bluuebunny/crossref_metadata_2025_split huggingface dataset:
What Is Inherited in the Predisposition Toward Alcoholism? A Proposed Model
Authors: Begleiter Henri , Porjesz B. 
Published: May 2006

Background:The etiological factors associated with the predisposition to develop alcohol dependence remain largely unknown. In recent years, neurophysiological anomalies have been identified in young and adult offspring of alcoholic probands. These neuroelectric features have been replicated in several laboratories across many different countries and are observed in male and female alcoholics and some of their relatives and offspring. Moreover, these electrophysiological abnormalities are heritable and predictive of future alcohol abuse or dependence.Methods:A model is presented which hypothesizes that the genetic predisposition to develop alcoholism involves an initial state of central nervous system (CNS) disinhibition/hyperexcitability. We propose that the event‐related brain potential (ERP) anomalies reflect CNS disinhibition. This homeostatic imbalance results in excess levels of CNS excitability which are temporarily alleviated by the ingestion of alcohol. It is hypothesized that this hyperexcitability is heritable, and is critically involved in the predisposition toward alcoholism and the development of dependence. A brief review of the relevant literature is presented.Results:Neurophysiological, neurochemical, and genetic evidence support the proposed model. In addition, strikingly similar observations between animal research and the human condition are identified. Finally, it is asserted that the proposed model is primarily biological in nature, and therefore does not account for the entire clinical variance.Conclusion:A putative CNS homeostatic imbalance is noted as a critical state of hyperexcitability. This hyperexcitability represents a parsimonious model of what is inherited in the predisposition to develop alcoholism. It is our hope that this model will have heuristic value, resulting in the elucidation of etiological factors involved in alcohol dependence.
Chlordiazepoxide‐Induced Expression of c‐Fos in the Central Extended Amygdala and Other Brain Regions of the C57BL/6J and DBA/2J Inbred Mouse Strains: Relationships to Mechanisms of Ethanol Action
Authors: Hitzemann Barbara , Hitzemann Robert 
Published: May 2006

Background: Previous studies have established an association between the ethanol‐induced locomotor response and activation of the central nucleus of the amygdala (CeA) as determined by changes in the number of Fos‐like immunoreactive (Fos‐li) neurons. The purpose of the current study was to determine if the benzodiazepine chlordiazepoxide (CDP) would produce similar effects to ethanol on behavior and the CeA. Methods: In experiment 1, C57BL/6J (B6) and DBA/2J (D2) mice were administered CDP over a dose range of 3 to 30 mg/kg and the effects on locomotor behavior and the number of Fos‐li neurons in the extended CeA determined. For experiment 2, B6D2 F2 intercross animals were phenotyped for their locomotor response to ethanol using a test‐retest design. The activity responsive and nonresponsive extreme phenotypes were then tested in the same fashion as the inbred strains. Results: Similar to ethanol, CDP increased locomotor activity in the D2 strain but not the B6 strain; furthermore, the D2 strain was 3 to 10 times more sensitive than the B6 strain in terms of CDP activating the CeA and the associated lateral posterior aspect of the bed nucleus of the stria terminalis (BSTLP). In the shell of the nucleus accumbens (NAc), CDP inhibited the number of Fos‐positive neurons in both strains. CDP also discriminated between the responsive and nonresponsive extremes both in terms of behavior and activation of the CeA. Conclusions: Overall, these data point to the importance of GABAA mediated mechanisms in the ethanol‐induced locomotor response. It is suggested that both drugs block the feed‐forward inhibition in the CeA, resulting in activation of the GABAergic projection neurons. The overall net effect of CDP or ethanol administration on the output from the CeA will be inhibitory, from which it follows that the locomotor activation response must be associated with the selective inhibition of some behavior or ensembles of behaviors that are known to be mediated by the CeA and reduce locomotor activity (i.e., the “freezing” response).
A Preliminary Study of Acute Responses to Clamped Alcohol Concentration and Family History of Alcoholism
Authors: Ramchandani Vijay A. , O'Connor Sean , Blekher Tanya , Kareken David , Morzorati Sandra , Nurnberger John , Li Ting‐Kai 
Published: May 2006

Background: The clamping method of alcohol administration was combined with a battery of dependent measures of frontal lobe brain function, and a novel index of acute adaptation, in a preliminary study in order to explore the paradigm's sensitivity to a familial history of alcoholism (FHA). Methods: Ten family history‐positive (FHP) and 10 family history‐negative (FHN) adult social drinkers of both genders underwent alcohol clamping. Twenty minutes after the start of an intravenous infusion of alcohol, the breath alcohol concentration was clamped at a target of 60 ± 5 mg/dl for 150 min. Initial and adaptive responses to alcohol were assessed using scalar indices of change. One index assessed initial improvements or impairments in brain function after alcohol. The other index assessed acute adaptation (tolerance or sensitization) to alcohol while the brain's exposure to alcohol was held constant. The battery of dependent measures included subjective perceptions, neuropsychological tests, saccadic eye‐movement tasks, and event‐related potential (ERP) tasks. Effect sizes for FHA were estimated for 10 dependent variables that showed adequate baseline test‐retest reliability (r>0.6). Results: FHP subjects showed less intense initial responses to alcohol in subjective perceptions, but greater changes in the latency of volitional saccades and ERP P3 components than did the FHN controls. FHP subjects generally showed greater acute tolerance to alcohol than did controls, who showed more instances of acute sensitization at this moderate breath alcohol concentration. Effect sizes for FHA exceeded 0.4 in more than half of the indices. Conclusions: The BrAC clamping paradigm assesses initial and adaptive responses of a battery of behavioral and electrophysiological measures of frontal lobe function to ethanol that appear both reliable and sensitive to FHA.
A New Model of Ethanol Self‐Administration in Newborn Rats: Gender Effects on Ethanol Ingestion Through a Surrogate Nipple
Authors: Varlinskaya Elena I. , Petrov Evgeniy S. , Cheslock Sarah J. , Spear Norman E. 
Published: May 2006

Background: Ethanol intake in the context of suckling may have distinct and potentially long‐lasting consequences for further responsiveness to and acceptance of ethanol, compared to other, more indirect and less natural ways of ethanol exposure early in ontogeny. Method: Our findings presented in this paper show that a surrogate nipple technique can be used for the study of early ethanol intake in cesarean‐derived rat pups tested before any suckling experience. Results: Neonatal rats attached to and voluntary ingested ethanol through the surrogate nipple as early as 4 hr after birth. Moderate concentrations of ethanol (2% and 5%, v/v) promoted substantial initial suckling behavior, including sustained attachment to the nipple. Higher concentrations (10% and 15%) were not effective in sustaining suckling. Females responded less positively to 10% ethanol than did males. High concentrations of ethanol were less effective in eliciting suckling behavior, probably due to the aversiveness of ethanol odor. However, when ethanol was presented in solution with milk, newborn pups attached to the nipple and ingested even 15% ethanol. Contamination of milk with 15% ethanol was more aversive for females than for males. Newborn rat pups demonstrated similar patterns of nipple attachment and ingestive behavior for 5% ethanol and milk. Initial experience with milk in the context of suckling did not prevent further voluntary ethanol ingestion from the same nipple; furthermore, initial exposure to 5% ethanol did not impair subsequent responsiveness to milk. Conclusions: Gender differences in responsiveness or sensitivity to ethanol can be detected in rat pups as early as a few hours after birth. The results suggest a leftward shift in the dose‐response curve for females compared with males, indicating that female neonates are more sensitive or more responsive than males to ethanol. The similarity of suckling behaviors produced by moderate concentrations of ethanol and milk suggests a certain unity in their reinforcing mechanisms in the context of the first suckling episode.
Dissociation of Ethanol and Saccharin Preference in sP and sNP rats
Authors: Agablo Roberta , Caral Mauro A.M. , Lobina Carla , Pani Marialaura , Reali Roberta , Bourov Iouri , Gessa Gian Luigi , Colombo Giancarlo 
Published: May 2006

Background:It has been proposed that ethanol intake and consumption of sweet tasting solutions are positively correlated in rodents. Experiment 1 of the present study investigated whether selectively bred ethanol‐preferring (sP) and ‐nonpreferring (sNP) rats differed, consistently with the above hypothesis, as to saccharin intake and preference. Experiment 2 evaluated whether saccharin addition to the ethanol solution, likely resulting in a highly palatable fluid, would result in an increase in voluntary ethanol intake in sP rats.Methods:The saccharin solution was offered, in free choice with water, at a fixed concentration of 1 giliter for 6 consecutive days in Experiment 1A or at ascending concentrations (0.002 to 16.4 g/liter, doubling the concentration every day) in Experiment 1B. In Experiment 2, 1 g/liter, doubling the concentration every day) in Experiment 1B. In Experiment 2, 1 g/liter saccharin was added to the standard 10% ethanol solution and offered to sP rats in free choice with water for 7 consecutive days.Results:In both Experiments 1A and 1B, sP and sNP rats showed avidity for the saccharin solution with marginal line difference in saccharin intake and preference. In Experiment 2, daily ethanol intake remained stable at baseline levels (6–7 g/kg), irrespective of the saccharin addition to the ethanol solution.Conclusions:The results of Experiments 1A and 1B suggest that saccharin drinking behavior in sNP rats deviates from the hypothesis that saccharin and ethanol intakes may co‐vary; thus, at least in sNP rats, saccharin and ethanol intakes do not appear to be influenced by the same genetic factors. The results of Experiment 2 provide further support to the existence of a central set‐point mechanism that regulates daily ethanol intake in sP rats, likely based on the pharmacological effects of ethanol.
Alcohol Consumption, Alcohol Dependence, and All‐Cause Mortality
Authors: Dawson Deborah A. 
Published: May 2006

Background:This study examined the effects of alcohol consumption and DSM‐IV alcohol dependence on the risk of mortality.Methods:Data from the 1988 National Health Interview Survey Alcohol Supplement were matched to the National Death Index for the years 1988 to 1995 (baseline n= 37,682 U.S. adults age ≥25 linked to 3,586 deaths). All mortality analyses were based on proportional hazards models that adjusted for age, sex, race/ethnicity, marital status, education, income, labor force status, body mass index, smoking status, and poor health indicators at baseline.Results:When dependence was not considered and all past‐year abstainers were used as the reference group, both light and moderate drinkers exhibited a reduced risk of mortality, with hazards ratios of 0.76 (0.68–0.84) and 0.84 (0.74–0.96). Heavy drinkers had about the same risk of dying as did past‐year abstainers, and very heavy drinkers had an increased risk that was not significant (OR = 1.17, CI = 0.93–1.47). When lifetime abstainers were used as the reference category, the protective effect of moderate drinking fell short of significance, and there were nearly significant increased risks among former drinkers and very heavy drinkers. When dependence was considered, light and moderate drinkers without dependence had a reduced mortality risk regardless of reference group, and there was no significant effect among heavy or very heavy drinkers without dependence. Among dependent drinkers, there was no protective effect of light or moderate drinking, and very heavy drinkers had a significantly increased risk (OR = 1.56 relative to past‐year abstainers and 1.65 relative to lifetime abstainers).Conclusions:Because alcohol dependence nullifies the protective effect of light and moderate drinking, it is important to understand its role as an independent risk factor for mortality. Differences between dependent and nondependent drinkers who drank comparable amounts suggest that this risk may result from longer and heavier drinking histories before baseline, more severe health problems at baseline, more heavy episodic drinking, and, possibly, differences in beverage preference.
Ethanol Increases the Neurotoxic Effect of Tumor Necrosis Factor‐α in Cultured Rat Astrocytes
Authors: DeVito William J. , Stone Scott , Shamgochian Maureen 
Published: May 2006

Background:The central nervous system is particularly sensitive to the cytotoxic effect of ethanol. In vivo and in vitro studies indicate that ethanol decreases cell proliferation in a number of cells types, including neurons and glial cells in the central nervous system. The cellular mechanisms involved in ethanol‐induced cell toxicity, however, are unclear. In this study, we examined the effect of ethanol on tumor necrosis factor‐α (TNFα)‐induced cell death in a homogeneous population of cultured rat astrocytes.Methods:Flow cytometric and 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenytetrazolium bromide (MTT) dye reduction analyses were performed on cultured rat astrocytes to determine the effect of alcohol on TNFα‐induced cell death.Results:Flow cytometric analysis revealed that, in quiescent astrocytes, high concentrations of ethanol were required to increase DNA fragmentation and decrease cell viability. Preexposure of astrocytes to low concentrations of ethanol (10 to 50 mM), however, increased the sensitivity of astrocytes to TNFα with low TNFα concentrations (25 to 50 ng/ml) resulting in increased DNA fragmentation. Furthermore, MTT dye reduction analysis revealed that exposure of astrocytes to 5 mM ethanol was sufficient to increase the susceptibility of astrocytes to the cytotoxic effect of ethanol. In a number of cell types, TNFα receptor binding results in the activation of specific signal transduction cascades, including the hydrolysis of sphingomyclin to ceramide. We show that preexposure of astrocytes to a low concentration of ethanol increased the sensitivity of astrocytes to sphingomyelinase, and C2‐ceramide resulting in increased DNA fragmentation and decreased cell viability. More importantly, astrocytes prepared from rats exposed to ethanol prenatally showed increased susceptibility to TNFα‐induced cell death.Conclusions:These studies suggest that ethanol increases the susceptibility of astrocytes to TNFα‐induced cell death by shifting the balance of sphingolipid metabolism in favor of a pathway that increases the susceptibility of astrocytes to the cytotoxic effect of TNFα.
Polymorphism in the Interleukin‐1 Receptor Antagonist Gene Is Associated With Alcoholism in Spanish Men
Authors: Pastor Isabel J. , Laso F. Javier , Àvila José J. , Rodriguez Raquel E. , González‐Sarrniento Rogelio 
Published: May 2006

Background:A polymorphism located in intron 2 of the interleukin‐1 receptor antagonist (IL1RN) gene recently has been associated with the development of hepatic fibrosis in Japanese alcoholics. In the present study, we analyzed whether there is an association between this polymorphism, alcoholism, and alcoholic liver disease in a Spanish male population of alcoholics.Methods:The IL1RN genotype was assessed by polymerase chain reaction by using oligonucleotides that flank a variable nucleotide tandem repeat polymorphism located in intron 2 of this gene in 90 male alcoholic patients from Spain; 30 alcohol‐dependent men, 30 alcohol abusers, and 30 alcoholics with liver cirrhosis. We also studied 40 healthy subjects.Results:The distribution of the IL1RN allelic frequencies in Spanish healthy subjects is similar to that previously reported in White subjects. However, the A1 allele is overrepresented in Spanish alcoholics when compared with healthy subjects. No significant differences in allelic frequencies were observed between alcoholics with liver cirrhosis and alcoholics without liver disease or between alcohol‐dependent subjects and alcohol abusers.Conclusion:The presence of the A1 allele of the IL1RN gene is associated with a higher risk of alcoholism in Spanish men.
Predictors of Substance Abuse Treatment Retention Among Women and Men in an HMO
Authors: Mertens Jennifer R. , Weisner Constance M. 
Published: May 2006

Background:Although prior research has examined predictors of treatment retention in public alcohol and drug treatment programs, little is known about factors that influence treatment retention in an insured outpatient population. Because there is growing evidence that the factors which influence treatment retention may differ by gender, we identify sex‐specific predictors.Methods:We recruited all eligible intakes to a health maintenance organization's outpatient alcohol and drug treatment program during a 2‐year period and obtained a sample of 317 women and 599 men. The programs, day hospital and traditional outpatient modalities, were abstinence based. We separated our sample by sex and used least squares and logistic regression to identify independent predictors of length of stay and program completion, respectively.Results:One general pattern of predictors of increased retention was shared by women and men in this alcohol and drug treatment program—fewer and less severe drug problems. However, most predictors were sex‐specific. Among women, retention was predicted by having higher incomes, belonging to ethnic categories other than African American, being unemployed, being married, and having lower levels of psychiatric severity. Among men, predictors of higher retention included being older, receiving employer suggestions to enter treatment, and having abstinence goals.Conclusions:These findings highlight the importance of examining aspects of the course of treatment separately by sex. They also suggest treatment factors that may enhance retention among insured populations, including employer referrals, psychiatric services, and drug‐related services.
6‐β‐Naltrexol Reduces Alcohol Consumption in Rats
Authors: Rukstalis Margaret R. , Stromberg Michael F. , O'Brien Charles P. , Volpicelli Joseph R. 
Published: May 2006

Background:In humans, 6‐β‐naltrexol is the major metabolite of naltrexone, and its effectiveness at suppressing alcohol consumption in any species has not been previously investigated. Naltrexone is an opiate antagonist that reduces excessive drinking in many species, including humans with alcohol dependence. Whether 6‐β‐naltrexol is an active metabolite that contributes to the efficacy of naltrexone remains unknown.Methods:Placebo and four doses of 6‐β‐naltrexol were given by intraperitoneal injection to outbred Wistar rats and alcohol consumption was measured using a limited access model.Results:6‐β‐Naltrexol reduced alcohol consumption in a dose‐dependent manner. At doses 7.5, 12.5, and 25 mg/kg, 6‐β‐naltrexol significantly decreased consumption of a 6% ethanol solution compared with saline control groups.Conclusions:These data suggest that there may be a potential clinical use for 6‐β‐naltrexol in recovering alcoholics.
Association Between the Functional Polymorphism of Catechol‐O‐Methyltransferase Gene and Alcohol Consumption Among Social Drinkers
Authors: Kauhanen Jussi , Hallikainen Tero , Tuomainen Tomi‐Pekka , Koulu Markku , Karvonen Matti K. , Salonen Jukka T , Tiihonen Jari 
Published: May 2006

Background:A common functional genetic polymorphism in the catechol‐O‐methyltransferase (COMT) gene (Val158 Met) results in 3‐ to 4‐fold differences in COMT enzyme activity and dopamine inactivation rate. Previous studies have shown that type I alcoholism is more common among subjects with low activity COMT genotype (LL), compared with high activity (HH) or heterozygotic (LH) genotypes.Methods:We studied alcohol consumption and the COMT genotype in middle‐aged Finnish men (n= 896), who represented an unselected ethnically homogenous population sample and reported using alcohol during the past year. Average alcohol use in pure ethanol (grams per week) was compared between subjects with LL genotype and subjects with LH or HH genotypes.Results:Men with LL genotype (30% of all subjects) reported 27% higher weekly alcohol consumption compared with the two other genotype groups (p< 0.05). The difference remained statistically significant after a multivariate adjustment for sociodemographic factors and prior or existing diseases (p= 0.031).Conclusions:The results indicate that COMT polymorphism may contribute significantly to alcohol intake not only in alcoholics but also in a general male population.
Differential Effects of Ethanol on Insulin‐Like Growth Factor‐I Receptor Signaling
Authors: Seiler Andrea E.M. , Ross Brian N. , Green Jaime S. , Rubin Raphael 
Published: May 2006

Background:Activation of the insulin‐like growth factor I receptor (IGF‐IR) by its ligands IGF‐I and IGF‐II induces cell proliferation and protects against apoptosis. Ethanol inhibits IGF‐IR tyrosine autophosphorylation, which subsequently interferes with the activation of key downstream signaling mediators including insulin‐receptor substrate‐1, phosphatidylinositol 3‐kinase, and mitogen‐activated protein (MAP) kinase. The ethanol‐induced inhibition of IGF‐IR signaling reduces mitogenesis and enhances apoptosis. In the current study, we demonstrate that the antiproliferative action of ethanol can be modulated by differential sensitivity of the autophosphorylation of the IGF‐IR to ethanol.Methods:A series of subclones was generated from 3T3 cells that express the human IGF‐IR.Results:There was considerable variability in the ability of ethanol to inhibit IGF‐I‐dependent IGF‐IR tyrosine autophosphorylation and MAP kinase activation, despite equivalent IGF‐IR expression. The IGF‐IR was completely resistant to a high concentration of ethanol (150 mM) in several subclones. The sensitivity of IGF‐IR autophosphorylation to ethanol correlated directly with the inhibition of IGF‐I‐mediated MAP kinase activation and cell proliferation. Resistant subclones exhibited features of the transformed phenotype including high MAP kinase activity, partial loss of contact inhibition, and the development of foci at confluency. The IGF‐IR isolated from ethanol‐resistant cells was similarly resistant to ethanol in autophosphorylation reactions in vitro, whereas ethanol inhibited the autophosphorylation of IGF‐IR obtained from sensitive cells.Conclusions:Our findings are the first to demonstrate the modulation of ethanol sensitivity of a tyrosine kinase receptor, and they provide a molecular basis for differential effects of ethanol on cell proliferation.