bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship of Light to Moderate Alcohol Consumption and Risk of Hypertension in Japanese Male Office Workers
Authors: Nakanishi Noriyuki , Makino Kae , Nishina Kazue , Suzuki Kenji , Tatara Kozo
Published: April 2006

Background A close relationship between alcohol consumption and hypertension has been established, but the effect of light to moderate alcohol consumption on blood pressure (BP) remains unclear.

Methods A total of 5275 Japanese male office workers aged 23 to 59 years partook in a survey. Subjects were classified as nondrinkers or current drinkers who averaged less than 12, 12 to 22, 23 to 45, or ≥46 g/day of ethanol. BPs were measured at annual health examinations from May 1996 through May 2000. A total of 3784 hypertension‐free (systolic BP <140 mm Hg, diastolic BP <90 mm Hg, no medication for hypertension, and no history of hypertension) men were observed for 4 years. Men in whom hypertension (systolic BP ≥140 mm Hg, diastolic BP ≥90 mm Hg, or both or receipt of antihypertensive medication) was found during repeated surveys were defined as incident cases of hypertension.

Results After controlling for potential predictors of hypertension, systolic and diastolic BP levels and the incidence of hypertension were lowest in nondrinkers in all three age ranges (23–35, 36–47, and 45–59 years) and increased in a dose‐dependent manner as alcohol consumption increased. For individuals aged 23 to 35 years, systolic and diastolic BP levels and the incidence of hypertension were significantly higher among those who drank an average of ≥23 g/day of ethanol than among nondrinkers. For those aged 36 to 59, the diastolic BP level was significantly higher among those who drank any alcohol at all than among nondrinkers, and the systolic BP level and the incidence of hypertension were significantly higher among those who drank an average of ≥12 g/day of ethanol than among nondrinkers.

Conclusions Light to moderate alcohol consumption seems to have an important influence on BP in both young and middle‐aged Japanese men.
Alterations in Insulin‐Like Growth Factor‐I Signaling in Cardiomyocytes From Chronic Alcohol‐Exposed Rats
Authors: Pecherskaya Anna , Rubin Emanuel , Solem Michele
Published: April 2006

Background Insulin‐like growth factor‐I (IGF‐I) is a required cytokine for the development and maintenance of the cardiovascular system, and it may play a role in certain pathophysiological conditions.

Methods Adult male rats were fed a liquid diet that contained 36% alcohol for 4 to 8 months, and their littermates served as isocaloric pair‐fed controls, so we could examine IGF‐I signaling in rat cardiomyocyte preparations.

Results Recently, our laboratory reported that IGF‐I activates protein kinase‐C (PKC)‐α and that PKC‐α activity is required for IGF‐I‐dependent activation of Erk1/Erk2 and IGF‐I‐dependent protein synthesis. But in chronic alcohol‐exposed rats, there is loss of PKC‐α activation by IGF‐I, represented as a reduction in PKC‐α translocation to the membrane. In reverse transcription‐polymerase chain reaction experiments, both the alcoholic and control animals expressed the IGF‐I receptor (IGF‐1R, α subunit) and IGF‐I mRNAs in approximately equal amounts. However, in the alcoholic cardiomyocyte protein preparations, there was a higher basal level of IGF‐1R autophosphorylation of its internal tyrosine kinase domain, and IGF‐I‐activated autophosphorylation was reduced in the alcoholic protein preparations. Previously, we have demonstrated that acute IGF‐I exposure enhances the rate of Mn2+ influx through activated nitrendipine‐sensitive cardiac Ca2+ channels, and that this enhancement of channel activity is PKC‐dependent. Here, we report that in alcohol‐exposed myocytes, IGF‐I‐induced augmentation of the cardiac Ca2+ channel activity was absent. IGF‐I increased the rate of protein synthesis in the control animals by 56% as determined in protein synthesis experiments that measured the rate of 14C‐L‐phenylalanine incorporation over time, and this effect was blocked by preincubation with Gö6976, a specific inhibitor of PKC‐α. However, in the alcohol‐exposed cardiomyocytes, IGF‐I did not increase the rate of protein synthesis.

Conclusion These results suggest that IGF‐I‐dependent PKC‐α activation and IGF‐I‐dependent protein synthesis are altered in the hearts of chronic alcohol‐exposed rats. This may be the result of the IGF‐1R being in a chronically activated state, and it may alter the normal function of PKC‐α.
Melatonin (an Antioxidant) Does Not Ameliorate Alcohol‐Induced Purkinje Cell Loss in the Developing Cerebellum
Authors: Edwards Russell B. , Manzana Ehrine J. P. , Chen Wei‐Jung A.
Published: April 2006

Background One popular mechanism proposed to account for alcohol‐induced brain damage is the generation of free radicals after alcohol exposure. Therefore, it is reasonable to hypothesize that administration of an antioxidant should reduce the severity of alcohol‐induced brain damage. Recently, melatonin has been shown to be an effective free‐radical scavenger. In this study, the ability of melatonin to attenuate alcohol‐induced cerebellar Purkinje cell loss in the cerebellar vermis and lobule I was assessed.

Methods Sprague‐Dawley rat pups were used in this study. These neonatal pups were exposed to alcohol (4.5 g/kg), melatonin (10 mg/kg), both alcohol and melatonin, or control vehicle via artificial‐rearing methods from postnatal day (PD) 4 to PD 9. Alcohol, melatonin, or control vehicle was mixed with milk formula in 2 of the daily 12 feedings. Pups were killed 90 min after the beginning of the second alcohol feeding on PD 9.

Results Alcohol significantly reduced the Purkinje cell numbers in the vermis and lobule I, with a higher percentage of cell loss in lobule I compared with the vermis. However, melatonin, per se, neither affected the Purkinje cell number nor diminished alcohol‐induced Purkinje cell loss.

Conclusions Melatonin was not effective in attenuating alcohol‐induced loss of Purkinje cells in our neonatal rat model system, even though such a dosage of melatonin is capable of reversing free radical–induced damage in other tissues.
Increased Ethanol Excitation of Dopaminergic Neurons of the Ventral Tegmental Area After Chronic Ethanol Treatment
Authors: Brodie Mark S.
Published: April 2006

Background The mesolimbic dopamine pathway, which originates in the ventral tegmental area (VTA), is important for the rewarding effects of ethanol. Acute administration of ethanol has been shown to excite dopaminergic neurons of the VTA. Chronic ethanol treatment has been reported to alter the in vitro response of dopaminergic neurons to NMDA and dopamine. The present electrophysiological study tested the hypothesis that the effect of ethanol, γ‐aminobutyric acid (GABA), and NMDA on individual dopaminergic VTA (DA‐VTA) neurons from C57BL/6J mice would be changed by chronic treatment with ethanol.

Methods C57BL/6J mice were injected intraperitoneally twice daily with either saline or ethanol in saline (3.5 g/kg) for at least 21 days. Extracellular single unit recordings of spontaneous action potentials were made from DA‐VTA neurons in brain slices from these mice. Ethanol (20–120 mM), GABA (50–500 μM), or NMDA (2–20 μM) was administered in the superfusate, and the resulting change in firing rate was measured.

Results There was no significant difference in mean basal spontaneous firing rate of DA‐VTA neurons between saline‐treated and ethanol‐treated mice. The DA‐VTA neurons from ethanol‐treated mice were excited by ethanol more potently than those from saline‐treated mice. Dopaminergic VTA neurons from ethanol‐treated mice were inhibited less potently by GABA than those from saline‐treated mice. There was no difference in the potency of NMDA to excite DA‐VTA neurons from saline‐treated and ethanol‐treated mice.

Conclusions Chronic treatment of C57BL/6J mice with ethanol injections sensitizes DA‐VTA neurons to ethanol excitation and also decreases the inhibitory potency of GABA. The increase in sensitivity to ethanol excitation of dopaminergic VTA neurons after chronic ethanol treatment may increase the reward value of ethanol. This sensitization to ethanol activation may be an important change in reward area neurons and may contribute to the development of alcoholism.
Laboratory Tests for Acute Alcohol Consumption: Results of the WHO/ISBRA Study on State and Trait Markers of Alcohol Use and Dependence
Authors: Helander Anders , Eriksson C. J. Peter
Published: April 2006

Background The WHO/ISBRA Study on State and Trait Markers of Alcohol Use and Dependence aimed partly to evaluate the overall performance and cross‐national validity of traditional and new biological markers of alcohol use and abuse. This article focused on the sensitivity and specificity of ethanol and methanol concentrations in plasma, and the 5‐hydroxytryptophol (5HTOL) to 5‐hydroxyindole‐3‐acetic acid (5HIAA) ratio in urine, as laboratory tests to identify acute alcohol consumption. Comparison was made with self‐reported drinking levels.

Methods Subjects were recruited in Australia, Brazil, Canada, Finland, and Japan. They were interviewed thoroughly about their alcohol consumption habits, by using the standardized WHO/ISBRA Interview Schedule, and were classified into four categories: nondrinkers, light/moderate drinkers, heavy drinkers (≥210 g ethanol/week for men, and ≥140 g/week for women), or patients who were receiving treatment for alcohol dependence. Ethanol and methanol determinations in plasma were carried out by headspace gas chromatography. Urinary concentrations of 5HTOL and 5HIAA were determined by using gas chromatography‐mass spectrometry and high‐performance liquid chromatography, respectively.

Results The baseline levels (in nondrinkers) for methanol and the 5HTOL/5HIAA ratio did not differ markedly between the five populations, except for a considerably higher, but probably artifactual, methanol level in the Finnish plasma samples. Moreover, there were no apparent age or sex differences. The urinary 5HTOL/5HIAA ratio was the most, and ethanol the least, sensitive indicator of recent alcohol consumption, and this was true for the different drinking categories as well as for the five study populations. The highest frequency of elevated test results was observed among those classified as heavy drinkers (e.g., 38% were positive for 5HTOL/5HIAA). However, elevated values also were obtained in nondrinkers and in drinking subjects who denied any intake of alcohol within 2 days before the interview and blood/urine sampling, which suggested a low accuracy of self‐reports of alcohol consumption in certain individuals.

Conclusions The present investigation demonstrated that plasma ethanol and methanol and urinary 5HTOL/5HIAA provide useful exclusion markers for any study of biological parameters that are affected by previous acute ethanol intoxication. The major advantage of methanol and 5HTOL/5HIAA over ethanol is that they can detect recent alcohol consumption even several hours after the ethanol is no longer measurable. The results suggest that the cutoff limits to be used for these markers are not dependent on the country or population to be studied.
Platelet Adenylyl Cyclase Activity as a State or Trait Marker in Alcohol Dependence: Results of the WHO/ISBRA Study on State and Trait Markers of Alcohol Use and Dependence
Authors: Hoffman Paula L. , Glanz Jason , Tabakoff Boris
Published: April 2006

Background There has been considerable interest in identifying biochemical markers indicative of a genetic predisposition to alcohol dependence (“trait markers”), as well as biochemical markers of recent alcohol drinking (“state markers”). Platelet adenylyl cyclase activity has been suggested as a trait and/or as a state marker related to alcohol dependence. We have now measured platelet adenylyl cyclase activity in more than 1400 well‐characterized subjects, which allows us to investigate the influence of a broad range of factors on this activity.

Methods Subjects were recruited as part of the WHO/ISBRA Study on State and Trait Markers of Alcohol Use and Dependence and were interviewed by using the WHO/ISBRA Interview Schedule. Adenylyl cyclase activity (basal, cesium fluoride [CsF]‐, forskolin‐ and Gpp(NH)p‐stimulated activities) was measured in platelet samples that were obtained at the time of interview. Data were analyzed by multivariate regression analyses.

Results The multivariate analyses revealed that recent abstinence from alcohol was associated with diminutions in platelet adenylyl cyclase activities. A positive family history of alcohol dependence was associated with higher levels of adenylyl cyclase activities, and there was a significant interaction between the effect of alcohol consumption in the past month and family history of alcohol dependence; that is, the influence of alcohol consumption depended on whether the individual had a positive family history. A history of marijuana abuse also was associated with higher levels of platelet adenylyl cyclase activities, and a history of major depression was associated with lower levels of forskolin‐ and CsF‐stimulated activities. Sex, race, and site of recruitment also affected some adenylyl cyclase activities, but there was no significant association of alcohol dependence or abuse with any of the platelet adenylyl cyclase activities.

Discussion The large population and extensive characterization of subjects in this study provided an advantage over previous studies in which only the association of a few individual factors with adenylyl cyclase activity was investigated. The results demonstrate that although platelet adenylyl cyclase activity could be useful as a trait marker of alcohol dependence, its reliability in this regard is diminished by the influence of recent alcohol drinking and other variables. The associations between platelet adenylyl cyclase activities and marijuana abuse, as well as a history of depression, suggest that it may be worthwhile to study the genetic association of adenylyl cyclases (e.g., polymorphisms in the genes that code for particular adenylyl cyclase isoforms) with a predisposition to depression as well as to alcohol or marijuana abuse/dependence.
Differences in the Responses of the Pituitary β‐Endorphin and Cardiovascular System to Ethanol and Stress as a Function of Family History
Authors: Dai Xing , Thavundayil Joseph , Gianoulakis Christina
Published: April 2006

Background Genetic and environmental factors, such as stress, are important for the initiation and maintenance of heavy drinking, whereas β‐endorphin may be important in controlling alcohol consumption. These studies investigated the response of pituitary β‐endorphin to stress and the effect of alcohol on the stress response in subjects at low (LR) and high (HR) risk of alcoholism, as determined from their family history.

Methods Twenty LR and 20 HR subjects were exposed to stress 30 min after ingestion of either a placebo or an alcohol drink. Plasma β‐endorphin was measured before and for 4 hr after the drink. Changes in the concentration of plasma β‐endorphin after ingestion of the placebo or alcohol drink alone served as controls to compare the stress‐induced changes. Pulse and diastolic and systolic blood pressure were also measured.

Results HR subjects presented higher baseline values of pulse and systolic blood pressure and lower plasma β‐endorphin than LR subjects. Stress induced a small increase in cardiovascular activity, whereas alcohol induced a stronger stimulation. Alcohol before stress did not prevent the stress‐induced increase in cardiovascular activity. Stress, but not alcohol, increased the plasma β‐endorphin concentration. LR subjects presented a higher stress‐induced increase in plasma β‐endorphin and a faster recovery than HR subjects. Alcohol before stress attenuated the stress‐induced increase in plasma β‐endorphin in both LR and HR subjects. This attenuation was stronger in LR subjects.

Conclusions Thus, there are differences in the response of β‐endorphin to stress and the effect of ethanol on stress responses as a function of a family history of alcoholism.
An Evaluation of Relations Among Antisocial Behavior, Psychopathic Traits, and Alcohol Problems in Incarcerated Men
Authors: Reardon Maureen Lyons , Lang Alan R. , Patrick Christopher J.
Published: April 2006

Background The association between antisocial behavior and alcohol problems is well established, but the role that psychopathic traits and other factors such as drinking patterns and motives and family history play in this relationship has not been subjected to much empirical scrutiny.

Methods A large sample (n= 329) of male Federal Correctional Institution inmates participated in structured interviews designed to permit diagnosis of antisocial personality disorder and to assess facets of psychopathic personality as defined by the Hare Psychopathy Checklist–Revised. Prisoners also completed self‐report questionnaires that addressed alcohol use, drinking problems, motives for drinking, and paternal alcoholism history.

Results Analyses revealed that the relation between antisocial behavior and alcohol problems was moderated by scores on the emotional detachment component of psychopathy, and that self‐descriptions of drinking for the purpose of coping with negative emotions mediated the positive relation between antisociality and self‐reported alcohol problems.

Conclusions These findings highlight complexities in the link between antisociality and drinking problems and encourage consideration of distinct facets of psychopathy to enhance understanding of it. They further suggest possible mechanisms (e.g., paternal alcoholism history, coping motives) that may contribute to the development and maintenance of alcohol problems in criminal populations.
Cortisol Dysregulation and Cognitive Impairment in Abstinent Male Alcoholics
Authors: Errico Austin L. , King Andrea C. , Lovallo William R. , Parsons Oscar A.
Published: April 2006

Background Alcoholics have impaired cortisol response to stress, indicating dysregulation in the extrahypothalamic systems responsible for activating cortisol secretion in response to stressor exposure. There is a growing literature indicating a relationship between hypothalamic‐pituitary‐adrenocortical axis activity and neurocognitive functioning. This study examined the hypothesis that dysregulation of the hypothalamic‐pituitary‐adrenocortical axis may be associated with some neuropsychological impairments in alcoholics.

Methods Serum cortisol was obtained during cognitive testing and after exposure to cold pressor and mental arithmetic stress in 48 male alcoholics abstinent for 32 ± 6.7 days and in 30 controls; cortisol was also obtained from 18 of the alcoholic patients during withdrawal. Neurocognitive tasks included the Wechsler Memory Scale and Wisconsin Card Sorting Test. Relationships among alcoholics’ cognitive test scores, cortisol levels, and drinking practices were examined by correlation and regression analyses.

Results Verbal memory deficits were more severe in alcoholics who had more withdrawals and ingested a higher typical quantity of alcohol during the prior year (p < 0.05). Higher levels of cortisol during withdrawal, an index of withdrawal severity, were associated with more errors on the Wisconsin Card Sorting Test (p < 0.005). As previously reported, the alcoholics had lower cortisol levels after stress compared with controls. Lower poststress cortisol levels were associated with poorer logical memory on the Wechsler Memory Scale and more errors on the Wisconsin Card Sorting Test (p < 0.05). Among controls, memory deficits occurred only in relation to higher poststress cortisol levels.

Conclusions Poorer cognitive performance in alcoholics was related to more withdrawals, heavier alcohol consumption, and higher cortisol levels during a recent withdrawal. Alcoholics’ cognitive impairment was also related to attenuated stress cortisol responses. Altered stress regulation of the hypothalamic‐pituitary‐adrenal axis should be studied further as a potential factor related to impaired cognitive function in recovering alcoholics.
Co‐occurrence of Obsessive‐Compulsive Personality Traits in Young and Middle‐Aged Japanese Alcohol‐Dependent Men
Authors: Suzuki Kenji , Muramatsu Taro , Takeda Aya , Shirakura Katsuyuki
Published: April 2006

Background Previous studies may have underestimated the potential importance of the prevalence of obsessive‐compulsive traits among persons with alcoholism. Although many studies have examined the characteristics of young alcoholics compared with middle‐aged alcoholics, none has compared the prevalence of obsessive‐compulsive traits in young and middle‐aged alcoholics.

Methods This study compared the prevalence of obsessive‐compulsive traits (Leyton Obsessional Inventory) and depressive symptoms (Zung Self‐Rating Depression Scale) among young (n= 41) and middle‐aged (n= 34) hospitalized Japanese male alcoholics and in young (n= 28) and middle‐aged (n= 25) nonalcoholic subjects.

Results Both young and middle‐aged male alcoholics reported more obsessive‐compulsive personality traits and depressive symptoms than their comparison groups. However, the alcoholic subjects’ obsessive‐compulsive personality traits were not related to their level of depressive symptoms.

Conclusions Young and middle‐aged male Japanese alcoholics have more obsessive‐compulsive personality traits than nonalcoholic males of similar ages. Their alcohol‐related psychological and behavioral characteristics may derive, in part, from their obsessive‐compulsive symptoms.
Coping Among Individuals Seeking Private Chemical Dependence Treatment: Gender Differences and Impact on Length of Stay in Treatment
Authors: Kohn Carolynn S. , Mertens Jennifer R. , Weisner Constance M.
Published: April 2006

Background Length of stay in treatment and coping skills are both predictive of chemical dependence and abuse treatment outcomes. However, little is known about whether coping strategies are related to length of stay in treatment. Because predictors of length of stay in treatment vary by gender, it also may be reasonable to expect gender differences in coping strategies as well as in the relationship between coping and LOS in treatment.

Methods We examined gender differences in baseline coping strategies, and coping strategies as predictors of length of stay in treatment, among 747 (433 men, 314 women) individuals who entered chemical dependence and abuse treatment in a private, managed care facility.

Results Women reported using more emotional discharge (behavioral attempts to reduce tension by expression of negative feelings), cognitive avoidance (cognitive attempts to avoid thinking realistically about the problem), resigned acceptance (cognitive attempts to react to the problem by accepting it), and seeking support/guidance (behavioral attempts to seek information, guidance, or support). Gender differences for emotional discharge disappeared after we controlled for depressive symptom and drug problem severities. Greater use of seeking alternative rewards (behavioral attempts to get involved in substitute activities and create new sources of satisfaction), less use of emotional discharge, and older age were significant predictors of longer length of stay, with no gender differences found.

Conclusions This study provides evidence for identifying and decreasing the use of emotional discharge early in treatment, possibly through the use of intervention strategies such as anger management, cognitive restructuring, or motivational interviewing, as well as encouraging an increase in participation in alternative activities.
Serum Sialic Acid as a Marker of Alcohol Consumption: Effect of Liver Disease and Heavy Drinking
Authors: Romppanen Jarkko , Punnonen Kari , Anttila Petra , Jakobsson Tuula , Blake Joan , Niemelä Onni
Published: April 2006

Background Serum sialic acid (SA) has been suggested as a new marker of alcohol consumption. There are, however, only a few studies on the clinical value of such measurements. The relationship between serum SA and liver disease is also unknown.

Methods We determined serum SA concentrations in a sample of 51 alcoholics and 20 healthy controls by using high‐performance liquid chromatography with an anion‐exchange column and pulsed amperometric detection. The alcoholic sample included 32 patients with liver disease, the severity of which was assessed by previously established combined clinical, laboratory, and morphological indices. In addition, there were 19 heavy drinkers without significant liver disease despite a well documented history of excessive alcohol consumption.

Results The (mean ± SD) SA concentrations (1.449 ± 0.3019 mmol/liter) were significantly higher in the alcoholics than in the healthy controls (1.154 ± 0.1702 mmol/liter). With the optimal cutoff limit for serum SA (1.425 mmol/liter), a specificity of 1.00 and sensitivity of 0.51 were obtained. The diagnostic accuracy of serum SA according to receiver operating characteristic analysis was good, with the area under the curve being 0.805 (0.052). Unlike the traditional serum markers of alcohol consumption (γ‐glutamyl transferase, carbohydrate‐deficient transferrin, and aspartate amino transferase), serum SA was not found to be different between the alcoholics with or without liver disease.

Conclusions Our study suggests that serum SA is a sensitive marker of excessive alcohol consumption. Such measurements may also prove to be of value in conditions in which the results of the traditional markers reflect the severity of liver disease rather than alcohol consumption.
Accentuated Decrease in Social Interaction in Rats Subjected to Repeated Ethanol Withdrawals
Authors: Overstreet David H. , Knapp Darin J. , Breese George R.
Published: April 2006

Background Previous work has shown that repeated withdrawals from chronic ethanol exposure can kindle seizures in rodents. In this article, the effects of a three‐cycle model of ethanol exposure and withdrawal on the social interaction test of anxiety are summarized.

Methods Rats were exposed to ethanol (7% or 4.5%) diets over three periods of 5 days, with 2 days of withdrawal between cycles. Between 5 and 6 hr after the ethanol was removed, pairs of rats were placed in open field chambers for the assessment of social interaction behavior and locomotor activity.

Results After the third cycle of ethanol (7%) presentation, both male and female rats exhibited lower social interaction behavior (more anxiety) and activity than after a single cycle. Rats exposed to a similar amount of ethanol but tested while ethanol was still available did not exhibit a reduction in social interaction. The decrease in social interaction was still present for up to 24 hr but had disappeared by 48 hr after ethanol was withdrawn. When rats were allowed 8 or 16 days to recover from the effects of the three‐cycle protocol, a further exposure to 5 days of 7% ethanol diet resulted in a reduction in social interaction on withdrawal similar to that seen from the three‐cycle protocol. In contrast, rats exposed continuously to 7% ethanol diet for 15 consecutive days exhibited higher levels of social interaction when maintained on control diet for 8 or 16 days and then reexposed to ethanol. Rats that were exposed to the three‐cycle protocol and allowed 32 days to recover before being reexposed to ethanol still had a partial deficit in social interaction. Finally, animals subjected to repeated withdrawals from 4.5% ethanol exhibited a reduction in social interaction without a change in activity after the final withdrawal from ethanol, whereas rats exposed continuously to a 4.5% ethanol diet did not exhibit a reduction in social interaction or activity. Neither blood ethanol concentrations nor changes in body weight could account for these behavioral differences.

Conclusion Repeated withdrawal from ethanol can lead to accentuated or more persistent anxiety‐like behavior in rats, as indicated by a decrease in social interaction. The withdrawal‐induced decrease in locomotor activity is not accentuated by repeated withdrawals. This model of repeated withdrawals from ethanol may prove useful in defining the neurochemical basis of this accentuation.
Brain Catalase Inhibition Blocks Ethanol‐Related Decrease of Blood Luteinizing Hormone Levels in Mice
Authors: Sanchis‐Segura Carles , Aragon Carlos M. G.
Published: April 2006

Background It has been demonstrated that ethanol decreases blood luteinizing hormone (LH) levels in rodents. This effect seems to be produced by the capacity of ethanol to release β‐endorphins from the hypothalamic arcuate nucleus and, in a second step, by a μ‐receptor–mediated inhibitory effect of these peptides on hypothalamic LH‐releasing hormone‐synthesizing neurons. However, it has been reported that, in primary hypothalamic cultures, the ethanol‐produced β‐endorphin release is mediated by the enzyme catalase. Therefore, the aim of this study was to assess whether catalase inhibition modifies ethanol effects on blood LH levels.

Methods Swiss albino mice were pretreated with the catalase inhibitor 3‐amino‐1,2,4‐triazole (AT; 0.0–0.5 g/kg) and, 3.5 hr later, saline, ethanol (2.5 g/kg), or morphine (30 mg/kg) was administered. Blood samples were collected 2 hr after ethanol administration, and LH levels were immunoenzymatically assayed.

Results The catalase inhibitor AT dose‐dependently blocked the ethanol‐produced decrease in blood LH levels without altering those observed after saline or morphine administration. This effect was highly correlated with the decrease in brain catalase activity produced by AT.

Conclusions These results show an antagonistic effect between AT and ethanol on blood LH levels and suggest a role of brain catalase activity on this effect of ethanol. Data are discussed in terms of a possible functional relationship between brain catalase and β‐endorphins in the mediation of some of the psychopharmacological consequences observed after ethanol administration.
Effect of Forward and Reverse Selection for Ethanol‐Induced Locomotor Response on Other Measures of Ethanol Sensitivity
Authors: Palmer Abraham A. , Phillips Tamara J.
Published: April 2006

Background Ethanol sensitivity may be a predictor of genetic predisposition to ethanol abuse. To examine ethanol sensitivity in rodents, two lines of mice were bred in replicate for high (FAST‐1 and ‐2) and low (SLOW‐1 and ‐2) locomotor stimulant responses to ethanol. After large differences between the lines developed and further response to selection seemed to have arrested, reverse selection was initiated by breeding the slowest FAST mice with each other and the fastest SLOW mice with each other. The reverse‐selected lines, named r‐FAST and r‐SLOW, were virtually equally sensitive to the stimulant effects of the selection dose of ethanol after 16 generations of reverse selection.

Methods These experiments used this unique genetic model to examine two responses, putatively genetically correlated with sensitivity to ethanol stimulation: handling‐induced convulsions during chronic ethanol withdrawal, and ethanol‐induced hypothermia. Ethanol clearance, for which a small difference was previously found between the FAST and SLOW lines, was also examined.

Results Handling‐induced convulsions during chronic ethanol withdrawal were significantly greater in both FAST lines compared with both SLOW lines. Reverse selection eliminated the difference between the replicate 1 lines but did not alter the difference between the replicate 2 lines. Ethanol‐induced hypothermia was greater in both SLOW lines compared with the FAST lines. This difference was significantly reduced by reverse selection in r‐SLOW mice only. Ethanol clearance rates were similar among all lines and replicates.

Conclusions These data demonstrate the usefulness of reverse‐selected lines for examining putatively genetically correlated traits. Changes in the correlated traits demonstrated the existence of persistent trait‐relevant genetic heterogeneity and some genetic overlap between the correlated traits and the selection trait. Absence of a change after reverse selection suggests that trait‐relevant genetic heterogeneity was eliminated by forward selection or, alternatively, that the trait was not influenced by genes associated with successful reverse selection.
Women Who Marry Men With Alcohol‐Use Disorders
Authors: Schuckit Marc A. , Smith Tom L. , Eng Mimy Y. , Kunovac Jelena
Published: April 2006

Background Women who marry men with alcohol‐use disorders (AUDs) might have unique characteristics that could affect the clinical course of their partner's AUD and the risk for problems in the offspring. Most data available on spouses of such men come from subjects in treatment, which might bias results to more severely impaired individuals. Our data were gathered as part of a prospective study of an original sample of 453 sons of alcoholics and controls who were originally selected as students or nonacademic staff at a university.

Methods Personal interviews were performed with 327 women who were married to men who had been personally evaluated on multiple occasions over the prior 15 years. The data compare characteristics of the 235 women (71.9%) whose husbands had never developed alcohol abuse and dependence with the 92 (28.1%) for whom these disorders had been documented.

Results The women who married men with an AUD were less likely to be homemakers, were more likely to meet criteria for alcoholism (especially abuse) themselves, were more likely to report use of illicit substances, and to be current smokers. However, spouses of men with AUDs in this highly functional sample had no higher risk for other major psychiatric disorders and did not report a higher rate of alcohol abuse or dependence or psychiatric conditions in their parents.

Conclusions The results demonstrate increased risks for the use of illicit substances and for AUDs in women married to alcoholics, despite the overall high level of functioning of the sample. This information may be relevant to enhancing our understanding of the environment in which their offspring are being raised. The descriptive aspects of the work might also help researchers and clinicians working with alcoholic families.
Alcohol Consumption and Incidence of Workers’ Compensation Claims: A 5‐Year Prospective Study of Urban Transit Operators
Authors: Ragland David R. , Krause Niklas , Greiner Birgit A. , Holman Barbara L. , Fisher June M. , Cunradi Carol B.
Published: April 2006

Background Numerous studies have linked alcohol impairment on the job to occupational injury. Few studies have looked at the association of nonwork drinking and occupational injury.

Methods This study examines first workers’ compensation claims after a baseline assessment of alcohol consumption and other occupational variables in 1836 transit operators participating in a medical examination for driver's license renewal. A proportional hazard model was used for the analysis.

Results Individuals with higher alcohol consumption were more likely to be male, have more years of driving, and have a higher job‐stress score. When these variables were controlled for, individuals with higher alcohol consumption were more likely to have a workers’ compensation claim over the follow‐up period. Individuals reporting a consumption of 10 to 14 drinks per week had a hazard of 1.30 (p= 0.03), and those reporting 15 or more drinks per week had a hazard of 1.27 (p= 0.05) compared with individuals reporting no drinks consumed per week.

Conclusions This study indicates that drinking off the job is associated with workers’ compensation injury claims. Because it is presumed that most drinking was done outside work, due to high public scrutiny of city transit operators, these results suggest that experience in life outside of work may influence work outcomes. Research should be conducted to identify the mechanisms (e.g., drinking before work, hangover, fatigue) of such effects.
Mouse Cerebellar Adenosine‐Glutamate Interactions and Modulation of Ethanol‐Induced Motor Incoordination
Authors: Dar M. Saeed
Published: April 2006

Background It was demonstrated previously that cerebellar adenosine modulates ethanol‐induced motor incoordination via A1 subtype of adenosine receptors. Several reports suggest the involvement of brain glutamate mechanisms, in particular N‐methyl‐d‐aspartate (NMDA) receptor sites, in the central nervous system (CNS) actions of ethanol. Mutually antagonistic functional responses as a result of glutamate and adenosine within the brain regions have also been well documented.

Methods With the use of rotorod performance as the test response, this study was conducted to evaluate possible functional interactions between cerebellar adenosine and glutamate and its consequence on ethanol‐induced motor incoordination. Except for ethanol, which was injected intraperitoneally, all drugs used were microinfused directly into the cerebellum.

Results Direct intracerebellar microinfusion of glutamate (125, 250, and 500 ng) and the antagonist l‐glutamic acid diethyl‐ester (125, 250, and 500 ng) markedly and dose‐dependently attenuated and accentuated, respectively, ethanol‐induced motor incoordination, suggesting an involvement of glutamate. Subsequently, intracerebellar microinfusions of NMDA (125, 250, and 500 ng) and its antagonists AP‐5 [(+)‐2‐amino‐5‐phosphoropentanoic acid; 125, 250, and 500 ng] and (+)‐MK‐801 [(+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a. d]‐cyclo‐hepten‐5,10‐imine hydrogen maleate; 25, 50, and 100 ng] significantly attenuated and accentuated, respectively, ethanol‐induced motor incoordination in a dose‐related manner, indicating participation of NMDA receptor. The attenuation of ethanol‐induced motor incoordination by glutamate and NMDA was receptor mediated as it was antagonized by their receptor antagonists. Adenosine A1‐selective agonist N6‐cyclohexyladenosine and antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine functionally opposed the attenuation by glutamate and NMDA and the accentuation by L‐glutamic acid diethyl‐ester, AP‐5, and (+)‐MK‐801, respectively, of ethanol‐induced motor incoordination.

Conclusions These results suggest a functional antagonism between glutamate NMDA and adenosine A1 receptors exhibiting a co‐modulation of ethanol‐induced motor incoordination within the cerebellum.
Ethanol Induces Hyperprolactinemia by Increasing Prolactin Release and Lactotrope Growth in Female Rats
Authors: De Alok , Boyadjieva Nadka , Oomizu Souichi , Sarkar Dipak K.
Published: April 2006

Background Alcohol drinking is known to cause hyperprolactinemia in both humans and laboratory animals. The mechanism by which alcoholism causes hyperprolactinemia is not known. This study investigated whether increased pituitary production of prolactin, which leads to alcohol‐induced hyperprolactinemia, results from an increase in cell number and/or cell production of prolactin in the pituitary.

Methods The effects of ethanol on lactotropes were determined in vivo using female rats as an animal model and in vitro using primary cultures of mixed rat anterior pituitary cells and enriched lactotropes. In vivo experiments involved administration of ethanol for 2 and 4 weeks using a liquid diet containing 8.7% ethanol (v/v), which provides 37% of the calories in cyclic, ovariectomized, and estradiol‐17β–treated ovariectomized Fischer‐344 rats. The control group was pair‐fed an isocaloric diet minus the ethanol or fed a normal diet ad libitum. These animals were used to determine ethanol's effects on plasma prolactin levels, pituitary wet weights, pituitary total protein levels, and the number of mitotic lactotropes. In vitro studies determined ethanol's effects in the presence and absence of estradiol on prolactin release and lactotropic cell proliferation. Prolactin levels in plasma and media samples were measured using radioimmunoassay. Mitotic lactotropes were determined using bromodeoxyuridine incorporation assay.

Results Ethanol treatment increased in a time‐dependent manner the plasma levels of prolactin in cyclic, ovariectomized, and estradiol‐treated ovariectomized rats. Ethanol treatment also increased pituitary wet weight and/or pituitary total protein levels and DNA synthesis in lactotropes. Determination of ethanol's action on lactotropic cell proliferation and hormone secretion in vitro using primary cultures of mixed pituitary cells revealed that ethanol stimulated both basal and estradiol‐induced prolactin secretion and lactotropic cell proliferation. When ethanol's actions were studied in isolated lactotropes, ethanol alone or in combination with estradiol stimulated prolactin secretion but failed to increase lactotropic cell proliferation.

Conclusions These results suggest that ethanol causes hyperprolactinemia by elevating prolactin release from lactotropes and by increasing the number of lactotropes in the anterior pituitary gland. The mitotic action of ethanol requires cell–cell communication between lactotropes and other pituitary cells. Furthermore, ethanol's mode of action on prolactin release and lactotrope growth is similar to that observed for estradiol.
Kinetics of HDL Cholesterol and Paraoxonase Activity in Moderate Alcohol Consumers
Authors: Sierksma Aafje , van der Gaag Martijn S. , van Tol Arie , James Richard W. , Hendriks Henk F. J.
Published: April 2006

Background The inverse association between moderate drinking and coronary heart disease mortality is well established. This study was performed to investigate the kinetics of the alcohol‐induced increases in apo A‐1, HDL cholesterol, and paraoxonase (PON) activity, as well as to study whether the alcohol‐induced increases in PON activity differ within different PON polymorphisms, and to investigate whether moderate alcohol consumption has similar effects on the outcome measures in postmenopausal women as in middle‐aged men.

Methods In a randomized, diet‐controlled, crossover study, 10 middle‐aged men and 9 postmenopausal women, all apparently healthy, nonsmoking, and moderate alcohol drinkers, consumed beer or no‐alcohol beer (control) with evening dinner during two successive periods of 3 weeks. During the beer period, alcohol intake equaled 40 and 30 g/day for men and women, respectively. The total diet was supplied to the subjects and had essentially the same composition during these 6 weeks. Before each treatment was a 1‐week washout period, in which the subjects were not allowed to drink alcoholic beverages.

Results Moderate alcohol consumption significantly increased serum apo A‐I level after 5 days (3.7%, p < 0.05); after 10 days, serum HDL cholesterol level was increased (6.8%, p < 0.001), and after 15 days serum PON activity was increased (3.7%, p < 0.05), all compared with no alcohol consumption. Gene polymorphisms did not modulate the alcohol effect on PON.

Conclusions Serum apo A‐I, HDL cholesterol, and PON activity were significantly increased during 3 weeks of moderate alcohol consumption as compared with no alcohol consumption. Moreover, the results suggest that there is a sequence in induction of these parameters. After an increase in apo A‐I, HDL cholesterol is increased followed by an increase in PON activity. Increased serum HDL cholesterol level and PON activity may be a mechanism of action not only in healthy middle‐aged men but also in postmenopausal women, underlying the reduced coronary heart disease risk in moderate drinkers.
Place Conditioning: What Does It Add to Our Understanding of Ethanol Reward?
Authors: Risinger Fred O. , Cunningham Christopher L. , Bevins Rick A. , Holloway Frank A.
Published: April 2006

This article describes the proceedings of a symposium at the 2001 RSA annual meeting in Montreal, Quebec, Canada. The cochairs were Fred O. Risinger and Christopher L. Cunningham. Presentations were as follows: (1) Place conditioning: understanding the motivational impact of stimuli, by Rick A. Bevins; (2) Role of historical factors in ethanol place conditioning, by Frank A. Holloway; (3) Ethanol place conditioning in mice: genetic and environmental influences, by Christopher L. Cunningham; and (4) Utilization of place conditioning for understanding the neuropharmacology of the rewarding effects of ethanol, by Fred O. Risinger.
Role of Endotoxin in NF‐κB Activation by Ethanol in Rat Hepatocytes
Authors: Matsumoto Hiroshi , Sato Yasuhiro , Azumi Junichi , Kato Junji , Niitsu Yoshiro , Tamaki Keiji
Published: April 2006

Background Endotoxin plays an important role in the progression of alcoholic liver injury. However, the role of endotoxin in acute activation of NF‐κB by ethanol remains unclear.

Methods In primary rat hepatocyte cultures treated with ethanol and/or endotoxin, the DNA‐binding activity of NF‐κB in the nuclear extract was estimated by electrophoretic mobility shift assay. After pretreatment of a CYP2E1 inhibitor, 4‐methyl pyrazole or diallyl sulfide, NF‐κB activity was also measured in the same manner.

Results Ethanol or endotoxin caused activation of NF‐κB in primary rat hepatocytes. Taking 50 mM of ethanol and endotoxin together raised the rapid increase in NF‐κB activation, but both 100 mM of ethanol and endotoxin treatment reduced the increase. Addition of diallyl sulfide decreased the activity at rapid phase but increased it after 60 min, whereas addition of 4‐methyl pyrazole caused no change of the activity at rapid phase but raised it after 60 min. Pretreatment with both endotoxin and a CYP2E1 inhibitor raised the activation of NF‐κB constantly after ethanol addition. These findings suggest that endotoxin plays a critical role in the metabolism‐independent activation of NF‐κB by ethanol.

Conclusions Endotoxin raised metabolism‐independent activation of NF‐κB by high ethanol in rat hepatocytes.
Acetaldehyde‐Induced Growth Retardation and Micro‐Heterogeneity of the Sugar Chain in Transferrin Synthesized by HepG2 Cells
Authors: Searashi Yasuyuki , Yamauchi Masayoshi , Sakamoto Kazuhiko , Ohata Mitsuru , Asakura Tadashi , Ohkawa Kiyoshi
Published: April 2006

Background A carbohydrate‐deficient transferrin (CDT) is the most useful marker of alcohol abuse; however, the mechanism of production and the pathophysiologic roles of CDT remain obscure. The effects of alcohol and its metabolites on growth and proliferation, transferrin synthesis, and phosphomannomutase enzyme activity in a human hepatoblastoma, HepG2, were examined.

Methods HepG2 cells were treated with either ethanol at 80 mM or acetaldehyde at 400 μM. Transferrin secreted by the cells was prepared from conditioned culture medium by single‐step immunoaffinity column chromatography using a goat‐specific antibody against human transferrin. Phosphomannomutase and some related enzyme activities in the cell extracts were determined. Reverse transcription‐polymerase chain reaction analysis of phosphomannomutase mRNA expression was also determined in HepG2 cultured with or without acetaldehyde (400 μM).

Results HepG2 cells usually synthesized and secreted transferrin with three separated bands: main broad bands estimated to be 78 to 82 kDa, 75 kDa, and 72 kDa. The last two bands were compatible with part or the entire N‐glycans‐deficient transferrin (CDT) from alcoholic liver damage. Increased secretion of CDT from HepG2 correlated well with the extent of growth retardation to the level of confluent cell density. The activity of phosphomannomutase also decreased with prolongation of cellular doubling time. Furthermore, acetaldehyde treatment at 400 μM accelerated the inhibitory effect of cell growth compared with nontreated cells, and this condition facilitated CDT secretion from HepG2 cells. Determination of the enzyme activity and mRNA expression indicated that acetaldehyde showed competitive type inhibition of phosphomannomutase activity but not suppression of phosphomannomutase gene expression.

Conclusions By culturing HepG2 cells with acetaldehyde containing media, growth inhibition‐dependent increase of CDT showed good correlation with reduced enzyme activity of phosphomannomutase. Acetaldehyde facilitated growth retardation, inhibition of phosphomannomutase activity, and increased secretion of CDT. The HepG2 cell line is useful as an in vitro model to investigate the pathophysiologic state of alcoholic liver damage and mechanisms of production as well as the physiologic role of CDT.