bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Ethanol Self‐Administration and Anxiety‐Like Behavior During Acute Ethanol Withdrawal and Protracted Abstinence: Regulation by Corticotropin‐Releasing Factor
Authors: Valdez Glenn R. , Roberts Amanda J. , Chan Karen , Davis Heather , Brennan Molly , Zorrilla Eric P. , Koob George F.
Published: April 2006

Background Animal models of alcohol dependence suggest that long‐term alterations in brain corticotropin‐releasing factor (CRF) systems, key mediators of the behavioral stress response, may be involved in the development and reinstatement of dependence on drugs of abuse. The objective of the present study was to investigate the role of CRF in the regulation of ethanol self‐administration and to examine the behavioral stress response during acute withdrawal and protracted abstinence.

Methods Male Wistar rats were made dependent on ethanol via chronic exposure to ethanol vapor. Ethanol self‐administration and exploratory behavior in the elevated plus maze were measured at 2 hr and 3 to 5 weeks after exposure. The role of CRF in ethanol self‐administration was examined via central injection of the CRF receptor antagonist D‐Phe‐CRF(12–41).

Results Rats showed increased responding for ethanol 2 hr and 3 to 5 weeks after chronic ethanol exposure, which was attenuated by central injection of D‐Phe‐CRF(12–41). In addition, rats displayed a decrease in open‐arm exploration in the elevated plus maze when tested 2 hr and 4 weeks after exposure.

Conclusions These results indicate that chronic ethanol exposure leads to increased ethanol self‐administration and decreased open‐arm exploration in the elevated plus maze during acute withdrawal and protracted abstinence. Attenuation of ethanol self‐administration via central injection of D‐Phe‐CRF(12–41) implicates CRF as an underlying mechanism regulating long‐term motivational effects associated with alcohol dependence.
Neonatal Activation of Alcohol‐Related Prenatal Memories: Impact on the First Suckling Response
Authors: Abate Paula , Varlinskaya Elena I. , Cheslock Sarah J. , Spear Norman E. , Carlos Molina Juan
Published: April 2006

Background Rat fetuses seem to be capable of associative learning mediated through alcohol's unconditioned properties. The newborn's suckling response immediately after birth is dependent on olfactory stimuli present in the fetal milieu and/or odorants perceived immediately after birth. The present study analyzed the impact of olfactory fetal learning supported by maternal–fetal alcohol intoxication on the newborn's first postnatal suckling response, in the presence or absence of chemosensory cues originally associated with alcohol during prenatal life.

Methods During gestational days 17 to 20, fetuses experienced a salient novel cue (cineole) explicitly paired or not with the induction of alcohol intoxication resulting from maternal intragastric intubation of a 2 g/kg ethanol dose. A separate set of dams were intubated with only water. In experiment 1, cesarean‐delivered pups were tested shortly after birth for their response to a surrogate nutritive nipple scented with cineole or with no explicit odor. In experiment 2, pups were similarly evaluated after the prenatal treatment when cineole, a novel odorant (lemon), or no explicit odor was presented either in conjunction with the nipple or before being tested with the nipple.

Results In both experiments, fetal olfactory conditioning supported by alcohol intoxication had a significant effect on the newborn's first suckling episode, depending on the olfactory cues presented before or during suckling. Presence of cineole but not of novel odorants seemed to activate the associative memory acquired in utero. Once the memory was activated, pups that were subjected to fetal odor‐alcohol pairings were found to attach significantly more to surrogate nutritive nipples than did fetal control animals.

Conclusions Prenatal experience with alcohol intoxication can result in chemosensory associative learning mediated by the drug's postabsorptive effects. This learning determines attachment patterns of newborns when they reexperience olfactory cues that had signaled onset of the state of acute alcohol intoxication when they were fetuses. Considered in view of previous experiments, the present results generate two alternative hypotheses relative to the affective component of the memory established in utero: (1) alcohol intoxication is an appetitive reinforcer during fetal life, or (2) the calming effects of postnatal suckling behavior counteract negative hedonic components of the memory accrued in utero.
Psychometric Properties of the Brazilian Version of the Drug Use Screening Inventory
Authors: De Micheli Denise , Formigoni Maria Lucia O.S.
Published: April 2006

Background Adolescent involvement with alcohol and other drugs is rising in Brazil, and there is an increasing need for psychometrically sound assessment tools to detect early drug involvement.

Methods The psychometric properties of the Brazilian version of the Drug Use Screening Inventory (DUSI) were examined in a sample composed of 71 non–drug‐dependent adolescents and 142 adolescents who met DSM‐III‐R criteria for drug dependence.

Results With a cutoff score of 13% or lower for the absolute density index of the substance use area, DUSI correctly classified 80% of the drug‐dependent adolescents and 90% of the non–drug‐dependent adolescents, thus correctly classifying 83.6% of the sample. Factor analysis applied to each of the 10 DUSI areas indicated their unidimensionality, with substantial percentages of variance on the first factor. The Brazilian version of DUSI presented strong internal consistency reliability for the whole sample (drug‐dependents and non–drug‐dependent adolescents) with an average across all 10 scales for Cronbach's α reliability coefficient of 0.96 (standard deviation = 0.02) and for the split‐half reliability coefficient of 0.88 (standard deviation = 0.08).

Conclusions These results suggest that the Brazilian version of DUSI preserves its original psychometric properties and is a sensitive and useful screening instrument for drug use.
Carbohydrate‐Deficient Transferrin Levels Reflect Heavy Drinking in Alcohol‐Dependent Women Seeking Treatment
Authors: Rukstalis Margaret R. , Lynch Kevin G. , Oslin David W. , Pettinati Helen M. , Anderson Suzanne M. , Volpicelli Joseph R. , Anton Raymond F.
Published: April 2006

Background Carbohydrate‐deficient transferrin (CDT) is a biochemical marker that has been shown to be sensitive in detecting heavy drinking in men, but studies examining CDT in women have been inconsistent because of small sample sizes and failure to consider hormonal status. In healthy female subjects, CDT levels are significantly higher in premenopausal women with higher estradiol (E2) levels (>30 pg/ml) and those taking exogenous estrogens (oral contraceptives, hormone replacement therapy) compared with men and postmenopausal women. This study examined the relationship between drinking behavior and CDT levels in a large sample of alcohol‐dependent women and contrasted findings in a comparison group of alcohol‐dependent men. The study also examined the extent that E2 levels mediated the relationship between CDT levels and heavy drinking in the alcohol‐dependent women.

Methods This study examined the association between CDT level at treatment entry and alcohol consumption the month before initiating treatment in 96 women with a DSM‐III‐R diagnosis of alcohol dependence, as compared with similar data in 123 male alcoholics. To explore the relationship between E2 and CDT, E2 was measured in women at the time of CDT sampling. Linear regression was used to examine whether patterns of alcohol consumption in the 28 days before the CDT blood sampling predicted the CDT level in women and men presenting for treatment for alcohol dependence.

Results CDT levels were higher in women than men and were related to quantitative alcohol consumption (total standard drinks, percentage of days drinking, percentage of days of heavy drinking) in the month before initiating treatment, irrespective of E2 levels in women.

Conclusions These results suggest that in a larger sample of female alcoholics, the amount of alcohol consumed predicted CDT, similar to what has been reported in male alcoholics. The E2 status did not seem to mediate these results.
Amisulpride Does Not Prevent Relapse in Primary Alcohol Dependence: Results of a Pilot Randomized, Placebo‐Controlled Trial
Authors: Marra Donata , Warot Dominique , Berlin Ivan , Hispard Eric , Notides Christine , Tilikete Samir , Payan Christine , Lépine Jean‐Pierre , Dally Sylvain , Aubin Henri‐Jean
Published: April 2006

Background Few medications have been proved to be effective in preventing relapse in alcoholism. The mesolimbic dopamine system is known to play an important role in alcohol dependence. Amisulpride, a substituted benzamide, seems to facilitate dopaminergic neurotransmission at low doses.

Methods After short‐term, inpatient detoxification, 71 patients participated in a randomized, double‐blind, placebo‐controlled study to evaluate the efficacy of amisulpride in relapse prevention. Patients received amisulpride 50 mg/day or placebo for 6 months.

Results There were no differences between the two groups of treatment for time to first drink, length of time before dropout, number of drinking days, and number of heavy drinking days. However, significantly more patients who were treated with amisulpride than those who were treated with placebo were nonabstinent and had relapsed at each visit. Craving for alcohol was significantly higher in the amisulpride than in the placebo group. Transaminases, γ‐glutamyl‐transferase, and mean erythrocyte corpuscular volume were regularly higher in the amisulpride group than in the placebo group.

Conclusions The results indicate that treatment with amisulpride was not effective in preventing relapse to drinking in detoxified, alcohol‐dependent patients. The significance of this finding is discussed, particularly in terms of the effects of neuroleptics on alcohol consumption.
Survey Data Need Not Underestimate Alcohol Consumption
Authors: Casswell Sally , Huckle Taisia , Pledger Megan
Published: April 2006

Background There are two main ways to assess alcohol consumption in a population: per capita estimates, usually derived from data on taxable alcohol available for consumption, and population‐based surveys. Population‐based survey estimates of alcohol consumption are often compared with estimates based on taxable alcohol available for consumption as a measure of validity. Discrepancies between these two measures occur, with the majority of population‐based surveys substantially underestimating taxable alcohol available for consumption.

Methods This article argues, however, that high proportions of taxable alcohol available for consumption can be accounted for by population‐based surveys and reports a method of data collection for a national alcohol survey that has accounted for 94% of the taxable alcohol in New Zealand.

Results The ability of the survey methodology to account for this proportion of taxable alcohol is likely due to the within‐location beverage‐specific alcohol consumption measures used in the survey, the process of recording the quantity of alcohol consumed, the use of a computer‐assisted telephone interview system, and the population coverage achieved.

Conclusions Population‐based surveys using the methodology outlined in this article may account for, if not exceed, the high proportions of taxable alcohol available for consumption estimates for some populations.
Alcohol‐Induced Increases in Insulin‐Like Growth Factor Binding Protein‐1 Are Partially Mediated by TNF
Authors: Kumar Vinayshree , Silvis Christine , Nystrom Gerald , Deshpande Nobuko , Vary Thomas C. , Frost Robert A. , Lang Charles H.
Published: April 2006

Background Alcohol (EtOH) alters the plasma and tissue content of insulin‐like growth factor (IGF)‐I, an important anabolic hormone. However, the bioavailability and bioactivity of IGF‐I can also be modulated by changes in soluble proteins that bind IGF‐I (IGFBPs). The purpose of the present study was to determine whether EtOH intoxication in rats alters the plasma concentration and tissue mRNA content of various IGFBPs. Based on initial results subsequent studies were performed to assess potential mechanisms by which EtOH increased IGFBP‐1.

Methods Rats were administered EtOH (75 mmol/kg) and blood and tissues collected at various times thereafter. Separate groups of rats were also pretreated with 4‐methylpyrazole (4‐MP; alcohol dehydrogenase inhibitor), cyanamide (inhibitor of acetaldehyde metabolism), RU486 (glucocorticoid receptor antagonist) or the tumor necrosis factor (TNF) antagonist (TNFBP) prior to EtOH administration.

Results Acute EtOH intoxication did not alter the mRNA content of IGFBP‐3, ‐4 or ‐5 in liver or kidney. However, EtOH increased IGFBP‐1 in blood (5‐fold), which was associated with an up‐regulation of IGFBP‐1 mRNA content in liver and kidney (2‐ to 3‐fold). Likewise, the injection of the nonmetabolizable alcohol tert‐butanol also increased IGFBP‐1 in plasma, liver, and kidney. The increased IGFBP‐1 in blood and tissues was not prevented by inhibiting alcohol metabolism with 4‐MP. However, pretreatment with cyanamide markedly accentuated the EtOH‐induced increase in IGFBP‐1 in blood (20‐fold), liver (3.5‐fold), and kidney (12‐fold), indicating that accumulation of acetaldehyde can enhance IGFBP‐1 synthesis. A time course study indicated that EtOH increased plasma IGFBP‐1 levels as early as 0.5–1 hr, and that this response was associated with elevated IGFBP‐1 mRNA in liver but not kidney. Pretreatment with RU486 did not prevent or attenuate the EtOH‐induced increase in IGFBP‐1. However, the alcohol‐induced increase in IGFBP‐1 was attenuated by TNFBP.

Conclusions These data suggest that the acute alcohol‐induced increase in IGFBP‐1 is mediated, at least in part, by TNF and is independent of EtOH metabolism and increases in endogenous glucocorticoids.
Prenatal Alcohol Exposure and Attachment Behavior in Children
Authors: O'Connor Mary J. , Kogan Nina , Findlay Richard
Published: April 2006

Background This study examined the association between prenatal alcohol exposure and attachment behavior in 4‐ and 5‐year‐old children. Prenatal alcohol exposure was hypothesized to be associated with insecure attachment behavior of the child toward the mother. It was also hypothesized that children with heavier prenatal alcohol exposure would exhibit higher levels of negative affect as well as poorer coping skills. The quality of maternal support in interaction with the child was predicted to mediate prenatal exposure effects.

Methods Participants were 42 mother‐child dyads, the majority of whom came from poverty backgrounds in which the mother was a single parent. Attachment security was measured using the Attachment Q‐Set.

Results Results revealed that prenatal alcohol exposure was highly related to attachment insecurity. Eighty percent of children who were exposed to alcohol during gestation were insecure, whereas 36% of unexposed children were insecure. Prenatal alcohol exposure also predicted child negative affect, which was related to lower levels of maternal emotional support of the child. However, when the mothers of the prenatally exposed children provided high levels of support, these children evidenced better coping skills and more secure attachment relations.

Conclusions Although prenatal alcohol exposure was found to relate to higher levels of insecure attachment, children of mothers who provided them with emotional support were more able to deal with frustration. These children also exhibited higher levels of attachment security. Thus, the mother's supportive presence may mediate the association between prenatal alcohol exposure and the child's security of attachment.
Hormone Responses to Citalopram in Abstinent Alcohol Dependent Subjects
Authors: Gotjen Deidre , Szabo Zsolt , Lee Shing , Wand Gary
Published: April 2006

Background The integrity of serotonin neurotransmission may be important in reducing risk for alcoholism and in preventing relapse to alcohol dependence. There are several lines of evidence suggesting that alcohol dependent persons have an altered and/or injured serotonin system. The purpose of this study was to examine ACTH, cortisol, and prolactin responses to the selective serotonin reuptake inhibitor (SSRI), citalopram, as a function of personal or family history of alcohol dependence in a group of abstinent alcohol dependent men.

Methods Twelve healthy, abstinent male participants who met diagnostic criteria for a history of alcohol dependence but not for other Axis I disorders were included in the study (mean years abstinent, 3.5 ± 3.7; mean years of dependent drinking, 15.2 ± 6.9). Fourteen healthy volunteers served as control subjects. Controls did not meet the DSM‐IV diagnostic criteria for any Axis I disorders and history of drug or alcohol abuse or dependence. All subjects were also characterized by the presence or absence of family history of alcoholism validated by collateral interviews.

Results ACTH responses to citalopram were minimally faster in abstinent alcohol dependent men compared to controls. However, cortisol and prolactin responses to citalopram did not differ by personal or family history of alcohol dependence. There was no correlation between hormone responses and the duration of abstinence from alcohol; between hormone responses and the years of dependent drinking and between hormone responses and NEO Personality Inventory scores.

Conclusion By probing the functional capacity of the serotonin system with citalopram, we did not detect physiologically relevant hormone differences between abstinent alcohol dependent men and controls.
Lateral Asymmetries in the Frontal Brain: Effects of Depression and a Family History of Alcoholism in Female Adolescents
Authors: Bauer Lance O. , Hesselbrock Victor M.
Published: April 2006

Background Subtle electroencephalographic (EEG) abnormalities have been detected among subjects with depressed affect. The present study attempted to discern whether these abnormalities reflect a main effect or an interaction between depression and either of two family history variables—a family history of alcoholism or a family history of depression.

Methods The subjects were 151 adolescent females, aged 14 to 20 years, of whom 58 met DSM‐III‐R diagnostic criteria for a lifetime history of a major depressive episode. The electroencephalogram was recorded from 31 electrode sites while the subjects sat relaxed, with their eyes open, for 5 min.

Results Analyses of EEG data revealed that a personal history of depression and a family history of alcoholism had opposite effects on the EEG power spectrum. Depression was associated with an increase in α power (7.5–12.5 Hz). In contrast, a family history of alcoholism was associated with an increase in fast β power (19–30 Hz) and a decrease in θ power (4–7 Hz). There were no significant main or interactive effects of a family history of depression. Current source density topographic analyses of the significant group differences in α and fast β power demonstrated that the effects of depression could be localized to the right frontal brain, whereas the effects of a family history of alcoholism were localized to the left frontal area.

Conclusions The laterally opposite effects of depression and a family history of alcoholism suggest a high level of functional differentiation of the frontal brain. They also suggest that the different neurophysiological substrates of depression and familial risk can be distinguished through the use of modern methods of EEG source localization.
Screening for Alcohol Problems in the U.S. General Population: Comparison of the CAGE, RAPS4, and RAPS4‐QF by Gender, Ethnicity, and Service Utilization
Authors: Cherpitel Cheryl J.
Published: April 2006

Background The purpose of this study was to compare the performance (sensitivity and specificity) of two brief screening instruments, CAGE and the Rapid Alcohol Problems Screen 4 (RAPS4), against ICD‐10 and DSM‐IV criteria for alcohol dependence and abuse in a representative sample of the U.S. adult household population by gender, ethnicity, and service utilization (emergency room and primary care) in the last year.

Methods Data are from the Alcohol Research Group's 2000 National Alcohol Survey (n= 7612), which is a computer‐assisted telephone interview survey of the U.S. general population 18 and over in all 50 U.S. states and the District of Columbia.

Results Sensitivity of the RAPS4 (0.86) was better than the CAGE (0.67) given similar specificity (0.95 vs. 0.98) and outperformed the CAGE for alcohol dependence across all gender, ethnic, and service utilization groups, except among blacks and Hispanics. The RAPS4 also performed equally well for females and males (0.88 vs. 0.85), whereas sensitivity of the CAGE was lower for females. Although sensitivity of the RAPS4 was better than the CAGE for alcohol abuse, sensitivity was low for both (0.56 and 0.36, respectively). When quantity‐frequency (QF) questions (drinking five or more drinks on at least one occasion during the last year and drinking as often as once a month during the last year) were added to the RAPS4, the RAPS4‐QF performed significantly better for alcohol abuse and outperformed the CAGE at a cut point of one across all gender, ethnic, and service utilization groups. The RAPS4‐QF appeared to be most sensitive for alcohol abuse among both males and females reporting emergency room use (0.90).

Conclusions The data suggest that the RAPS4 outperforms the CAGE in this general population sample. The addition of a QF question to the RAPS4 improves performance in relation to sensitivity for alcohol abuse, and the RAPS4 and RAPS4‐QF may be the instruments of choice in brief screening for alcohol use disorders. Additional research is needed to further explore these issues.
Chlormethiazole Treatment Prevents Reduced Hepatic Vitamin A Levels in Ethanol‐Fed Rats
Authors: Liu Chun , Chung Jayong , Seitz Helmut K. , Russell Robert M. , Wang Xiang‐Dong
Published: April 2006

Background Chronic ethanol intake results in decreased hepatic vitamin A levels through both enhanced degradation of vitamin A via a cytochrome P450 enzyme (CYP)‐dependent process and increased mobilization of vitamin A from the liver into the circulation. This study investigated whether treatment with chlormethiazole, a CYP inhibitor, restores vitamin A in the livers of ethanol‐fed rats.

Methods Ethanol‐exposed and non‐ethanol‐exposed rats were treated with or without chlormethiazole (10 and 100 mg/kg body weight) for 1 month. Liver and plasma levels of retinol and retinyl palmitate were analyzed by high‐performance liquid chromatography. Expressions of hepatic lecithin:retinol acyltransferase (LRAT) and cellular retinol‐binding protein were analyzed with reverse transcription‐polymerase chain reaction. Hepatic retinol esterification by LRAT was examined by using incubations of the microsomal fractions of livers with exogenous sources of retinol.

Results Ethanol‐feeding in rats for a month resulted in lower hepatic levels of retinol and retinyl palmitate than those found in controls and the occurrence of several polar retinoid metabolites. In contrast, treatment with chlormethiazole at two different doses in ethanol‐fed rats completely blocked the formation of hepatic retinoid polar metabolites and restored hepatic levels of retinol and hepatic retinyl palmitate in a dose‐dependent manner. Furthermore, increased plasma concentrations of retinyl palmitate in rats fed with ethanol, which indicate increased mobilization of vitamin A, were partially inhibited by chlormethiazole treatment. However, neither ethanol nor chlormethiazole treatment altered the expression and activity of LRAT in the liver of rats. Hepatic expression of cellular retinol‐binding protein increased significantly in ethanol‐fed rats with or without chlormethiazole treatment compared with control rats.

Conclusions These data suggest that chlormethiazole can restore both hepatic retinol and retinyl ester concentrations to normal levels in ethanol‐fed rats through blocking enhanced both degradation of vitamin A and mobilization of vitamin A from the liver into the circulation.
Ethanol Induces Redox‐Sensitive Cell‐Cycle Inhibitors and Inhibits Liver Regeneration After Partial Hepatectomy
Authors: Koteish Ayman , Yang Shiqi , Lin Huizhi , Huang Jiawen , Diehl Anna Mae
Published: April 2006

Background Doses of ethanol (EtOH) that are not overtly cytotoxic inhibit mitogen‐induced hepatocyte proliferation and delay liver regeneration after 70% partial hepatectomy (PH). The mechanisms for this are poorly understood. This study evaluates the hypothesis that EtOH inhibits hepatocyte proliferation after PH by inducing redox‐sensitive factors, such as p38 mitogen‐activated protein kinase (MAPK) and p21 (WAF1/CIP1), that protect cells from oxidative stress but prevent cell‐cycle progression by inhibiting cyclin D1.

Methods Mechanisms that regulate the transition from the prereplicative G1 phase of the cell cycle into S phase were compared in EtOH‐fed mice and normal pair‐fed mice after PH.

Results Prior EtOH exposure significantly increases p38 MAPK and p21 after PH. This is accompanied by reduced expression of cyclin D1 messenger RNA and protein, increases in other cell‐cycle regulators (such as signal transducer and activator of transcription‐3 and p27) that are normally inhibited by cyclin D1, and hepatocyte G1 arrest.

Conclusions EtOH amplifies G1 checkpoint mechanisms that are induced by oxidative stress and promotes hepatic accumulation of factors, including p38 MAPK, p21, and signal transducer and activator of transcription‐3, that enhance cellular survival after oxidant exposure. Therefore, cell‐cycle inhibition may be an adaptive response that helps EtOH‐exposed livers survive situations, such as PH, that acutely increase reactive oxygen species in hepatocytes.
Quantitative Immunocytochemistry of GABA and Synaptophysin in the Cerebellar Cortex of Old Ethanol‐Fed Rats
Authors: Dlugos Cynthia A. , Pentney Roberta J.
Published: April 2006

Background Ethanol‐related synaptic loss, Purkinje neuron dendritic regression, and parallel fiber degeneration have been reported in the molecular layer of the adult cerebellar cortex. The known plasticity of the cerebellar cortex suggests that this region may respond to ethanol‐related losses by compensatory remodeling of cerebellar circuitry. Stellate and basket interneurons may play an essential role in the remodeling process. Little is known about ethanol‐related effects on cerebellar interneurons or on the GABAergic synapses that they form despite the fact that ethanol‐related alterations in these components may contribute to the sensitivity of the cerebellum to ethanol. The paucity of data on GABAergic synapses extends to other synaptic components as well including synaptophysin, a glycoprotein component of synaptic vesicles and a synaptic marker.

Methods Thirty 12‐month‐old F 344 rats were divided into ethanol‐fed, pair‐fed, and chow‐fed groups (10/group). Ethanol rats were treated for 40 weeks with a liquid diet in which 35% of the calories were derived from ethanol. At the end of treatment, rats were perfused, and tissue processed for quantitative immunohistochemistry of GABA and synaptophysin labels.

Results Levels of GABA within inhibitory synapses formed by stellate and basket neurons and levels of synaptophysin were not altered by long‐term ethanol treatment.

Conclusions Stable levels of GABA within GABAergic basket and stellate interneuron synapses suggest that interneurons in the molecular layer of the cerebellar cortex may not play a major role in remodeling of cerebellar circuitry following long‐term ethanol consumption. The lack of ethanol‐related alterations in synaptophysin levels reported here suggests that synaptic vesicles may be relatively insensitive to ethanol and that known ethanol‐related effects on synapse number are due to other mechanisms.
Influence of Ethanol Consumption on Experimental Viral Hepatitis
Authors: Jerrells Thomas R. , Mitchell Kristen , Pavlik Jacqueline , Jerrells Jennifer , Hoerman Debbie
Published: April 2006

Background One important contributor to pathologic effects on the liver associated with alcohol abuse is viral hepatitis, especially hepatitis C virus (HCV) infection. Alcohol consumption has been shown to be associated with more severe HCV infection and hepatitis. The mechanisms of the more severe viral infection of the liver are unclear, and studies have been hampered by the lack of an animal model of hepatotropic viral infections.

Methods We have established a murine model system of viral hepatitis in which C57BL/6 mice are infected with murine cytomegalovirus, a herpesvirus that produces self‐limiting hepatitis in immunocompetent mice. Mice were fed a liquid diet containing 36% ethanol‐derived calories with a pair‐feeding protocol. After infection with a sublethal dose of murine cytomegalovirus, the severity of liver infection was determined by measuring serum levels of alanine aminotransferase and by histological evaluation. Other parameters determined included the serum levels of cytokines, cytokine RNA in liver samples, and viral concentration in liver samples.

Results Ethanol‐fed mice showed more severe hepatitis in the later stages of the infection as compared with the hepatitis noted in control mice. The ethanol‐fed mice did not control the virus replication in the liver, which was associated with a greater mononuclear cell inflammatory response, composed predominantly of cells with morphological characteristics of lymphocytes and macrophages. The early production of interferon γ, as well as production throughout the infection, was significantly lower in the ethanol‐fed mice. The early production of interleukin 12 was also less in ethanol‐fed mice.

Conclusions The more severe hepatitis seen in the ethanol‐fed mice is likely to be the result of an inability to control the growth of the virus, which is associated with a continued inflammatory response. The inability to control the virus in the liver may be related to the decreased production of interferon γ and interleukin 12.
Dose‐Dependent Effects of Prenatal Ethanol Exposure on Synaptic Plasticity and Learning in Mature Offspring
Authors: Savage Daniel D. , Becher Matthew , de la Torre Alejandro J. , Sutherland Robert J.
Published: April 2006

Background We have observed profound deficits in hippocampal synaptic plasticity and one‐trial learning in offspring whose mothers drank moderate quantities of ethanol during pregnancy. In the present study, we examined the question of whether lower maternal blood ethanol concentrations (BECs) could produce functional deficits in offspring.

Methods Rat dams consumed either a 2%, 3%, or 5% ethanol liquid diet throughout gestation. Three other groups of dams were pair‐fed a 0% ethanol liquid diet, and a seventh group consumed lab chow ad libitum. Adult offspring from each diet group were assigned either to studies of evoked [3H]‐D‐aspartate (D‐ASP) release from hippocampal slices or spatial learning studies using the Morris Water Task.

Results Consumption of the 2%, 3%, and 5% ethanol liquid diets produced mean peak maternal BECs of 7, 30 and 83 mg/dL, respectively. Consumption of these ethanol diets had no effect on offspring birthweight, litter size or neonatal mortality. Likewise, evoked D‐ASP release from hippocampal slices and performance on a standard version of the Morris Water Task were not affected by prenatal ethanol exposure. By contrast, activity‐dependent potentiation of evoked D‐ASP release from slices and one‐trial learning on a “moving platform” version of the Morris Water Task were markedly reduced in offspring whose mothers consumed the 5% ethanol liquid diet. Intermediate deficits in these two parameters were observed in offspring from the 3% ethanol diet group, whereas offspring from the 2% ethanol diet group were not statistically different than controls.

Conclusions We conclude that the threshold for eliciting subtle, yet significant learning deficits in offspring prenatally exposed to ethanol is less than 30 mg/dL. This BEC is roughly equivalent to drinking 1 to 1.5 ounces of ethanol per day.
Acamprosate Inhibits the Binding and Neurotoxic Effects of Trans‐ACPD, Suggesting a Novel Site of Action at Metabotropic Glutamate Receptors
Authors: Harris Barton R. , Prendergast Mark A. , Gibson D. Alex , Rogers D. Trent , Blanchard John A. , Holley Robert C. , Fu May C. , Hart Stewart R. , Pedigo Norman W. , Littleton John M.
Published: April 2006

Background Several reported effects of acamprosate within the glutamatergic system could result from interactions with metabotropic glutamate receptors (mGluRs). The following experiments were performed to determine whether acamprosate could compete with trans‐ACPD (±‐1‐aminocyclopentane‐trans‐1,3‐dicarboxylic acid, an equimolecular mixture of 1 S, 3 R and 1 R, 3 S‐ACPD and an agonist at both group I and group II mGluRs) sensitive binding sites and protect against trans‐ACPD–induced neurotoxicity in organotypic hippocampal slice cultures.

Methods A P2 membrane preparation of cortices, cerebellums, and hippocampi of adult, male Sprague Dawley rats was used to determine the abilities of N‐methyl‐d‐aspartic acid (NMDA) and trans‐ACPD to displace [3H]glutamate in both the absence and the presence of the sodium salt of acamprosate (sodium mono N‐acetyl homotaurine or Na‐acamprosate). A comparison of the effects of 100 μM guanosine 5′‐triphosphate on unlabeled glutamate, trans‐ACPD, and Na‐acamprosate was performed in the same paradigm. For the neurotoxicity studies, organotypic hippocampal slice cultures from male and female 8‐day‐old neonatal rats were exposed to either 500 μM trans‐ACPD or 50 μM NMDA for 24 hr in normal culture medium containing serum on day 20 in vitro. The effects of Na‐acamprosate and 2‐methyl‐6‐(2‐phenylethenyl)pyridine (SIB‐1893), a noncompetitive antagonist at metabotropic type 5 receptors (mGluR5s), were assessed by determining differences in propidium iodide uptake as compared with neurotoxic challenges alone.

Results Na‐acamprosate displaced 31% of [3H]glutamate but did not compete with NMDA for [3H]glutamate binding sites. Na‐acamprosate displayed total competition with trans‐ACPD. The presence of 100 μM guanosine 5′‐triphosphate differentially altered the displacing capabilities of the two mGluR agonists, unlabeled glutamate and trans‐ACPD, as compared with Na‐acamprosate. Na‐acamprosate (200–1000 μM) and SIB‐1893 (20–500 μM) both were neuroprotective against trans‐ACPD induced neurotoxicity that likely results from mGluR potentiation of NMDARs. In turn, Na‐acamprosate and SIB‐1893 had no direct effects on NMDA‐induced neurotoxicity.

Conclusions Na‐acamprosate demonstrates the binding and functional characteristics that are consistent with a group I mGluR antagonist. The functional similarities between Na‐acamprosate and SIB‐1893 support an interaction of Na‐acamprosate at mGluR5s. The neuroprotective properties of acamprosate and possibly its ability to reduce craving in alcohol‐dependent patients may result from its alterations in glutamatergic transmission through mGluRs.
Differential Effects of Alcohol Consumption on Eukaryotic Elongation Factors in Heart, Skeletal Muscle, and Liver
Authors: Vary Thomas C. , Nairn Angus C. , Deiter Gina , Lang Charles H.
Published: April 2006

Background Acute and chronic alcohol administration diminishes rates of protein synthesis in a variety of tissues including skeletal muscle, heart, and liver, through a diminished translational efficiency rather than a reduction in the number of ribosomes.

Methods The purpose of the present study was to examine the effect of chronic alcohol exposure (8, 12, or 16 weeks) on elongation factors (eEF) as a potential mechanism for controlling mRNA translation in psoas, soleus, heart, and liver. The cellular content of eEF1A and eEF2 and the phosphorylation state of eEF2 in each tissue was measured using immunoblot techniques.

Results The protein content of eEF1A was reduced in psoas, heart, and liver (but not soleus) from rats fed a diet containing alcohol for 16 weeks, but not for 8 or 12 weeks, compared with time‐matched pair‐fed controls. eEF2 content was only reduced in myocardium after feeding rats an alcohol‐containing diet for 16 weeks. In other tissues, no change in eEF2 content was observed. The decreases in eEF protein content were not associated with a concomitant reduction in the mRNA abundance for eEF1A or eEF2. The phosphorylation state of eEF2 was not affected by chronic alcohol consumption in the skeletal muscle or heart. In contrast, the level of eEF2 phosphorylation in the liver was reduced after 8, 12, and 16 weeks of feeding rats an alcohol‐containing diet. In contrast, acute alcohol intoxication failed to modulate the content of eEF1A or eEF2 in any of the tissues examined. The phosphorylation state of eEF2 was reduced in psoas following acute alcohol intoxication.

Conclusions A decreased eEF1A protein content could account, in part, for the inhibition of translational efficiency following chronic (16 weeks) alcohol feeding but not the response to acute alcohol intoxication.
Sodium Sensitivity as a Main Determinant of Blood Pressure Changes during Early Withdrawal in Heavy Alcoholics
Authors: Di Gennaro Cristiana , Vescovi Pier Paolo , Barilli Angela Luciana , Giuffredi Cristina , Delsignore Roberto , Montanari Alberto
Published: April 2006

Background Stimulated sympathetic nervous system, renin‐angiotensin‐aldosterone system, vasopressin, and cortisol are thought to affect blood pressure in early withdrawal of alcoholics. Hyperactivity of sodium‐retaining systems with consequent volume expansion also could interact with sodium sensitivity as previously found in long‐term withdrawing alcoholics.

Methods To investigate this hypothesis, blood pressure and sodium balance were measured during the first 8 days of withdrawal in 18 chronic alcoholics on a 150 mM Na diet. Results were related to the Salt Sensitivity Index of blood pressure as measured in the same alcoholics after 1 year of abstinence.

Results Early withdrawal study: there was a positive sodium balance (+288.6 ± 45.6 mM;p < 0.0001) and rise in mean arterial pressure (+11.8 ± 2.9 mm Hg;p= 0.001) during early withdrawal on 150 mM Na diet. Salt Sensitivity Study after long‐term detoxification: the shift from low (55 mM) to high sodium (260 mM) intake produced a larger (p= 0.04) increase in mean arterial pressure in alcoholics (+9.3 ± 2.0 mm Hg) than in 30 teetotal controls (+5.1 ± 1.1) (Salt Sensitivity Index, 0.047 ± 0.008 vs. 0.023 ± 0.0053;p < 0.05). Changes in mean blood pressure during withdrawal were highly related to sodium sensitivity index (r= 0.8;p < 0.001).

Conclusions Early withdrawing alcoholics exposed to a normal sodium intake experience positive Na balance and increase in blood pressure that is related to sodium sensitivity measured after long‐term detoxification. This suggests that salt sensitivity plays a key role in blood pressure regulation in early withdrawing alcoholics.
Alcohol is the Main Factor in Excess Traffic Accident Fatalities in France
Authors: Reynaud Michel , Le Breton Patrick , Gilot Bertrand , Vervialle Françoise , Falissard Bruno
Published: April 2006

Background The aim of this study was to better evaluate the role of alcohol drinking in fatalities linked to road traffic accidents.

Methods The data of accidents were collected by a French official agency from police records, including many variables, among which was a blood alcohol test. They were analyzed in a descriptive way and toward a logistic regression. This exhaustive database comprised all of the 500,961 accidents with casualties that involved less than three vehicles (28,506 fatal accidents) recorded in France during a 52 month period (September 1995 to December 1999). The results of the alcohol tests were known in 78.7 of the drivers.

Results The blood alcohol concentration was over the legal limit (0.50 g/L in France) in 9.8% of the accidents with casualties overall. Considering only fatal accidents, the rate of positive alcohol test in drivers was approximately 31.5%. This rate varied depending on the period and the type of accident, raising up to 71.2% in single‐vehicle accidents (loss of control) at night during the weekend. The percentage of positive alcohol tests also dramatically increased following the number of fatalities per accident (87.5% in single‐vehicle accidents during weekend nights involving three or more killed). The logistic regression in single‐vehicle accident shows that the higher odds ratios concern the positive blood alcohol test (OR = 4.19), clearly overwhelming the other precipitating factors of accidents (age of driver, meteorological conditions, time of day, and other factors).

Conclusions Drinking alcohol before driving is a well known factor of accidents. We clearly demonstrate here that it is the main factor leading to deaths linked to road traffic accidents in France. The results are strengthened, and some analyses are allowed, by the exceptional features of our database. The authors emphasize the need for prevention measures.
Interhemispheric Transfer in Children with Heavy Prenatal Alcohol Exposure
Authors: Roebuck Tresa M. , Mattson Sarah N. , Riley Edward P.
Published: April 2006

Background Prenatal alcohol exposure has long been associated with alterations in brain structure and behavioral changes. The corpus callosum can be affected by heavy prenatal alcohol exposure, and agenesis (absence) of this structure occurs more often in children with fetal alcohol syndrome than in the general population or in other developmentally delayed populations. Although the majority of children with fetal alcohol syndrome do not have agenesis of the corpus callosum, callosal area is reduced in this population, particularly in the anterior and posterior regions. However, the functional implication of these size reductions has not been examined.

Methods The current study used a finger localization task to measure the transfer of information across the corpus callosum in children and adolescents with histories of heavy prenatal alcohol exposure and age‐ and sex‐matched controls. In a subset of children, correlational analysis was also conducted between behavioral data and cross‐sectional area of the corpus callosum.

Results When compared with nonexposed controls, alcohol‐exposed children made more errors on trials for which information had to cross the corpus callosum (“crossed” trials) than on trials for which it did not (“uncrossed” trials), and they also made more errors as the task increased in complexity. Additionally, correlations with magnetic resonance imaging data in a subset of children revealed that impairment in interhemispheric transfer was related to reductions in the size of the corpus callosum. These correlations were independent of effects expected from the relationship between corpus callosum size and general intellectual functioning alone.

Conclusions These findings suggest that children with heavy prenatal alcohol exposure display subtle deficits in the interhemispheric transfer of information in the somatosensory domain. Such deficits in interhemispheric transfer are likely to be related to the myriad of other behavioral and cognitive impairments observed in these children.
Inhibition of NF‐κB Binding Correlates With Increased Nuclear Glucocorticoid Receptor Levels in Acute Alcohol‐Treated Human Monocytes
Authors: Mandrekar Pranoti , Bellerose Gary , Szabo Gyongyi
Published: April 2006

Background Acute alcohol treatment blocks inflammatory cytokines via inhibition of NF‐κB in monocytes in the presence of ongoing IκBα degradation, suggesting regulation of NF‐κB activation downstream of IκBα degradation. DNA binding of NF‐κB has been suggested to be regulated by other nuclear regulatory factors, including the glucocorticoid receptor (GR). Here, we show for the first time that acute alcohol (25 mM) exposure modulates GR activation in monocytes.

Methods Human peripheral blood monocytes were treated with lipopolysaccharide (LPS) in the presence or absence of alcohol (25 mM) for 1 hour. Nuclear GR levels were estimated by Western blotting and NFκB activation was studied in the same extracts by gel shift analysis (EMSA). Cells were stimulated with 1 μM of Dex to be used as positive control for GR activation. GR/GRE binding was also determined in nuclear extracts by EMSA. IκBα mRNA known to be induced by GR/GRE activation was studied in total RNA extracts by the SuperArray method (SuperArray Inc., Bethesda, MD).

Results LPS is a potent inducer of GR nuclear translocation and GR binding to the glucocorticoid response element (GRE). Acute alcohol treatment both induced (p < 0.05) and augmented (p < 0.05) LPS‐stimulated GR nuclear levels. However, alcohol inhibits LPS‐induced (nonligand bound) GR/GRE binding activity in monocytes. This inhibition of GR transactivation by alcohol was further confirmed by decreased expression (40%) of a target gene, IκBα. Thus, alcohol treatment increases nonligand‐bound nuclear GR, but inhibits its transactivation function. Ligand‐induced GR/GRE binding was decreased in alcohol‐treated monocytes. Inhibition of ligand‐induced GR/GRE binding by alcohol exposure is likely due to cytoplasmic retention of the GR.

Conclusions Our results show that acute alcohol exposure inhibits GR in monocytes by differently affecting ligand‐ and nonligand‐induced GR nuclear translocation. These data also suggest that acute alcohol regulates GR activation in monocytes concomitant to inhibition of NF‐κB activation.
Timing Accuracy and Variability in Children With Prenatal Exposure to Alcohol
Authors: Wass Tara S. , Simmons Roger W. , Thomas Jennifer D. , Riley Edward P.
Published: April 2006

Background Prenatal exposure to alcohol (prenatal alcohol exposure) is associated with gross and fine motor skill dysfunction. The present study examined performance on two types of timing tasks to determine the extent to which prenatal alcohol exposure affects perception, movement planning, and movement execution during tasks that require temporal processing.

Methods Fourteen children with confirmed heavy prenatal alcohol exposure and 22 control children (aged 5–10 years) completed two timing tasks: a coincident‐anticipation timing task that primarily assessed central processing, and a movement‐speed timing task that evaluated the motor component of temporal processing. Absolute error, signed error, and variability of the participant's signed error were the dependent variables.

Results For both timing tasks, children with prenatal alcohol exposure were significantly less accurate and more variable than control children, indicating that both the sensory‐perceptual and motor components of temporal processing were disrupted in alcohol‐exposed children.

Conclusions Alcohol‐exposed children had difficulty producing accurate and consistent motor responses when intercepting a moving target or moving through a spatial target in a specified amount of time. Disruptions in these motor timing behaviors may be indicative of alcohol‐related cerebellar or basal ganglia damage.