bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatic Microvascular Dysfunction in Endotoxemic Rats After Acute Ethanol Administration
Authors: Horie Yoshinori , Kato Shinzo , Ohki Eiji , Tamai Hironao , Yamagishi Yoshiyuki , Ishii Hiromasa 
Published: April 2006

Background: A high concentration of ethanol is reported to cause hepatic microvascular dysfunction. However, little is known about the effect of ethanol on hepatic microcirculation in endotoxemic animals. The objective of this study was to determine whether endotoxemia enhances the hepatic microvascular dysfunction induced by acute ethanol administration.Methods: Intravital videomicroscopy was used to monitor leukocyte recruitment, number of nonperfused sinusoids, and flow velocity of erythrocytes (RBC) labeled with fluorescein isothiocyanate (FITC) in the livers of male Wistar rats that were administered ethanol (20%, 3 g/kg; or 40%, 6 g/kg) from a gastric tube. Flow velocity of RBC in sinusoids was measured with an off‐line velocimeter. Plasma tumor necrosis factor (TNF)‐α levels were also measured. In some experiments, rats were injected with 2 mg/kg of lipopolysaccharides (LPS) intraperitoneally at 16 hr before the experiments, and the same protocol was performed.Results: Although FITC‐RBC velocity was initially increased by both 20% and 40% ethanol in control rats, it was reduced by only 40% ethanol at 60 min. In LPS‐treated rats, the FITC‐RBC velocity also was increased initially but was reduced at 60 and 30 min by 20% and 40% ethanol, respectively. Only 40% ethanol caused leukostasis in the pericentral region of control rats. In LPS‐treated rats, however, leukostasis was noted in the midzonal and pericentral regions of liver after both 20% and 40% ethanol administration. Ethanol increased plasma TNF‐α levels only in LPS‐treated rats.Conclusions: These results suggest that LPS synergistically enhances ethanol‐induced hepatic microvascular dysfunction and liver injury, especially in the midzonal region via coagulation, which may be mediated by TNF‐α.
Elevated myo‐Inositol in Gray Matter of Recently Detoxified but Not Long‐Term Abstinent Alcoholics: A Preliminary MR Spectroscopy Study
Authors: Schweinsburg Brian C. , Taylor Michael J. , Videen John S. , Alhassoon Omar M. , Patterson Thomas L. , Grant Igor 
Published: April 2006

Background: Individuals in short‐term abstinence from chronic alcohol consumption commonly have neuropsychological impairments with parallel abnormalities in brain structure. Stable, long‐term sobriety often results in improvements in both brain structure and function, although the mechanisms underlying these changes are currently not well understood.Methods: To investigate further the neurobiological underpinnings of alcohol‐associated brain abnormalities in short‐term and long‐term abstinence from alcohol, proton magnetic resonance spectroscopy (echo time, 35 msec; repetition time, 1.5 sec) was used to assay metabolites in the anterior centrum semiovale, anterior cingulate gyrus, and right thalamus of two groups of non‐Korsakoff alcoholic men, at different stages of abstinence, compared with a control group of alcohol‐nonabusing men. Absolute concentrations of N‐acetylaspartate, choline, myo‐inositol, and creatine were measured in four recently detoxified alcoholics (mean age, 48.7 years; median abstinence, 41.5 days), five long‐term abstinent alcoholics (mean age, 45.1 years; median abstinence, 1.7 years), and five nonalcoholic controls (mean age, 45.0 years).Results: Although there were no between‐group differences in concentrations of N‐acetylaspartate, choline, or creatine, recently detoxified alcoholics had significantly higher myo‐inositol in the thalamus, compared with controls and long‐term abstinent alcoholics, and significantly higher myo‐inositol in the anterior cingulate gyrus, compared with the controls.Conclusions: Elevations in myo‐inositol in recently detoxified alcoholics are compatible with an acute alcohol cytotoxicity model. myo‐Inositol is elevated in hyperosmolar states such as hypernatremia, renal failure, and diabetes; alcohol‐induced hyperosmolarity may trigger accumulation of myo‐inositol to stabilize the intracellular environment. Increases in myo‐inositol may also reflect proliferation or activation of glia. The reduction of myo‐inositol to control group levels in long‐term abstinent alcoholics may reflect osmolar stability in abstinent alcoholics and/or a reduction in glial cell activation.
Alcohol‐Induced Reductions in Cardiac Protein Synthesis In Vivo Are Not Ameliorated by Treatment With the Dihydropyridine Calcium Channel Blocker Amlodipine
Authors: Patel Vinood B. , Siddiq Tahir , Richardson Peter J. , Preedy Victor R. 
Published: April 2006

Background: Various studies have indicated that acute ethanol dosage perturbs cardiac function and/or structure with concomitant reductions in protein synthesis. Cellular calcium homeostasis is also perturbed, which may contribute to altered protein synthesis. This is supported by the observation that calcium channel blockers can prevent numerous features of alcohol‐induced pathology. However, many of these studies have been carried out in vitro, employing supraphysiological levels of alcohol, or have failed to address whether their results obtained in isolated systems have direct relevance in vivo. The aim of the present investigation was to examine the response of cardiac protein synthesis in vivo due to a physiologically relevant dose of ethanol and determine whether a calcium channel antagonist could prevent these effects.Methods: Changes in cardiac protein synthesis rates in vivo were assessed by measuring the fractional rates of protein synthesis (i.e., ks) using a “flooding dose” of [3H]phenylalanine. Rats were treated either acutely (10 mg/kg body weight, 3 hr) or chronically (10 mg/kg body weight/day, 30 days) with amlodipine, a dihydropyridine‐type calcium channel blocker, before dosing with ethanol (75 mmol/kg body weight, 2.5 hr).Results: Ethanol (75 mmol/kg body weight) inhibited cardiac protein synthesis after 1 hr. Similar responses were recorded at 2.5 and 6 hr after ethanol dosage. At 24 hr, ethanol decreased food intakes. However, a direct comparison between pair‐fed controls and alcohol‐dosed rats also showed a decrease in cardiac protein synthesis after 24 hr. Acute alcohol dosage reduced cardiac protein synthesis in mixed, myofibrillary, and sarcoplasmic protein fractions. Similar results were obtained when data were expressed relative to ribonucleic acid (i.e., kRNA). Neither acute nor chronic treatments with the calcium antagonist amlodipine ameliorated the deleterious actions of ethanol on protein synthesis.Conclusions: Ethanol may affect cardiac protein synthesis independently of altered calcium entry.
Combining Ondansetron and Naltrexone Effectively Treats Biologically Predisposed Alcoholics: From Hypotheses to Preliminary Clinical Evidence
Authors: Johnson Bankole A. , Ait‐Daoud Nassima , Prihoda Thomas J. 
Published: April 2006

Background: Individuals considered to be early onset alcoholics (EOA) are characterized by an early onset age, a broad range of antisocial behaviors, high familial loading, and presumed biological disease predisposition. Ondansetron, a 5‐HT3 antagonist, improves drinking outcomes and increases abstinence rates among EOA. Individuals with high familial loading for developing alcoholism have lower levels of β‐endorphin and demonstrate a more pronounced increase in β‐endorphin levels in response to alcohol administration compared with individuals who do not have alcoholic relatives. The propensity for naltrexone (a mu opioid antagonist) to reduce alcohol's rewarding effects and drinking in humans is greatest in individuals with high familial loading. Predicated on the added knowledge that 5‐HT3 receptors may themselves mediate alcohol reward via activation of the endogenous opioid system, we hypothesized that the combination of ondansetron and naltrexone would act synergistically and would be an effective treatment in EOA.Methods: We conducted an 8‐week double‐blind placebo controlled clinical trial in which 20 EOA were randomized to receive ondansetron (4 μg/kg twice a day) + naltrexone (25 mg twice a day) or placebo as an adjunct to weekly standardized group Cognitive Behavioral Therapy.Results: At endpoint, subjects who received ondansetron + naltrexone (n= 10), compared with those who received placebo (n= 10), had fewer drinks/day (covariate adjusted mean 0.99 ± 0.60 vs. 3.68 ± 0.63;F 1, 16 = 9.35, p= 0.008; effect size = 1.42), drinks/drinking day (covariate adjusted mean 3.14 ± 0.87 vs. 6.76 ± 0.71;F 1, 13 = 10.45, p= 0.007; effect size = 1.71), and a trend toward increased percent days abstinent (covariate adjusted mean 69.76 ± 8.64 vs. 48.24 ± 9.12;F 1, 16 = 3.58, p= 0.08; effect size = 0.88).Conclusions: Ondansetron plus naltrexone seems to synergistically improve the drinking outcomes of EOA. Larger scale studies that test these medications, both alone and together, among various alcoholic subtypes are needed to establish and extend these promising findings.
An Abundant Proneurotensin Polymorphism, 479A>G, and a Test of Its Association With Alcohol Dependence in a Finnish Population
Authors: Vanakoski Jyrki , Mazzanti Chiara , Naukkarinen Hannu , Virkkunen Matti , Goldman David 
Published: April 2006

Background: Neurotensin is a 13‐amino acid neuropeptide that endogenously modulates dopamine release in the central nervous system. In substance dependence, the mesolimbic dopamine system has been postulated to be a central structure that mediates rewarding and reinforcing effects. Neurotensin receptors in the neurons of the ventral tegmental area facilitate dopamine release, making the neurotensin gene an excellent candidate gene for alcohol dependence and for other behaviors that involve reinforcement.Methods: A total of 639 psychiatrically interviewed Finns were genotyped for proneurotensin 479A>G polymorphism. We used the polymorphism as a marker to study the association between proneurotensin gene and alcohol dependence by comparing 229 unrelated Finnish healthy controls to 134 unrelated alcohol‐dependent (DSM‐III‐R criteria) subjects who were also criminal offenders. In addition, 276 relatives of the alcohol‐dependent and control subjects were genotyped.Results: The frequencies of the genotypes in the whole sample (n= 639) were 0.84 for 479A/A, 0.16 for 479A/G, and 0.003 for 479G/G. The frequency of the rarer 479G allele was 0.07 and 0.06 in controls and alcohol‐dependent subjects, respectively, and this difference was not statistically significant (χ2= 0.264, df= 1, p= 0.61, controls vs. alcohol‐dependent subjects).Conclusions: The results of the comparison between psychiatrically interviewed controls and alcoholics from a relatively well defined population indicate that the proneurotensin 479A>G polymorphism is not strongly associated with alcohol dependence. The results do not rule out a role for this gene in the pathogenesis of alcoholism or in differential vulnerability.
Season of Birth and Substance Abuse: Findings From a Large National Sample
Authors: Goldberg Abbie E. , Newlin David B. 
Published: April 2006

Background: Season of birth is a putative etiological factor for several psychiatric illnesses. An excess of late winter and early spring births has been demonstrated repeatedly for schizophrenia, which has usually been interpreted as the result of prenatal or infant exposure to seasonally mediated “harmful effects,” such as infectious diseases. This study determined whether the seasonal birth rates of substance abusers differed from those of unaffected control groups.Methods: The 1992 National Longitudinal Alcohol Epidemiologic Survey, an interview‐based study of 42,862 men and women, provided data to assess the association between quarter year of birth and lifetime diagnoses of substance abuse.Results: Logistic regression revealed decreases in winter births in men with histories of alcohol dependence. The significant interaction of sex with season of birth reflected an excess of fall births among male but not female alcoholics. In contrast, there was no evidence of seasonality of birth among alcohol abusers. Men and women with histories of illicit drug use had excesses of fall birth.Discussion: Birth rates of men with past or present alcohol dependence, and of men and women with histories of illicit drug use, implicated seasonal factors in the pathogenesis of substance abuse. The similar birth patterns of illicit drug users and male alcoholics suggest that they may share some common etiological factor, such as seasonal effects on environmental temperature, hormonal function, or susceptibility to viral infection during pregnancy or early infancy.
Subjective and Objective Responses to Ethanol in Moderate/Heavy and Light Social Drinkers
Authors: Holdstock Louis , King Andrea C. , de Wit Harriet 
Published: April 2006

Background: Individuals who drink heavily are at an increased risk for adverse consequences of drinking and progression of their drinking habits to abuse or dependence. Therefore, it is important to delineate factors associated with their heavy drinking.Methods: We examined individual differences in subjective and objective responses to ethanol associated with level of consumption by reanalyzing data from the nine heaviest and nine lightest social drinkers from each of two independently collected subject samples: Holdstock and de Wit (1998) and King et al. (1997). The light drinkers in both samples consumed five or less alcoholic drinks per week, whereas the moderate/heavy drinkers consumed eight or more drinks per week with frequent binge episodes. Acute subjective and objective responses to ethanol (0.6 or 0.8 g/kg) or placebo were compared in the two groups at baseline and during rising and falling blood alcohol concentrations.Results: Moderate/heavy drinkers reported greater stimulant‐like and fewer sedative‐like and aversive subjective effects after ethanol than did lighter drinkers. These differences occurred in the absence of any group differences in breath alcohol levels, performance effects, or neuroendocrine changes or in overall reports of feeling any drug effects.Conclusions: These data indicate that habitual moderate/heavy ethanol use was associated with greater stimulant‐like effects after an acute dose of alcohol. This finding is consistent with the idea (Newlin and Thomson, 1990, 1999) that individuals who experience greater stimulant‐like effects during the ascending limb and lesser sedative‐like effects on the descending limb of the blood alcohol concentration curve may be at greater risk for developing ethanol use disorders. Although we cannot determine the causality of this association, sensitivity to the stimulant effects of ethanol may play an important role in the continuation of heavy ethanol use and the increased risk of negative consequences from this use.
Ethanol‐Induced c‐Fos Expression in Catecholamine‐ and Neuropeptide Y‐Producing Neurons in Rat Brainstem
Authors: Thiele Todd E. , Cubero Inmaculada , Van Dijk Gertjan , Mediavilla Cristina , Bernstein Ilene L. 
Published: April 2006

Background: Previous studies have used c‐Fos‐like immunoreactivity (cFLI) to examine the neuroanatomical location of cells that are activated in response to ethanol administration. However, the use of cFLI alone fails to reveal the phenotypical identity of cells. In the present study we used double‐labeling procedures to identify the neurochemical phenotype of neurons that showed ethanol‐induced cFLI in the rat brainstem.Methods: Individual groups of rats received intraperitoneal injection of ethanol (1.5 g/kg or 3.5 g/kg) or isotonic saline (23 ml/kg). To assess the specificity of cFLI induced by ethanol, we injected other rats with the drug lithium chloride (LiCl; 76 mg/kg). Two hours after injection, rats were killed and their brains were processed for immunohistochemistry.Results: Both doses of ethanol promoted cFLI in several brainstem regions, including the nucleus of the solitary tract (NTS), the locus coeruleus (LC), and the ventrolateral medulla (VLM). Although LiCl caused significant cFLI in the NTS, this drug promoted only minimal cFLI in the VLM and no significant activation in the LC. We found that a significant proportion of tyrosine hydroxylase (TH)‐positive neurons coexpressed ethanol‐induced cFLI in the VLM (∼75–85%), the NTS (∼65–75%), and the LC (∼30–65%). Additionally, a significant proportion of neuropeptide Y (NPY)‐producing neurons in the VLM coexpressed ethanol‐induced cFLI (∼60–75%). On the other hand, LiCl promoted activation of TH‐positive neurons in the VLM and the NTS but failed to stimulate cFLI in TH‐producing neurons in the LC or in NPY‐producing neurons of the VLM.Conclusions: Neurons in the rat brainstem that show ethanol‐induced c‐Fos expression produce catecholamines and NPY. This research demonstrates the usefulness of double‐labeling immunohistochemistry procedures for identifying the neurochemical identity of neurons that are activated after ethanol administration.
The Modulation of B16BL6 Melanoma Metastasis Is Not Directly Mediated by Cytolytic Activity of Natural Killer Cells in Alcohol‐Consuming Mice
Authors: Spitzer Jessica H. , Núñez Nomelí P. , Meadows Sarah A. , Gallucci Randle M. , Blank Sally E. , Meadows Gary G. 
Published: April 2006

Background:Previous studies in our laboratory indicate that alcohol consumption suppresses the metastasis of B16BL6 melanoma, whereas the cytolytic activity of natural killer (NK) cells is decreased in female C57BL/6 mice given 20% w/v alcohol in their drinking water. In the present study, we further evaluated the involvement of NK cells and alcohol consumption in the cytolytic activity of NK cells, the surface expression of NK phenotypic markers, and metastasis of B16BL6 melanoma in C57BL/6 beige (bgJ/bgJ) mutant mice, which possess inherently low NK‐cell cytolytic activity.Methods:Beige and control (bgJ/+) mice were given either water or 20% w/v of alcohol in drinking water for 61/2 to 7 weeks before assay for cytolytic activity, surface marker expression, and inoculation with B16BL6 melanoma intravenously or into the pinna of the ear.Results:NK cytolytic activity was suppressed in beige mice, and alcohol consumption did not modulate further the cytolytic activity. Beige mice had a lower percentage of NK cells in the peripheral blood and spleen than control mice. Peripheral blood lymphocytes from beige mice also exhibited a reduced percentage of CD4+T lymphocytes. Alcohol consumption similarly reduced the percentages of NK1.1‐ and LGL‐1‐expressing lymphocytes in the peripheral blood and spleen and reduced the percentage of CD8+T lymphocytes in the peripheral blood in both control and beige mice. Tumor lung colonization was increased in beige mice relative to control mice after intravenous inoculation of B16BL6 melanoma. The increase was more pronounced in water‐drinking beige mice than in control mice irrespective of alcohol consumption. Tumor lung colonization was significantly decreased (p< 0.05) by alcohol consumption in one experiment and partially decreased (p= 0.07) in the other. Mice that were inoculated into the pinna of the ear also exhibited a blunted antimetastatic response to alcohol consumption.Conclusions:These data suggest that the presence of the beige mutation diminishes the antimetastatic effect of alcohol consumption and that there is no interaction between alcohol consumption and NK‐cell activity in the modulation of lung metastasis of B16BL6 melanoma cells.
Brain High Energy Phosphate Responses to Alcohol Exposure in Neonatal Rats: An In Vivo 31P‐NMR Study
Authors: Cudd Timothy A. , Wasser Jeremy S. , Chen Wei‐Jung A. , West James R. 
Published: April 2006

Background: The mechanisms that mediate fetal brain injury which results from maternal alcohol consumption are not well understood. Although fetal hypoxia is a popularly proposed mechanism, it has been difficult to assess brain oxygenation in vivo. We measured intracellular high energy phosphate concentrations and estimated intracellular pH (pHi) in brains of unanesthetized neonatal rat pups by using in vivo 31P‐NMR spectroscopy. We reasoned that decreases in brain oxygenation sufficient to result in brain injury would also reduce high energy phosphates and pHi.Methods: On postnatal day 4, before alcohol administration, pups were placed into a 20 mm diameter NMR probe, their heads were positioned carefully in the center of the 31P detection coil, and spectra were collected over 20 min. Animals were then fed diet with or without 4.5 g/kg of ethanol in two (in succession) of 12 daily feedings via artificial rearing methods. A second spectrum was collected at 90 min after the beginning of the second alcohol feeding, at the time that coincided with the peak blood alcohol concentration (BAC). Identical feedings were performed daily until day 9, when pre‐ and postfeeding spectra were again obtained. Positive control groups were fed control diet and were studied in atmospheres of 5% oxygen, 95% nitrogen or 0% oxygen, 100% nitrogen.Results: Phosphocreatine (PCr), β‐adenosine triphosphate (ATP), and pHi decreased and inorganic phosphate (Pi) increased in day 4 animals subjected to 0% oxygen (20 min) compared with pretreatment and all other treatment groups. Day 9 animals did not tolerate these conditions. There were no significant changes in response to 5% oxygen on day 4, but Pi increased and β‐ATP decreased compared with pretreatment values and compared with alcohol and control groups on day 9. There were no changes in PCr, β‐ATP, or pHi in response to alcohol treatment at either age. PCr was significantly increased in the alcohol and 5% oxygen groups and apparently increased in the control group on day 9 compared with day 4, most likely due to increases in cranial muscle mass within the NMR coil.Conclusions: We conclude that acute alcohol exposure that results in peak BACs of 315 mg/dl does not alter brain high energy phosphate concentrations or pHi in neonatal rat pups, although these BACs are known to result in significant brain injury. These findings do not support hypoxia as a mechanism of alcohol‐mediated brain injury during the third trimester equivalent in the rat pup model.