bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic Ethanol Enhances Adenosine Antiadrenergic Actions in the Isolated Rat Heart
Authors: Fenton Richard A. , Chung Eugene S. 
Published: April 2006

Background : Chronic alcohol consumption elicits an increase in catecholamine release, which may be detrimental to heart function. Adenosine attenuates adrenergic stimulation via an adenosine receptor–mediated antiadrenergic action. This study investigated the effect of ethanol on adenosine antiadrenergic actions and adenosine release in the rat heart.Methods: Rats were pair‐fed a liquid diet with or without ethanol for 4 weeks or 8 months. Hearts were isolated for determination of contractile function, and coronary effluents were collected for adenosine content. Dose‐response relationships for phenylisopropyladenosine (PIA) were determined for hearts adrenergically stimulated by isoproterenol. Experiments were also conducted with normal hearts with or without ethanol (25 mM) administered acutely. The effect of PIA on adenylyl cyclase activities of adrenergic‐stimulated crude membrane preparations obtained from alcoholic and nonalcoholic hearts was determined.Results: Acute ethanol reduced basal adenosine release by 39%, but it did not significantly decrease adenosine release during adrenergic stimulation. In hearts chronically treated with ethanol for 4 weeks, adenosine release values before and during adrenergic stimulation were significantly reduced from control values. After 8 months of ethanol, adenosine release was similar with or without adrenergic stimulation. PIA 50% inhibiting concentration (IC50) values for contractile function were reduced from pair‐fed control values. Acute ethanol did not significantly change the PIA IC50 value. Chronic ethanol reduced the PIA IC50 for adenylyl cyclase by 96%.Conclusions: Chronic ethanol treatment increases the antiadrenergic action of adenosine by mechanisms that seem independent of changes in adenosine concentration. Therefore, adenosine‐induced cardioprotection against increased catecholamine stimulation is enhanced by ethanol.
Relationship of Brain Ethanol Metabolism to the Hypnotic Effect of Ethanol. I: Studies in Outbred Animals
Authors: Zimatkin Sergey M. , Liopo Anton V. , Slychenkov V. S. , Deitrich Richard A. 
Published: April 2006

Background : This study was designed to investigate the relationship between the ethanol‐oxidizing capacity of the brain, accumulation of acetaldehyde, and ethanol‐induced hypnosis in animals in vivo.Methods: Randomly outbred albino rats were treated with ethanol, and the duration of ethanol‐induced loss of the righting response (sleep time) was measured. They were killed 2 weeks later (without further in vivo administration of ethanol), and brain homogenates were prepared to measure the accumulation of acetaldehyde from ethanol added in vitro. In a similar way, we determined the sleep time and, 5 days later, the rates of acetaldehyde accumulation in brains of heterogeneous mice.Results: Significant correlations between the duration of ethanol‐induced sleep and acetaldehyde accumulation in vitro were found. The Km value of the process of acetaldehyde accumulation was lower in long‐sleeping, as compared with short‐sleeping, rats. A similar result was also obtained in genetically heterogeneous mice. Animals with a longer duration of ethanol‐induced sleep had a higher level of the accumulation of ethanol‐derived acetaldehyde in brain homogenates, as compared with the short‐sleeping mice. Rats and mice with the intermediate duration of ethanol‐induced sleep had an intermediate value of acetaldehyde accumulation in brain homogenates. There was no correlation between brain catalase activity and ethanol‐induced loss of the righting response in either the rats or the mice.Conclusions: This study is a direct demonstration of the positive correlation between ethanol‐derived acetaldehyde accumulation in vitro in the brain and a central (behavioral) effect of alcohol in outbred rats and mice in vivo.
Effect of Naloxone on Appetitive and Consummatory Phases of Ethanol Self‐Administration
Authors: Sharpe Amanda L. , Samson Herman H. 
Published: April 2006

Background : The opioid system has been implicated in ethanol self‐administration. Morphine, an opiate agonist, can sometimes increase the amount of ethanol consumed, and opiate antagonists such as naloxone and naltrexone decrease the amount of ethanol consumed in both animals and humans. The objective of this study was to examine the effect of naloxone on appetitive (or seeking) and consummatory behaviors by using an operant model developed to separate these two phases of self‐administration.Methods: Intraperitoneal injections of naloxone (0.3–10 mg/kg) or vehicle were given before operant self‐administration sessions to assess the effect on lever pressing (appetitive behavior) and subsequent consumption. Effects were measured in two groups of rats: one self‐administered a 3% sucrose solution and the other a 10% ethanol solution.Results: Naloxone dose‐dependently decreased ethanol and sucrose consumption by an earlier cessation of drinking in the session compared with vehicle injection days. There were some effects on appetitive responding after treatment with naloxone, but none was statistically significant.Conclusions: Naloxone may decrease ethanol self‐administration by decreasing the postingestive or pharmacological effects of alcohol. This model provides a new method for examining the effects of potential pharmacotherapeutics on alcohol self‐administration behavior.
Inhibition of Insulin‐Like Growth Factor‐I Signaling by Ethanol in Neuronal Cells
Authors: Hallak Hazem , Seiler Andrea E. M. , Green Jamie S. , Henderson Aaron , Ross Brian N. , Rubin Raphael 
Published: April 2006

Background : Ethanol inhibits insulin‐like growth factor‐I receptor (IGF‐IR) activation. However, the potency of ethanol for inhibition of the IGF‐IR and other receptor tyrosine kinases varies considerably among different cell types. We investigated the effect of ethanol on IGF‐I signaling in several neuronal cell types.Methods: IGF‐I signaling was examined in SH‐SY5Y neuroblastoma cells, primary cultured rat cerebellar granule neurons, and rat NG‐108 neuroblastoma × glioma hybrids. The tyrosine phosphorylation of IGF‐IR, IRS‐2, Shc, and p42/p44 MAP kinase (MAPK), and the association of Grb‐2 with Shc, were examined by immunoprecipitations and Western blotting.Results: IGF‐I–mediated tyrosine phosphorylation of MAPK was inhibited by ethanol in all cell lines. IGF‐IR autophosphorylation was markedly inhibited by ethanol in SH‐SY5Y cells, was only mildly inhibited in cerebellar granule neurons, and was unaffected in rat NG‐108 cells. In vitro tyrosine autophosphorylation of immunopurified IGF‐IR obtained from all cell lines was inhibited by ethanol. There was also differential ethanol sensitivity of IRS‐2 and Shc phosphorylation, and the association of Shc with IRS‐2, among the different cell types.Conclusions: The findings demonstrate that IGF‐I–mediated MAPK activation is a sensitive target of ethanol in diverse neuronal cell types. The data are consistent with ethanol‐induced inhibition of IGF‐IR activity, although the extent of IGF‐IR tyrosine autophosphorylation per se is a poor marker of the inhibitory action of ethanol on this receptor. Furthermore, despite uniform inhibition of MAPK in the different neuronal cell types, tyrosine phosphorylation of proximal mediators of the IGF‐IR are differentially inhibited by ethanol.
Origins and Consequences of Age at First Drink. I. Associations With Substance‐Use Disorders, Disinhibitory Behavior and Psychopathology, and P3 Amplitude
Authors: McGue Matt , Iacono William G. , Legrand Lisa N. , Malone Steve , Elkins Irene 
Published: April 2006

Background: Although an early age at first drink has been repeatedly associated with substantially elevated rates of alcoholism, the mechanisms underlying this association remain unclear. We investigated whether the association of age at first drink (AFD) with alcoholism was more consistent with the hypothesis that the former causes the latter or the hypothesis that both are manifestations of some common vulnerability.Methods: We investigated whether substance use and mental health disorders, education, IQ, and personality were associated with AFD in a sample of 2670 adults; whether P3 amplitude was associated with AFD in a sample of 1127 17 year olds; and whether indicators of disinhibitory psychopathology assessed at age 11 predicted AFD by age 14 in a sample of 1343 adolescents.Results: In adults, AFD was associated not only with alcohol dependence, but also with a broad array of indicators of disinhibitory behavior and psychopathology including nicotine dependence, illicit drug abuse and dependence, conduct disorder, antisocial personality disorder, underachievement in school, and the personality trait of constraint. In 17 year olds, AFD was also associated with reduced P3 amplitude, a well‐documented psychophysiological marker of alcoholism risk. Finally, in the early‐adolescence sample, measures of behavioral disinhibition, including oppositionality, hyperactivity/impulsivity, and inattentiveness assessed at age 11 predicted drinking onset by age 14.Conclusions: Our findings indicated that AFD is not specifically associated with alcoholism but rather is correlated with a broad range of indicators of disinhibited behavior and psychopathology. Moreover, individuals who first drink at a relatively early age manifest elevated rates of disinhibitory behavior and psychopathology before they first try alcohol. Taken together, these findings suggest that the association of AFD with alcoholism reflects, at least in part, a common underlying vulnerability to disinhibitory behavior. Whether an early AFD directly influences risk of adult alcoholism remains unclear.
A Comparison of Substance Use and Injury Among Mexican American Emergency Room Patients in the United States and Mexicans in Mexico
Authors: Cherpitel Cheryl J. , Borges Guilherme 
Published: April 2006

Background: Emergency room (ER) studies have found differences in the association of alcohol with injury (intentional and unintentional) across cultures. These differences may be due to differences in drinking patterns across cultures. Few comparative data have been reported on associations of alcohol and injury between Mexican American ER patients and ER patients living in Mexico, and general population studies suggest that Mexican Americans may adopt more frequent heavy drinking patterns after migrating to the United States.Methods: A comparative analysis of drinking, drug use, and injury was performed in probability samples of 550 ER patients from Santa Clara County (San Jose, CA) and 1417 ER patients in Pachuca (Hidalgo), Mexico.Results: Both injured and uninjured (i.e., medical conditions) patients in Pachuca were less likely to report heavy drinking, drug use, drunkenness, or alcohol‐related problems compared with those in Santa Clara. Those scoring high on level of acculturation in Santa Clara were more likely to report both drinking and drug use before the event, and heavy drinking, drug use, and consequences related to drinking in the last year compared with those scoring lower. Those scoring low on acculturation were similar on substance use variables to those in the Pachuca sample.Conclusions: Findings suggest that alcohol's association with injury may not just reflect typical drinking patterns in a culture. Among Mexican Americans, this association my vary by acculturation, and those migrating to the United States may be at increased risk for alcohol‐related injury as their drinking patterns undergo change to those of the dominant culture. The ER, in this context, may take on increasing importance as a site for health services providers to implement intervention and prevention services for alcohol‐related consequences in this ethnic group.
Interferon α and Alcohol Augment Nuclear Regulatory Factor‐κB Activation in HepG2 Cells, and Interferon α Increases Pro‐Inflammatory Cytokine Production
Authors: Szabo Gyongyi , Catalano Donna , Bellerose Gary , Mandrekar Pranoti 
Published: April 2006

Background: The mechanisms for decreased therapeutic response to IFNα in chronic hepatitis C patients with alcohol are unknown. We investigated the hypothesis that IFNα and alcohol regulate cells both in the liver parenchyma and the immune system.Methods: We used the hepatocellular carcinoma cells (HepG2) to determine if IFNα (500–10,000 U/ml) or ethanol (25–100 mM) modulates NF‐kB activation alone or in combination with TNFα (0.1–20 μg/ml) as determined in electromobility gel shift assays. IkB levels were evaluated in the cytoplasmic extracts by western blot. Monocytes from normal donors were activated with LPS (1 μg/ml) in combination with IFNα or ethanol overnight and TNFα, IL‐6, and IL‐12 were measured in the supernatants.Results: In HepG2 cells, both IFNα and acute alcohol treatment induced NF‐κB activation and augmented TNFα‐induced NF‐κB binding. Pretreatment of HepG2 cells with IFNα resulted in the highest levels of NF‐κB activation in response to TNFα or TNFα plus ethanol stimulation. Supershift experiments confirmed that the NF‐κB dimer induced by TNFα and its combination with IFNα or ethanol contains RelA (p65) and involves rapid degradation of IκBα. Experiments using the proteasome inhibitor, MG132, revealed that augmentation of NF‐κB by ethanol and IFNα is mediated via the proteasome pathway. We show that in normal monocytes, IFNα augments LPS‐induced production of the inflammatory cytokines TNFα, IL‐6, and IL‐12 (p < 0.06) without further modulation by acute alcohol treatment.Conclusions: These results suggest that IFNα can increase HepG2 cell sensitivity to TNFα and ethanol‐mediated activation. Augmentation of monocyte inflammatory cytokines, particularly of IL‐12 production, by IFNα could be a key element of the antiviral response in chronic HCV. These results support the hypothesis that the therapeutic benefits of IFNα likely involve activation of both immune and parenchymal cells in the liver.
Increased Serum IgE in Alcoholics: Relationship With Th1/Th2 Cytokine Production by Stimulated Blood Mononuclear Cells
Authors: Domínguez‐Santalla M. J. , Vidal C. , Viñuela J. , Pérez L. F. , González‐Quintela A. 
Published: April 2006

Background: Increased serum immunoglobulin (Ig) E values are frequently found in alcoholics. Cytokines produced by T‐helper‐2 (Th2) lymphocytes are required for IgE synthesis. Chronic alcoholism is associated with altered cytokine balance. This study analyzed the relationship between Th1 and Th2 cytokine production by stimulated peripheral blood mononuclear cells (PBMCs) and serum IgE levels, both in atopic and nonatopic alcoholics.Methods: Twenty‐five patients admitted to the hospital with alcohol withdrawal syndrome were included in the study. Five were classified as atopic and 20 as nonatopic by means of skin‐prick tests. Interleukin‐4 (IL‐4), IL‐10, IL‐12, IL‐13, and interferon γ were measured in the supernatants of 48‐hr cultures of PBMCs stimulated with phytohemagglutinin. Total serum IgE was measured by chemiluminescent enzyme immunoassay. Results were compared with those of 15 healthy controls (seven atopics and eight nonatopics).Results: Total serum IgE concentrations were higher in alcoholics than in controls, in both atopic and nonatopic subjects. The ratio of IL‐4 to interferon γ production by phytohemagglutinin‐stimulated PBMCs (as an approach to Th2/Th1 balance) was significantly lower in alcoholics than in healthy controls, both in the atopic and in the nonatopic group. No difference was observed regarding IL‐10, IL‐12, and IL‐13 production between alcoholics and controls. No correlation was demonstrated between cytokine production and total serum IgE levels in any group.Conclusions: Increased total serum IgE is observed in alcoholics together with a paradoxically low ratio of Th2 to Th1 cytokine production by phytohemagglutinin‐stimulated PBMCs. These findings are independent of the atopic status of patients.
Effects of Abstinence From Alcohol on the Broad Phospholipid Signal in Human Brain: An In Vivo 31P Magnetic Resonance Spectroscopy Study
Authors: Estilaei M. R. , Matson G. B. , Payne G. S. , Leach M. O. , Fein G. , Meyerhoff D. J. 
Published: April 2006

Background: In vivo phosphorus magnetic resonance spectroscopy (31P MRS) at a magnetic field strength of 1.5 T allows measurement of fairly mobile membrane phospholipids in the human brain. We previously showed that subjects who are heavy drinkers had a smaller signal and a shorter transverse relaxation time (T2) of white matter phospholipids than light drinkers, which suggested lower concentrations and molecular mobility of phospholipids in heavy drinkers. The purpose of the present study was to measure if such chronic alcohol‐induced white matter tissue changes are persistent in long‐term abstinent alcoholics.Methods: Fourteen abstinent alcoholics (mean age 45 years, seven men and seven women) were studied by localized 31P MRS in the centrum semiovale and were compared with 13 male, alcohol‐dependent, heavy drinkers and 23 nondependent light drinkers (17 men, 6 women) of similar age. Methods for measurements of the broad membrane phospholipid signal and its relaxation time were described previously.Results: Phospholipid concentrations and relaxation times in alcoholics abstinent for an average of 31 months were not significantly different from those measured in light drinkers. The contribution of fast and slowly relaxing signal components to the broad phospholipid signal, however, was still different in abstinent alcoholics compared with light drinkers. No effects of sex or of family history of alcoholism were noted on any of our spectroscopic measures within the light‐drinking or abstinent groups.Conclusions: Most of our results suggest at least partial recovery of chronic alcohol‐induced white matter phospholipid damage with long‐term abstinence. They offer myelination changes and/or dendritic rearborization as a possible mechanism for the commonly observed white matter volume gain with prolonged abstinence. But the results also suggest a persistent abnormality in the nature and/or physical properties of white matter phospholipids in long‐term abstinent alcoholics.
Early Alteration in Leukocyte Populations and Th1/Th2 Function in Ethanol‐Consuming Mice
Authors: Starkenburg Shawn , Munroe Melissa E. , Waltenbaugh Carl 
Published: April 2006

Background: Chronic alcohol consumption polarizes the immune response away from Th1‐mediated cell‐mediated immunity. In the present report we investigate the first onset of alteration in immune parameters during ethanol consumption in terms of changes in splenic leukocyte cellularity and surface phenotype as well as alterations in Th1 and Th2 function.Methods: BALB/c and C57BL/6 mice were fed ethanol‐containing liquid diets, were pair‐fed an isocaloric liquid control diet, or were fed solid diet and water ad libitum for up to 12 days. At intervals during the feeding period, splenic leukocytes were assessed for phenotypic markers by flow cytometry and for their ability to support antigen‐induced interferon‐γ (IFNγ) production in a coculture system. Mice were bled at intervals throughout the feeding period, and serum immunoglobin E (IgE) and alcohol levels were determined.Results: Data show that phenotypic and functional alterations occur within the first few days of alcohol consumption. Both liquid diets affect splenic cellularity, and by dietary day 5, ethanol‐containing liquid diets further reduce B and NK cell numbers. The decline in B cells is accompanied by a concomitant decline in the amount of major histocompatibility complex class II expressed on this population. Functional alteration in Th1‐mediated IFNγ production occurred in the population fed ethanol‐containing liquid diets by dietary day 5. Th2 function, as indicated by systemic serum IgE levels in these unimmunized mice, is increased by dietary day 6 to 8 and correlated with significant blood alcohol levels.Conclusions: Ethanol consumption by mice causes a rapid decrease in splenic cellularity accompanied by a decrease in Th1 function and a rapid increase in systemic IgE levels.
Effect of Ethanol on Polyunsaturated Fatty Acid Biosynthesis in Hepatocytes From Spontaneously Hypertensive Rats
Authors: Narce Michel , Poisson Jean‐Pierre , Bellenger Jérôme , Bellenger Sandrine 
Published: April 2006

Background: Polyunsaturated fatty acids (PUFA) play a major role in membrane structures that are modified during alcoholism. PUFA are also precursors of second messengers—eicosanoids—involved in the regulation of blood pressure. Alcohol has been related to hypertension and to alterations in liver PUFA metabolism. We investigated the effects of ethanol on PUFA biogenesis in hepatocytes of Wistar Kyoto (WKY) rats and Spontaneously Hypertensive Rats (SHR). The effects of a diet enriched with n‐3 PUFA, which is known to modulate hypertension, were also studied.Methods: Isolated hepatocytes from male normotensive Wistar Kyoto (WKY) rats and SHR were incubated for 60 min in the presence of labeled linoleic acid and DGLA, which are precursors of the limiting desaturation steps of PUFA biosynthesis, into a medium containing different concentrations of ethanol. Hepatocytes from SHR that were fed a diet supplemented with n‐3 PUFA were incubated with the same precursors.Results: First, the hepatic biogenesis of PUFA is dependent on the level of ethanol in the incubation medium. Second, Δ5 desaturase was more sensitive than Δ6 desaturase to changes in alcohol concentration. Third, in SHR, a tremendous decrease of arachidonic acid biosynthesis was evidenced in alcohol‐intoxicated hepatocytes; the effect was reinforced when ethanol concentration was high, mainly for Δ5 desaturase. Fourth, in the presence of ethanol, the biogenesis of PUFA was altered in isolated hepatocytes from SHR that were fed the diet supplemented with n‐3 PUFA, particularly via an inhibition of Δ5 desaturation.Conclusions: Our study showed that hepatocyte PUFA biogenesis is dependent on ethanol concentration. Ethanol strongly inhibits the synthesis of PUFA in hepatocytes from SHR, which can explain the deficit of prostaglandin precursors observed in cardiovascular diseases linked to ethanol intoxication. n‐3 PUFA supplemented diet reinforces the inhibition of arachidonic acid synthesis, likely by a substrate competition toward Δ5 desaturation. This in vitro approach provides a better understanding of the effects of ethanol on fatty acid metabolism in relation to hypertension.