bluuebunny/crossref_metadata_2025 huggingface dataset:
Voluntary Alcohol Consumption in BXD Recombinant Inbred Mice: Relationship to Alcohol Metabolism
Authors: Gill K. , Liu Y. , Deitrich R. A.
Published: April 2006

Studies were initiated to characterize behaviorally and biochemically C57BL/6J and DBA/2J inbred mice, as well as BXD Recombinant Inbred (RI) strains derived from them. The C57BL/6J, DBA/2J, and 7 BXD RI strains were tested for voluntary alcohol consumption (VAC) by receiving 4 days of forced exposure to a 10% (w/v) solution of alcohol, followed by 3 weeks of free choice between water and 10% alcohol. Measures of VAC included the absolute intake of alcohol (g/kg), as well as alcohol preference. A wide range of VAC was displayed by the various BXD RI strains with a continuous (rather than bimodal) distribution, indicating that there is likely to be additive effects of several genes involved in regulating alcohol‐related behaviors. Kinetic characteristics of aldehyde dehydrogenase and catalase in liver and brain of the C57BL/6J, DBA/2J, and BXD strains of mice were determined to test the hypothesis that the genetic regulation of the levels of alcohol‐metabolizing enzymes mediate differences in VAC. Aldehyde dehydrogenase activity was determined spectrophotometrically by observing the change in absorption at 340 nm. Catalase activity was determined by measuring oxygen production with a Yellow Springs Biological Oxygen monitor and oxygen electrode. There was a strong negative relationship between VAC and brain catalase activity in the BXD RI and parental strains. These data suggest that RI strains are likely to be useful genetic models in the examination of quantitative trait loci controlling VAC and other responses to alcohol.
Has Awareness of the Alcohol Warning Label Reached Its Upper Limit?
Authors: Hankin Janet R. , Sloan James J. , Firestone Ira J. , Ager Joel W. , Sokol Robert J. , Martier Susan S.
Published: April 2006

Has awareness of the alcoholic beverage warning label reached its maximum? This study tracks changes in the level of awareness among a sample of 7334 inner‐city African‐American gravidas seeking prenatal care between May 1989 and June 1993. Previously, we found that a significant increase in awareness of the warning label occurred in March 1990. In the current analysis over a 50‐month period, the level of awareness continued to increase through December 1992 and then leveled off, suggesting a negatively accelerated growth function. The logistic function fitted to the awareness curve predicts that the upper limit of awareness in this population has been reached (the predicted upper limit being 81.5%). In addition a logit regression analysis showed that women who did not know about the warning label were more likely to be over 29 years of age. Heavier drinkers were 1.25 times more likely to be aware of the label. Among those drinkers who were not aware of the label, 30% drank at both conception and antenally, thus putting their fetus at high risk for alcohol‐related birth defects.
Tridimensional Personality Traits in Sons of Alcoholic and Nonalcoholic Fathers
Authors: Howard Matthew O. , Cowley Deborah S. , Roy‐Byrne Peter P. , Hopfenbeck James R.
Published: April 2006

Sons of alcoholics (SOAs; n= 27) and sons of nonalcoholics (SONAs; n= 23) were compared across Tridimensional Personality Questionnaire (TPQ) and Sensation Seeking scales and measures of plasma homovanillic acid and platelet monoamine oxidase activity. SOAs and SONAs did not differ significantly on any measure. The pattern of correlations between TPQ and Sensation Seeking scales provided some support for the construct validity of TPQ measures. Scores on the TPQ Novelty Seeking scale and platelet monoamine oxidase activity were significantly inversely associated (r=–0.52, p < 0.02) among SOAs, but not among SONAs (r=–0.06).
Alcohol and Aldehyde Dehydrogenase Genotypes and Drinking Behavior in Japanese
Authors: Higuchi Susumu , Matsushita Sachio , Muramatsu Taro , Murayama Masanobu , Hayashida Motoi
Published: April 2006

The effects of the genotype of alcohol dehydrogenase‐2 (ADH2) and mitochondrial aldehyde dehydrogenase (ALDH2) on drinking behavior were investigated in a population of 451 Japanese. Although the ALDH2*2 allele had a significant inhibitory effect on alcohol consumption, hence on drinking problems, the apparent association was not confirmed between ADH2 genotype and overall drinking patterns for either males or females. However, the frequency of the ADH2*2 allele was significantly lower in male Japanese classified as alcoholic on the basis of the Kurihama Alcoholism Screening Test than in nonalcoholic males. These results corroborate a previous study that revealed a significantly lower ADH2*2 allele frequency in hospitalized Japanese alcoholics than in the general population. Together, these studies suggest that the ALDH2*2 allele has an inhibitory effect on drinking behavior, irrespective of the level of alcohol consumption, whereas the effect of the ADH2 polymorphism only becomes apparent in individuals with higher alcohol consumption, such as alcoholics.
Tetrahydroisoquinolines and Alcoholism: Where Are We Today?
Authors: Myers R. D.
Published: April 2006

The present status of research on the tetrahydroisoquinoline (THIQ) family of compounds and other aldehyde metabolites in the field of alcoholism is described. A brief history of the background of experimental studies on the actions of the THIQ's and β‐carbolines on alcohol drinking is presented. A computer data base search of articles published in this field reveals that both the historical and current research trends have waxed and waned since the 1960s. The clinical utility of naltrexone in terms of the cerebral function of opioid compounds in drinking behavior and alcoholism is likewise considered. Finally, the residual controversy concerning the significance of multiple intermediary metabolites in alcohol dependence and craving should ultimately be resolved in the future by broad‐based investigations which employ state‐of‐the‐art experimental approaches.
Defective Calcium Increase and Inositol Phosphate Production in Anti‐CD3‐Stimulated Lymphocytes of Alcoholics without Progressive Liver Disease
Authors: Stefanini G. F. , Castelli E. , Foschi F. G. , Terzi A. , Biagi P. L. , Bordoni A. , Celadon M. , Hrelia S.
Published: April 2006

Intracellular free calcium concentration, phosphoinositide turnover, and inositol phosphate production were analyzed in peripheral blood lymphocytes from seven well‐nourished alcoholic patients without severe acute or chronic liver disease, before and after stimulation with anti‐CD3 antibody. Seven comparable nondrinkers were studied as controls. A lower increase in intracellular free calcium concentration was detected in alcoholics, after anti‐CD3 stimulation of lymphocytes, than in control subjects. Lymphocyte activation generated inositol phosphates in both controls and alcoholics, but inositol phosphate production was significantly lower in alcoholics. The agreement between these findings indicates that the reduction in inositol phosphates is one of the most important events in the early phases of lymphocyte activation in alcoholics.
No Association of the Structural Dopamine D2 Receptor (DRD2) Variant 311Cys with Alcoholism
Authors: Finckh Ulrich , von Widdern Ole , Giraldo‐Velasquez Mario , Podschus Jan , Dufeu Peter , Sander Thomas , Harms Helmut , Schmidt Lutz G. , Rommelspacher Hans , Rolfs Arndt
Published: April 2006

The human dopamine D2 receptor (DRD2) has been implied in the vulnerability for alcoholism and/or the modification of its severity. This is supported through animal experimental and pharmacological data. We analyzed the DRD2 311Ser/Cys polymorphism in 312 German alcoholics and 131 ethnically matched controls to investigate the association of genetic DRD2 variants with alcoholism or clinical characteristics of homogeneous subgroups of alcoholics. We observed no association between the 311Cys variant and alcoholism, and none of the clinical characteristics evaluated was significantly associated with 311Cys. The allele frequencies of the 311Cys variant were 0.026 and 0.031 in the alcoholics and controls, respectively. These are the highest reported 311Cys frequencies in Caucasians. The DRD2 TaqI A1/A2 restriction fragment length polymorphism was analyzed simultaneously in our samples. In most cases, the 311Cys allele is associated with the TaqI A2‐allele. Data do not suggest a clinical relevance of the 311Cys variant in alcoholism. However, the relevance of this variant in other diseases or the existence of other DRD2 variants with altered receptor function or expression cannot be excluded.
Effect of Chronic Alcohol Consumption on Responses of Cerebral Arterioles
Authors: Mayhan William G. , Didion Sean P.
Published: April 2006

The goal of this study was to determine whether chronic ingestion of alcohol alters dilatation of cerebral arterioles in response to agonists that produce activation of adenylate cyclase and activation of ATP‐sensitive potassium channels. Rats were fed liquid diets with or without ethanol for 2 to 2.5 months. In vivo diameter of pial arterioles was measured in alcohol‐fed and nonalcohol‐fed rats during superfusion with isoproterenol, forskolin, cromakalim, and nitroglycerin. Dilatation of pial arterioles in response to activation of adenylate cyclase via stimulation of β‐adrenergic receptors using isoproterenol was impaired in alcohol‐fed rats. Isoproterenol (1.0 μM) dilated cerebral arterioles by 15 ± 3% in nonalcohol‐fed rats, but by only 7 ± 2% in alcohol‐fed rats. In contrast, dilatation of pial arterioles in response to forskolin was similar in nonalcohol‐fed and alcohol‐fed rats. Dilatation of pial arterioles in response to activation of ATP‐sensitive potassium channels was impaired in alcohol‐fed compared with nonalcohol‐fed rats. Cromakalim (1.0 μM) dilated pial arterioles by 22 ± 5% in nonalcohol‐fed rats, but by only 5 ± 2% in alcohol‐fed rats (p < 0.05). In contrast, dilatation of pial arterioles in response to nitroglycerin was similar in alcohol and nonalcohol‐fed rats. The findings of the present study suggest that chronic alcohol ingestion impairs dilatation of cerebral resistance arterioles in response to activation of adenylate cyclase via stimulation of β‐adrenergic receptors and in response to activation of ATP‐sensitive potassium channels. We suggest that impaired vasodilator mechanisms during chronic alcohol consumption may have important implications for the pathogenesis of cerebrovascular abnormalities observed during chronic alcoholism.
Aldehyde Dehydrogenases of the Rat Colon: Comparison with Other Tissues of the Alimentary Tract and the Liver
Authors: Koivisto Tiina , Salaspuro Mikko
Published: April 2006

Intracolonic bacteria have previously been shown to produce substantial amounts of acetaldehyde during ethanol oxidation, and it has been suggested that this acetaldehyde might be associated with alcohol‐related colonic disorders, as well as other alcohol‐induced organ injuries. The capacity of colonic mucosa to remove this bacterial acetaldehyde by aldehyde dehydrogenase (ALDH) is, however, poorly known. We therefore measured ALDH activities and determined ALDH isoenzyme profiles from different subcellular fractions of rat colonic mucosa. For comparison, hepatic, gastric, and small intestinal samples were studied similarly. Alcohol dehydrogenase (ADH) activities were also measured from all of these tissues. Rat colonic mucosa was found to possess detectable amounts of ALDH activity with both micromolar and millimolar acetaldehyde concentrations and in all subcellular fractions. The ALDH activities of co‐Ionic mucosa were, however, generally low when compared with the liver and stomach, and they also tended to be lower than in small intestine. Mitochondrial low Km ALDH2 and cytosolic ALDH with low Km for acetaldehyde were expressed in the colonic mucosa, whereas some cytosolic high Km isoenzymes found in the small intestine and stomach were not detectable in colonic samples. Cytosolic ADH activity corresponded well to ALDH activity in different tissues: in co‐Ionic mucosa, it was ∼6 times lower than in the liver and about one‐half of gastric ADH activity. ALDH activity of the colonic mucosa should, thus, be sufficient for the removal of acetaldehyde produced by colonic mucosal ADH during ethanol oxidation. It may, however, be insufficient for the removal of the acetaldehyde produced by intracolonic bacteria. This may lead to the accumulation of acetaldehyde in the colon and colonic mucosa after ingestion of ethanol that might, at least after chronic heavy alcohol consumption, contribute to the development of alcohol‐related colonic morbidity, diarrhea, and cancer.
Effect of Bestatin, an Aminopeptidase Inhibitor, on Alcohol Intake in Alcohol‐Preferring P Rats
Authors: Szczepanska R. , Harding S. , Grupp L. A.
Published: April 2006

Bestatin is an aminopeptidase and enkephalinase inhibitor that elevates the levels of angiotensin II and angiotensin III. Although it has been used for years in the treatment of various forms of cancer, its application as an antialcohol drug has not been explored, despite its ability to stimulate angiotensin activity. The present study assesses the ability of bestatin to reduce chronic alcohol consumption in the genetically selected high alcohol‐consuming P rats. Two groups of P rats were given 24‐hr access to food, water, and 10% (v/v) alcohol. After a baseline period, half the rats received the saline vehicle and the other half ascending doses of bestatin (2.5,10,20, and 30 mg/kg, bid). Each dose was administered for a minimum of 7 days. Bestatin had little effect on water intake or weight gain, but did produce a dose‐dependent reduction in alcohol intake that averaged 33% and was sustained over the course of the 1‐month period of administration. Years of experience with bestatin have shown it to be safe and free of major side effects. The present findings suggest that bestatin (Ubenimex®) might also be useful in the treatment of alcohol abuse in humans.
Differential Age‐Related Loss of Pigmented Locus Coeruleus Neurons in Suicides, Alcoholics, and Alcoholic Suicides
Authors: Arango Victoria , Underwood Mark D. , Pauler Donna K. , Kass Robert E. , Mann J. John
Published: April 2006

We previously reported fewer locus coeruleus (LC) neurons in both suicide victims and alcoholics than among a group of nonpsychiatric controls. In the present paper we examine the rate of decline in the number of LC neurons with age, looking for possible differential rates among suicide victims, alcoholics, and controls. We also compare these groups with a group of alcoholics who died by suicide, and consider the effects of sex, race, and postmortem interval. LC neuron counts were obtained from a total of 32 subjects. In all groups, the number of neurons decreased with age, but by roughly age 40 the average LC count among the three suicide and/or alcoholic groups was lower than among controls. The rate of LC neuron loss was greater among suicides than among controls, but the rate of loss among alcoholics who were at least 30 years old was the same as that among the controls. Our group of alcoholic suicides had counts that were statistically indistinguishable from those of suicides. Differences among groups appear to be most pronounced in the middle third of the LC. Further studies are needed to determine the mechanisms of noradrenergic neuron loss and whether it is associated with an underlying major depression in suicide victims, or acquired after a period of excessive alcohol consumption.
The Relationship Between Alcohol Symptoms and Consumption Among Older Drinkers
Authors: Chermack Stephen T. , Blow Frederic C. , Hill Elizabeth M. , Mudd Sharon A.
Published: April 2006

The present study assessed the relationship between current alcohol symptoms and consumption levels in a heterogeneous sample of older adults. The sample consisted of 443 participants over age 55 who reported drinking within the past year, including social drinkers, alcoholics in treatment, and alcoholics not in treatment. Symptoms for the past year were assessed using the Diagnostic Interview Schedule (DIS‐Ill‐R) alcohol section, and subjects were subsequently assigned to two groups (symptom‐free and symptomatic), depending on whether they experienced any DSM‐III‐R alcohol symptoms in the last year. For both men and women, average daily consumption and the frequency of heavy drinking contributed to whether participants had experienced any alcohol symptoms. The results indicate that the consumption levels of men and women differed only for symptomatic drinkers. The findings support recommendations that consumption limits for older adults should be lower than those recommended in the literature for younger adults. Furthermore, the results suggest that, in addition to limiting average daily consumption to no more than one drink per day, eliminating episodes of heavy drinking (consuming five or more drinks) could further reduce the risk of alcohol‐related symptoms for older adults. Key Words: Elderly, Problem Drinking.
Alcohol Elimination in Native American Mission Indians: An Investigation of Interindividual Variation
Authors: Wall Tamara L. , Garcia‐Andrade Consuelo , Thomasson Holly R. , Cole Maury , Ehlers Cindy L.
Published: April 2006

The high prevalence of alcohol abuse and alcohol dependence among Native Americans may be mediated by unique environmental and genetic factors in this population. One factor that may influence the development of alcoholism is variability in alcohol metabolism. To determine factors that contribute to differences in alcohol elimination rates within a Native American population, this study evaluated healthy southern California Mission Indian men between the ages of 18 and 25 years. Each man drank a dose of alcohol, 0.56 g/kg of body weight as a 20% by volume solution, at ∼900 AM after eating a low‐fat breakfast and having fasted overnight. The drink was consumed within 7 min, and the concentrations of alcohol in blood were determined before and at 15, 30, 60, 90,120, and 150 min after beverage ingestion. Rates of alcohol elimination were calculated from the pseudolinear slope of the blood alcohol versus time curve. The influences of estimated body water, recent drinking history, recent smoking history, polymorphism at the ADH2 and ADH3 loci, family history of alcoholism, and percentage Native American heritage on alcohol elimination rate were determined using multiple regression analyses. Estimated body water accounted for a significant proportion of the variance in alcohol elimination rate. There was also a nonsignificant trend for subjects with anADH2*3 allele (n = 6) to have faster rates of alcohol elimination than those with ADH2*1 alleles only (n = 33). Given the high prevalence of alcoholism and alcohol‐related health problems among Native Americans, the results from this study suggest that evaluation of alcohol metabolism and genotypes of the alcohol‐metabolizing enzymes in Native American populations merits further study.
Effects of Early Drinking and an Antisocial Orientation on the Alcohol Use of Young Russians
Authors: Parker Douglas A. , Levin Boris M. , Harford Thomas C.
Published: April 2006

Drawing upon data from the Survey of Deviant Behavior Among Youth in the Moscow Region of Russia, this paper examines the effects of early drinking behavior and an antisocial orientation on the use of alcohol by young Russians. Using available data from the U.S. National Household Survey of Drug Abuse, the use of alcohol and the effects of early drinking among youth in the Moscow Region and the United States are compared. The analysis of the data from the two surveys indicates that a greater proportion of Russian youth began drinking by the age of 12 but that early drinking is associated with subsequent alcohol use among both Russian and American youth. Although there are no data on an antisocial orientation from the U.S. survey, there are such data from the Russian survey and an analysis of this data indicates that the greatest alcohol use is found among young Russians who began drinking by the age of 12 and who have an antisocial orientation.
Estrogen‐Related Acetaldehyde Elevation in Women during Alcohol Intoxication
Authors: Eriksson C. J. Peter , Fukunaga Tatsushige , Sarkola Taisto , Lindholm Harri , Ahola Liisa
Published: April 2006

Alcohol is more often unpleasant and causes tissue damage more rapidly in women than men. The present study was designed to find out whether acetaldehyde, the primary metabolite of alcohol, could play a crucial role in these actions. Special emphasis was focused on the appropriate determination of blood acetaldehyde and hormonal factors. Occurrence of elevated blood acetaldehyde levels during alcohol oxidation was established in both normally cycling women and ones taking oral contraceptives, but not in men. An association between elevated acetaldehyde levels and high estrogen phases was observed in both groups of women. Estrogen‐related acetaldehyde elevation is suggested to be the key factor explaining the gender differences of the adverse effects of alcohol.
Resting Hand Tremor in Abstinent Cocaine‐Dependent, Alcohol‐Dependent, and Polydrug‐Dependent Patients
Authors: Bauer Lance O.
Published: April 2006

Laboratory studies of cocaine‐exposed rodents, and positron emission tomographic studies of human cocaine abusers have suggested that chronic cocaine abuse downregulates dopaminergic function in the basal ganglia. The present study sought to provide behavioral evidence for this phenomenon by demonstrating enhanced levels of resting hand tremor among patients with previous histories of cocaine dependence. To determine the specificity of the phenomenon, patients with previous histories of alcohol dependence, cocaine/alcohol codependence, and cocaine/opiate codependence were also evaluated. Patients were assigned to one of four groups according to DSM‐IIIR diagnostic criteria: (1) cocaine dependent (n = 19); (2) cocaine and alcohol dependent (n = 12); (3) cocaine and opiate dependent (n = 7); (4) alcohol dependent (n = 9). All were abstinent from their primary drug of abuse for a period of 1 to 5 months. The three patient groups with histories of cocaine dependence exhibited significantly more resting hand tremor than the alcohol‐dependent and normal control groups. Furthermore, hand tremor in the former three groups was positively related to the number of self‐reported uses of cocaine and negatively related to the number of months of cocaine abstinence.
Voices of the Afflicted
Authors: Erickson Carlton K
Published: April 2006

Over the past 10 years, I have been privileged to conduct educational forums for audiences containing many recovering alcoholics or otherwise chemically dependent persons. In these forums about the addictive diseases and their treatment and research possibilities, significant interaction with the audience members occurs. During these interactions, certain anecdotal phenomena Seem to predominate. The repetitive nature of these reports suggests the need for systematic investigation. As with editorial comments in major medical journals, observed phenomena and unanswered questions from those afflicted can be valuable in the generation of testable hypotheses. Perhaps the ideas presented herein will be useful in the development of future research on alcohol abuse and alcohol dependence.
Effect of Fetal Alcohol Exposure on Postnatal Pituitary Adenosine 3′,5′ ‐Cyclic Phosphate Content and Growth Hormone Release
Authors: Conway Sonya , Garbouzova Yelena
Published: April 2006

This study examines the influence of fetal ethanol (ETOH) exposure and pair‐feeding dams on postnatal, releasing factor‐induced pituitary growth hormone (GH) release and adenosine 3′,5′‐cyclic phosphate (CAMP) accumulation. Fetuses were exposed to ETOH in utero by feeding dams a 36% (calories derived from ETOH: 6.6% v/v) ETOH liquid diet. Postnatal body weights were measured at sacrifice to evaluate the influence of ETOH on growth. Pituitary weight and protein content were measured to determine if changes in GH secretion or cAMP are proportional to the overall effect of ETOH on the pituitary. Pituitaries from 1‐, 10‐, and 60‐day‐old pups were explanted and incubated without hormones or with either somatostatin [somatotropin‐release inhibiting factor (SRIF); 10−9 M], or GH‐releasing factor (GRF; 5 × 10−9 M). Radioimmunoassays were used to determine tissue cAMP content, after extraction, and media GH concentration.

Results indicate that fetal ETOH exposure specifically reduces the weight of both male and female pups. However, by 60 days of age, this reduction is not different from that found in pups of pair‐fed controls, and both groups weighed less than pups of ad libitum controls. Furthermore, both pituitary weight and protein content were proportionately reduced in ETOH‐exposed pups.

In regard to releasing factor sensitivity, compared with pituitaries from ad libitum controls, the capacity of GRF to simulate GH release was diminished in 10‐day‐old males (p < 0.00s) exposed to ETOH. On the other hand, the capacity of GRF to stimulate cAMP accumulation was generally enhanced by prenatal ETOH exposure. The capacity of SRIF to depress GH release was diminished in ETOH pups, compared with both pair‐fed and ad libitum‐fed controls (p < 0.0001). This difference in GH release was more apparent in pituitaries from females than males (p < 0.001). However, the depressed SRIF response was not associated with altered cAMP accumulation.

These data suggest that fetal ETOH exposure has a sexually dimorphic effect on pituitary sensitivity to GH‐releasing factors that may be related to altered regulation of GH release and susceptibility to growth retardation.
Central Serotonergic Lesions Increase Voluntary Alcohol Consumption in Sprague Dawley Rats: Moderation by Long‐Term Ethanol Administration
Authors: Wang Jia‐Yi , Shum Andrew Y.‐C. , Lin Tzu‐Chao , Wang Yun
Published: April 2006

The relationship between central serotonergic activities and voluntary alcohol consumption was studied in Sprague‐Dawley rats, which normally have low alcohol preference. After initial screening for an evenly matched baseline alcohol preference, selective central serotonergic lesioning was induced by intracisternal injection of the serotonergic neurotoxin 5,7‐dihydroxytryptamine (5,7‐DHT). Control rats received injections of vehicle only. Both 5,7‐DHT and vehicle‐treated rats were further divided into two subgroups, which either had continued free access to ethanol (alcohol‐drinking) or were deprived of it (alcohol‐free). All rats were then tested again for alcohol preference. All rats were then killed, and the levels of monoamines in the brains were determined by high performance liquid chromatography with electrochemical detection. Behavioral results indicated that all 5,7‐DHT‐treated rats had significantly higher alcohol preference and consumption than the corresponding sham controls. Except in the cerebellum, the 5,7‐DHT‐treated rats had significantly lower levels of serotonin (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIM) in most brain regions compared with those in the corresponding sham controls. Treatment with 5,7‐DHT also resulted in a decrease in serotonin turnover in all brain regions in the alcohol‐free rats, except in the cerebellum. In alcohol‐drinking rats, however, 5,7‐DHT treatment only reduced serotonin turnover in the pons. The levels of norepinephrine and dopamine in several brain regions were not significantly different. Thus, it appeared that in the Sprague Dawley rats, 5,7‐DHT treatment depleted 5‐HT and 5‐HIAA levels in most brain regions while increasing alcohol consumption. Chronic alcohol‐drinking attenuated the increase in alcohol consumption associated with serotonergic lesions. Voluntary alcohol consumption seemed more associated with 5‐HT turnover than with tissue 5‐HT levels. Our data also suggested that tolerance to alcohol‐induced hypothermia was primarily attributable to long‐term alcohol drinking rather than serotonergic lesioning.
Feeding Patterns of Rats Chronically Ingesting an Ethanol‐Containing Liquid Diet
Authors: Reidelberger Roger D. , Tuma Dean J. , Woltman Todd A. , Donohue Terrence M.
Published: April 2006

We compared the feeding patterns of rats ingesting a 36% ethanol‐containing liquid diet for 30 days with those of rats pair‐fed an isocaloric liquid control diet or provided control diet or ground rat chow ad libitum. Ethanol‐fed rats consumed fewer calories per day and gained less body weight than rats fed control diets ad libitum. Daily caloric intakes were ∼50% lower during the first 10 days and 20% thereafter. Lower intakes in ethanol‐fed rats occurred through a decrease in mean meal size rather than number of meals per day, although meals were more evenly distributed diurnally. Pair‐fed rats ingested most of their food in one or two meals within a few hours of presentation. In a related experiment, a 4‐hr duodenal infusion of ethanol at a rate comparable to that of ethanol ingestion resulted in plasma ethanol levels of 28 ± 4 mM and suppressed 5‐hr intake by ∼40% by increasing the mean postmeal interval and satiety ratio. These results suggest that the suppressive effect of ethanol ingestion on food intake may be mediated in part by a post‐gastric mechanism of ethanol action.
Evidence of Multiple Ethanol Pools in the Brain: An in Vivo Proton Magnetization Transfer Study
Authors: Meyerhoff Dieter J. , Rooney William D. , Tokumitsu Takaaki , Weiner Michael W.
Published: April 2006

Studies of isolated cell membranes and animal brain extracts have shown that ethanol (EtOH) partitions into cell membranes. We tested the hypothesis that EtOH in the living brain after EtOH administration exists in two or more pools: a free, mobile pool of EtOH and one or more EtOH pools that are restricted in their molecular mobility, possibly because of association with membranes. In vivo brain proton magnetic resonance spectroscopy (1H MRS) routinely detects the methyl protons of the mobile EtOH pool but does not detect motion‐ally restricted EtOH. We used in vivo brain 1H MRS in rat brain (n = 11) after intraperitoneal EtOH administration to measure the signal intensity of methyl EtOH protons in the presence and absence of off‐resonance saturation. Off‐resonance saturation resulted in a 33 ± 4% decrease of the EtOH methyl proton signal. We interpret this signal reduction as a magnetization transfer effect. It is consistent with the existence of an MRS‐invisible EtOH pool with restricted molecular mobility, which is in exchange with the free EtOH pool. Off‐resonance saturation at the water frequency resulted in an even larger decrease of the EtOH methyl signal, consistent with water molecules being in close proximity to EtOH molecules at the restricted motion site(s). These results provide support for the hypothesis that partial MRS‐invisibility of brain EtOH is at least to some extent caused by the presence of a (MRS‐invisible) pool of motionally restricted EtOH. They also strongly suggest that water suppression, routinely used in in vivo 1H MRS, may reduce the observable EtOH methyl signal intensity through a magnetization transfer mechanism. These studies may provide both a mechanism of, and a means to investigate the alterations of EtOH MRS visibility observed in heavy drinkers.
Effects of Ethanol on Phosphorylation of Lipids in Rat Synaptic Plasma Membranes
Authors: Tong Wei , Sun Grace Y.
Published: April 2006

Synaptic plasma membranes (SPM) isolated from rat cerebral cortex contain lipid kinases for conversion of phosphatidylinositol (PI), phosphatidylinositol 4‐phosphate (PIP), and diacylglycerol (DG) to PIP, phosphatidylinositol 4,5‐bisphosphate (PIP2), and phosphatidic acid (PA), respectively. These anionic phospholipids are important in signal transduction mechanisms and are required for synaptic function. The effect of ethanol and other aliphatic alcohols on phosphorylation of these lipids in SPM has not been established. incubation of SPM with [Y32P]ATP resulted in labeling of PIP, lyso‐PIP, PIP2, and PA. Ethanol (50–200 mM) added to the incubation system showed a dose‐dependent decrease in labeling of PIP2 but not PIP or PA. To a lesser extent, labeling of PIP2 was also inhibited by 1‐propanol, but neither isopropanol nor 1‐butanol could alter the PIP2 labeling pattern. Under similar incubation conditions, labeling of PIP and PA in SPM was not altered by ethanol, 1‐propanol, isopropanol, but l‐butanol stimulated PIP labeling with a peak at 25 mM. Addition of exogenous PIP to the incubation mixture led to an increase in labeling of PIP2, suggesting that the endogenous PIP pool in SPM is limiting for the synthesis of PIP2 in SPM. Interestingly, when SPM were incubated with exogenous PIP, addition of ethanol (50–100 mM) to this incubation mixture resulted in an increase in PIP2 labeling. Taken together, these results suggest a specific effect of ethanol on PIP kinase in SPM, and this effect seems to be dependent on the location and/or amount of PIP in the membrane.
Alcohol Mediates Increases in Hepatic and Serum Nonheme Iron Stores in a Rat Model for Alcohol‐Induced Liver Injury
Authors: Valerio Luis G. , Parks Tony , Petersen Dennis R.
Published: April 2006

The notion that prolonged ethanol consumption promotes hepatocellular damage through interactions with iron was evaluated in rats fed ethanol with or without supplemental dietary carbonyl iron. The individual and combined pro‐oxidant potential of these agents was evaluated in terms of their ability to perturb iron homeostasis and initiate hepatocellular injury. Sprague‐Dawely rats received a high fat liquid diet for 8 weeks supplemented with 35% ethanol‐derived calories (Alcohol group), 0.02 to 0.04% (w/v) carbonyl iron (Iron group), ethanol plus carbonyl iron (Alcohol + Iron group), or a diet containing carbohydrate‐derived isocaloric calories (Control group). Hepatic and serum nonheme iron stores were significantly elevated (p < 0.05) in all treatment groups, compared with the Controls. Catalytically active low‐molecular weight iron was detected in rats consuming alcohol and was markedly elevated (p < 0.05) in rats ingesting iron alone or iron in combination with alcohol. Elevations in serum ALT indicated significant hepatocellular injury in rats ingesting only alcohol, but was most prominent in the rats consuming ethanol in combination with iron (p < 0.05). Significant hepatic fatty infiltration, increased hydroxyproline content, and perturbations in reduced glutathione were also observed in the Alcohol and Iron treatment groups. Histochemical assessment of hepatic iron sequestration revealed that alcohol feeding resulted in deposition of ferric iron in the centrilobular area of the liver lobule. This unique alcohol‐mediated iron deposition was histologically graded above Control group and was observed in both hepatocytes and Kupffer cells. Data presented herein suggest that alcohol alone or in combination with iron results in rather specific lobular patterns of hepatic iron deposition relevant to iron overload observed in human alcoholics. Furthermore, data suggest that alcohol‐ and iron‐initiated prefibrotic events occur before extensive hepatocellular necrosis.
Differential Effects of Chronic Ethanol Consumption on Hepatic Mitochondrial and Cytoplasmic Ribosomes
Authors: Cahill Alan , Baio Debra L. , Ivester Priscilla , Cunningham Carol C.
Published: April 2006

The effects of chronic ethanol consumption on the properties of mitochondrial and cytoplasmic ribosomes were investigated in rat liver. Sedimentation properties of purified mitochondrial (55s) and cytoplasmic (80s) ribosomes were determined by analyses on sucrose density gradients. Mitochondrial ribosomes from control animals moved further in the gradients than did those isolated from ethanol‐fed rats, which suggests that ethanol ribosomes have a lower molecular weight. In addition, mitochondria from ethanol‐fed animals contained a lower percentage of ribosomes present as the intact monosome, suggesting that ethanol may have an effect on the stability of the functional mitochondrial ribosomes. This was confirmed by the presence of the larger 39s subunit in preparations from ethanol‐fed animals. No such ethanol‐related alterations were seen with cytoplasmic ribosomes. The protein composition of mitochondrial and cytoplasmic ribosomes was investigated using two‐dimensional gel electrophoresis, followed by two‐dimensional densitometry. As indicated by differences in protein staining intensity, ethanol consumption seemed to alter the concentration of seven mitochondrial ribosomal proteins. In contrast, no such changes were observed in the protein pattern from cytoplasmic ribosomes. Observations in this study provide for the possibility that alterations in the amounts of selected proteins in the mitochondrial ribosome lead to impaired assembly of the ribosome. These ethanol‐related structural changes may be responsible for the decreased activity of mitochondrial ribosomes that results in impaired hepatic mitochondrial protein synthesis (W. B. Coleman and C. C. Cunningham, Biochim. Bio‐phys. Acta 1058:178–186, 1991). Furthermore, this study re‐emphasizes the increased susceptibility of the hepatic mitochondrial translation system, compared with the cytoplasmic system to chronic ethanol consumption.
Sustained Effects of a Single Injection of Ethanol on the Hypothalamic‐Pituitary‐Gonadal Axis in the Male Rat
Authors: Steiner J. C. , Halloran M. M. , Jabamoni K. , Emanuele N. V. , Ernanuele M. A.
Published: April 2006

The hormones responsible for regulating the hypothalamic‐pituitary‐gonadal axis are essential for proper reproductive function. Ethanol (EtOH) has been shown to exert its effects at all three levels of this axis. The present study defines striking differences in the time course of recovery of luteinizing hormone (LH) in gonadally intact, compared with, castrated male rats after acute EtOH administration. Serum levels of LH and testosterone were measured at various time points up to 2 weeks (1.5, 3, 24, 48, 72, 96, 168, and 336 hr) after a single intraperitoneal injection of either saline or 3 g/kg of EtOH in intact adult male rats. One EtOH injection significantly suppressed testosterone levels to as low as 20% (p < 0.01) of saline‐injected intact rats. This occurred as early as 1.5 hr after EtOH administration (the first measured time point), and statistically significant suppression was sustained for 96 hr. Similarly, LH levels showed a significant decrease. However, this significant fall in LH did not begin until 3 hr (p < 0.05) and continued up to 96 hr (p < 0.01), with a gradual return to control levels at 168 and 336 hr after treatment. Despite the significant and prolonged fall in testosterone levels in the EtOH‐treated intact rats, P‐LH mRNA levels were inappropriately not elevated, as would be expected in the context of low circulating testosterone. However, at 168 and 336 hr, steady‐state levels of P‐LH mRNA were significantly higher than seen in saline‐injected controls (p < 0.05 and p < 0.01, respectively), temporally correlating with the return of serum LH to control. LH levels in the castrated animals were significantly suppressed at 1.5 hr (p < 0.05) and 3 hr (p < 0.01) after EtOH treatment, compared with controls, yet they returned much more quickly by 24 hr after treatment. P‐LH mRNA levels of castrated animals also showed a significant depression at 1.5 and 3 hr, and returned to control levels by 24 hr. In these rats, the hypothalamic LH‐releasing hormone mRNA levels were not altered by a single EtOH injection at any time point. However, in the intact animals, there was a transient increase in LH‐releasing hormone mRNA at 72 and 96 hr (p < 0.01 and p < 0.05, respectively) that may lead to the upregulation of β‐LH mRNA expression. These studies indicate that EtOH causes prolonged decreases in important serum hormones that are essential to the reproductive axis of the adult male rat.
Alcohol Consumption Inhibits Bone Growth and Development in Young Actively Growing Rats
Authors: Sampson H. Wayne , Perks Nancy , Champney Thomas H. , DeFee Buren
Published: April 2006

Adolescence is an age of widespread alcohol abuse, but the effect of alcohol consumption on bone formation has not been studied in the young population. This study addresses the effect of alcohol on the early phases of bone growth and development in an animal model. Four‐week‐old, female Sprague‐Dawley rats were divided into three groups. Alcohol‐treated animals were fed a modified Lieber‐DeCarli diet ad libitum containing 35% ethanol‐derived calories, whereas the pair‐fed animals (weight‐matched to ethanol rats) received an iso‐caloric liquid diet in which maltose‐dextrin substituted calories supplied by ethanol. Chow animals were fed a standard rat chow ad libitum. Proximal tibiae (primarily cancellous bone) and femora (primarily cortical bone) were removed for analysis after 2, 4, 6, or 8 weeks on the diets. Serum was collected for analysis of calcium levels, osteocalcin, corticosterone, growth hormone, parathyroid hormone, and 25‐hydroxyvitamin D. The most rapid weight gain occurred between 6 and 8 weeks of age, and it was significantly delayed in alcohol and pair‐fed animals. Almost all morphological parameters of bone were lower in the alcohol groups. No significant difference in serum calcium levels, osteocalcin, or growth hormone levels were found, and small difference in calciotropic hormone levels was found between groups. The results indicate that chronic alcohol consumption during the age of bone development reduces bone density and peak bone mass in both cortical and cancellous bone. The mechanism whereby this effect occurs is not fully understood, but, our results suggest that the negative impact of alcohol on growing bone is not due to the secondary effects of altered bone mineral regulating hormones.
Reduced Sensitivity to Ethanol Reward, But Not Ethanol Aversion, in Mice Lacking 5=HT1B Receptors
Authors: Risinger Fred O. , Bormann Nancy M. , Oakes Roger A.
Published: April 2006

Various serotonergic receptor systems are thought to influence the motivational effects of ethanol. This experiment characterized the acquisition of ethanol‐induced conditioned taste aversion and ethanol‐induced conditioned place preference in mutant knockout mice lacking 5‐HT1B receptors. In the taste conditioning procedure, adult homozygous knockout mice (‐/‐) and homozygous wild‐type mice (+/+) received access to 0.2 M NaCl solution, followed immediately by intraperitoneal injection of 0 to 4 g/kg of ethanol. Ethanol produced dose‐dependent conditioned taste aversion that was the same in both genotypes. In the place conditioning procedure, knockout and wild‐type mice received six pairings of a tactile stimulus with ethanol (2 g/kg, ip). A different tactile stimulus was paired with saline. Ethanol produced increases in locomotor activity, with wild‐type mice showing higher levels of ethanol‐stimulated activity than knockout mice during conditioning trials 5 and 6. Wild‐type mice demonstrated conditioned place preference for the ethanol‐paired stimulus. In contrast, knockout mice showed no evidence of place conditioning. These results are generally consistent with an important role for serotonergic systems in ethanol reward and specifically indicate that 5‐HT1b receptors are important for ethanol's rewarding effects but not for ethanol's aversive effects.
Binge Ethanol‐Induced Brain Damage in Rats: Effect of Inhibitors of Nitric Oxide Synthase
Authors: Zou Jian‐Yun , Martinez Daniel B. , Neafsey Edward J. , Collins Michael A.
Published: April 2006

Testing the possible role of endogenous nitric oxide (NO) in the neurotoxicity of ethanol, we examined how two different NO synthase (NOS) inhibitors affected the extent of cerebrocortical and olfactory neuronal damage in a modified “binge intoxication” rat model (Collins et al., Alcohol Clin. Exp. Res. 20:284–292, 1996). Male rats intragastrically fed ethanol (6.5 to 12 g/kg/day) in nutrient solution three times daily for 4 days also received NG‐nitro‐L‐arginine methyl ester by chronic intracerebroventricular infusion or 7‐nitro‐indazole by daily intraperitoneal injection; control rats were given nutrient solution only and/or vehicles. Blood ethanol levels did not differ among the ethanol‐treated groups. The amount of ethanol‐dependent neuronal degeneration in the entorhinal cortex, dentate gyrus, and olfactory bulb glomeruli—visualized with the de Olmos cupric silver stain and quantitatively assessed in the binge‐intoxicated rats—was either unchanged or significantly increased by the NOS inhibitors. Although the efficacies of the inhibitors cannot be directly compared because various NOS forms were probably inhibited to differing extents, the results do not support the idea that endogenous NO is a neurotoxic mediator of ethanol's effects. Rather, NO may have a modest neuroprotectant role in this model of early brain damage induced by ethanol. In addition, the NOS that is localized histochemically as NADPH diaphorase was present primarily in regions and/or cells not damaged by binge ethanol treatment. Assuming that NADPH diaphorase represents most of the NO forming enzyme(s), this suggests a transcellular mechanism for NO. A further observation was that hippocampal CA pyramidal neuron degeneration was extensive in rats infused centrally with NG‐nitro‐L‐arginine methyl ester.
Assessment of Medication Compliance in Alcoholics through UV Light Detection of a Riboflavin Tracer
Authors: Del Boca Frances K. , Kranzler Henry R. , Brown Joseph , Korner Patricia F.
Published: April 2006

Compliance with the medication regimen in treatment trials for alcoholism appears to be a key determinant of treatment outcome. However, there is no consensus as to the best method to assess medication compliance. This study examines the feasibility of using ultraviolet light detection of a urinary riboflavin tracer to determine compliance with medication therapy. Six sets of urine specimens (with n ranging from 15 to 38) were rated independently by two judges. Test‐retest reliability was high: 90 and 95% agreement for two judges. Inter‐rater reliability ranged from 73 to 95% agreement between judges (mean = SSYO), with corresponding Kappa values ranging from 0.46 to 0.85 (mean = 0.69). Diaries, capsule counts, and spectrofluorimetric data were used to validate judges' ratings in four trials, including one in which subjects were alcohol‐dependent participants in one of three pharmacotherapy trials. Rating accuracy was influenced by dosage, time interval between ingestion and urine collection, and previous dosing. Overall, ratings tended to be accurate, with incorrect judgments limited to specimens with low concentrations of urinary riboflavin. The results indicate that ultraviolet light detection of urinary riboflavin is a useful method for the assessment of patient compliance with medication regimens, including compliance of patients assigned to receive placebo in clinical trials of medications for alcoholism treatment.
Fatty Acid Composition of Liver Total Lipids in Alcoholic Patients with and without Liver Damage
Authors: de la Maza Maria Pia , Hirsch Sandra , Nieto Susana , Petermann Margarita , Bunout Daniel
Published: April 2006

Alcohol ingestion may promote lipid peroxidation, and the presence of polyunsaturated fatty acids in liver lipids may be essential for the generation of liver damage through this mechanism. The aim of this study is to examine fatty acid composition of liver lipids in chronic alcoholics with and without histological liver damage. A percutaneous liver biopsy was performed to 28 patients hospitalized for treatment of their alcoholism. Liver total lipids were extracted from a portion of the tissue sample and fatty acid composition was measured by gas chromatography. Another piece of the sample was sent for histological study. Six patients had histological cirrhosis or alcoholic hepatitis in their biopsies, the rest of the patients had minimal changes. Patients with liver damage had higher levels of oleic acid and total monoenoic fatty acids, a higher 18:1/18:0 ratio, lower levels of polyunsaturated fatty acids, a lower 20:4/18:2 ratio, and a lower peroxidability index in liver total lipids, than patients without liver damage. Alcoholic patients with asymptomatic liver damage have less unsaturated fatty acids in liver total lipids than their counterparts with normal livers.