bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethanol and Acetaldehyde Inhibit the Formation of Early Osteoblast Progenitors in Murine and Human Bone Marrow Cultures
Authors: Giuliani N. , Girasole G. , Vescovi P. P. , Passeri G. , Pedrazzoni M.
Published: May 2006

Alcohol abuse is commonly associated with reduced bone mass and osteoporosis as a consequence of both systemic and direct cellular effects. To clarify some of the pathways by which alcohol exerts its actions directly on bone cells, we investigated the formation of early osteoblast progenitors (colony‐forming units for fibroblasts; CFU‐F) in long‐term murine and human bone marrow cultures exposed to ethanol and to its main metabolite, acetaldehyde. In murine bone marrow cultures, obtained from Swiss female mice, ethanol inhibited CFU‐F formation (maximal reduction ± SEM: 50 ± 2%; p < 0.01) at concentrations ranging from 0.04% to 0.6% that are similar to those reached in vivo in alcoholics. Acetaldehyde strongly reduced CFU‐F formation at concentrations of 0.004% and 0.02%, and completely abolished it at the dose of 0.06%. Similarly, ethanol (at concentrations ≥0.02%) and acetaldehyde (from 0.004% to 0.06%) significantly decreased the number of CFU‐F in human bone marrow cultures; the mean reduction observed with ethanol was 63 ± 12% (p < 0.05), whereas acetaldehyde completely prevented CFU‐F formation at the concentration of 0.06%. These in vitro observations were confirmed by the in vivo findings that the CFU‐F formation in bone marrow cultures from nine young, chronic, noncirrhotic alcoholics was significantly reduced (70 ± 15%), compared with seven age‐matched normal subjects (p < 0.01). In addition, acetaldehyde inhibited cell proliferation in human osteoblastic cells (MG‐63 and HOBIT cell lines), whereas ethanol reduced proliferation only in MG‐63 cells. Our results indicate that ethanol and acetaldehyde may directly inhibit the osteoblastogenic potential of the bone marrow, and this effect may contribute to the decreased bone formation observed in alcoholics.
Effect of Chronic Ethanol Consumption on Fatty Acid Profile of Heart Tissue in Rats
Authors: Gómez‐Tubío A. , Carreras O. , Tavares E. , Delgado M. J.
Published: May 2006

The effect of chronic ethanol ingestion on fatty acid composition and lipid content of heart tissue in rats, and whether this effect depends on age, was studied. Rats were maintained on a 30% ethanol solution in drinking water for 3 and 5 months. Control animals were given water. Phospholipid concentration was unchanged in the ethanol‐fed groups, compared with control groups, whereas total cholesterol content was increased at 5 months of treatment. An increase in stearic acid, palmitoleic acid, and 22:5n6 were observed at 3 months of ethanol ingestion. When ethanol was administered for 5 months, polyunsaturated fatty acids series n3 were decreased with respect to control. The effect of age on the profile of fatty acids of heart showed an increase of monounsaturated fatty acids and a decrease of long‐chain polyunsaturated fatty acids in both control and ethanol‐fed rats. The effect of ethanol ingestion on fatty acid composition of heart tissue is not very pronounced, but the small changes observed could contribute to the development of functional and electrophysiological features of alcoholic heart disease.
Gender Differences in Blood Levels, But Not Brain Levels, of Ethanol in Rats
Authors: Crippens Donita , White Martha L. , George Magnia A. , Jaworski Jason N. , Brunner Lane J. , Lancaster Francine E. , Gonzales Rueben A.
Published: May 2006

Female rodents tend to drink more alcohol than males, a difference that emerges at puberty and appears to vary over the female estrous cycle. In addition, male and female rodents display different responses to alcohol; for example, female rats are reported to have faster elimination rates than males. We were interested in whether circulating ovarian hormones influence alcohol distribution to or elimination from the brain of rats, which might explain observed differences in drinking behavior. We administered 0.8 g/kg of ethanol via intraperitoneal injection to age‐matched male and female Sprague‐Dawley rats. Extracellular brain ethanol was sampled using microdialysis, and vascular ethanol concentrations were determined via tail blood collection, in two separate experiments. Ethanol pharmacokinetic parameters were calculated for both compartments. There were no differences in pharmacokinetic parameters due to gender or estrous cycle stage in brain ethanol concentration profiles. There were, however, differences in blood ethanol profiles: females showed faster elimination rates and a smaller area under the ethanol concentration versus time curve than males. In addition, the maximum concentration varied significantly across the estrous cycle. These results suggest that (1) circulating ovarian hormones do not influence alcohol distribution to the brain, but do influence distribution to more peripheral tissues such as the tail; and (2) apparent differences in tail blood alcohol levels may not reflect differences in brain levels.
Effects of Microinjection of the D2 Dopamine Antagonist Raclopride Into the Ventral Tegmental Area on Ethanol and Sucrose Self‐Administration
Authors: Samson Herman H. , Chappell Ann M.
Published: May 2006

From previous microinjection studies, a reciprocal feedback between the nucleus accumbens and the ventral tegmental area (VTA) has been implicated in the reinforcing stimulus actions of ethanol and sucrose. In these studies, the effects of self administration of ethanol or sucrose solutions on maintained responding were similar when a dopamine antagonist was injected in the nucleus accumbens or a dopamine agonist was injected into the VTA. Our study was performed to determine if the effects on responding that had been observed when a dopamine agonist was injected into the nucleus accumbens would occur after an injection of a dopamine antagonist into the VTA. Male, Long‐Evans rats were initially trained to lever press using either 10% ethanol or 75% sucrose solutions as the reinforcers. Bilateral guide cannulae were implanted to allow microinjection into the VTA of differing doses of the dopamine D2 antagonist, raclopride. Only at the highest dose tested (10 μg) was any effect observed on responding maintained by either reinforcer. The effect was minimal and different from that observed after the micro‐injection of a dopamine agonist into the nucleus accumbens. This suggests that either the actions of the nucleus accumbens agonist manipulation involved other processes or that the level of enhanced dopamine release in the nucleus accumbens from the VTA antagonist injection was not sufficient to mimic the effect of the nucleus accumbens agonist injections.
Association Analysis of Sequence Variants of the GABAAα6, β2, and γ2 Gene Cluster and Alcohol Dependence
Authors: Sander Thomas , Ball David , Murray Robin , Patel Jaimin , Samochowiec Jerzy , Winterer Georg , Rommelspacher Hans , Schmidt Lutz G. , Loh El‐Wui
Published: May 2006

Quantitative trait analyses in mice suggest a vulnerability locus for physiological alcohol withdrawal severity on a chromosomal segment that harbors the genes encoding the α1, α6, β2, and γ2subunits of the γ2‐aminobutyric acid type‐A receptor (GABR). We tested whether genetic variation at the human GABAAα6, β2, and γ2gene cluster on chromosome 5q33 confers vulnerability to alcohol dependence. The genotypes of three nucleotide substitution polymorphisms of theGABRA6, GABRB2, andGABRG2genes were assessed in 349 German alcohol‐dependent subjects and in 182 ethnically matched controls. To eliminate some of the genetic variance, three more homogeneous subgroups of alcoholics were formed by: (1) a history of alcohol withdrawal seizure or delirium (n= 106); (2) a history of parental alcoholism (n= 120); and (3) a comorbidity of dissocial personality disorder (n= 57). We found no evidence that any of the investigated allelic variants confers vulnerability to either alcohol dependence or severe physiological alcohol withdrawal symptoms or familial alcoholism (p > 0.05). The frequency of the T allele of theGABRA6polymorphism was significantly increased in dissocial alcoholics [f(T) = 0.799] compared with the controls [f(T) = 0.658; p = 0.002; OR(T+) = 7.26]. Taking into account the high a priori risk of false‐positive association findings due to multiple testing, further replication studies are necessary to examine the tentative phenotype‐genotype relationship ofGABRA6gene variants and dissocial alcoholism.
Ethanol‐Nicotine Interactions at α‐Bungarotoxin‐Insensitive Nicotinic Acetylcholine Receptors in Rat Cortical Neurons
Authors: Marszalec William , Aistrup Gary L. , Narahashi Toshio
Published: May 2006

Numerous studies have indicated a correlation between ethanol intake and cigarette smoking in heavy drinkers. We have studied the underlying pharmacological basis of this relationship using cultured rat cortical neurons. These neurons express nicotinic receptors having characteristics similar to those described for the α4β2 subunit combination. In the presence of α‐bungarotoxin both acetylcholine (ACh) and nicotine evoked currents with respective EC50values of 4.3 and 3.4 μM. The maximal nicotine‐activated response, however, was only 56% that of the maximal ACh current. It was previously shown that 10 to 100 mM of ethanol potentiated ACh‐mediated currents in these neurons. We demonstrate that 100 mM ethanol similarly potentiates currents evoked by 300 nM (40%) and 1 μM nicotine (61%). This suggests that an ethanol‐induced potentiation of nicotinic currents may enhance the acute positive reinforcement associated with nicotine and could increase tobacco use during heavy ethanol intake. However, further experimentation indicated that the continuous perfusion of 30, 100, or 300 nM nicotine desensitizes ACh‐evoked currents by 38, 54, and 62%, respectively, with little direct receptor‐channel activation. The residual ACh currents of nicotine‐desensitized receptor channels were potentiated by 100 mM ethanol to nearly the extent as were the undesensitized control responses. We propose that the opposing effect of ethanol on nicotine‐induced desensitization could also explain the increased tobacco use observed with excessive drinking. Thus, ethanol has a dual effect regarding nicotine. It enhances acute nicotine‐mediated receptor activation, although opposing the net effect of nicotine‐induced receptor channel desensitization.
Children of Alcoholics Exhibit Attenuated Cognitive Impairment During an Ethanol Challenge
Authors: Erblich Joel , Earleywine Mitchell
Published: May 2006

In an attempt to identify markers potentially related to the development of problem drinking, we examined cognitive functioning in children of alcoholics (COAs) and children of nonalcoholics, both while sober and after consuming 0.85 ml/kg of ethanol. Consonant with previous research indicating that COAs exhibit less intense responses to alcohol, we predicted that COAs would experience attenuated cognitive deficits while intoxicated. Male (n= 71) and female (n= 29) college students completed tests of contextual and rote memory recall in a repeated‐measures design. Findings indicated that intoxication impaired both memory and attentional capacities, and that COAs exhibited attenuated cognitive deficits relative to children of nonalcoholics. Results were consistent with previous research demonstrating attenuated responses to alcohol in COAs. Potential mechanisms for the pathogenesis of problem drinking are discussed.
A Comparative Evaluation of Substance Abuse Treatment IV. The Effect of Comorbid Psychiatric Diagnoses on Amount of Treatment, Continuing Care, and 1‐Year Outcomes
Authors: Ouimette Paige Crosby , Gima Kristian , Moos Rudolf H. , Finney John W.
Published: May 2006

Recent surveys of the substance abuse patient population have shown a striking increase in the proportion of patients with a comorbid psychiatric disorder. In this study, patients with substance abuse and psychotic, anxiety/depressive, or personality disorders were compared with patients with only substance use disorders on treatment experiences and outcomes. Regardless of dual diagnosis status, patients generally improved on both substance use and social functioning outcomes after substance abuse treatment. At the 1‐year follow‐up, dually diagnosed patients, and patients with only substance use disorders, had comparable substance use outcomes. However, patients with major psychiatric disorders, specifically psychotic and anxiety/depressive disorders, fared worse on psychological symptoms and employment outcomes than did patients with personality disorders and only substance use disorders. Although there were some group differences on the amount of index treatment received and continuing care, the overall pattern of relationships between treatment variables and outcomes was comparable for the patient groups. In addition, there was no diagnostic group by treatment orientation matching effects, which indicated that the dual diagnosis patient groups improved as much in 12‐Step as in cognitive‐behavioral substance abuse programs.
A Comparative Evaluation of Substance Abuse Treatment: V. Substance Abuse Treatment Can Enhance the Effectiveness of Self‐Help Groups
Authors: Humphreys Keith , Huebsch Penny Dearmin , Finney John W. , Moos Rudolf H.
Published: May 2006

Affiliation with Alcoholics Anonymous (AA) and other 12‐Step self‐help groups is becoming more common at the same time as professional substance abuse treatment services are becoming less available and of shorter duration. As a result of these two trends, patients’ outcomes may be increasingly influenced by the degree to which professional treatment programs help patients take maximum advantage of self‐help groups. The present study of 3018 treated veterans examined how the theoretical orientation of a substance abuse treatment program affects (1) the proportion of its patients that participate in self‐help groups, and, (2) the degree of benefit patients derive from participation in self‐help groups. Patients treated in 12‐Step and eclectic treatment programs had higher rates of subsequent participation in 12‐Step self‐help groups than did patients treated in cognitive behavioral programs. Furthermore, the theoretical orientation of treatment moderated the outcome of self‐help group participation: As the degree of programs’ emphasis on 12‐Step approaches increased, the positive relationships of 12‐Step group participation to better substance use and psychological outcomes became stronger. Hence, it appears that 12‐Step oriented treatment programs enhance the effectiveness of 12‐Step self‐help groups. Findings are discussed in terms of implications for clinical practice and for future evaluations of the combined effects of treatment and self‐help groups.
Allele Dose Analysis in Recombinant Inbred Strains: A Tool for Multiple Phenotype Analysis With Implications for Quantitative Trait Loci Mapping
Authors: Markel P. D. , Erwin V. G.
Published: May 2006

A considerable investment in genetic mapping is necessary to confirm linkages of quantitative trait loci for complex traits such as ethanol sensitivity, a significant predictor of alcoholism. Before embarking on such intensive mapping efforts in large intercrosses, we suggest an approach based on genetic marker data in recombinant strains that yield a rationale for selecting a battery of related phenotypes for confirmation studies of quantitative trait loci action. Using this approach with selected strains of mice, we retrospectively consider the relationship between ethanol sensitivity and neurotensin levels in several mammalian brain regions.
Effect of Acute Alcohol Treatment on the Release of ACTH, Corticosterone, and Pro‐Inflammatory Cytokines in Response to Endotoxin
Authors: Rivier Catherine
Published: May 2006

This study investigated the effects of acute alcohol pretreatment on endotoxin lipopolysaccharide (LPS)‐induced release of ACTH, corticostcrone, and pro‐inflammatory cytokines tumor necrosis factor‐α (TNF‐α) and interlcukin‐6 (1L‐6) in plasma and at various tissues sites. Specifically, we wanted to determine whether alcohol pretreatment would alter the ACTH, corticosterone, and cytokine responses to LPS, and whether the alcohol‐induced changes in ACTH/corticosterone secretory rates of endotoxemic rats were accompanied by similar changes in cytokine production. Alcohol, 3.0 g/kg, intragastric (ig), was administered 3 hr before LPS treatment [1.0 or 5.0 μ‐g/kg, intravenous (iv)], and ACTH, corticosterone, and cytokines levels were measured over a 4 hr post LPS treatment. In intact rats, the alcohol‐induced plasma ACTH and corticostcrone responses had returned to basal levels by the time of LPS injection, and alcohol pretrcatment increased the corticosterone but not the ACTH response after LPS treatment. In contrast, in adrenalectomized corticosterone‐replaced animals, the alcohol‐induced ACTH response was still elevated at the time of LPS injection. However, the overall ACTH response of rats pretreated with the vehicle or alcohol was statistically similar. As expected, LPS also significantly stimulated both TNF‐α and IL‐6 release into the general circulation. The IL‐6, but not the TNF‐α, response was inhibited by alcohol pretreatment in intact rats, a phenomenon that was not present in adrenalectomized animals. Finally, we showed that LPS also augmented the TNF‐α and/or IL‐6 content of the pituitary, adrenal glands, and spleen, and that these responses were not altered by alcohol pretreatment.
Chronic Ethanol and Iron Administration on Iron Content, Neuronal Nitric Oxide Synthase, and Superoxide Dismutase in Rat Cerebellum
Authors: Xia Jinming , Simonyi Agnes , Sun Grace Y.
Published: May 2006

Excessive chronic ethanol administration to animals has been shown to cause oxidative insults to many body organs, including the liver and brain. In many instances, iron supplementation to the diet may further aggravate ethanol‐induced liver damage. However, whether increased dietary iron can enhance the damage in the brain is unknown. In this study, four groups of Sprague‐Dawley rats were fed a Lieber‐DeCarli liquid diet containing 5% (w/v) ethanol or isocaloric amount of maltase and/or 0.25% (w/v) carbonyl iron for 2 months. At the end of the feeding regimen, iron contents were determined in the plasma, liver, cerebral cortex, and cerebellum. Cerebellar superoxide dismutase (SOD) and nitric oxide synthase (NOS) activities were measured and mRNA levels of MnSOD, CuZnSOD, and nNOS in the cerebellar granule cell layer were quantitated by in situ hybridization. Ethanol treatment alone caused an increase in iron levels in plasma, no change in the liver and cerebral cortex, but a decrease in the cerebellum. Iron supplementation increased liver iron>4‐fold but did not alter iron contents in the cerebellum and cortex. All of the mRNA species examined and SOD activity were not affected by either iron or ethanol administration. However, NOS activity in the cerebellum was significantly enhanced by ethanol, whereas iron supplementation had an opposite effect. Our results indicate that iron supplementation to animals consuming ethanol may have tissue‐specific effects. Furthermore, ethanol‐induced increase in NOS activity in the cerebellum may explain the sensitivity of cerebellar neurons to oxidative insult.
Prenatal Alcohol Use and Offspring Size at 10 Years of Age
Authors: Day Nancy L. , Zuo Yanling , Richardson Gale A. , Goldschmidt Lidush , Larkby Cynthia A. , Cornelius Marie D.
Published: May 2006

The Maternal Health Practices and Child Development Project is a longitudinal study of the effects of prenatal exposure to alcohol and other substances. Women were selected from a prenatal clinic and interviewed at the 4th and 7th months of pregnancy. Their offspring were examined at delivery, at 8 and 18 months, and at 3, 6, and 10 years. This report examined 610 offspring, at age 10, who were exposed prenatally to alcohol. Most alcohol use in this low‐income cohort was light to moderate, although the entire spectrum of alcohol use is represented. The weight, length, head circumference, and skinfold thickness of the offspring were measured. At each assessment phase, we found a significant association between size and prenatal exposure to alcohol. At age 10, the children who were prenatally exposed to alcohol continued to be significantly smaller in weight, height, head circumference, and skinfold thickness. These results indicate that prenatal alcohol exposure has a long‐term impact on offspring growth.
stellate Cell Activation in Alcoholic Fibrosi—An Overview
Authors: Friedman Scott L.
Published: May 2006

There has been remarkable progress in our understanding of how chronic alcohol ingestion may lead to hepatic injury and scarring, or fibrosis. Hepatic fibrosis represents the liver's wound healing response and is characterized by accumulation of interstitial matrix, or scar. Fibrosis in the liver results from the activation of stellate cells, or resident mescnchymal cells. Stellate cell activation is a dramatic phenotype transition whose net effect is the replacement of normal liver matrix by scar. Features of stellate cell activation include increased cell accumulation from proliferation and directed migration, increased matrix production, enhanced contractility, accelerated degradation of the normal liver matrix, release of profibrogenic cytokines, and loss of cellular vitamin A. Alcohol may enhance fibrogenesis through stimulation of stellate cells by hypoxia, generation of lipid peroxides from damaged hepatocytes, production of acetaldehyde that may have direct fibrogenic activity, and through activation of Kupffer cells or resident macrophages. Unanswered questions remain to be studied, but the clarification of underlying mechanisms of fibrosis portends continued progress in our ability to treat alcoholic liver fibrosis.
An A/G Polymorphism in the Promoter of Mitochondrial Aldehyde Dehydrogenase (ALDH2): Effects of the Sequence Variant on Transcription Factor Binding and Promoter Strength
Authors: Chou Wan‐Yin , Stewart Mark J. , Carr Lucinda G. , Zheng Daisy , Stewart Trent R. , Williams Adrienne , Pinaire Jane , Crabb David W.
Published: May 2006

Introduction:

The strong protective effect of the ALDH2*2 mutation on risk of alcoholism suggests that other mutations that reduce mitochondrial aldehyde dehydrogenase (ALDH) activity in the liver might also deter drinking. This study describes a polymorphic locus found in the promoter of the ALDH2 gene that affects expression of reporter constructs.

Method: Polymerase chain reaction (PCR)‐based sequencing was used to search for polymorphisms. The ability of the promoter variants to bind transcription factors apolipoprotein A regulatory protein 1 (ARP‐1) and chicken ovalbumin upstream promoter‐transcription factor (COUP‐TF) was tested in gel retardation assays using in vitro synthesized transcription factors. The variant promoters were tested for transcriptional activity using a heterologous promoter system and transient transfection assays.

Result: A common polymorphism (A or G) in the human ALDH2 promoter region was found at ‐361 base pair (bp) from the translation start site. This polymorphism was found at different frequencies in African Americans, Caucasians, and Asians. The polymorphism occurs adjacent to the core binding motif for the transcription factors COUP‐TF and ARP‐1. Competition and binding affinity determinations did not show differences in the ability of these two sequences to bind the factors. Reporter genes containing these elements upstream of a basal thymidine kinase promoter had similar activity when transfected into a fibroblast (CV‐1) cell line. However, the reporter containing the G allele was more active than that containing the A allele in hepatoma (H4IIEC3) cells.

Conclusions: The ‐361 bp A/G polymorphism is common in all racial groups tested. The G allele was more active than the A allele in a transfection assay. The basis for this difference is not known. If the differences in activity of the promoter constructs were paralleled by differences in ALDH2 enzyme activity in the liver, this polymorphism could affect risk of alcoholism.
Total Body Water and Peak Alcohol Concentration: A Comparative Study of Young, Middle‐Age, and Older Females
Authors: Davies Becky T. , Bowen Charles K.
Published: May 2006

A search of the alcohol research literature reveals that very little experimental work has been done to describe the effects of alcohol in older females. In the present study, the effects of age and body water volume on the resultant peak alcohol concentration were observed for females ranging in age from 21 to 81. The peak alcohol concentration was estimated by breath testing in three groups of female volunteer subjects: young (21 to 25 years old), middle‐age (35 to 47 years old), and older (>60 years old) after ingestion of 30 g of alcohol. Bioelectrical impedance analysis and anthropometric equations were used to estimate total body water, percent body water, and percent body fat for each subject. Significantly higher blood alcohol concentrations were obtained in older females [mean blood alcohol concentration (±SD) = 0.0975 ± 0.018], compared with younger females (0.0818 ± 0.016 and 0.0811 ± 0.012). The results suggest, however, that this effect cannot be fully explained by the notion that older persons have a smaller body water volume. Particular attention is paid to the difference between total body water in liters and body water expressed as a percentage of body weight. Evidence is offered to demonstrate that percent body fat is not a determinant of the blood alcohol level an individual will attain. The findings are discussed with particular reference to the lack of experimental work involving older females and alcohol.
Action of Ethanol on Responses to Nicotine From Cerebellar Interneurons and Medial Septal Neurons: Relationship to Methyllycaconitine Inhibition of Nicotine Responses
Authors: Yang Xiaohong , Criswell Hugh E. , Breese George R.
Published: May 2006

Background: A majority of alcoholics also smoke, suggesting that alcohol and nicotine share a common action on nicotinic cholinergic receptors.

Method: Extracellular single‐unit recording was used to investigate the effects of ethanol on responses to nicotine from rat cerebellar interneurons and medial septal neurons.

Result: Nicotine produced inhibition from medial septal neurons, but increased neural activity of cerebellar interneurons. When ethanol was applied locally to cerebellar interneurons, the excitatory response to nicotine was enhanced in a dose‐related manner. Nicotine‐induced inhibition from medial septal neurons was reduced by ethanol from the majority of neurons, but a dose relationship for this inhibition by ethanol was not observed. Ethanol affected responses to nicotine from over 90% of all neurons investigated at these sites. Initially, it was established that the nicotinic antagonists, methyllycaconitine (MLA) and α‐bungarotoxin, which affect a nicotinic cholinergic (nACh) receptor with an α7 subunit, had similar actions on responses to nicotine from individual medial septal cells and cerebellar interneurons. When MLA was tested against responses to nicotine from neurons in the two brain regions, MLA antagonized responses to nicotine from only 27% of the neurons rather than the 90% found for ethanol. This latter observation provided evidence that ethanol was affecting neurons with MLA‐insensitive receptors. When the actions of ethanol on responses to nicotine were compared directly with the action of MLA on the same medial septal neurons, both ethanol and MLA caused a greater than 50% antagonism of the response to nicotine, indicative that nACh receptors with the α7 subunit were sensitive to ethanol.

Conclusions: Collectively, these data provide evidence that ethanol affects responses to nicotine not only from nACh receptors on medial septal cells and cerebellar interneurons containing an α7 subunit (i.e., MLA‐sensitive receptors), but also from nACh receptor subtypes without this specific nACh receptor subunit (i.e., MLA‐insensitive receptors).
Microsomal Ethanol‐Oxidizing System (MEOS): The First 30 Years (1968‐1998)–A Review
Authors: Lieber Charles S.
Published: May 2006

Oxidation of ethanol via alcohol dehydrogenase (ADH) explains various metabolic effects of ethanol but does not account for the tolerance and a number of associated disorders that develop in the alcoholic. These were elucidated by the discovery of the microsomal metabolism of ethanol. The physiologic role of this system comprises gluconeogenesis from ketones, fatty acid metabolism, and detoxification of xenobiotics, including ethanol. After chronic ethanol consumption, the activity of the microsomal ethanol‐oxidizing system (MEOS) increases, with an associated rise in cytochromes P‐450, especially CYP2E1. This induction is associated with proliferation of the endoplasmic reticulum, both in experimental animals and in humans. The role of MEOS in vivo and its increase after chronic ethanol consumption was shown most conclusively in alcohol dehydrogenase‐negative deer mice. Enhanced ethanol oxidation is associated with cross‐induction of the metabolism of other drugs, resulting in drug tolerance. Furthermore, there is increased conversion of known hepatotoxic agents (such as CCl4) to toxic metabolites, which may explain the enhanced susceptibility of alcoholics to the adverse effects of industrial solvents. CYP2E1 also has a high capacity to activate some commonly used drugs, such as acetaminophen, to their toxic metabolites, and to promote carcinogenesis (e.g., from dimethylnitrosamine). Moreover, catabolism of retinol is accelerated and there also is induction of microsomal enzymes involved in lipoprotein production, resulting in hyperlipemia. Contrasting with the chronic effects of ethanol consumption, acute ethanol intake inhibits the metabolism of other drugs through competition for the at least partially shared microsomal pathway. In addition, metabolism by CYP2E1 results in a significant free radical release and acetaldehyde production which, in turn, diminish reduced glutathione (GSH) and other defense systems against oxidative stress. Acetaldehyde also forms adducts with proteins, thereby altering the functions of mitochondria and of repair enzymes. Increases of CYP2E1 and its mRNA prevail in the perivenular zone, the area of maximal liver damage. CYP1A2 and CYP3A4, two other perivenular P‐450s, can also sustain the metabolism of ethanol, thereby contributing to MEOS activity and possibly liver injury. By contrast, CYP2E1 inhibitors oppose alcohol‐induced liver damage, but heretofore available compounds were too toxic for clinical use. Recently, however, polyenylphosphatidylcholine (PPC), an innocuous mixture of polyunsaturated lecithins extracted from soybeans, was discovered to decrease CYP2E1 activity. PPC (and its active component dilino‐leoylphosphatidylcholine) also oppose hepatic oxidative stress and fibrosis. PPC is now being tested clinically for the prevention and treatment of liver disease in the alcoholic.
Innate Differences of Neuropeptide Y (NPY) in Hypothalamic Nuclei and Central Nucleus of the Amygdala Between Selectively Bred Rats with High and Low Alcohol Preference
Authors: Hwang Bang H. , Zhang Jing‐Kang , Enters Cindy L. , Lumeng Lawrence , Li T.‐K.
Published: May 2006

Background: Neuropeptide Y (NPY) is a neuropeptide that has been demonstrated to produce anxiolytic effects when administered centrally. To examine the hypothesis that NPY might play a role in alcohol‐seeking behavior, this study took advantage of the genetic differences of the alcohol‐preferring (P) rats and alcohol‐nonpreferring (NP) rats, as well as the high alcohol‐drinking (HAD) rats and low alcohol‐drinking (LAD) rats, in voluntary alcohol consumption to examine if NPY neurons in the brains differ between these selected lines.

Method: The NPY immunoreactivity (NPY‐I) was measured using an established radioimmunohisto‐chemical assay in discrete brain structures including the paraventricular hypothalamic nucleus (PVN), arcuate nucleus (ARC), and central nucleus of the amygdala (CeA).

Result: The quantitative data indicated that there was more NPY‐I in the PVN and ARC of P rats than NP rats, whereas there was less NPY‐I in the PVN and ARC of HAD rats than LAD rats. However, the NPY‐I in the CeA was less in both the P and HAD rats than in the NP and LAD rats, respectively. Therefore, the data indicate that there are innate differences in the NPY‐I in the brain between selectively bred rats with high and low alcohol preference.

Conclusion:

Because both P rats and HAD rats have high alcohol preference, the disparate finding between these two lines of rats suggests that the hypothalamic NPY neurons are probably not associated with alcohol preference. In contrast, consistent findings in the CeA of both P rats and HAD rats suggest that NPY in the CeA of P and HAD rats may contribute to the regulation of alcohol consumption. This is substantiated by a recent report showing that NPY‐knockout mice drink significantly more ethanol, and transgenic mice that overexpress the NPY gene drink less alcohol, than wild‐type mice. Together, the findings support the notion that NPY agonists that would enhance NPY function in the amygdala might be useful for the treatment of anxiety and alcoholism.
Reversal of a Postnatal Alcohol‐Induced Deficit in Learned Persistence in the Rat by d‐Amphetamine
Authors: Highfield David A. , Lilliquist Michael W. , Amsel Abram
Published: May 2006

Periodic (high peak) exposure to alcohol during early infancy in the rat has been shown to disrupt the partial reinforcement extinction effect (PREE), a measure of persistence learning, when rats were tested at weaning age. The current study examined the effects of d‐amphetamine (0.3 mg/kg, i.p.) on the PREE after early postnatal exposure to alcohol (4.5 mg/kg) delivered in a milk‐based diet or an isocaloric control diet via oral intubation once a day on postnatal days 4 to 9. On postnatal days 20 and 21, rats were trained on either a continuously reinforced or partially reinforced schedule of food reward, followed by extinction. Rats were randomly assigned to eight conditions, depending on diet, drug, and reward schedule. The results were (1) a replication of the finding that periodic (high peak) exposure to alcohol diminishes the PREE, and (2) that amphetamine restores the PREE to normal levels in alcohol‐treated animals, and may reduce the PREE in control subjects. The possible role of noradrenergic and dopaminergic systems in situations of extinction and nonreward are discussed.
Repeated Ethanol Withdrawal Delays Development of Focal Seizures in Hippocampal Kindling
Authors: Veatch Lynn M. , Gonzalez Larry P.
Published: May 2006

Clinical studies report an increase in the prevalence of alcohol withdrawal‐related seizures in patients with a history of multiple detoxifications. In order to investigate the alcohol withdrawal‐related alterations in neural activity that lead to this increase in seizure propensity, basic researchers have examined both spontaneous and elicited seizures in animals undergoing withdrawal from chronic ethanol. This study was designed to further examine alcohol withdrawal‐related seizure activity in a rodent model by assessing the development of electrical kindling after chronic ethanol exposure administered in multiple or single treatment episodes. Laboratory rats were exposed to either five periods of 3 days of ethanol, one 15‐day period of continuous ethanol, or a period of control handling with no ethanol exposure. Ten days after a final withdrawal episode, all animals were surgically prepared with recording and stimulating electrodes. Twenty days after final withdrawal from ethanol or an equivalent period of similar handling, daily electrical stimulation of hippocampal area CA3 was initiated. Animals exposed to ethanol required more daily stimulations to become fully kindled than did ethanol‐naive controls, with those animals experiencing five withdrawals requiring the most stimulations overall and more stimulations to progress from focal to generalized seizure behaviors. These results indicate that chronic ethanol exposure and withdrawal alter neuronal mechanisms important for hippocampal kindling in a manner that persists long after cessation of ethanol exposure, and they indicate that this effect is increased by exposure to repeated withdrawal episodes.
Operant Self‐Administration of Sweetened Versus Unsweetened Ethanol: Effects on Blood Alcohol Levels
Authors: Roberts Amanda J. , Heyser Charles J. , Koob George F.
Published: May 2006

Background:Sweeteners are often added to ethanol solutions to increase ethanol intake. However, literature on studies that use human subjects and laboratory animals suggests that sucrose, other sugars, and carbohydrate‐rich foods alter ethanol absorption and metabolism, which leads to lower blood alcohol levels (BAL) relative to ethanol absorbed alone. This experiment was designed to test whether the addition of the nutritive sweetener sucrose, or the nonnutritive sweetener saccharin, to a 10% ethanol solution, self‐administered in an oral operant paradigm, affected BAL in rats relative to self‐administration of an unsweetened 10% ethanol solution.

Methods:All rats were trained to lever press for ethanol by use of a saccharin fading procedure. Half of the rats then received 30‐min sessions in which ethanol + 2% sucrose and water were available and were alternated daily with sessions in which ethanol + 0.2% saccharin and water were available. The other half of the rats went on to receive daily sessions of unsweetened ethanol and water. BAL were taken after these standard daily sessions as well as after a 1‐week period of alcohol deprivation (to enhance ethanol intake).

Results:Rats responded for more ethanol + sucrose than unsweetened ethanol, but had lower BAL per gram ethanol consumed in both the baseline test and alcohol deprivation effect test. No effect of saccharin on BAL was detected. An additional experiment that examined the effects of four concentrations of both sucrose and saccharin on self‐administration of ethanol and BAL showed that, whereas rats consumed more ethanol + sucrose than ethanol + saccharin, BAL were significantly lower per gram ethanol consumed in the sucrose group.

Conclusions:These results confirm previous reports and suggest that the addition of sucrose to an ethanol solution can result in lower BAL relative to unsweetened ethanol in an oral operant self‐administration paradigm.
Ontogeny of Rapid Tolerance to the Hypnotic Effects of Ethanol
Authors: Silveri Marisa M. , Spear Linda Patia
Published: May 2006

Background: Alcohol use typically begins during adolescence. Little is known regarding the antecedents and impact of this early alcohol use, although age‐related changes in the neural systems modulating alcohol sensitivity could contribute to the propensity of adolescents to consume alcohol. We have previously observed a marked ontogenetic decline in acute tolerance to ethanol (EtOH), with preweanling pups exhibiting the most acute tolerance (Silveri and Spear, 1998). The objective of this study was to assess whether rapid tolerance shows a similar ontogenetic profile.

Methods: In Experiment I of the present study, female and male Sprague‐Dawley preweanling rats at postnatal day (P) 16 or young adults at P56 were examined. On Day 1, preweanlings were pretreated with saline, 1.5,3.5, or 5.0 g/kg EtOH and adults were pretreated with saline or 3.5 g/kg EtOH. This was followed by challenge with 3.5 g/kg EtOH and assessment of ethanol‐induced sleep time on Day 2. In Experiment II, adolescents at P36 were pretreated with saline, 3.5, or 5.0 g/kg EtOH on Day 1 before Day 2 assessment of sleep time after 3.5 g/kg EtOH. Upon awakening, animals were killed and whole brains removed and analyzed for brain alcohol levels (BrALs).

Results: Rapid tolerance was observed in P36 and P56 animals, with EtOH‐pretreated animals exhibiting significantly shorter sleep times than age‐matched animals treated with saline. In contrast, no evidence for rapid tolerance was seen after any pretreatment dose at P16. Interestingly, although EtOH‐pretreated adults woke at higher BrALs than saline‐treated adults, this pattern was not evident in the adolescents, which suggests that at this age, metabolic tolerance may play a prominent role in the expression of rapid tolerance. Thus, it seems as though the ability to develop rapid tolerance to EtOH hypnosis emerges during adolescence and continues into adulthood.

Conclusions: Together with previous findings that adolescent animals also display substantial acute tolerance to alcohol (Silveri and Spear, 1998), the propensity of adolescents for developing these two forms of tolerance may have important implications for the increased voluntary consumption of alcohol at this age relative to other ages.
Adrenocortical Responses and Family History of Alcoholism
Authors: Wand Gary S. , Mangold Deborah , Ali Mahmood , Giggey Paul
Published: May 2006

Background: This study was designed to assess whether nonalcoholic offspring from families with a high density of alcohol‐dependent individuals have altered hypothalamic‐pituitary‐adrenal (HPA) axis dynamics compared with nonalcoholic subjects without a family history of alcohol dependence.

Methods: Seventy‐eight nonalcoholic subjects aged 18 to 25 were enrolled in the protocol. Thirty‐nine subjects were offspring from families with a high density of alcohol dependence and were designated as family history‐positive (FHP) subjects. Thirty‐nine subjects were biological offspring of nonalcohol‐dependent parents and were designated as family history‐negative (FHN) subjects. Subjects received naloxone hydrochloride (0 and 125 μg/kg) and cosyntropin (0, 0.25 μg, and 250 μg) in double‐blind, randomized order and Cortisol was monitored. A subset of subjects (11 FHP, 11 FHN) was admitted to the General Clinical Research Center to measure serum Cortisol levels every 30 min for 24 hr.

Results: FHP subjects had an increased Cortisol response to opioid receptor blockade induced by naloxone. However, no group differences in Cortisol were uncovered during administration of cosyntropin or during monitoring of the Cortisol circadian profile.

Conclusion: These observations suggest that differences in the Cortisol dynamics between FHP and FHN subjects are unmasked by opioid receptor blockade directed at the hypothalamus, but not when Cortisol levels are directly provoked at the level of the adrenal gland. In addition, unprovoked Cortisol secretion monitored over a 24‐hr interval cannot distinguish FHP from FHN subjects.
Immune Changes in Alcohol‐Dependent Patients Without Medical Disorders
Authors: Schleifer Steven J. , Keller Steven E. , Shiflett Samuel , Benton Tonya , Eckholdt Haftan
Published: May 2006

Introduction: We examined a battery of in vitro immune measures in inner city alcohol‐dependent (as determined by the Structured Clinical Interview for DSM‐III‐R (SCID) persons who were without liver or other medical disorders and free of other substance abuse. These subjects were seeking treatment at an ambulatory alcohol treatment center.

Methods: Alcohol‐dependent subjects (n = 44) were compared with healthy, nonabusing community subjects (n= 34). Subjects, both male and female, had a mean age of 41 years and were primarily African American. Many were homeless. An extended battery of enumerative and functional immune measures was obtained, as well as information about alcohol consumption.

Results: Controlling for age and gender, ANCOVA revealed no differences (p > 0.1) between alcohol‐dependent and control subjects in leukocyte and lymphocyte subsets or in circulating CD56+ (natural killer) cells. There were also no significant differences in responses to the mitogens phytohemagglutinin, con‐canavalin A, or pokeweed mitogen (p > 0.1) or in natural killer cell activity (p> 0.1). There was, however, altered granulocyte function in the alcohol‐dependent sample, with decreased phagocytic activity in the alcohol‐dependent males (p < 0.04) and gender and age dependent differences in the number of circulating granulocytes (p < 0.01). Granulocyte killing of Staphylococcus aureus, however, did not differ between the groups.

Conclusions: The findings suggest that although males with chronic alcohol dependence have compromised phagocytic function, chronic alcohol‐dependent subjects who are free of medical disorders do not have substantial abnormalities in many immune system functions.
Hypoperfusion of the Cerebellum and Aging Effects on Cerebral Cortex Blood Flow in Abstinent Alcoholics: A SPECT Study
Authors: Harris Gordon J. , Oscar‐Berman Marlene , Gansler A. , Streeter Chris , Lewis Robert F. , Ahmed Iqbal , Achong Dwight
Published: May 2006

Background:This study evaluated hypotheses concerning alcoholism, aging, and the relationship between cerebral hypoperfusion and residual deficits in the functioning of cerebellar and neocortical brain systems.

Methods:The participants were 10 healthy abstinent alcoholics (9 men, 1 woman) and 12 nonalcoholic controls (10 men, 2 women) ranging in age from 35 to 67 years. Cerebral blood flow was observed through the use of regionally specific computer‐derived quantitative analysis of single photon emission computed tomography (SPECT) perfusion images. Cerebellar perfusion was measured and compared with cerebral cortex perfusion in age‐equivalent subgroups of alcoholics and controls (under 55 years; 55 years and over).

Results:In abstinent alcoholics under age 55, cerebellar perfusion ratios were significantly reduced compared with the controls. In alcoholics and nonalcoholic controls 55 years old and older, this relationship was reversed, probably as a result of diminished cortical perfusion with aging in the alcoholics and of cerebellar decline in the controls.

Conclusions:The findings support hypotheses that the residual effects of alcoholism include cerebellar brain abnormalities and that aging combined with long‐term alcoholism leads to cerebral cortical decline.
Nutritional Status and Body Fluid Distribution in Chronic Alcoholics Compared With Controls
Authors: Addolorato Giovanni , Capristo Esmeralda , Caputo Fabio , Greco Aldo V. , Ceccanti Mauro , Stefanini G. Francesco , Gasbarrini Giovanni
Published: May 2006

Background:At present few data are available on the total body water (TBW) content and in particular on the distribution of water in the intra‐ and extracellular compartments (ICW and ECW) of alcoholics. The aim of this study was to evaluate TBW, ICW, and ECW in chronic alcoholic patients.

Methods:Thirty‐six alcoholics meeting DSM‐III‐R criteria for diagnosis (20 men, 16 women; body mass index [BMI] 22.3 ± 2.57 kg/m2) were enrolled. Fifty‐four healthy social drinkers (31 men, 23 women; BMI 23.7 ± 1.68 kg/m2) matched for age and height were used as controls. Systolic and diastolic blood pressure was measured for all cases. All patients were assessed using specific anthropometric measurements. The waist‐to‐hip ratio (WHR) was used as an indicator of body fat distribution. TBW was measured by isotopic dilution by giving 100 μCi of tritiated water. ICW and ECW were assessed by multifrequence bioelectric impedance analysis (BIA). Basal metabolic rate (BMR) was measured by indirect calorimetry.

Results:Body weight was lower in the alcoholics than in the controls (61.9 ± 5.5 kg vs. 65.8 ± 5.2 kg;p < 0.01), essentially due to a reduction in fat mass. Significantly higher WHR values were found in both male (p < 0.001) and female (p<0.001) alcoholics than in healthy subjects. A higher ECW/TBW ratio was found in the alcoholics compared with the controls, both as a whole (0.53 ± 0.04 vs. 0.41 ± 0.03;p < 0.0001) and separated by gender (p < 0.001).

Conclusions:The increased ECW could derive from an increase in cellular permeability related to endothelial damage linked to the vasoconstriction present in the alcoholics and/or to a direct toxic effect of ethanol on cellular membranes. In addition, because the high ECW volumes correlated positively with WHR in the alcoholics, a potential association of these two factors in determining an increased risk of liver disease, hypertension, and cardiovascular disease may exist. Finally, the lower TBW characteristic of women may be one of the reasons for the observed greater rate of toxic effects of ethanol that occur in women.