bluuebunny/crossref_metadata_2025 huggingface dataset:
Patterns of Suicidality and Alcohol Use in Alcoholics with Major Depression
Authors: Cornelius Jack R. , Salloum Ihsan M. , Day Nancy L. , Thase Michael E. , Mann J. John
Published: April 2006

The aims of this study were (1) to comprehensively characterize a population of alcoholics with major depression in a psychiatric hospital, (2) to determine the prevalence of suicidal behavior in this sample, and (3) to determine whether quantity of alcohol ingested was associated with level of suicidality. Ratings of drinking, depression, and suicidality were obtained using both self‐rated and observer‐rated instruments. The prevalence of suicide attempts in the week before hospitalization was remarkably high, approaching 40%, whereas 70% had made a suicide attempt at some point in their lifetime. These suicide attempts were typically impulsive in nature, involving little if any premeditation. Most subjects reported drinking more heavily than usual on the day of their suicide attempt. Recent suicidal behavior was significantly associated with recent very heavy drinking (<70 drinks per week) and with number of drinks per drinking day. Quantity of drinking per drinking day was also significantly higher in those making a recent suicide attempt. However, no association was found between quantity of alcohol consumption and suicidal ideation. These findings suggest that recent heavy alcohol use primarily affects suicidality by increasing the likelihood of acting on suicidal ideation rather than by inducing suicidal ideation.
Effects of Disulfiram on Positron Emission Tomography and Neuropsychological Studies in Severe Chronic Alcoholism
Authors: Gilman Sid , Adams Kenneth M. , Johnson‐Greene Doug , Koeppe Robert A. , Junck Larry , Kluin Karen J. , Martorello Susan , Heumann Mary , Hill Elizabeth
Published: April 2006

Disulfiram is an aldehyde dehydrogenase inhibitor that is widely used as an adjunctive agent in the treatment of patients with severe chronic alcoholism. Recent positron emission tomography (PET) studies of local cerebral metabolic rates for glucose (ICMRglc) and benzodiazepine receptor binding in alcoholic patients have shown regional cerebral abnormalities; however, some of the patients were studied while receiving disulfiram, which could influence the biochemical processes under investigation. In a retrospective investigation, we examined the influence of disulfiram administration on the results of PET studies of ICMRglc and benzodiazepine receptor binding and neuropsychological tests of cognition and executive function in patients with severe chronic alcoholism. [18F]Fluorodeoxyglucose was used to measure ICMRglc in 48 male patients, including 11 receiving and 37 not receiving disulfiram in therapeutic doses. [11C]Flumazenil was used to measure benzodiazepine receptor binding in 17 male patients, including 3 receiving and 14 not receiving disulfiram. All patients studied with FMZ were also examined with fluorodeoxyglucose. PET studies of ICMRglc revealed significantly decreased global values in the patients receiving disulfiram compared with those not receiving disulfiram. PET studies of benzodiazepine receptor binding revealed decreased flumazenil influx and distribution volume in patients receiving disulfiram. The neuropsychological tests demonstrated no differences between the two groups of subjects. The findings suggest that disulfiram may influence the results of PET studies of glucose metabolism and benzodiazepine receptor binding.
Isolation and Characterization of Three Alcohol Dehydrogenase Isozymes from Syrian Golden Hamsters
Authors: Keung Wing‐Ming
Published: April 2006

Electrophoresis of freshly prepared tissue homogenates of the Syrian golden hamster (Mesocricetus auratus) on starch gel followed by activity staining with ethanol as the substrate revealed three major alcohol dehydrogenase (ADH) isozymes. One of these isozymes, TT‐ADH, found only in the testes of golden hamsters was previously purified and partially characterized (Keung WM: Biochem. Biophys. Res. Commun. 156:38–45, 1988). The other two, AA‐ and BB‐ADH, which are most abundant in the liver, have now been purified by affinity chromatography on 4‐(3‐(N‐(6‐aminocaproyl)amino)propyl)pyrazole‐sepharose and testosterone‐17β‐hemisuccinate‐agarose. Hamster AA‐, BB‐, and TT‐ADH are all homodimers of molecular weight near 80,000 and each contains 4 atoms of zinc. Amino acid analyses show that BB‐ADH is most closely related to the γ‐form of human class I ADH, whereas AA‐ and TT‐ADH are most closely related to the β‐form of the human enzyme. BB‐ADH is the only hamster ADH that is active toward sterols and sensitive to testosterone and isoflavone inhibition. These results suggest that hamster BB‐ and human γγ‐ADH also share similar catalytic properties. AA‐ and TT‐ADH are neither active toward sterols nor sensitive to testosterone or isoflavone inhibition; thus, they are functionally different from the human αα‐ or γγ‐ADHs. Compared with AA‐ and BB‐ADH, TT‐ADH exhibits much higher Km values toward primary aliphatic alcohols and cyclohexanol. AA‐ and BB‐ADH share similar substrate specificities toward primary aliphatic alcohols. However, they exhibit different stereospecificities for secondary alcohols. BB‐ADH prefers the (R)‐(–)‐isomer of 2–butanol, whereas AA‐ADH prefers the (S)‐(–)‐isomer. These results further demonstrate that catalytically, hamster BB‐ and AA‐ADH belong to different subfamilies of class I ADH.
Association of Alcoholism with the N‐Glycosylation Polymorphism of Pseudodeficient Human Arylsulfatase A
Authors: Park David S. , Poretz Ronald D. , Stein Stanley , Nora Rena , Manowitz Paul
Published: April 2006

The IIIa and IIIb electrophoretic variants of arylsulfatase A (EC 3.1.6.8) are 12 times more prevalent in alcoholic than in nonalcoholic populations. These variant enzymes, found in a subset of alcoholics, possess the pseudodeficient Asn350‐Ser mutation of arylsulfatase A and, consequently, lack an N‐linked glycan unit. These genetically determined variants of arylsulfatase A show reduced intracellular half‐life, and cells from such individuals possess reduced enzymic activity. We propose that this polymorphism is an underlying genetic and biochemical factor contributing to the neuropathology and/or addiction pathway of this disease.
Structural Characterization of Variant Forms of Arylsulfatase A that Associate with Alcoholism
Authors: Park David S. , Manowitz Paul , Stein Stanley , Poretz Ronald D.
Published: April 2006

Several electrophoretic forms of human platelet arylsulfatase A (ASA), including variant type IIIa and normal type IVa, have been identified by nondenaturing polyacrylamide gel electrophoresis. An alcoholic population that we have analyzed is enriched in variant type IIIa compared with nonalcoholic psychiatric and normal controls. Individuals with the IIIa enzyme possess greatly reduced levels of ASA activity. To understand further the structural basis for the differences and their potential biological consequences, the nature of the ASA variant expressed by fibroblasts from different individuals was explored. The electrophoretic patterns of fibroblast ASA from the IIIa and IVa individuals differ in degree of phosphorylation. Furthermore, fibroblast ASA from IIIa individuals lacks an N‐linked glycan found in ASA from IVa individuals. In addition, differences in peptide and/or posttranslational modification unrelated to the N‐linked carbohydrate or phosphorylation exist between the fibroblast ASA from IIIa and IVa individuals. The finding that both fibroblasts and platelets exhibit related electrophoretic isoform patterns characteristic of the donor's ASA type allows for the use of fibroblasts to study the impact of ethanol on the metabolism of cells possessing different ASA types.
Alcohol Stimulates ACTH Secretion in the Rat: Mechanisms of Action and Interactions with Other Stimuli
Authors: Rivier Catherine
Published: April 2006

This review discusses some of the mechanisms through which alcohol (EtOH) alters the activity of the hypothalamic‐pituitary‐adrenal (HPA) axis. In adult rats, acute EtOH treatment increases plasma ACTH and corticosteroids levels primarily by stimulating the release of corticotropin‐releasing factor (CRF) and possibly vasopressin (VP) from nerve terminals in the median eminence. Increased CRF gene transcription in the hypothalamus may also be important. The HPA axis remains activated during chronic EtOH exposure, although habituation may take place. Changes in the responsiveness of hypothalamic neurons, a phenomenon itself dependent in part on a number of intermediate secretagogues, as well as decreased pituitary responsiveness to VP, all play a role. Finally, the activity of the HPA axis is influenced by exposure to EtOH during embryonic development, with mature offspring showing hyporesponsiveness to many stimuli. These altered responses appear to be caused in part by changes in the synthesis/release CRF, possibly under the influence of nitric oxide. CRF, VP, ACTH, and corticosteroids are important regulators of the immune system, behavior, metabolic pathways, and reproductive parameters. Alcohol therefore may influence such functions through the pathological secretion of these hormones. A better understanding of the mechanisms through which the drug alters their release thus may permit the development of therapies designed to alleviate some of the consequences of alcoholism.
Gender Difference in Alcohol‐Evoked Hypothalamic‐Pituitary‐Adrenal Activity in the Rat: Ontogeny and Role of Neonatal Steroids
Authors: Ogilvie Kathleen M. , Rivier Catherine
Published: April 2006

Alcohol administration results in activation of the hypothalamic‐pituitary‐adrenal (HPA) axis, with female rats secreting more adrenocorticotropin (ACTH) and corticosterone (B) than males in response to the same dose of alcohol. We first examined the ontogeny of the gender difference in HPA responsiveness to alcohol by administering four doses (0,1,2, or 3 g/kg body weight) to animals at 21,41, and 61 days of age (prepubertal, peripubertal, and postpubertal, respectively). We then investigated the organizational role of steroids by manipulating the neonatal steroidal milieu. Rats of both genders were gonadectomized or injected with testosterone propionate within 24 hr of birth and the HPA response to 3 g/kg body weight alcohol was tested in adulthood (postpubertal period). Our data show that the gender difference in HPA responsiveness to alcohol administration arises peripubertally. In addition, HPA response to alcohol is quantitatively smaller in intact male rats than in feminized groups (gonadectomized males and females, intact females) and masculinized female rats. We conclude that the gender difference in HPA response to alcohol observed in postpubertal rats injected with alcohol depends on the activational role of testicular androgens, rather than on their organizational influence.
Repeated Ethanol Withdrawal Produces Site‐Dependent Increases in EEG Spiking
Authors: Veatch Lynn M. , Gonzalez Larry P.
Published: April 2006

Recent studies have suggested an important kindling‐like exacerbation of ethanol withdrawal symptoms after repeated cycles of ethanol intoxication and withdrawal. Few studies, however, have evaluated the effect of multiple episodes of intoxication and withdrawal on spontaneous EEG activity after cessation of ethanol intake. In this study, electrographic activity in cortical and subcortical structures of male Sprague‐Dawley rats was examined after multiple cycles of ethanol intoxication and withdrawal. After surgical implantation of electrodes, animals received repeated cycles of chronic ethanol exposure in vapor inhalation chambers for 10 or 20 days, with 4‐day withdrawal periods between each. Upon removal from the inhalation chamber, spontaneous EEG activity was recorded intermittently for 72 hr. These data were then examined for the presence of spikes and sharp waves. Results indicate that the levels of spike and sharp wave activity observed vary with both length of ethanol exposure and with the number of withdrawal cycles, and that these effects varied with neuronal site. Changes in spike and sharp wave activity were first observed within hippocampal areas, with other subcortical and cortical sites showing increased activity after additional ethanol exposure or additional cycles of intoxication and withdrawal. Hippocampal areas CA1 and CA3 differed significantly from one another in their response to chronic ethanol exposure, with area CA1 most affected by changes in amount of ethanol exposure and area CA3 most affected by number of withdrawal cycles. These results indicate an increased severity of the ethanol withdrawal syndrome after repeated ethanol withdrawal episodes and suggest differential, site‐specific changes in neuronal excitability.
Reduced Fatty Acid Ethyl Ester Synthase Activity in the White Blood Cells of Alcoholics
Authors: Gorski Norbert P. , Nouraldin Hazem , Dube David M. , Preffer Frederic I. , Dombkowski David M. , Villa Ellen M. , Lewandrowski Kent B. , Weiss Roger D. , Hufford Cathryn , Laposata Michael
Published: April 2006

Purpose: Fatty acid ethyl esters (FAEEs), esterification products of ethanol and fatty acids, have been implicated as mediators of ethanol‐induced organ damage. It has been shown that FAEE synthase, the enzyme responsible for the formation of FAEE, is present selectively in the organs commonly damaged by ethanol abuse. Recently, we have made the observation that FAEEs are also present in the serum after ethanol ingestion. The current study was performed to determine whether cellular elements of the blood and/or plasma are capable of synthesizing FAEEs from fatty acids and ethanol. Materials and Methods: Heparinized blood samples were collected from 10 healthy volunteers, and the red blood cells, platelets, plasma, and several white blood cell populations were assayed for FAEE synthase activity. Blood samples from control subjects and individuals admitted to an alcoholic detoxification unit at a local hospital were also assayed for FAEE synthase activity. Results: We observed that the FAEE synthase activity is present in whole blood, primarily within white blood cells. Fractionation of the white blood cells revealed that the lymphocyte‐monocyte fraction isolated using Ficoll‐hypaque contained ˜3.5‐fold higher activity than the granulocyte fraction. The cell type that contained the highest FAEE synthase activity (1220 pmol/hr/106 cells) was the natural killer (NK) cell population. B cells contained ˜40% of the enzyme activity found in NK cells, and the B‐cell activity was slightly greater than that found in CD4+ and CD8+ T cells. Having shown that FAEE synthase exists in a blood cell, we subsequently demonstrated that alcoholic individuals have approximately half the white blood cell FAEE synthase activity of that found in normal controls. We also demonstrated that white blood cell FAEE synthase could be induced nearly 2‐fold upon ingestion of 2 oz of scotch whiskey for 6 days. The enzyme activity returned to baseline levels despite ingestion of 2 oz of scotch whiskey/day for 3 additional days. Conclusions: These data indicate that ethanol ingestion results in increased FAEE production, particularly by NK cells. FAEE synthesis after ethanol ingestion may explain the presence of FAEE in the serum. The lower enzyme activity observed in white blood cells of alcoholics from a detoxification center may be the result of years of ethanol abuse or it may be that alcoholics congenitally have low levels of FAEE synthase. If the latter is true, this finding may explain in part the genetic predisposition of many alcoholic individuals to ethanol abuse.
Neuronal Degeneration in Rat Cerebrocortical and Olfactory Regions During Subchronic “Binge” Intoxication with Ethanol: Possible Explanation for Olfactory Deficits in Alcoholics
Authors: Collins Michael A. , Corso Thomas D. , Neafsey Edward J.
Published: April 2006

Severe, repetitive (“binge”) ethanol intoxication in adult rats (intragastric delivery 3 times daily for 4 days in a modification of the Majchrowicz method) precipitates neuronal degeneration in selected cerebral cortical regions involved in memory and olfaction, confirming the results of Switzer and colleagues (Anat. Rec. 202 186a, 1982). Neuronal damage was visualized with the de Olmos cupric silver technique for degenerating neurons and processes (argyrophilia), and was quantitated by total counts and densities of argyrophilic cells/fields. The specificity of the degeneration provides a neuropathological basis for the olfactory memory deficits in chronic alcoholics. In highly intoxicated rats, argyrophilia was most extensive among hippocampal dentate gyrus granule cells, pyramidal neurons in layer 3 of the entorhinal cortex, and olfactory nerve terminals in the olfactory bulb. Degenerating pyramidal neurons were also consistently seen in the insular cortex and olfactory cortical regions, such as the piriform and perirhinal cortices. There were few argyrophilic neurons in the CA regions of the hippocampus and none in the cerebellum—regions generally shown to have cell loss in long‐term ethanol feeding models—but degenerating mossy fibers in the CA2 region were observed. Degeneration was maximal before the peak period of abstinence symptoms in this model, because argyrophilic densities were no greater36 hr, compared with 8 hr after the last ethanol dose. High blood ethanol levels were required, because argyrophilia, absent from isocaloric controls, also was only evident in ethanol‐intoxicated rats with mean blood ethanol levels for days 2 to 4 above 300 mg/dl; however, it increased substantially between 350 and 550 mg/dl. The resemblance of the argyrophilic distribution to the regional neuropathology that occurs in experimental seizures indicates that the ethanol‐induced degeneration may have an excitotoxic basis. Progressive reductions in the seizure threshold (e.g., kindling phenomena that have been documented during binge ethanol intoxication) might be associated with excitotoxic hyperactivity during the repetitive nadirs between high blood and brain ethanol peaks. However, direct toxic actions of ethanol or its metabolites could also be involved. Overall, the model should be useful for studying mechanisms of ethanol‐induced selective cortical and olfactory brain damage.
Buspirone in the Treatment of Alcohol Dependence: A Placebo‐Controlled Trial
Authors: Malec E. , Malec T. , Gagné M. A. , Dongier M.
Published: April 2006

A double‐blind controlled study of the effects of buspirone on alcohol dependence and associated symptoms in ambulatory alcoholics showed a marked improvement in both treatment and control groups. However, significant differences in favor of the medication were observed in several psychopathological measures, but not in measures of alcohol consumption. Contrary to a majority of prior controlled trials of buspirone in alcoholics, subjects were not selected on the basis of comorbid generalized anxiety; rather, the study tested the hypothesis of a direct effect on craving and consumption, independent from an anxiolytic effect. This hypothesis was not confirmed.
Alcohol Consumption, Life Context, and Coping Predict Mortality among Late‐Middle‐Aged Drinkers and Former Drinkers
Authors: Mertens Jennifer R. , Moos Rudolf H. , Brennan Penny L.
Published: April 2006

This study examined mortality risk for individuals in four alcohol consumption categories and identified life context and coping factors that independently predicted mortality among late‐middle‐aged drinkers and former drinkers (n= 1869). Compared with light drinkers, former drinkers (current abstainers) were at increased mortality risk; moderate drinkers were at decreased risk. Consistent with previous research on older samples, heavy drinkers were not at increased risk. Abstainers' increased risk was reduced in a model that controlled for life context and coping factors. Other independent predictors of mortality included reporting an illness stressor, stressor severity, less participation in activities with friends, greater use of resigned acceptance and alternative rewards coping, and less use of cognitive avoidance and emotional discharge coping. The findings support previous research on the alcohol‐mortality relationship among older adults, and highlight the fact that abstainers' life stressors and avoidance coping responses may be more important predictors of their mortality than their abstention.
Use of ICD‐9‐CM Codes in the Estimation of Alcohol‐Involved Injury: Search for a Surrogate II
Authors: Treno Andrew J. , Gruenewald Paul J. , Ponicki William R.
Published: April 2006

This study presents a follow‐up analysis of 22,427 injury cases drawn from the California Regional Trauma Registry. Whereas the earlier analysis developed a surrogate for alcohol‐involved injuries using E‐codes as reflective of injury type, this analysis explores the possibility of using ICD‐9‐CM diagnosis codes that have a longer history and are available in more jurisdictions. Findings reported herein indicate that the original demographic patterns predicting testing and alcohol involvement patterns were maintained in ICD‐9‐CM diagnostic code‐based models. Moreover, although variables representing demographic background, time of day, and day of week clearly were the most powerful model predictors, ICD‐9‐CM diagnostic codes reflecting physician assessment that the patient had a chronic alcohol problem did improve the fit of models, and thus provide additional information concerning testing and blood alcohol concentration patterns. In contrast, ICD‐9‐CM diagnostic codes reflecting the specific nature of the injury, although statistically significant, explained little additional variability in alcohol involvement. Nevertheless, the overall model did accurately classify ˜75% of those in the sample for whom blood alcohol concentration status information was available, suggesting its appropriateness for surrogate development.
Increased Vulnerability to Alcohol‐Related Birth Defects in the Offspring of Mothers Over 30
Authors: Jacobson Joseph L. , Jacobson Sandra W. , Sokol Robert J.
Published: April 2006

The risk of fetal alcohol syndrome (FAS) is known to increase with Increased maternal age and parity. This study investigated the hypothesis that the deficits in growth and intellectual function seen in non‐FAS infants exposed to alcohol at moderate‐to‐heavy levels are also found disproportionately in the offspring of older mothers. Mothers of 480 African‐American, inner‐city infants were interviewed at each prenatal clinic visit regarding their use of alcohol during pregnancy. Infants were assessed for physical growth and cognitive development repeatedly through age 13 months. In analyses run separately for the infants of younger and older mothers, alcohol‐related deficits were seen most strongly in the offspring of women over 30 years of age. This pattern was not caused by lower levels of drinking by the younger mothers. Age‐related increases in maternal body fat‐to‐water ratio and a faster rate of alcohol metabolism in chronic drinking women may account for the greater vulnerability of the offspring of the older mothers. These data suggest that physiological changes associated with aging and/or chronic drinking may play an important role in the alcohol‐related birth defects seen in infants exposed at moderate‐to‐heavy levels.
Hepatic Sinusoidal Endothelial Cell in Alcoholemia and Endotoxemia
Authors: Deaciuc Ion V. , Spitzer John J.
Published: April 2006

The experimental data reviewed in this study tend to indicate that the hepatic sinusoidal endothelial cell (SEC) is, chronologically, the first hepatic cell that undergoes pathologic changes in alcoholemia. Due to its strategic position in the liver sinusoid, SEC dysfunction and structural alterations have far‐reaching repercussions for the whole liver. The authors gather experimental evidence suggesting that alcohol‐induced SEC alterations are mostly due to Kupffer cell activation induced by alcohol rather than to a direct action of alcohol on SEC. Once activated, the Kupffer cell secretes a spectrum of mediators that affect both function and structure of SEC. Kupffer cell activation is regarded as a result of both direct and indirect actions of alcohol on the cell. The indirect action of alcohol is ascribed to alcohol‐induced elevated plasma levels of Gram‐negative bacterial lipopolysaccharide (LPS), a strong activator of Kupffer cell. However, a comparison of alcohol and LPS effects on SEC functions and structure reveals that these two agents may have, under many circumstances, different actions on the SEC, at least in laboratory animals. However, this issue continues to be a matter of debate. Also the review presents justification for the necessity to extend research on mechanisms underlying alcoholic liver disease to the effects of alcohol on the SEC. Finally, several future research directions are suggested in this review to better understand the mechanisms underlying alcohol‐induced liver dysfunction.
Long‐Term Effect of Postnatal Alcohol Exposure on the Number of Cells in the Neocortex of the Rat: A Stereological Study
Authors: Mooney Sandra M. , Napper Ruth M. A. , West James R.
Published: April 2006

Behavioral and morphological studies suggest that exposure to alcohol during development may cause damage in the neocortex. In this study, rat pups were exposed to alcohol during the brain growth spurt and examined at adulthood to ascertain the long‐term effect of alcohol exposure on the neocortex. Four‐day‐old rat pups were surgically implanted with an intragastric cannula while under ether anesthesia and artificially reared from postnatal day (PN) 4 through PN11. Two of the consecutive 12 daily feeds contained either alcohol (4.5 g/kg; alcohol‐exposed) or an isocaloric maltose/dextrin solution (gastrostomy control) from PN4 through PN9. On PN115, animals were perfused intracardially and the brains removed. Unbiased stereological methods were used to determine the neocortical volume, the total number of neurons and glial cells in the entire neocortex and in layer V, and the mean cell volume of neurons or mean nuclear volume of glial cells in layer V. No effect of alcohol was seen in the neuronal population on either cell number or mean cell volume, nor was there any difference in the total number or mean nuclear volume of glial cells in layer V. These findings suggest that neither the entire neocortex nor layer V alone are vulnerable to permanent alcohol‐induced cell death.
Acamprosate (Calcium Acetylhomotaurinate) Enhances the N‐Methyl‐d‐Aspartate Component of Excitatory Neurotransmission in Rat Hippocampal CA1 Neurons In Vitro
Authors: Madamba Samuel G. , Schweitzer Paul , Zieglgänsberger Walter , Siggins George Robert
Published: April 2006

The taurinate analog acamprosate (calcium acetylhomotaurinate) has received considerable attention in Europe for its ability to prevent relapse in abstained alcoholics. To determine the mechanism of acamprosate actions in the CNS, we superfused acamprosate onto rat hippocampal CA1 pyramidal neurons using an in vitro slice preparation. In current‐ and voltage‐clamp recordings, acamprosate (100 to 1000 μM) superfusion had little effect on resting membrane potential or input slope resistance. Acamprosate had no effect on Ca2+‐dependent action potentials when tetrodotoxin was used to block Na+ spikes. In whole‐cell voltage‐clamp recordings, and in the presence of tetraethylammonium and Cs+ to block K+ channels, acamprosate had little effect on a Cd2+‐sensitive inward current likely to be a high voltage‐activated Ca2+ current. However, in both current‐ and voltage‐clamp recordings, acamprosate significantly increased the N‐methyl‐d‐aspartate (NMDA) component of excitatory postsynaptic potentials evoked by stimulation of Schaffer collaterals in the stratum radiatum, in the presence of the selective non‐NMDA (R.S)‐α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐proprionic acid kainate) glutamate receptor antagonist 6‐cyano‐7‐nitro‐quinoxaline‐2,3‐dione and the GABAA receptor antagonist bicuculline. Acamprosate had inconsistent or no effects on the stratum radiatum‐evoked non‐NMDA component of the excitatory postsynaptic potentials, in the presence of bicuculline and the NMDA antagonist dl‐2‐amino‐5‐phosphonovalerate. Acamprosate, on average, had little effect on the late inhibitory postsynaptic potentials thought to be mediated by GABAB receptors. In the presence of tetrodotoxin to block synaptic transmission, acamprosate dramatically increased inward current responses in most CA1 neurons to exogenous NMDA applied by pressure or superfusion, with reversal on washout of acamprosate. These data suggest that acamprosate may act postsynaptically to increase the NMDA component of excitatory transmission to hippocampal CA1 pyramidal neurons. Considering the known interaction of ethanol with NMDA receptors, this acamprosate modulation of NMDA receptor‐mediated neurotransmission could provide a mechanism of action underlying the clinical efficacy of acamprosate.
Isoflavonoid Compounds Extracted from Pueraria lobata Suppress Alcohol Preference in a Pharmacogenetic Rat Model of Alcoholism
Authors: Lin Renee C. , Guthrie Sherri , Xie Chang‐Yi , Mai Kai , Lee David Y. , Lumeng Lawrence , Li Ting‐Kai
Published: April 2006

The extract from an edible vine, Pueraria lobata, has long been used in China to lessen alcohol intoxication. We have previously shown that daidzin, one of the major components from this plant extract, is efficacious in lowering blood alcohol levels and shortens sleep time induced by alcohol ingestion. This study was conducted to test the antidipsotropic effect of daidzin and two other major isoflavonoids, daidzein and puerarin, from Pueraria lobata administered by the oral route. An alcohol‐preferring rat model, the selectively‐bred P line of rats, was used for the study. All three isoflavonoid compounds were effective in suppressing voluntary alcohol consumption by the P rats. When given orally to P rats at a dose of 100 mg/kg/day, daidzein, daidzin, and puerarin decreased ethanol intake by 75%, 50%, and 40%, respectively. The decrease in alcohol consumption was accompanied by an increase in water intake, so that the total fluid volume consumed daily remained unchanged. The effects of these isoflavonoid compounds on alcohol and water intake were reversible. Suppression of alcohol consumption was evident after 1 day of administration and became maximal after 2 days. Similarly, alcohol preference returned to baseline levels 2 days after discontinuation of the isoflavonoids. Rats receiving the herbal extracts ate the same amounts of food as control animals, and they gained weight normally during the experiments. When administered orally, none of these compounds affected the activities of liver alcohol dehydrogenase and aldehyde dehydrogenase. Therefore, the reversal of alcohol preference produced by these compounds may be mediated via the CNS. Data demonstrate that isoflavonoid compounds extracted from Pueraria lobata is effective in suppressing the appetite for alcohol when taken orally, raising the possibility that other constituents of edible plants may exert similar and more potent actions.
Effects of Naloxone on Limited‐Access Ethanol Drinking in Rats
Authors: Davidson Dena , Amit Zalman
Published: April 2006

The hypothesis that naloxone (NAL) decreases oral ethanol intake in rats by inducing a conditioned taste aversion (CTA) to ethanol was investigated. Rats were trained to drink 8% ethanol (v/v) on a 1‐hr limited‐access schedule. They received 4 days of intraperitoneal injections of 10 mg/kg of NAL, 10 min before limited‐access (–10MIN group), immediately after limited‐access (1HR group), or 3 hr after limited‐access (3HR). Ethanol intake decreased in the ‐10MIN and 1HR groups during the injection period and on the postinjection day. In experiment 2, rats received 4 days of NAL injections when ethanol was not available (pre‐exposure), and then the paradigm was repeated. In this experiment, there was no suppression of ethanol intake for any group on the postinjection day. The decrease in ethanol intake during injections observed for the 1HR in experiment 1 and the sustained suppression postinjection was interpreted as a CTA. Pre‐exposure in experiment 2 abolished the CTA. Differences in the pattern ethanol intake for the ‐10MIN and 3HR groups during the experiments, however, suggest that a CTA is not the sole mechanism underlying NAL's suppressant effects on ethanol intake. In conclusion, in rats both the dose of NAL and the relative timing of NAL injections and ethanol drinking effect subsequent NAL suppression of ethanol intake.
The Combined Effect of Alcohol and Physical Exercise on Serum Testosterone, Luteinizing Hormone, and Cortisol in Males
Authors: Heikkonen Erkki , Ylikahri Reino , Roine Risto , Välimäki Matti , Härkönen Matti , Salaspuro Mikko
Published: April 2006

The combined effect of alcohol and physical exercise on the serum levels of testosterone, luteinizing hormone, and cortisol was studied in healthy male volunteers by performing an exhaustive ergometer exercise (1) followed by alcohol intoxication (induced by 1.5 g of alcohol/kg body weight), (2) during alcohol intoxication (induced by 0.8 g of alcohol/kg body weight), and (3) during hangover (13 hr after a dose of 1.5 g of alcohol/kg body weight). Physical stress immediately before alcohol administration prolonged the depressant effect of alcohol on testosterone secretion. This seemed to be mainly a consequence of direct inhibition at the testicular level, even though the role of luteinizing hormone as a contributory regulatory factor cannot be totally ruled out. Cortisol response to exercise was not modified by alcohol under any of the experimental conditions.
Screening for Alcohol Dependence and Abuse in Women: Description, Validation, and Psychometric Properties of a New Screening Instrument, SWAG, in a Population Study
Authors: Spak Fredrik , Hällström Tore
Published: April 2006

In this study, we have evaluated the use of a screening instrument in the first phase of a population study of female alcoholism and alcohol problems. The instrument, called SWAG (Screening, Women, and Alcohol in Göteborg), is a 13‐item questionnaire. It includes a modified version of CAGE. The study sample consisted of 3,130 women. Of these, a stratified sample of 479 were invited for interview. Validation was done against interview‐based clinical diagnosis according to DSM‐III‐R (alcohol dependence and abuse), with additional use of medical record information. SWAG had similar sensitivity and specificity used on a population sample, as previously has been found for alcohol problem screening instruments tested in clinical settings. Positive predictive value, rarely reported in studies of other alcohol screening instruments, was 40 to 50%. With logistic regression, we developed a promising set of criteria, called SWAG‐L, that had similar sensitivity, specificity, and positive predictive value as the longer version SWAG‐1, at the same time it consisted of only four items. CAGE had considerably lower sensitivity than SWAG. SWAG can, so far, be recommended for use in epidemiological studies. It may also prove valuable in clinical settings, although that requires a different scoring method. The question, “I have/have had alcohol problems” was the single item that best predicted alcohol dependence and abuse.
A Placebo‐Controlled, Double‐Blind Study of Fluoxetine in Severe Alcohol Dependence: Adjunctive Pharmacotherapy During and After Inpatient Treatment
Authors: Kabel David I. , Petty Frederick
Published: April 2006

Twenty‐eight male patients with severe alcohol dependence (mean pretreatment consumption of 18.6 standard drinks per day) completed a placebo‐controlled, double‐blind clinical trial of fluoxetine (60 mg/day). They were assigned to medication group in the second of 4 weeks on a voluntary inpatient chemical dependency ward and continued medication during a 12‐week follow‐up phase. Fluoxetine did not reduce clinically significant relapse rates: only 8 of 15 (53%) of fluoxetine subjects remained sober at 12 weeks, compared with 9 of 13 (69%) of the placebo group (Fisher's exact test, p= 0.46). Subjects with comorbid cocaine dependence relapsed more than twice as often (3 of 4, 75%) as those with alcohol dependence alone (8 of 24, 33%), although this trend did not reach statistical significance because of the small number of dually dependent subjects (Mann Whitney U test = 68,p= 0.13). Supportive living arrangements after hospital discharge did reduce relapse rates: 8 of 9 subjects (89%) discharged to a Veterans Affairs domiciliary were sober at 12 weeks, compared with 9 of 19 (47%) subjects discharged back to the community (Mann‐Whitney U test = 125,p= 0.02). Fluoxetine‐treated subjects who remained sober at 12 weeks reported a significant decrease in mean subjective alcohol craving scores from 2.9 to 0.7 on a 10‐point scale (t= 2.828, p= 0.02). In summary, fluoxetine did not reduce clinical relapse rates in this sample of male severe alcoholics without other axis I disorders who completed 4 weeks of in‐patient alcoholism treatment.
Effect of Administered Ethanol on Protein Kinase C in Human Platelets
Authors: Deitrich Richard A. , Bludeau Pequita , Elk Michelle Eagle , Baker Rodney , Menez Jean‐Francoise , Gill Kathryn
Published: April 2006

There are numerous reports of the effect of ethanol on protein kinase C (PKC) in animals or with in vitro systems. However, the effect of ethanol on PKC in humans has not been extensively investigated despite the large number of studies involving PKC and human platelets. In this study, we administered ethanol to human volunteers and determined the level of PKC before and after a 0.4 g/kg dose of ethanol. We studied Native Americans and Caucasians of both sexes. There was an increase in PKC activity 60 min after ethanol administration. There were no ethnic, age, nor gender differences detected, nor was there any correlation between family history of alcoholism and the basal or stimulated platelet PKC levels. Neither was there any correlation of basal or stimulated PKC activity with the genotypes for ADH2, ADH3, ALDH2, CYP2E1, and CYP1A2.
Alcohol Consumption, Gamma‐Glutamyl Transpeptidase (GGT), and Pulmonary Function: A Cross‐Sectional and Longitudinal Study in Working Men
Authors: Zureik Mahmoud , Liard Renata , Kauffmann Francine , Henry Christine , Neukirch Françoise
Published: April 2006

Epidemiological studies of the relationships between pulmonary function and reported alcohol intake showed inconsistent results. The use of biological markers of alcohol is needed. The objective of this study was to assess the relationships of alcohol consumption, assessed by a standardized questionnaire, and γ‐glutamyl transpeptidase (GGT), to forced expiratory volume in 1 sec (FW1) level and decline over 10 years, in working men. Three hundred twenty‐eight policemen aged 22–55 years were examined in 1980 (first survey) and again in 1990 (second survey). The two cross‐sectional analyses used the 1980 data and the 1990 data separately. Longitudinal analysis used 1980 alcohol consumption and GGT values, and 10‐year FEV1 decline. In both cross‐sectional surveys, elevated alcohol consumption was significantly associated with impaired age‐adjusted and height‐adjusted FEV1. Further adjustment for smoking habit, education level, and asthmatic status did not alter these results. An increase of 25 g/day of alcohol was associated with 50.0 ml (95%confidence interval: 1.5 to 98.5) and 55.3 ml (95% confidence interval: 7.8 to 102.8) decrease of corresponding multivariate‐adjusted FEV1 in 1980 and in 1990, respectively. GGT was also negatively associated with FEV1 in both cross‐sectional surveys. Similar patterns of associations were also observed between vital capacity measurements and alcohol variables. In the longitudinal analysis, there was no relationship between either alcohol consumption or GGT and FEV1 decline. Findings suggest that alcohol consumption was associated with impaired lung function, but there was no evidence of accelerated FEV1 decline over 10 years related to alcohol consumption in this “healthy” population of middle‐aged men.
Serum Markers for Hepatic Fibrosis in Alcoholic Liver Disease: Which Is the Best Marker, Type III Procollagen, Type IV Collagen, Laminin, Tissue Inhibitor of Metalloproteinase, or Prolyl Hydroxylase?
Authors: Tsutsumi Mikihiro , Takase Shujiro , Urashima Sachio , Ueshima Yasuhiro , Kawahara Hiromu , Takada Akira
Published: April 2006

Although various serum markers for the evaluation of hepatic fibrosis have been introduced, it remains unclear which is the best marker to evaluate the hepatic fibrosis observed in alcoholic liver disease (ALD). In this study, we measured serum concentrations of the immunoreactive β‐subunit of prolyl hydroxylase, procollagen type III peptide, the 7s domain (7s‐IV) and triple‐helix domain (TH‐IV) of type IV collagen, laminin, and tissue inhibitor of metalloproteinase (TIMP) in patients with and without ALD (non‐ALD), and controls to evaluate the best serum marker reflecting the characteristic histologic features of ALD. Alter Azan‐Mallory and silver‐impregnated reticulin staining, histologic specimens were examined; and the degree of hepatic fibrosis was classified as mild, moderate, or severe. Although serum concentrations of all markers, except for TIMP, in patients with each type and stage of liver disease were higher than cut‐off values and these concentrations increase with the progression of liver disease, statistical analyses indicate that serum TH‐IV concentration is the best marker to distinguish ALD from non‐ALD. A good correlation was also found between the hepatic type IV collagen content and serum TH‐IV, but not serum 7s‐IV concentration. Moreover, after abstinence from alcohol, serum concentrations of TH‐IV decreased more quickly than other serum markers. These results clearly suggest that, compared with other markers, serum concentration of TH‐IV may more strongly reflect the histologic features of ALD. However, other serum markers, except for TIMP, may be useful in evaluating the degree of hepatic fibrosis.
Genetic Predisposition to Organ‐Specific Endpoints of Alcoholism
Authors: Reed Terry , Page William F. , Viken Richard J. , Christian Joe C.
Published: April 2006

Medical records of the 15,924 twin‐pairs in the National Academy of Sciences‐National Research Council (NAS‐NRC) twin registry were collected for an additional 16 years through 1994 when the surviving twins were aged 67 to 77 years. Compared with earlier analyses (Hrubec, Z., and Omenn, G. S., Alcohol. Clin. Exp. Res., 5:207‐215, 1981), when subjects were aged 51 to 61, there were 23% more diagnoses of alcoholism (34.4 per 1,000 prevalence), 32% more diagnoses of alcoholic psychosis (5.4 per l,000), and 25% more twins with liver cirrhosis (17.7 per 1,000). Overall, 5.3% of the cohort had at least one of the diagnoses related to alcoholism. Probandwise concordance rates (%) were: alcoholism—26.7 monozygotic (MZ), 12.2 dizygotic (DZ) (p < 0.0001); alcoholic psychosis—17.3 MZ, 4.8 DZ (p < 0.05); and cirrhosis—16.9 MZ, 5.3 DZ (p < 0.001). Concordance for any diagnosis related to alcoholism was 30.2 MZ, 13.9 DZ (p < 0.000l). Maximum‐likelihood modeling indicated that ∼50% of the overall variance was due to additive genetic effects; in all diagnosis categories, a totally environmental model gave a significantly poorer fit to the data. Bivariate and trivariate genetic analyses indicated most of the genetic liability for the organ‐specific endpoints of psychosis and cirrhosis was due to the shared genetic liability for alcoholism. Once the shared variance with alcoholism was considered, there was no further shared genetic liability for psychosis and cirrhosis. Our results confirm Hrubec and Omenn's conclusion that there was significantly greater concordance in MZ twins‐pairs for alcoholic psychosis and cirrhosis in the NAS‐NRC twins, and concordance rates remained similar to those reported 16 years earlier. In contrast, we found most of the genetic liability to organ‐specific complications of alcoholism was shared with the genetic liability for alcoholism per se; only a small portion of the genetic variance of the individual complications was independent of the genetic predisposition for alcoholism.
Ethanol‐Induced Change in Cardiac and Endogenous Opiate Function and Risk for Alcoholism
Authors: Peterson J. B. , Pihl R. O. , Gianoulakis C. , Conrod P. , Finn P. R , Stewart S. H. , LeMarquand D. G. , Bruce K. R.
Published: April 2006

Susceptibility to alcoholism varies with age, gender, and familial background. Youthful nonalcoholic males with multigenerational family histories of male alcoholism seem at particular risk. Previous investigations suggest that such males are characterized by abnormal psychophysiological response, while sober and alcohol‐intoxicated; additional recent studies indicate that the endogenous opiate systems are involved in mediating ethanol reinforcement and modulating intake. We first compared cardiac response to alcohol administration among young (mean = 22.8 years), nonalcoholic men and women with multigenerational, unigenerational, and negative family histories of alcohol dependence and abuse. Then, we compared the ethanol‐induced cardiac response of the males in these three groups to that of currently alcohol‐dependent older males and age‐matched nonalcoholic male controls. Finally, we examined ethanol‐induced change in plasma β‐endorphin and cortisol levels among a subset of the nonalcoholic males, divided into those with high and low levels of postethanol administration heart‐rate increase. Nonalcoholic males with multigenerational family histories of male alcoholism were characterized by significantly higher [t(301) = 5.70, p < 0.0001, Cohen's d= 0.73] levels of ethanol‐induced heart‐rate increase than nonalcoholics from all other comparison groups. The magnitude of their increase matched that of current male alcohol‐dependents. Nonalcoholic males with high levels of ethanol‐induced heart‐rate increase also produced significantly more plasma β‐endorphin after consuming alcohol. Peak production of β‐endorphin was highly correlated (r= 0.861, p < 0.001) with magnitude of heart‐rate increase. A subset of those at risk for alcoholism may be characterized by sensitivity to ethanol‐induced reward, marked by heightened ethanol‐induced, heart‐rate increase, mediated by ethanol stimulation of endogenous opiate production. This subset might contain those who, once alcoholic, would differentially benefit from treatment with opiate antagonists.
A PC‐Based Software Test for Measuring Alcohol and Drug Effects in Human Subjects
Authors: Mills K.C. , Parkman K.M. , Spruill S.E.
Published: April 2006

A new software‐based visual search and divided‐attention test of cognitive performance was developed and evaluated in an alcohol dose‐response study with 24 human subjects aged 21–62 years. The test used language‐free, color, graphic displays to represent the visuospatial demands of driving. Cognitive demands were increased over previous hardware‐based tests, and the motor skills required for the test involved minimal eye movements and eye‐hand coordination. Repeated performance on the test was evaluated with a latin‐square design by using a placebo and two alcohol doses, low (0.48 g/kg/LBM) and moderate (0.72 g/kg/LBM). The data on 7 females and 17 males yielded significant falling and rising impairment effects coincident with moderate rising and falling breath alcohol levels (mean peak BrALs = 0.045 g/dl and 0.079 g/dl). None of the subjects reported eye‐strain or psychomotor fatigue as compared with previous tests. The high sensitivity/variance relative to use in basic and applied research, and worksite fitness‐for‐duty testing, was discussed. The most distinct advantage of a software‐based test that operates on readily available PCs is that it can be widely distributed to researchers with a common reference to compare a variety of alcohol and drug effects.