bluuebunny/crossref_metadata_2025 huggingface dataset:
Response of Three Hormones to Diazepam Challenge in Sons of Alcoholics and Controls
Authors: Schuckit Marc A. , Hauger Richard L. , Monteiro Maristela G. , Irwin Michael , Duthie Lori A. , Mahler Heike I. M.
Published: April 2006

This study evaluates the hypothesis that the decreased reaction to ethanol reported for sons of alcoholics will also be observed following infusions of a benzodiazepine. The investigation compared 37 men who were family history positive for alcoholism with 37 family history negative controls on postinfusion levels of cortisol, prolactin, and growth hormone following 0.12 and 0.20 mg/kg of diazepam given IV over 7 minutes. The results demonstrated no evidence of a decreased response for the sons of alcoholics on the levels of these three hormones.
Hypothesis: Prenatal Ethanol‐Induced Birth Defects and Retinoic Acid
Authors: Pullarkat Raju K.
Published: April 2006

A hypothesis is presented to explain the biochemical basis of ethanol‐induced birth defects. Prenatal ethanol exposure causes central nervous system and limb abnormalities in humans and in animals. Retinoic acid and didehydroretinoic acid are known to play an important role in the central nervous system and limb developments. Ethanol is known to inhibit the formation of retinoic acid from retinol and deplete hepatic retinoid levels. It is hypothesized that ethanol reduces the levels of retinoic acid in the developing embryo either by inhibiting conversion of retinol to retinoic acid and/or by depleting the level of retinol, thereby causing central nervous system and limb abnormalities.
A Hypothetical Mechanism for Fetal Alcohol Syndrome Involving Ethanol Inhibition of Retinoic Acid Synthesis at the Alcohol Dehydrogenase Step
Authors: Duester Gregg
Published: April 2006

Ethanol acts as a teratogen causing brain, craniofacial, and limb abnormalities in those suffering from fetal alcohol syndrome. Normal embryonic development of the vertebrate nervous system and limbs has recently been shown to be governed by retinoic acid, the active form of vitamin A. Retinol dehydrogenase is an enzyme needed to convert vitamin A (retinol) to retinoic acid, a molecule that specifies embryonic pattern formation by controlling gene expression. Ethanol acts as a competitive inhibitor of the retinol dehydrogenase activity attributed to mammalian alcohol dehydrogenase (ADH), an enzyme that uses both retinol and ethanol as substrates. An hypothesis is presented in which many of the abnormalities observed in fetal alcohol syndrome may be caused by high levels of ethanol acting as a competitive inhibitor of ADH‐catalyzed retinol oxidation in the embryo or fetus. This would presumably result in a reduction of retinoic acid synthesis in embryonic tissues such as the nervous system and limbs that require critical levels of this molecule to specify spatial patterns.
Hepatic, Metabolic and Toxic Effects of Ethanol: 1991 Update
Authors: Lieber Charles S.
Published: April 2006

Until two decades ago, dietary deficiencies were considered to be the only reason for alcoholics to develop liver disease. As the overall nutrition of the population improved, more emphasis was placed on secondary malnutrition and direct hepatotoxic effects of ethanol were established. Ethanol is hepatotoxic through redox changes produced by the NADH generated in its oxidation via the alcohol dehydrogenase pathway, which in turn affects the metabolism of lipids, carbohydrates, proteins, and purines. Ethanol is also oxidized in liver microsomes by an ethanol‐inducible cytochrome P‐450 (P‐45011E1) that contributes to ethanol metabolism and tolerance, and activates xenobiotics to toxic radicals thereby explaining increased vulnerability of the heavy drinker to industrial solvents, anesthetic agents, commonly prescribed drugs, over‐the‐counter analgesics, chemical carcinogens, and even nutritional factors such as vitamin A. In addition, ethanol depresses hepatic levels of vitamin A, even when administered with diets containing large amounts of the vitamin, reflecting, in part, accelerated microsomal degradation through newly discovered microsomal pathways of retinol metabolism, inducible by either ethanol or drug administration. The hepatic depletion of vitamin A is strikingly exacerbated when ethanol and other drugs were given together, mimicking a common clinical occurrence. Microsomal induction also results in increased production of acetaldehyde. Acetaldehyde, in turn, causes injury through the formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, and alterations in microtubules, plasma membranes and mitochondria with a striking impairment of oxygen utilization. Acetaldehyde also causes glutathione depletion and lipid peroxidation, and stimulates hepatic collagen production by the vitamin A storing cells (lipocytes) and myofibroblasts. Experimentally, liver injury and even fibrosis can be attenuated by some “supernutrients,” such as S‐adenosyl‐l‐methionine or polyunsaturated lecithin. Thus, the classic dichotomy between nutritional and toxic effects of ethanol has now been bridged.
Pharmacotherapies for Alcoholism: Promising Agents and Clinical Issues
Authors: Litten Raye Z. , Allen John P.
Published: April 2006

The past 10 years have witnessed important advances in research on pharmacotherapy for alcoholism. Promising drugs are discussed under six headings: agents to treat alcohol withdrawal; anticraving agents; agents that make drinking an aversive experience; agents to alleviate concomitant psychiatric problems; agents to treat concurrent drug abuse; and amethystic (“sobering‐up”) agents. Research on the drug classes is summarized and clinical issues surrounding specific agents and alcoholism pharmacotherapy in general are discussed. Finally, long‐range therapeutic implications of recent findings on the actions of alcohol on basic mechanisms of the brain are offered.
Psychiatric Symptoms in Alcoholics Attending Outpatient Treatment
Authors: Öjehagen Agneta , Berglund Mats , Appel Claus‐Peter , Nilsson Bertil , Skjaerris Anne
Published: April 2006

The importance of psychiatric symptomatology for the treatment course of alcoholics was analyzed in a long‐term outpatient treatment study. Seventy‐two patients, 60 men and 12 women, were personally interviewed during treatment and after 3 years. Before treatment psychiatric symptoms were rated according to the Comprehensive Psychopathological Rating Scale (CPRS). Women had significantly higher scores than men. Men with many symptoms and women had more psychological benefits from drinking and a more impaired personality structure than men with few symptoms. Men with many symptoms also had a lower level of social functioning. The severity of abuse did not differ between the three groups. Men with many symptoms had a less favorable outcome between 25 and 36 months after start of treatment than men with few symptoms and women. Among men who completed treatment, those with many symptoms showed a less successful course after 6 months and during the 3rd year after start of treatment, while differences after 3 months and during later stages of treatment were less pronounced. It is suggested that before start of treatment a psychiatric evaluation should be performed including psychiatric diagnosis, personality analysis, and an assessment of psychological benefits from drinking.
Endogenous Opioids Are Involved in the Genetically Determined High Preference for Ethanol Consumption
Authors: George Susan R. , Roldan Luis , Lui Alex , Naranjo Claudio A.
Published: April 2006

The link between endogenous opioid peptides and the genetic predisposition to preferentially consume ethanol was examined in alcohol preferring C57BL/6J mice compared with the alcohol nonpreferring DBA/2 mice. Concentrations of Met‐enkephalin pentapeptide or precursor in various brain regions of potential relevance were not different between the two strains. C57BL/6J mice had a significantly lower pain threshold that could be increased by a selective mu‐receptor opioid agonist [D‐Ala2, MePhe4, Met(0)5‐ol]‐enkephalin. Treatment with this drug also decreased ethanol consumption in C57BL/6J mice. Increasing the synaptic half‐life of endogenous enkephalins by the enkephalinase inhibitor kelatorphan also decreased ethanol consumption. Assay of endogenous enkephalin degrading activity showed increased enkephalinase activity in striatal issue of C57BL/6J compared with DBA/2 tissue. These results suggest that a relative lack of enkephalin peptides trans‐synaptically, possibly resulting from enhanced enkephalin degradation may contribute to increase alcohol consumption in C57BL/6J mice.
The Relationship Between Ethanol‐induced Hyperglycemia and Hypothermia: Evidence of Genetic Correlation
Authors: Risinger Fred O. , Cunningham Christopher L.
Published: April 2006

The hyperglycemic and hypothermic responses to acute ethanol exposure (0, 2, 4, 6 g/kg, intraperitoneally) were examined in non‐fasted mice selectively bred for sensitivity (COLD line) or insensitivity (HOT line) to ethanol‐induced hypothermia. Blood samples and rectal temperatures were obtained immediately before injection and hourly for 4 hr after injection. As expected, COLD mice demonstrated greater and more prolonged reductions in body temperature than HOT mice, especially at the 4 g/kg dose (HOT ‐2.58°C, COLD: ‐5.08°C). Ethanol produced significant dose‐dependent elevations in blood glucose levels over the 4‐hr sampling period in both lines. The greatest elevations in blood glucose levels were seen at 4 g/ kg, with COLD mice (mean = 225.1 mg/dl) showing significantly greater elevations in blood glucose levels compared to HOT mice (mean = 177.0 mg/dl). These results support the hypothesis that the thermic and glycemic effects produced by ethanol are due to related neural processes that share a common genetic component.
Effect of Chronic Ethanol Feeding on Hepatic and Extrahepatic Distribution of Vitamin E in Rats
Authors: Meydani Mohsen , Seitz Helmut K. , Blumberg Jeffrey B. , Russell Robert M.
Published: April 2006

The effect of chronic ethanol feeding on the status of α‐ and γ‐ tocopherol in plasma, liver, lung, and testes of Sprague‐Dawley rats was characterized. Rats were pair‐fed liquid diets containing 36% of total calories either as ethanol or isocaloric carbohydrates. After 3 weeks, ethanol ingestion resulted in a significant (p≤ 0.05) increase in liver weight and induced fatty liver without affecting total body weight. Ethanol feeding did not affect the plasma concentration of α‐tocopherol but doubled that of γ‐tocopherol. When expressed per milligram of tissue, liver α‐tocopherol did not vary with ethanol ingestion, whereas γ‐tocopherol concentration increased 2.5 times that of control animals. However, the concentration of α‐tocopherol expressed per milligram of total lipids was significantly (p≤ 0.01) decreased in the liver with ethanol feeding. In contrast to the liver, ethanol feeding significantly increased α‐ and γ‐tocopherol levels per milligram of total lipids in the testes. The concentration of γ‐ tocopherol (but not α‐tocopherol) per milligram of lung tissue and per total lung was significantly (p≤ 0.05) increased with ethanol feeding. These data indicate that chronic ethanol ingestion significantly alters the distribution of α‐tocopherol and γ‐tocopherol in hepatic and extrahepatic tissues of the rat.
Multi‐Enzyme Catalyzed Rapid Ethanol Lowering in Vitro
Authors: Whitmire David R. , Chambers Robert P. , Dillon A. Ray
Published: April 2006

Ethanol was oxidized to acetate by an enzyme system using yeast alcohol dehydrogenase (YADH), yeast aldehyde dehydrogenase (YALDH), and lactic dehydrogenase (LDH) recycling NAD in two model duodenal fluids and in canine duodenal aspirate in vitro. Sufficient enzyme activities were maintained to convert as much as 34% of the original ethanol to acetate with negligible acetaldehyde accumulation.
Applications of Cloninger's Subtypes in a Female Alcoholic Sample
Authors: Glenn Susan Wagner , Nixon Sara Jo
Published: April 2006

This study examined the incidence of Type 1/Type 2 symptoms and age of alcoholism onset in a population of alcoholic women in order to determine whether there were females similar to the Type 1 and Type 2 male alcoholics described by Cloninger and colleagues. Using a sample of 51 alcoholics divided into early and late alcoholism onset groups (< 25 and ≥25), the early onset group did not manifest merely Type 2 symptomatology nor did the late onset group manifest Type 1 symptoms without the occurrence of Type 2 symptoms, as would have been predicted by the Cloninger theory. Rather, the majority of women endorsed both types of symptoms regardless of their age of alcoholism onset, making classification by sympton type unsuccessful. However, combining symptoms across types (making a total of 7) produced 71% classification of subjects into early symptom onset (ESO) and late symptom onset (LSO) groups. Analyses indicated differences between the groups in each of five areas: (1) demographic and psychosocial variables, (2) alcohol abuse severity, (3) family history, (4) psychopathological symptoms, and (5) substance abuse history. In each case the ESO alcoholics resembled the characteristics of male Type 2 alcoholics reported in other studies. The findings indicate that modification of the Cloninger classification criteria to reflect age of symptom onset regardless of symptom “type” provides better classification of individual female alcoholics and suggests that female alcoholics are represented in both Type 1 and Type 2 alcoholic subtypes
EEG Characteristics in Males at Risk for Alcoholism
Authors: Cohen Howard L. , Porjesz Bernice , Begleiter Henri
Published: April 2006

Baseline EEG activity was recorded with eyes closed in 15 males, aged 19 to 24 at risk (HR = high risk) for the development of alcoholism and 15 matched controls (LR = low risk). Four EEG frequency bands were examined: slow alpha (7.5–10 Hz), fast alpha (10.25–12.75 Hz), slow beta (13–19.5 Hz) and fast beta (19.75–26 Hz). The HR and LR groups were compared on four measures of EEG activity for each frequency band: band power, absolute and relative area and laterality differences. Statistical analysis of the data via ANOVA revealed no significant difference between the HR and LR groups for any comparison. The results indicate that EEG measures prior to alcohol administration do not effectively discriminate between individuals at high and low risk for alcoholism.
Psychiatric Comorbidity in Alcoholism: Importance of Ascertainment Source
Authors: Mezzich Ada C. , Arria Amelia M. , Tarter Ralph E. , Moss Howard , Van Thiel David H.
Published: April 2006

Although psychiatric comorbidity is often observed among individuals in treatment facilities for alcoholism, the prevalence and pattern of psychiatric comorbidity among alcoholic cirrhotics has not been well characterized. The present study aimed first to compare the prevalence of psychiatric comorbidity in cirrhotic individuals with alcoholism ascertained from a gastroenterology service with alcoholics ascertained from a treatment facility for alcoholism. Consistent with the findings of other investigators, the data suggest that there is a great degree of variability regarding the severity of alcoholism in alcoholic cirrhotic individuals. Furthermore, cirrhotics with alcoholism exhibited a less severe clinical picture of alcoholism as measured by less alcohol dependence and lower prevalence of psychiatric comorbidity than individuals in treatment for alcoholism. The main conclusion of this study is that ascertainment source is an important determinant of psychiatric comorbidity observed in alcoholic samples.
Self‐Administered Alcoholism Screening Test: A Comparision of Conventional Versus Computer‐Administered Formats
Authors: Davis Leo J. , Morse Robert M.
Published: April 2006

The equivalence of paper‐and‐pencil‐administered and computer‐administered versions of the Self‐Administered Alcoholism Screening Test (SAAST) was investigated with alcoholic inpatients and nonalcoholic psychiatric outpatients. When the two formats were administered in counterbalanced order, total score mean differences were nonsignificant. In addition, mean differences on a short‐form version were also nonsignificant. Equivalence was also determined by comparing the two formats in terms of classification agreement (i.e., classification of subjects into alcoholic and nonalcoholic categories). Agreement between the two formats was 95% in both the total score and short‐form versions. Implications of these results as well as the advantages and disadvantages of using computer‐administered alcoholism screening tests are discussed.
Gamma‐Aminobutyric Acid‐Activated Chloride Channels in Rats Selectively Bred for Differential Acute Sensitivity to Alcohol
Authors: Allan Andrea M. , Mayes George G. , Draski Laura J.
Published: April 2006

Effects of various sedative hypnotic agents on GABA‐mediated chloride flux were evaluated in whole brain membrane vesicles (microsacs) prepared from rats selectively bred for high (HAS) and low sensitivity (LAS) to an acute hypnotic dose of alcohol. The HAS rats were more sensitive to the effects of pentobarbital, phenobarbital, flunitrazepam, and ethanol on GABA‐mediated chloride flux compared with the LAS rats. No differences between the lines in GABA‐stimulated chloride flux were observed. Modulation of 1‐[3H]‐phenyl‐4‐butyl‐2,6,7‐trioxabicyclo(2.2.2)octane([3H]‐TBOB) and [3H]‐diazepam binding also was measured. The lines did not differ in inhibition of [3H]‐TBOB binding by pentobarbital, phenobarbital, muscimol or picrotoxin. Although the lines displayed almost identical KO and Bmax for [3H]‐diazepam binding, the GABA agonist, muscimol, was a more potent stimulator of [3H]‐diazepam binding in membranes prepared from HAS rats than from LAS rats. These findings are discussed in light of previous work using other selected lines.
Alterations in Hepatic Lipids and Proteins by Chronic Ethanol Intake: A High‐Pressure Fourier Transform Infrared Spectroscopic Study on Alcoholic Liver Disease in the Rat
Authors: Takahashi Hisao , French Samuel W. , Wong Patrick T. T.
Published: April 2006

Using high‐pressure Fourier transform infrared (FT‐IR) spectroscopy, alterations of hepatic lipids and proteins in alcoholic liver disease of the rat were examined. FT‐IR spectra were obtained from the liver tissues of the rats pair‐fed a nutritionally adequate liquid diet and ethanol/dextrose via an implanted intragastric tube for 6 months. The pressure on the liver samples was raised up to 10 kbar, taking FT‐IR spectra at regular increments as the pressure was raised. Total lipids measured by the band derived from the stretching mode of carbonyl groups in lipid (v C=O) were increased 4 times in the liver of ethanol‐fed rats (E) compared with the pair‐fed control rats (C). The frequency of the C=O band of E decreased with increasing pressure, which indicated that hydrogen‐bonding was present on the C–O groups of lipids in E. The intensity of the CH stretching bond of the HC=CH groups was 2.8 times higher in E than that in C, which means that there was an increase in the population of unsaturated double bonds in acyl chains of lipids in E. The conformational structure of the protein molecules was slightly changed in E. The reactivity of carboxylate side groups in proteins observed by reaction with Ba++ ions was higher in E than that in C. These infrared spectroscopic results suggest that chronic ethanol intake induces not only an increase in the amount of total lipid but also changes the composition of lipids and the conformation of protein molecules in the liver of rats.
Effect of Prenatal Exposure to Ethanol on the Cell Cycle Kinetics and Growth Fraction in the Proliferative Zones of Fetal Rat Cerebral Cortex
Authors: Miller Michael W. , Nowakowski R. S.
Published: April 2006

Prenatal exposure to ethanol produces profound changes in the number of neurons in the mature cortex. These changes in neuronal number may reflect ethanol‐induced disturbances in early developmental processes, that is in the proliferation of neuronal precursors. Hence, the present study examined the effect of ethanol on cell proliferation in the two neocortical proliferative zones, the ventricular zone (VZ) and subventricular zone (SZ). From gestational day 5 to 21, pregnant rats were fed an ethanol diet (6.7% v/v), pair‐fed an isocaloric control diet, or fed chow and water. Pregnant rats were given a series of one to nine injections of bromodeoxyuridine (BrdU). After immunohistochemical processing, the ratio of cells in each proliferative zone that were labeled with BrdU to the total population was determined. The portion of the population that was cycling (growth fraction), the total length of the cell cycle, and the length of the S‐phase of the cell cycle were calculated for VZ and SZ cells. Exposure to moderate levels of ethanol has markedly different effects upon the two neocortical proliferative zones. In the VZ, the length of the total cell cycle was significantly greater in ethanol‐treated rats than in controls; however, the growth fraction and the length of the S‐phase were unaffected by ethanol. In contrast, in the SZ, the growth fraction was significantly greater in ethanol‐treated rats, but ethanol had no effect on the length of the total cell cycle or of the S‐phase. These differences may underlie the ethanol‐induced abnormalities in neuronal generation.
Locomotor Activity Responses to Ethanol in Selectively Bred Long‐ and Short‐Sleep Mice, Two Inbred Mouse Strains, and Their F1 Hybrids
Authors: Phillips Tamara J. , Dudek Bruce C.
Published: April 2006

Locomotor activity responses to sub‐hypnotic doses of ethanol (ETOH) were assessed in selected lines of mice (LS and SS), inbred strains, and their F1 hybrids. Data were obtained as photocell beam interruptions in a 15‐min test for a dose range of 0 to 2.75 or 3.5 g/kg for LS and SS mice, respectively. Biphasic dose‐response curves were obtained for LS and SS mice with the SS mice showing a sedative limb of the dose‐response curve shifted to the right. The effects of 2.0 g/kg ETOH were also assessed in a diallel cross of the selected LS/SS lines and C57BL/6Abg and MOLD/RkAbg inbred strains. The 2.0 g/kg dose produced a wide range of responses, from sedation in C57BL/6Abg mice to extreme activation in SS and MOLD/RkAbg mice, and no effect in LS mice. The responses of F1 hybrids reflected a typical pattern of partial dominance, with heterosis in some crosses. When present, dominance was in the direction of greater locomotor activation. These patterns were confirmed by biometrical genetic analysis of the 4 × 4 diallel cross of the two lines and the two inbred strains. The data indicate that loci in addition to those responsible for selection for sedative sensitivity in LS and SS mice can influence locomotor activation produced by sub‐hypnotic ETOH doses, and that SS and MOLD mice show locomotor activation for different genetic reasons.
Ethanol‐Associated Alterations in the Kinetics of Putrescine Uptake and Metabolism by the Regenerating Liver
Authors: Diehl Anna Mae , Yang Shi Qi , Brown Nesbitt , Smith Jeff , Raiford David , Gordon Richard , Casero Robert
Published: April 2006

Biosynthesis of the polyamines, putrescine, spermidine, and spermine is required for DNA synthesis and liver regeneration after partial hepatectomy. We have previously reported that chronic ethanol consumption impairs polyamine synthesis and significantly retards liver regeneration after partial hepatectomy. In those studies, supplementation with putrescine restored hepatic DNA synthesis in ethanol‐fed rats but exerted no effect in pair‐fed controls. These differences in the response to putrescine treatment may have resulted from ethanol‐associated differences in hepatic uptake, release, or metabolism of putrescine. To resolve these issues and define more completely how putrescine treatment affects DNA synthesis, we now assess the kinetics of putrescine uptake and metabolism after intraperitoneal or intravenous injection of radiolabeled putrescine (1.2 mmol/kg, specific activity 1 μCi/mmol) into rats fed 36% ethanol diets or isocaloric, nonethanol diets for 6 weeks prior to partial hepatectomy. After putrescine treatment, hepatic putrescine concentrations were greater in ethanol‐fed rats than controls. Differences in post‐treatment hepatic putrescine levels between ethanol and pair‐fed groups could not be explained by differences in the rates of hepatic putrescine uptake or excretion into bile; residual de novo synthesis of putrescine from ornithine or metabolism of hepatic putrescine to its polyamine products, spermidine and spermine. Indeed, supplemental putrescine was not appreciably converted to spermidine or spermine in either ethanol or control rats. Hence, these latter polyamines are unlikely to be responsible for the treatment‐associated improvement in DNA synthesis that has been noted in ethanol‐fed rats. This suggests that putrescine itself acts to restore hepatic DNA synthesis in ethanol‐fed rats.
Genetically Determined Differences in the Antagonistic Effect of Pressure on Ethanol‐Induced Loss of Righting Reflex in Mice
Authors: Alkana Ronald L. , Finn Deborah A. , Jones Brenda L. , Kobayashi Leigh S. , Babbini Mario , Bejanian Marina , Syapin Peter J.
Published: April 2006

Hyperbaric exposure antagonizes ethanol's behavioral effects in a wide variety of species. Recent studies indicating that there are genetically determined differences in the effects of body temperature manipulation on ethanol sensitivity suggested that genotype might also influence the effects of hyperbaric exposure on ethanol intoxication. To investigate this possibility, ethanol injected long sleep(LS)/lbg (2.7 g/kg), short sleep (SS)/lbg (4.8 g/kg), 129/J (2.9 g/kg), and C57BL/6J (3.6 g/kg) mice were exposed to one atmosphere absolute (ATA) air or to one or 12 ATA helium‐oxygen (heliox) at ambient temperatures selected to offset ethanol and helium‐induced hypothermia. Hyperbaric exposure significantly reduced loss of righting reflex (LORR) duration in LS, 129, and C57 mice, but not in SS mice. A second experiment found that hyperbaric exposure significantly reduced LORR duration and increased the blood ethanol concentration (BEC) at return of righting reflex (RORR) in LS mice, but did not significantly affect either measure in SS mice. These results indicate that exposure to 12 ATA heliox antagonizes ethanol‐induced LORR in LS, 129 and C57 mice, but not in SS mice. Taken with previous results, the present findings suggest that the antagonism in LS, 129, and C57 mice reflects a pressure‐induced decrease in brain sensitivity to ethanol and that the lack of antagonism in SS mice cannot be explained by pressure‐induced or genotypic differences in ethanol pharmacokinetics. The differential sensitivities of SS and LS mice to pressure‐antagonism of ethanol‐induced LORR suggest that hyperbaric exposure can be used as a tool to link differences between these lines in their behavioral and in vitro responses to ethanol and thus may aid in the identification of critical neurochemical mechanisms that underlie intoxication.
Endothelium‐Dependent Tolerance to Ethanol‐Induced Contraction of Rat Aorta: Effect of Inhibition of EDRF Action and Nitric Oxide Synthesis
Authors: Knych Edward T.
Published: April 2006

In vitro ethanol induces a dose‐dependent contraction of the aorta. Tolerance to this effect of ethanol is expressed by a rightward shift of the dose‐response curve in aorta from animals intoxicated with ethanol for 2 days. The expression of tolerance in the aorta is dependent upon the presence of functional endothelial cells which suggests that tolerance is mediated, in part, by endothelium‐derived relaxing factor (EDRF). To test this hypothesis, three inhibitors of EDRF action and an inhibitor of nitric oxide synthesis were studied for their ability to alter tolerance to ethanol‐induced contraction of the aorta. In vitro pretreatment of aortic rings with gossypol (10‐6– 10‐5 M), pyrogallol (10‐5 M), hemoglobin (10‐6 M), and NG‐nitro‐L‐arginine (NOARG, 10‐4 M) inhibited endothelium‐dependent relaxation induced by carbachol. The inhibition of carbachol‐induced relaxation produced by pyrogallol was reversed by superoxide dismutase (SOD, 45 units/ml). In vitro pretreatment of rings obtained from ethanol‐treated rats with gossypol, pyrogallol, hemoglobin, or NOARG inhibited the expression of ethanol tolerance, shifting the ethanol dose‐response curve to control values. SOD reversed the effect of pyrogallol pretreatment. None of the antagonists significantly altered the ethanol dose‐response curve of aortic rings obtained from control animals. These data support the hypothesis that tolerance to ethanol‐induced contraction of the aorta is mediated by the release of EDRF from endothelial cells.
Acute Ethanol Intoxication Prevents Lipopolysaccharide‐Induced Down Regulation of Protein Kinase C in Rat Kupffer Cells
Authors: D'Souza Nympha B. , Bautista Abraham P. , Lang Charles H. , Spitzer John J.
Published: April 2006

Protein kinase (PK) C has been implicated in a number of cellular events, many of which are also known to be affected by ethanol (ETOH). ETOH intoxication is also known to impair immune function, thereby increasing the host's susceptibility to infection. The purpose of this study was to assess the effect of acute ETOH intoxication on PKC activity and its intracellular distribution in nonparenchymal liver cells following an E. coli lipopolysaccharide (LPS) challenge. The liver was chosen for the study because it is the primary site both for metabolism of ETOH and detoxification of gut derived bacterial products. Catheterized conscious rats were administered saline or ETOH (175 mg/100 g body weight as a bolus followed by a continuous, 7 hr infusion of 28 mg/100 body weight/hr). LPS was injected intravenously (100 μg/100 g body weight) 3 hr before the end of the saline or ETOH infusion. Kupffer and endothelial cells were isolated by collagenase‐pronase digestion followed by centrifugal elutriation. PKC was assayed after extraction with digitonin containing buffer and partial purification on DE‐52 cellulose minicolumns. LPS decreased PKC activity by 69% from control values. Although ETOH infusion alone did not affect PKC activity in Kupffer cells, it completely abrogated the LPS effect. A similar trend was observed for the endothelial cells. No significant differences were observed between groups with respect to the intracellular distribution of PKC. The down‐regulation of PKC by LPS may represent a mechanism of functional adaptation of the immunocompetent cells to one of the cytokines, i.e., TNF, whose receptors are down regulated by activation of PKC. By counteracting such an action, ETOH would impair the adequate responsiveness of various cells to their own secretory products and to mediators from other cells, thereby, compromising the immune defense capacity of the body.
Interaction between Ethanol and Dextroamphetamine: Effects on Psychomotor Performance
Authors: Perez‐Reyes Mario , White W. Reid , McDonald Susan A. , Hicks Robert E.
Published: April 2006

The objective of this study was to investigate the interaction between ethanol and dextroamphetamine with regard to psychomotor performance. Twelve healthy, male, paid volunteers, moderate users of ethanol and amphetamines, participated in this study. Ethanol (0.85 g/kg or placebo) was administered over a 30‐min interval. Five minutes before the termination of ethanol or placebo ingestion, dextroamphetamine elixir (0.09 mg/kg, 0.18 mg/kg or placebo) diluted in 50 ml of orange juice was administered. Subjects were tested in a single‐blind, latin‐square, crossover design with each of the following six conditions: placebo ethanol/placebo dextroamphetamine; placebo ethanol/low‐dose dextroamphetamine; placebo ethanol/high‐dose dextroamphetamine; ethanol/placebo dextroamphetamine; ethanol/low‐dose dextroamphetamine; and ethanol/high‐dose dextroamphetamine. The variables measured in this study were: subjective rating of ethanol and dextroamphetamine intoxication, accuracy and latency of response in the Simulator Evaluation of Drug Impairment (SEDI task), blood ethanol concentration by breath analyzer, and plasma concentrations of dextroamphetamine by gas chromatography. Results indicate ethanol induced decrements in performance of the skills necessary to drive an automobile were significantly decreased by dextroamphetamine in a dose‐response fashion. The administration of dextroamphetamine did not decrease the subjective ratings of ethanol intoxication.
Disulfiram Treatment of Patients with Both Alcohol Dependence and Other Psychiatric Disorders: A Review
Authors: Larson Eric W. , Olincy Ann , Rummans Teresa A. , Morse Robert M.
Published: April 2006

In treatment of alcohol dependence, disulfiram is most useful in conjunction with a structured, supervised, aftercare program. However, it has been reported to cause psychiatric side effects and to interact with various psychiatric medications. Many patients with alcohol dependence suffer from other psychiatric disorders and are treated with such psychiatric medications. This paper reviews the pertinent clinical pharmacology of disulfiram and the literature on potential psychiatric complications and drug interactions of disulfiram. At the usual dosage, about 250 mg/day, disulfiram does not appear to increase significantly the risk of psychiatric complications or of psychiatric drug interactions. Therefore, it can be considered a treatment option for patients with alcohol dependence and other psychiatric disorders.
Outcomes of Co‐Morbid Alcoholic Men: A 1‐Year Follow‐Up
Authors: Powell Barbara J. , Penick Elizabeth C. , Nickel Elizabeth J. , Liskow Barry I. , Riesenmy Kelly D. , Campion Sara L. , Brown Edward F.
Published: April 2006

In this prospective, 1‐year study, 360 males admitted to an inpatient alcoholism treatment program were administered a DSM‐III compatible structured interview and subtyped by co‐occurring psychiatric disorder. Forty percent satisfied diagnostic criteria for alcohol dependence while 27% met criteria for alcohol dependence and one additional psychiatric syndrome. The dually diagnosed patients were divided into: alcohol dependence plus drug abuse, alcohol dependence plus antisocial personality and alcohol dependence plus depression. These subtypes were compared on multiple dimensions at intake and at 1‐year follow‐up. At follow‐up, all groups showed significant improvement in drinking and psychosocial functioning. The results suggest that subtyping alcoholics by co‐morbid psychiatric disorders may be a good postdictor of clinical history, but a poor predictor of drinking outcome.
Gamma‐Hydroxybutyric Acid in the Treatment of Alcohol Dependence: A Double‐Blind Study
Authors: Gallimberti Luigi , Ferri Mila , Ferrara Santo Davide , Fadda Fabio , Gessa Gian Luigi
Published: April 2006

The effect of gamma‐hydroxybutyric acid on alcohol consumption and alcohol craving in alcoholics was investigated in a randomized double‐blind study versus placebo. Patients were treated as outpatients during a three month period either with gamma‐hydroxybutyric acid (50 mg/kg/day, divided into three daily doses) or with placebo. Of the 82 alcoholics that entered the study, 71 completed it, 36 in the gamma‐hydroxybutyric acid and 35 in the placebo group. Alcohol consumption was assessed by the subject's self report. At the 3rd month of treatment, 11 patients in the gamma‐hydroxybutyric acid group referred to be abstinent and 15 referred controlled drinking; while in the placebo group only two and six patients referred abstinence and controlled drinking, respectively. Serum‐gammaglutamyl‐transferase activity correlated with the admitted alcohol consumption. Gamma‐hydroxybutyric acid treatment decreased alcohol craving during the 3 months of treatment. Transient side effects were noted by six patients on gamma‐hydroxybutyric acid and two on placebo. The results suggest that gamma‐hydroxybutyric acid may be useful in the treatment of alcohol dependence.
Differential Attrition Rates in Alcohol Abusing and Nonabusing Schizophrenic Inpatients: A Methodological Note
Authors: Searles John S. , Alterman Arthur I.
Published: April 2006

This study investigates the impact of the screening process on the decomposition of the final sample of alcohol abusing and nonabusing hospitalized schizophrenics. The group of nonabusing schizophrenics had higher rates of study rejections by staff, refusals, inappropriate subjects, and a lower rate of study completers. The findings suggest that these differential attrition rates may have a significant impact on the interpretation of results of studies focusing on substance use in schizophrenic samples.
Antecedents and Covariates of High Alcohol Consumption in Young Men
Authors: Andréasson Sven , Allebeck Peter , Brandt Lena , Romelsjö Anders
Published: April 2006

The role of social, behavioral, and psychological characteristics and other risk indicators for high alcohol consumption in young men was analyzed using a survey of 49,464 Swedish conscripts. A strong association between an increasing weight of adverse social and behavioral risk indicators on the one hand and high alcohol consumption on the other was found. Yet many high consumers had no or few risk indicators. In multivariate analysis, substance use and indicators of deviant behavior came out as the strongest risk indicators for high alcohol consumption. Indicators of poor social background generally had relatively low odds ratios. Poor home well‐being, for instance, had an odds ratio of 0.9. Social group of father was non‐significant. Very good family economy had a higher odds ratio, 1.7, than average or poor family economy. Psychosomatic symptoms had relatively low odds ratios. Among psychological variables, low emotional control had a significantly elevated odds ratio of 1.8. Increased odds ratios were found for conscripts who were never anxious or never felt insecure. In conclusion, although many high consumers of alcohol had no or few risk indicators, we identified a high‐risk group characterized by high levels of alcohol consumption and several indicators of personality disturbances, early deviant behavior, and social maladjustment.
Chronic Alcohol Intake Induces Reversible Disturbances on Cellular Na+ Metabolism in Humans: Its Relationship with Changes in Blood Pressure
Authors: Coca Antonio , Aguilera Maria T. , De la Sierra Alejandro , Sánchez Miguel , Picado Maria J. , Lluch Maria M. , Urbano‐Márquez Alvaro
Published: April 2006

The effect of chronic alcohol consumption on Na+ ‐K+ ATPase, Na+‐Li+ countertransport, outward Na+‐K+‐Cl‐ cotransport system and the Na+ leak was investigated in red blood cells from 18 normotensive subjects with a daily alcohol intake of more than 150 g. The study was repeated after 3 months of alcohol withdrawal, and results were compared with a group of 20 healthy normotensive teetotalers. Maximal efflux rate (Vmax) and apparent dissociation constant for internal Na+ (KNa) of the Na+‐K+ pump and the Na+‐Li+ countertransport were significantly higher in alcohol consumers. A positive correlation between daily alcohol intake and Vmax of both transport systems (p < 0.05) was observed. These values significantly decreased after alcohol withdrawal. A simultaneous stimulation of the Na+‐K+‐Cl‐ cotransport system after alcohol withdrawal was also observed. Blood pressure values were higher in alcoholics (133.7/82.3) than in abstainers (121.4/75 mmHg) and significantly decreased (128.5/76.9 mmHg) after withdrawal. A positive correlation between the stimulation of the Na+‐K+‐Cl‐ cotransport and the decrease of blood pressure after withdrawal was observed. In conclusion, chronic alcohol intake induces disturbances on red blood cell Na+ metabolism that dissipate with the cessation of drinking. Similar abnormalities also reported in humans and animals with primary hypertension have been associated in the pathogenesis of essential hypertension. Therefore, the pressor effect of chronic alcohol intake could be mediated through these changes in cellular Na+ metabolism.
Systolic Blood Pressure and Neuropsychological Test Performance of Alcoholics
Authors: Braggio John T. , Pishkin Vladimir
Published: April 2006

This study examined resting systolic blood pressure (SBP) as a mediator of neuropsychological (NP) test performance in nonhypertensive alcoholics and controls. A median‐split was used to assign alcoholics and controls to low and high SBP groups. Results showed that: (1) When SBP level was not considered, alcoholics only performed worse than controls on the WAIS Comprehension subtest. (2) Alcoholics and controls in the high SBP groups had fewer correct items on the WAIS Comprehension and Raven's, Set I tests than subjects in the low SBP groups. (3) Significant Diagnostic Group by SBP Group interaction was found for the Sentence Writing test. For this test only controls in the High SBP Group did worse than controls in the Low SBP Group. (4) Individual group comparisons for all NP tests showed that alcoholics in the High SBP Group were more impaired than controls in the Low SBP Group on the WAIS Comprehension, Shipley Abstraction Age and Stark Visual‐Spatial tests; but alcoholics in the Low SBP Group did not differ from, or outperformed, controls in the High SBP Group on the WAIS Comprehension, Shipley Abstraction Age, Raven's, Set I, and Stark Visual‐Spatial tests. These data demonstrate that both alcoholism and high SBP adversely and differentially affect the NP test performance of alcoholics and controls.
Alcoholism and Occupations: A Review and Analysis of 104 Occupations
Authors: Mandell Wallace , Eaton William W. , Anthony James C. , Garrison Roberta
Published: April 2006

A review of the many attempts to establish an association between occupations and alcoholism reveals that most do not deal with data about clinically defined alcoholism but instead use data about cirrhosis mortality, self‐reported alcohol problems, and frequent and heavy drinking. The present study establishes an association between occupations and diagnoses of Alcohol Dependence Disorder and Alcohol Abuse Disorder, using data from a large population‐based household interview study. Statistical adjustment using logistic methods reveals that apparent associations between occupations and alcohol‐related disorders previously reported in the literature are due to characteristics of those employed in various occupations. The prevalence of alcohol dependence and abuse in two high risk industries, construction and transportation, is confirmed. More than one in four construction laborers and one in five skilled construction trades workers received a DIS/DSM‐III diagnosis related to alcohol abuse. In the transportation industry one in six heavy truck drivers and material movers received an alcohol diagnosis. Analyses of the data from individuals currently employed and not employed in their occupation reveals reduction in risk for those who leave some occupations and increased risk for those who leave other occupations. Evidence is presented that employment in some occupations may be protective for Alcohol Dependence. The findings support the view that occupation may be associated with Alcohol Dependence and Alcohol Abuse independent of demographic variations. Previously proposed explanatory models for associations between occupations and alcohol problems are called into question because they do not take into account the demographic characteristics and employment status of workers.
Alcohol Self‐Administration in a Nonrestricted Access Situation with Alcohol‐Preferring (P) Rats
Authors: Files F. J. , Andrews C. M. , Samson H. H. , Lumeng L. , Li T.‐K.
Published: April 2006

Genetic variables have been implicated as contributing factors in the development of alcoholic behavior. Rats bred selectively for alcohol preference have been used in laboratory studies to investigate the role of such variables. In the present study, rats from the alcohol preferring (P) line were placed in operant chambers in which food pellets, water, and 10% ethanol (v/v) were available continuously for 23 hr/day. Food pellets (45 mg) were presented on an FR 1 schedule of reinforcement, while ethanol was presented in a 0.1 ml dipper on an FR 4 schedule of reinforcement. Water was available in a drinking tube with licks monitored by a drinkometer. Data were analyzed in terms of both total daily intakes and computer defined bouts. The P rats showed greater daily ethanol intakes compared with Long‐Evans (LE) animals previously studied under similar access conditions. The major difference in intake was a result of the P rats having a greater number of daily ethanol drinking bouts, while having only a slight increase in individual bout size. These data indicate that genetic selection for ethanol preference may result in the regulation of ethanol intake by means of changes in the frequency of ethanol drinking bouts but not by changes in bout size.
Effects of Ethanol on Tissue Folate Incorporation and Recovery from Folate Deficiency in Rats
Authors: Collins Timothy D. , Eisenga Bernard H. , Bhandari Sneh D. , McMartin Kenneth E.
Published: April 2006

Studies in folate‐deficient alcoholics suggest that ethanol interferes with the recovery of folate status and the hematopoietic response to folate. Previous animal studies have suggested diverse effects of ethanol on intestinal absorption, hepatic metabolism, and urinary excretion of folate. In order to examine the effects of ethanol on folate distribution during folate deficiency, tissue incorporation of a tracer dose of folate was studied in rats chronically fed ethanol containing and/or folate‐deficient diets. Rats fed these diets were also used to study the effect of chronic ethanol consumption on the dietary reversal of folate deficiency by changing the diets (adding folate or replacing ethanol) from 12 to 16 weeks. After 16 weeks, tissue folate depletion was severe in rats fed folate‐deficient diets. Plasma and whole body retention of the tracer dose of folate was decreased in folate‐deficient rats consuming ethanol. In folate‐deficient rats, ethanol consumption increased the incorporation of folate by the kidney and brain, but had no effect in other tissues (liver, lung, spleen, intestine, testis). In ethanol‐fed folate‐deficient rats that continued to consume ethanol, but with added folate in their diets, urine, plasma, liver, and kidney folate levels returned to control levels in 4 weeks. In the rats that stopped ethanol, but continued low folate diet consumption, no recovery of tissue folate levels was seen in 4 weeks. These results suggest that chronic ethanol consumption can exacerbate folate requirements by inhibiting body retention of small doses of folate. However, these effects are minor because ethanol consumption does not block recovery from folate deficiency when rats are fed sufficient amounts of folate.