de EdadRESUMEN
Ultrafine bubbles (UFBs), which are bubbles with diameters of less than 1 µm, are widely recognized for their ability to exist stably in liquid as a result of the effects of Brownian motion. In this study, we focused on hydrogen, known for its antioxidant potential, and explored the function of H2-filled UFBs, which encapsulate hydrogen, to determine their potential use as oral carriers for the delivery bioactive gases to living organisms. To this end, rats were orally administered ethanol to induce hepatic oxidative stress, and the effects of drinking H2-filled UFBs (H2 NanoGAS®) water for two weeks were evaluated to assess the reduction of oxidative stress. Continuous alcohol consumption was found to significantly increase the blood lipid peroxidation levels in the control group, confirming the induction of oxidative stress. An increase in blood lipid peroxidation was significantly inhibited by the consumption of concentrated H2 NanoGAS® (C-HN) water. Furthermore, the measurement of mitochondrial activity in the liver revealed that drinking H2 NanoGAS® water helped to maintain at a normal level and/or boosted the functional activity of the electron transport system in mitochondria affected by ethanol intake. To our knowledge, this study is the first to provide evidence for the use of orally ingested UFBs as carriers for the delivery gases to tissues, thereby exerting their physiological activity in the body. Our findings highlight the potential for the application of UFBs to various physiologically active gases and their utilization in the medical field in the future.
Asunto(s)
Etanol , Hidrógeno , Peroxidación de Lípido , Hígado , Estrés Oxidativo , Animales , Estrés Oxidativo/efectos de los fármacos , Etanol/administración & dosificación , Hidrógeno/farmacología , Hidrógeno/administración & dosificación , Masculino , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Hígado/efectos de los fármacos , Administración Oral , Ratas , Ratas Wistar , Agua , Antioxidantes/farmacología , Antioxidantes/administración & dosificaciónRESUMEN
Alcohol use disorder (AUD) remains a critical public health issue worldwide, characterized by high relapse rates often triggered by contextual cues. This research investigates the neural mechanisms behind context-induced reinstatement of alcohol-seeking behavior, focusing on the nucleus accumbens and its interactions with the prelimbic cortex, employing Male Long-Evans rats in an ABA renewal model. In our experimental setup, rats were trained to self-administer 10 % ethanol in Context A, followed by extinction of lever pressing in the presence of discrete cues in Context B. The context-induced reinstatement of ethanol-seeking was then assessed by re-exposing rats to Context A or B under extinction conditions, aiming to simulate the environmental cues' influence on relapse behaviors. Three experiments were conducted: Experiment 1 utilized Fos-immunohistochemistry to examine neuronal activation in the nucleus accumbens; Experiment 2 applied the baclofen + muscimol inactivation technique to probe the functional importance of the nucleus accumbens core; Experiment 3 used Fos-immunofluorescence along with Retrobeads injection to investigate activation of neurons projecting from the prelimbic cortex to the nucleus accumbens core. Our findings revealed significant increases in Fos-immunoreactive nuclei within the nucleus accumbens core and shell during the reinstatement phase in Context A, underscoring the environment's potent effect on ethanol-seeking behavior. Additionally, inactivation of the nucleus accumbens core markedly reduced reinstatement, and there was a notable activation of neurons from the prelimbic cortex to the nucleus accumbens core in the ethanol-associated context. These results highlight the critical role of the nucleus accumbens core and its corticostriatal projections in the neural circuitry underlying context-driven ethanol seeking.