bluuebunny/crossref_metadata_2025 huggingface dataset:
Diastolic Function Impairment in Alcoholics
Authors: Fernández‐Solà Joaquim , Nicolás José‐María , Paré Joan‐Carles , Sacanella Emilio , Fatjó Francesc , Cofán Montserrat , Estruch Ramón
Published: April 2006

Background: Chronic excessive ethanol consumption exerts a deleterious effect on the myocardium. Although the effects of chronic alcoholism on systolic cardiac function are well known, diastolic involvement has been evaluated only partially. Therefore, we determined the presence of left ventricular diastolic impairment in chronic alcoholics and its relation with simultaneous systolic dysfunction. We also assessed the influence of ethanol consumption in diastolic impairment.

Methods: Thirty‐five alcoholics with cardiomyopathy (ejection fraction ≤ 50%) and 77 alcoholics with normal systolic function (ejection fraction > 50%) were evaluated. Assessment of New York Heart Association functional class, history of ethanol intake, technetium‐99m radionuclide angiocardiography, and bidimensional Doppler echocardiography with evaluation of systolic and diastolic left ventricular function were performed.

Results: Diastolic function impairment was present in one third of the alcoholics without cardiomyopathy, compared with two thirds of the patients with cardiomyopathy (p < 0.01). A pseudonormalization phenomenon of diastolic function was observed in patients with more advanced systolic dysfunction (ejection fraction < 32%). The deterioration of the diastolic parameters correlated with ethanol consumption, regardless of age (r= 0.44, p < 0.001 for ratio of peak velocity of the transmitral flow in early diastole and peak velocity of atrial contraction flow, with lifetime dose of ethanol).

Conclusions: There seems to be a dose‐dependent effect of ethanol on systolic and diastolic heart function. Diastolic function impairment is present in one third of alcoholics with normal systolic function and is even more frequent when systolic dysfunction coexists.
In Vitro Effects of Ethanol Withdrawal and Spermidine on Viability of Hippocampus From Male and Female Rat
Authors: Prendergast Mark A. , Harris Barton R. , Blanchard John A. , Mayer Sveta , Gibson D. Alex , Littleton John M.
Published: April 2006

Background: Long‐term ethanol dependence results in neuronal adaptation that likely contributes to ethanol withdrawal‐induced central nervous system excitability and, potentially, neurotoxicity. This has been suggested to result, in part, from increased release of or response to endogenous polyamines. Furthermore, it has been reported that neurological difficulties related to ethanol dependence and withdrawal may be more severe in female than in male alcoholics. Thus, we designed this study to examine effects of the polyamine spermidine on neurotoxicity associated with withdrawal from long‐term ethanol exposure by using organotypic hippocampal slice cultures derived from male and female rats.

Methods and Results: Twenty‐four hours of withdrawal after continuous 10 day ethanol exposure (100 mM in culture medium) resulted in cytotoxicity in hippocampal slice explants obtained from both sexes. This was most evident in pyramidal cell layers of the CA1 region, and no sex differences were observed in the severity of damage. Exposure of explants from both sexes to the NMDA blocker MK‐801 during ethanol withdrawal significantly reduced this toxicity. In control cultures, exposure to spermidine (100 μM) alone produced significant and similar cytotoxicity in hippocampal explants of male and female rats. Exposure to spermidine (100 μM) during ethanol withdrawal significantly increased cytotoxicity in all regions of explants. In the CA3 region, spermidine‐potentiation of ethanol withdrawal damage was significantly greater in explants from female rats compared with those from male rats.

Conclusions: These data demonstrate the presence of significant hippocampal neurotoxicity during withdrawal from long‐term ethanol exposure that is mediated, in part, by overactivation of NMDA receptors. Furthermore, these findings suggest that the central nervous system of females may be more susceptible than that of males to polyamine‐mediated neuronal damage during withdrawal from long‐term ethanol exposure.
Carbonyl Levels in Type I and II Fiber‐Rich Muscles and Their Response to Chronic Ethanol Feeding In Vivo and Hydroxyl and Superoxide Radicals In Vitro
Authors: Koo‐Ng Robin , Falkous Gavin , Reilly Matthew , Peters Timothy J. , Mantle David , Preedy Victor R.
Published: April 2006

Background: Chronic alcoholic myopathy is characterized by selective reductions in the size of Type II skeletal muscle fibers (i.e., glycolytic, anaerobic fast‐twitch). Type I (i.e., oxidative, aerobic, slow twitch) fibers are relatively resistant. It is possible that reactive oxygen species may preferentially damage the Type II fibers because the concentrations of several antioxidant enzymes are lower in Type II compared with Type I fibers.

Methods: To test the hypothesis, we measured protein carbonyl levels in Type I (i.e., soleus) and Type II (i.e., plantaris) fiber‐rich muscles of rats subjected to chronic alcohol dosage with the Lieber‐DeCarli regimen. Muscles were also exposed to hydroxyl or superoxide radicals in vitro.

Results: The Type I fiber‐predominant soleus of control animals had less carbonyl than the Type II fiber‐predominant plantaris. In rats that were fed ethanol for 6 weeks, the weights of the plantaris muscle were preferentially reduced but changes in soleus weight did not achieve significance. However, carbonyl levels were not significantly altered in any muscle in response to alcohol feeding. Calculation of the data in terms of total carbonyl per whole muscle showed decreases in both soleus and plantaris at the end of the 6‐week alcohol feeding period. In response to hydroxyl radical (OH.) generation in vitro, protein carbonyl increased substantially in both soleus and plantaris muscles, but more so in the soleus. The increase in carbonyl in control soleus muscles in response to OH. was significantly lower than in soleus muscles from alcohol‐fed animals. The increase in control plantaris muscle was not significantly different from the increase in carbonyl in corresponding muscles from ethanol‐fed rats in response to OH.. In response to superoxide radicals, carbonyl in control soleus increased, an effect similar to that recorded in the soleus from ethanol‐fed rats. In control plantaris, carbonyl increased in response to superoxide radicals, an effect not significantly different to the increase in plantaris from alcohol‐fed rats.

Conclusions: Using increased carbonyl concentrations as an indicator of muscle damage by reactive oxygen species, we concluded (1) there is no evidence of enhanced reactive oxygen species‐induced damage to mixed muscle proteins in either Type I or Type II muscles in response to alcohol feeding; (2) Type II muscles have a greater capacity than Type I muscles to protect against damage (as indicated by carbonyl formation) by both hydroxyl and superoxide radicals in vitro; (3) alcohol reduces the capacity of Type I muscle to resist hydroxyl radical‐induced protein damage, a mechanism that may arise through impairment of other antioxidant systems or other process not yet elucidated.
Individual Differences Predictive of Drinking to Manage Anxiety Among Non‐Problem Drinkers With Panic Disorder
Authors: Kushner Matt G. , Abrams Kenneth , Thuras Paul , Hanson Karen L.
Published: April 2006

Background: Alcohol problems co‐occur with anxiety disorders at a rate that far exceeds chance (“comorbidity”). One view suggests that risk for developing a comorbid alcohol use disorder is increased when alcohol is used routinely to cope with anxiety symptoms (“self‐medication”). Indicating that this view is overly broad, however, the literature suggests that only a subgroup of anxiety‐disordered individuals tend to drink to manage their symptoms. Therefore, we set out to identify psychological characteristics that might mark those for whom drinking to cope with anxiety is most likely. Our survey of the literature identified several possibilities, including anxiety‐related personality traits (anxiety sensitivity, self‐consciousness and Trait Anxiety); higher‐order personality dimensions (Harm Avoidance, Reward Dependence, and Novelty Seeking); and, finally, alcohol outcome expectancies (specifically, those related to tension‐reducing effects from alcohol).

Methods: In a sample of nonproblem drinkers with panic disorder, we regressed predictor variables on several alcohol use measures, including drinking aimed at the control of anxiety symptoms (“self‐medication”).

Results: Although each variable related positively to a self‐medicating style of drinking, expectancies for tension reduction from alcohol use accounted for about twice as much variance as did the other predictors. With simultaneous entry in a step‐wise regression analysis, only tension‐reduction alcohol outcome expectancies and the Harm Avoidance personality dimension were retained as significant predictors.

Conclusions: Findings suggest that development of a self‐medicating style of drinking among individuals with panic disorder is predicated, in part, on specific psychological characteristics of the individual. Alcohol outcome expectancies emerged as the single most important predictor of drinking behavior in this anxiety‐disordered sample.
Involvement of Dopamine D2 Autoreceptors in the Ventral Tegmental Area on Alcohol and Saccharin Intake of the Alcohol‐Preferring P Rat
Authors: Nowak K. L. , McBride W. J. , Lumeng L. , Li T.‐K. , Murphy J. M.
Published: April 2006

Background: The ventral tegmental area (VTA) dopamine (DA) system is considered to be involved in mediating the actions of ethanol (EtOH). The objective of the present study was to examine the role of VTA DA D2 receptors in regulating EtOH intake of alcohol‐preferring P rats.

Methods: EtOH (10% v/v) and saccharin (SACC, 0.0125% g/v) intake during 2 hr of limited access was assessed after microinjections of the D2 agonist quinpirole and the D2 antagonist sulpiride into the anterior VTA (AVTA) of female P rats. Both EtOH‐SACC alternate‐day‐access conditions and daily availability of EtOH and SACC solutions to separate groups of subjects were used. A second D2 agonist, quinelorane, and coadministration of 2.0 μg sulpiride with 2.0 μg quinpirole were tested in animals given limited access to EtOH. Finally, the effects of quinpirole injected 2 mm dorsal to the VTA and within the posterior VTA (PVTA) were assessed under EtOH‐SACC alternate‐day‐access conditions.

Results: Microinjections of 2.0–6.0 μg quinpirole into the AVTA dose dependently decreased EtOH intake 40–80% during the first 30 min of the limited access sessions but did not alter SACC intake. Injections of 2.0–4.0 μg quinelorane into the AVTA also reduced EtOH intake in the first 30 min. Administration of 0.5–2.0 μg sulpiride into the AVTA had no effect on either EtOH or SACC intakes but did attenuate the effects of quinpirole on reducing EtOH intake. Injections of 2.0–4.0 quinpirole 2 mm dorsal to the VTA did not alter EtOH or SACC intakes. Posterior VTA injections of quinpirole decreased EtOH and SACC intakes approximately 25–30% and 60–70%, respectively, in the first 30 min. None of the treatments altered intakes during the 30–120 min period.

Conclusions: The data suggest that DA neuronal activity within the AVTA may be important for maintaining EtOH drinking in P rats, whereas DA neuronal activity within the PVTA may be involved in regulating general drinking and/or motivational behaviors. Overall, the results confirm the involvement of mesolimbic DA in EtOH self‐administration and suggest that there is functional heterogeneity within the VTA regulating drinking behavior of the P rat.
Carbohydrate‐Deficient Transferrin, γ‐Glutamyltransferase, and Macrocytic Volume as Biomarkers of Alcohol Problems in Women
Authors: Allen John P. , Litten Raye Z. , Fertig Joanne B. , Sillanaukee Pekka
Published: April 2006

Background: Early identification of alcohol problems in women is important. Differences in patterns of drinking and in biological function between genders, however, may present unique difficulties in biochemical screening.

Methods: Published alcohol‐screening studies with female samples and use as biomarkers of carbohydrate‐deficient transferrin (CDT), γ‐glutamyltransferase (GGT), and macrocytic volume were reviewed.

Results: A wide range of sensitivities and specificities of GGT and CDT have been reported, although, in general, the two markers seem approximately equal in accuracy. As in the case of males, use of them in combination substantially enhances sensitivity and little reduces specificity. Use of macrocytic volume improves the sensitivity of both GGT and CDT as alcohol‐screening markers.

Conclusions: GGT and CDT have moderate sensitivity in screening for alcohol problems in women. Use of them in concert offers further advantage.
Personality, Family History, and Alcohol Use Among Older Men: The VA Normative Aging Study
Authors: LoCastro Joseph , Spiro Avron , Monnelly Edward , Ciraulo Domenic
Published: April 2006

Background: We examined personality traits (Sociability, Impulsivity, Neuroticism) as mediators of the effects of family history on alcohol outcomes.

Methods: A sample of 485 men reported on family history of alcohol problems in 1973, completed the Eysenck Personality Inventory in 1976, and responded to a survey on alcohol use in 1982.

Results: Using structural equation modeling, family history was found to have direct effects on number of drinks per day and on the number of alcohol problems, as well as indirect effects mediated through Neuroticism. There were no effects of Sociability or Impulsivity on either alcohol outcome.

Conclusions: In this sample of older men, family history had both direct and indirect effects, and personality traits found to affect alcohol outcomes were different from those that have been found in younger men.
Expansions of CD8CD28− and CD8TcRVβ5.2 T Cells in Peripheral Blood of Heavy Alcohol Drinkers
Authors: Arosa Fernando A. , Porto Graça , Cabeda José Manuel , Lacerda Rosa , Resende Dolores , Cruz Eugenia , Cardoso Carla , Fonseca Mafalda , Simões Carla , Rodrigues Pedro , Bravo Fernanda , Oliveira José Carlos , Alves Helena , Fraga José , Justiça Benvindo , de Sousa Maria
Published: April 2006

Background: Despite heavy alcohol consumption, only a low percentage of heavy drinkers develop liver disease. Imbalances in T‐cell subsets and iron metabolism parameters are common findings in heavy drinkers, yet the possible role played by discrete T‐lymphocyte subsets under heavy alcohol consumption remains unclear.

Methods: To gain new insights into the possible role played by T lymphocytes during alcohol consumption, characterization of CD28 expression and TcR repertoire in peripheral blood CD4+ and CD8+ T cells by two and three‐color flow cytometry was performed. A group of heavy alcohol drinkers (AHD, n= 71) and a group of age‐matched controls (n= 81), both HLA‐phenotyped and HFE‐genotyped, constituted the groups under study.

Results: Marked expansions of CD28− T cells within the CD8+ but not the CD4+ T‐cell pool were observed in AHD compared with controls. These CD8+CD28− expansions were paralleled by expansions of CD8+ T cells bearing specific TcR Vα/β chains, namely Vβ5.2. Moreover, AHD, but not controls, carrying the H63D mutation in the HFE gene showed significantly higher percentages of CD28− T cells within the CD8+ T‐cell pool than AHD carrying the normal HFE gene. Finally, high numbers of CD8+CD28− T cells in AHD were associated with lower levels of the liver‐related enzymes ALT and GGT.

Conclusions: This study showed that under active ethanol consumption, expansions of discrete CD8+ T‐cell subsets occur within the CD8+ T‐cell pool, that molecules of the MHC‐class I locus seem to influence the extent of the expansions, and that high numbers of CD8+CD28− T cells are associated with low levels of liver enzymes in AHD.
Ethanol Induces Fas/Apo [Apoptosis]‐1 mRNA and Cell Suicide in the Developing Cerebral Cortex
Authors: Cheema Zulfiqar F. , West James R. , Miranda Rajesh C.
Published: April 2006

Introduction Animal studies modeling fetal alcohol syndrome have demonstrated that developmental exposure to alcohol is associated with decreased brain weight and significant neuronal loss in multiple regions of the developing brain. Our previous data suggest that the Fas/Apo [apoptosis]‐1 receptor is transiently expressed in the developing cerebral cortex during the peak period of naturally occurring apoptotic cell death and maximum sensitivity to alcohol. Therefore, we hypothesized that ethanol increases the expression of suicide receptors such as Fas/Apo‐1 in the developing fetal cerebral cortex and leads to an upregulation or extension of the normal period of apoptosis and consequent disorganization of the neural circuitry.

Methods: Ethanol was administered in one of four doses (120, 320, 630, and 950 mg/dl) to organotypic explant cultures of the developing cerebral cortex established from postnatal day 2 rats and maintained for 6 days in vitro. The number of cells expressing Fas/Apo‐1 receptor mRNA was counted. Apoptosis was measured by the use of two independent assays; a cell death enzyme‐linked immunosorbent assay for DNA fragmentation and flow cytometric analysis of Annexin‐V binding to phosphatidylserine externalized to the outer leaflet of the plasma membrane. Necrosis was also estimated by two independent measures, the amount of lactate dehydrogenase released into culture medium and flow cytometric analysis of cells that were positive for both Annexin‐V and propidium iodide.

Results: A significantly larger number of developing cortical cells expressed Fas/Apo‐1 mRNA at the lower doses (120 and 320 mg/dl) than at the higher doses (630 and 950 mg/dl). Furthermore, ethanol induced apoptosis in a dose‐related manner, with peak apoptosis observed at a dose of 630 mg/dl in the case of DNA fragmentation and at 630 and 950 mg/dl in the case of phosphatidylserine translocation to the outer leaflet of the plasma membrane. Ethanol did not induce necrosis at any of the administered doses of ethanol.

Conclusions: Our data suggest that ethanol induces a susceptibility to apoptotic signals at low doses by upregulating the expression of mRNAs for cytotoxic receptors such as Fas/Apo‐1 in the developing cerebral cortex. However, ethanol itself specifically induces apoptosis in the developing cerebral cortex only at higher doses.
Ethanol and Murine Interleukin (IL)‐12 Production
Authors: Mason Carol M. , Dobard Elizabeth , Kolls Jay K. , Nelson Steve
Published: April 2006

Background: Interleukin (IL)‐12 is a cytokine with protean effects against bacterial and intracellular pathogens. Induction of IL‐12 at the time of infection has salient effects on elimination of various microbes. This work describes the effect of exposure to ethanol on lipopolysaccharide (LPS)‐induced production of IL‐12 in mice and whether ethanol‐induced increases in IL‐10 mediates these changes in IL‐12 production.

Methods: BALB/c mice were pretreated with ethanol and then challenged with LPS either intravenously (iv) or intratracheally (it), and blood and lung production of IL‐12 (p70 and p40 components) and serum IL‐10 were assayed. Splenic and lung mRNA for IL‐12 p35 and p40 components was determined.

Results: Ethanol pretreatment suppressed LPS‐induced IL‐12 p70 and p40 protein production in blood and lung. In spleen and lung, p40 mRNA was induced to a greater extent than p35 mRNA, and there was greater suppression of p40 mRNA compared with p35 mRNA in ethanol‐treated animals. Ethanol up‐regulated the production of IL‐10, and pretreatment of these animals with a polyclonal anti‐IL‐10 antibody resulted in significant increases in IL‐12 p70 and p40 levels, but not completely to those of control animals.

Conclusions: Ethanol suppresses the production of murine IL‐12 in response to LPS in blood and lung, with both the p70 and the p40 components affected. This suppression is accompanied by reductions of p40 mRNA in both spleen and lung. IL‐10 may play a role in ethanol‐induced suppression of IL‐12, as neutralization of IL‐10 partially attenuated the suppression of IL‐12.
Decreased Natural Killer Cell Responses and Altered Interleukin‐6 and Interleukin‐10 Production in Alcoholism: An Interaction Between Alcohol Dependence and African‐American Ethnicity
Authors: Irwin Michael , Miller Claudine
Published: April 2006

Background: Epidemiological data indicate that among alcoholics African‐American men have higher rates of infections compared with white alcoholics. Alcohol is thought to reduce natural killer (NK) cell responses and to alter cellular immunity by changing the relative balance of Th1 versus Th2 cytokine response profiles. However, translation of these basic immunological observations into the clinical setting is limited, and what clinical data are available are contradictory, in part, because of heterogeneity within the alcoholic patient population. Whether ethnic characteristics contribute to variation in the immunological effects of alcohol is not known.

Methods: This study compared NK activity, interleukin (IL)‐2–stimulated NK activity, and concanavalin A–stimulated peripheral blood mononuclear cell production of Th1 (IL‐12 and IL‐2), Th2 (IL‐10), and proinflammatory (IL‐6) cytokines in 31 hospitalized chronic alcoholic patients and 31 age‐matched controls who were stratified on the basis of ethnicity.

Results: NK‐cell responses were significantly different across the four groups, and African‐American alcoholics showed the lowest levels of NK activity (F= 9.5;p < 0.001) and IL‐2–stimulated NK activity (F= 2.9;p < 0.05). Compared with the other three groups, African‐American alcoholics also showed lower levels of IL‐6 (F= 7.2;p < 0.01) and higher levels of IL‐10 (F= 4.9;p < 0.05). Stimulated production of IL‐2 and IL‐12 were similar in the four groups. Regression analyses showed that alcohol dependence and ethnicity predicted NK activity, whereas the interaction between alcohol dependence and ethnicity predicted levels of IL‐6 and IL‐10.

Conclusions: In summary, the immunological effects of alcohol dependence are modified by ethnicity status, consistent with the increased health risks found in African‐American alcoholics.
The Genetics of Acute Functional Tolerance and Initial Sensitivity to Ethanol for an Ataxia Test in the LSxSS RI Strains
Authors: Gehle Vaughn M. , Erwin V. Gene
Published: April 2006

Background: It has been proposed that development of tolerance to the behavioral effects of ethanol depends on the degree of impairment produced by the drug; that is, more sensitive individuals should develop greater tolerance. Tests of this hypothesis with respect to acute functional tolerance have produced contradictory results. We tested the hypothesis by examining the genetic relationship between initial sensitivity and acute functional tolerance in the LSXSS recombinant inbred mice.

Methods: We tested mice for initial sensitivity to the ataxic effects of 1.75 g/kg of ethanol in a stationary dowel balance test by determining blood and brain ethanol concentrations at fall. Acute tolerance to the ataxic effects of ethanol was determined by measuring blood ethanol concentration (BEC) at regain of dowel balance ability after the first injection (BEC1RB) and after a second ethanol injection of 2.0 g/kg (BEC2RB). Acute tolerance was quantified by the difference in ethanol concentration at the two regains of balance (BEC2RB − BEC1RB) or by the difference between the second regain and one of the initial sensitivity measures (BEC2RB − initial sensitivity).

Results: Four different measures of initial sensitivity were taken: two that used BEC values and two that used forebrain or hindbrain ethanol concentrations. We calculated acute tolerance values by using each of these initial sensitivity measures plus BEC2RB. No evidence of a genetic relationship between initial sensitivity and acute tolerance was found, which suggests that these are two independent phenomena with respect to stationary dowel balance.

Conclusions: Three conclusions can be drawn from this work: (1) Orbital sinus BEC at early time points (<5 min postinjection) may or may not accurately reflect brain EC in mice, dependent on genotype; (2) there is no genetic relationship between initial sensitivity and acute tolerance to stationary dowel ataxia in the LSXSS RIs; and (3) sex‐specific factors affect low‐dose ethanol responses on the stationary dowel.
Norepinephrine Uptake Sites in the Locus Coeruleus of Rat Lines Selectively Bred for High and Low Alcohol Preference: A Quantitative Autoradiographic Binding Study Using [3H]‐Tomoxetine
Authors: Hwang Bang H. , Wang Guo‐Ming , Wong David T. , Lumeng Lawrence , Li T.‐K.
Published: April 2006

Background: The locus coeruleus (LC) is the largest norepinephrinergic cell group in the central nervous system and contains a high density of norepinephrine (NE) uptake sites. Alcohol‐preferring (AP) rats and high–alcohol‐drinking (HAD) rats are selectively bred for high alcohol preference, whereas alcohol‐nonpreferring (NP) rats and low–alcohol‐drinking (LAD) rats are bred for low alcohol preference. However, it is unknown whether NE uptake sites in the LC are associated with alcohol preference in AP and HAD rats when compared with their respective control rats, NP and LAD rats. This study was designed to examine this question.

Methods: Animals were decapitated and brains were removed, frozen with dry ice powder, and stored in a deep freezer. The LC tissue blocks were cut into 14 μ cryostat sections, collected on glass slides, and incubated with 0.6 nM [3H]‐tomoxetine in 50 mM Tris‐HCl buffer system. For nonspecific binding, 1 μM desipramine was added to the radioactive ligand. Sections were rinsed, quickly dried, and processed for quantitative autoradiography. In addition, galanin content in the LC was also studied.

Results: The LC possessed a high density of [3H]‐tomoxetine binding sites. There were fewer tomoxetine binding sites (fmol/mg protein) in the AP rats (433.0 ± 8.1) than in the NP rats (495.6 ± 3.7). HAD rats (386.5 ± 13.2) also possessed fewer tomoxetine binding sites than LAD rats (458.7 ± 10.1). Galanin content in the LC was similar between AP and NP rats and between HAD and LAD rats.

Conclusions: Because both AP rats and HAD rats were selectively bred for alcohol preference, the finding of consistently low levels of [3H]‐tomoxetine binding in the LC of these two lines of rats with high alcohol preference suggests that down‐regulation of NE transporters in the LC of AP and HAD rats may be associated with alcohol‐seeking behavior. A possible involvement of the coerulear NE uptake sites in depression is also discussed. Galanin in the LC may not relate to alcohol preference.
Carbohydrate Craving by Alcohol‐Dependent Men During Sobriety: Relationship to Nutrition and Serotonergic Function
Authors: Moorhouse Mona , Loh Elliot , Lockett Donna , Grymala John , Chudzik George , Wilson Allan
Published: April 2006

Background: Several studies report reduced serotonin (5HT) in alcohol‐dependent subjects. Furthermore, alcohol increases 5HT in animals. Thus, alcohol dependence may be an attempt to self‐medicate reduced 5HT. Relevant to this, reducing 5HT increases carbohydrate intake, and several studies report increased carbohydrate intake in alcohol‐dependent subjects. Like alcohol, carbohydrate increases 5HT. We hypothesized that a subgroup of the alcohol‐dependent population self‐medicates reduced 5HT with alcohol and alternatively with carbohydrate when not drinking.

Methods: Three groups were recruited: a high carbohydrate craving alcohol‐dependent group (n= 10), a low carbohydrate craving alcohol‐dependent group (n= 11), and a nonaddicted control group (n= 12). All groups were placed on a high‐carbohydrate, low‐protein diet for 2 days and then a high‐protein, low‐carbohydrate diet for 2 days. The effects of diet on mood, alcohol craving, stress, and 5HT were measured.

Results: Although both alcohol‐dependent groups had similar alcohol cravings at baseline, only the carbohydrate‐craving alcohol‐dependent group craved alcohol significantly more when under the stress of the research protocol. The carbohydrate‐craving alcohol‐dependent subjects presented with distinct personality disorders and were uniquely sensitive to the adverse effects of carbohydrate on mood. Diet had a unique effect on 5HT in the high carbohydrate craving alcohol‐dependent group. The results of platelet 5HT uptake demonstrated that the high‐protein, low‐carbohydrate diet significantly increased Km values of high carbohydrate craving alcohol‐dependent subjects, whereas it reduced the Km values of both non‐carbohydrate‐craving alcohol‐dependent subjects and nonaddicted controls.

Conclusion: Carbohydrate‐craving alcohol‐dependent subjects are a distinct subgroup of the alcohol‐dependent population.
Rearing Experiences and Stress‐Induced Plasma Cortisol as Early Risk Factors for Excessive Alcohol Consumption in Nonhuman Primates
Authors: Fahlke Claudia , Lorenz Joseph G. , Long Jeffrey , Champoux Maribeth , Suomi Stephen J. , Higley J. Dee
Published: April 2006

Background: The purpose of this study was to assess the impact of early rearing and stress‐induced rise of plasma cortisol collected during infancy as a biological predictors of adult alcohol consumption in nonhuman primates.

Methods: Ninety‐seven female and male rhesus macaques (Macaca mulatta) were investigated. They were reared for their first 6 months of life either without mothers or other adults but with constant access to same‐aged peers (peer‐reared), or as controls with their mothers (mother‐reared). When subjects reached 6 months of age, they underwent a series of four sequential weeks of 4‐day social separations. Blood was drawn 1 and 2 hr after initiation of the 4‐day separation periods, and the plasma was assayed for plasma cortisol concentrations. When the subjects were young adults (approximately 50 months of age), they were tested for voluntary intake of alcohol for 1 hr per day, 4 days a week, during a period of 5 to 7 weeks under normal living conditions.

Results: The social separation challenge increased infant plasma cortisol concentrations, with peer‐reared subjects exhibiting higher stress‐induced cortisol concentrations than mother‐reared animals. Subjects that responded to the social separation challenge with high cortisol levels consumed significantly more alcohol per kilogram of body weight as adults than subjects with a low cortisol response to the separation challenge, regardless of rearing condition. In addition, male and peer‐reared subjects consumed significantly more alcohol than female and mother‐reared subjects, respectively.

Conclusions: These findings suggest that early rearing experiences, such as adult absence, and high plasma cortisol concentrations early in life after a social separation stressor, are useful psychobiological predictors of future high alcohol consumption among nonhuman primates.
7α‐ and 7β‐Hydroperoxycholest‐5‐en‐3β‐ol in Muscle as Indices of Oxidative Stress: Response to Ethanol Dosage in Rats
Authors: Adachi Junko , Asano Migiwa , Ueno Yasuhiro , Reilly Matthew , Mantle David , Peters Timothy J. , Preedy Victor R.
Published: April 2006

Background: Alcohol‐induced muscle disease (AIMD) encompasses both acute and chronic lesions, and affected patients exhibit concomitant functional and structural lesions. The pathogenic mechanisms are unknown, although it is possible that defects in the membrane‐lipid domain are involved. Therefore, the effect of acute ethanol on membrane lipid from rat skeletal muscles (control, n= 7; ethanol, n= 7) was investigated.

Methods: Soleus and plantaris skeletal muscles were collected 24 hr after a single dose of 75 mmol/kg of ethanol. Lipids were analyzed by high‐performance liquid chromatography with postcolumn chemiluminescence.

Results: We found that two cholesterol‐derived hydroperoxides, 7α‐hydroperoxycholest‐5‐en‐3β‐ol (7α‐OOH) and 7β‐hydroperoxycholest‐5‐en‐3β‐ol (7β‐OOH) were present in soleus muscles of control animals (1.29 nmol/g and 3.20 nmol/g, respectively) and in plantaris (1.83 and 5.18 nmol/g, respectively). These hydroperoxides were significantly elevated by acute ethanol, in not only plantaris but also soleus skeletal muscle of rats. In contrast, protein carbonyl concentration, another indicator of oxidative stress, albeit to proteins, was not significantly affected in either soleus or plantaris muscles of ethanol dosed rats. In addition, gas chromatographic study of fatty acid composition from phospholipid of rat muscle showed a significant increase of 18:2 by ethanol in plantaris as well as soleus. Concomitant decreases occurred in the nonessential/essential fatty acid ratios.

Conclusions: This is the first report on 7α‐OOH and 7β‐OOH accumulation in rat skeletal muscle, and it seems to reflect greater oxidative stress in the pathology of muscle of rats treated with acute ethanol. Together with the elevation of 18:2, these results signify perturbations in membrane lipids in response to ethanol, which may have important implications for the pathogenesis of alcohol‐induced muscle disorders.
Hepatic Microvascular Dysfunction in Endotoxemic Rats After Acute Ethanol Administration
Authors: Horie Yoshinori , Kato Shinzo , Ohki Eiji , Tamai Hironao , Yamagishi Yoshiyuki , Ishii Hiromasa
Published: April 2006

Background: A high concentration of ethanol is reported to cause hepatic microvascular dysfunction. However, little is known about the effect of ethanol on hepatic microcirculation in endotoxemic animals. The objective of this study was to determine whether endotoxemia enhances the hepatic microvascular dysfunction induced by acute ethanol administration.

Methods: Intravital videomicroscopy was used to monitor leukocyte recruitment, number of nonperfused sinusoids, and flow velocity of erythrocytes (RBC) labeled with fluorescein isothiocyanate (FITC) in the livers of male Wistar rats that were administered ethanol (20%, 3 g/kg; or 40%, 6 g/kg) from a gastric tube. Flow velocity of RBC in sinusoids was measured with an off‐line velocimeter. Plasma tumor necrosis factor (TNF)‐α levels were also measured. In some experiments, rats were injected with 2 mg/kg of lipopolysaccharides (LPS) intraperitoneally at 16 hr before the experiments, and the same protocol was performed.

Results: Although FITC‐RBC velocity was initially increased by both 20% and 40% ethanol in control rats, it was reduced by only 40% ethanol at 60 min. In LPS‐treated rats, the FITC‐RBC velocity also was increased initially but was reduced at 60 and 30 min by 20% and 40% ethanol, respectively. Only 40% ethanol caused leukostasis in the pericentral region of control rats. In LPS‐treated rats, however, leukostasis was noted in the midzonal and pericentral regions of liver after both 20% and 40% ethanol administration. Ethanol increased plasma TNF‐α levels only in LPS‐treated rats.

Conclusions: These results suggest that LPS synergistically enhances ethanol‐induced hepatic microvascular dysfunction and liver injury, especially in the midzonal region via coagulation, which may be mediated by TNF‐α.
Elevated myo‐Inositol in Gray Matter of Recently Detoxified but Not Long‐Term Abstinent Alcoholics: A Preliminary MR Spectroscopy Study
Authors: Schweinsburg Brian C. , Taylor Michael J. , Videen John S. , Alhassoon Omar M. , Patterson Thomas L. , Grant Igor
Published: April 2006

Background: Individuals in short‐term abstinence from chronic alcohol consumption commonly have neuropsychological impairments with parallel abnormalities in brain structure. Stable, long‐term sobriety often results in improvements in both brain structure and function, although the mechanisms underlying these changes are currently not well understood.

Methods: To investigate further the neurobiological underpinnings of alcohol‐associated brain abnormalities in short‐term and long‐term abstinence from alcohol, proton magnetic resonance spectroscopy (echo time, 35 msec; repetition time, 1.5 sec) was used to assay metabolites in the anterior centrum semiovale, anterior cingulate gyrus, and right thalamus of two groups of non‐Korsakoff alcoholic men, at different stages of abstinence, compared with a control group of alcohol‐nonabusing men. Absolute concentrations of N‐acetylaspartate, choline, myo‐inositol, and creatine were measured in four recently detoxified alcoholics (mean age, 48.7 years; median abstinence, 41.5 days), five long‐term abstinent alcoholics (mean age, 45.1 years; median abstinence, 1.7 years), and five nonalcoholic controls (mean age, 45.0 years).

Results: Although there were no between‐group differences in concentrations of N‐acetylaspartate, choline, or creatine, recently detoxified alcoholics had significantly higher myo‐inositol in the thalamus, compared with controls and long‐term abstinent alcoholics, and significantly higher myo‐inositol in the anterior cingulate gyrus, compared with the controls.

Conclusions: Elevations in myo‐inositol in recently detoxified alcoholics are compatible with an acute alcohol cytotoxicity model. myo‐Inositol is elevated in hyperosmolar states such as hypernatremia, renal failure, and diabetes; alcohol‐induced hyperosmolarity may trigger accumulation of myo‐inositol to stabilize the intracellular environment. Increases in myo‐inositol may also reflect proliferation or activation of glia. The reduction of myo‐inositol to control group levels in long‐term abstinent alcoholics may reflect osmolar stability in abstinent alcoholics and/or a reduction in glial cell activation.
Alcohol‐Induced Reductions in Cardiac Protein Synthesis In Vivo Are Not Ameliorated by Treatment With the Dihydropyridine Calcium Channel Blocker Amlodipine
Authors: Patel Vinood B. , Siddiq Tahir , Richardson Peter J. , Preedy Victor R.
Published: April 2006

Background: Various studies have indicated that acute ethanol dosage perturbs cardiac function and/or structure with concomitant reductions in protein synthesis. Cellular calcium homeostasis is also perturbed, which may contribute to altered protein synthesis. This is supported by the observation that calcium channel blockers can prevent numerous features of alcohol‐induced pathology. However, many of these studies have been carried out in vitro, employing supraphysiological levels of alcohol, or have failed to address whether their results obtained in isolated systems have direct relevance in vivo. The aim of the present investigation was to examine the response of cardiac protein synthesis in vivo due to a physiologically relevant dose of ethanol and determine whether a calcium channel antagonist could prevent these effects.

Methods: Changes in cardiac protein synthesis rates in vivo were assessed by measuring the fractional rates of protein synthesis (i.e., ks) using a “flooding dose” of [3H]phenylalanine. Rats were treated either acutely (10 mg/kg body weight, 3 hr) or chronically (10 mg/kg body weight/day, 30 days) with amlodipine, a dihydropyridine‐type calcium channel blocker, before dosing with ethanol (75 mmol/kg body weight, 2.5 hr).

Results: Ethanol (75 mmol/kg body weight) inhibited cardiac protein synthesis after 1 hr. Similar responses were recorded at 2.5 and 6 hr after ethanol dosage. At 24 hr, ethanol decreased food intakes. However, a direct comparison between pair‐fed controls and alcohol‐dosed rats also showed a decrease in cardiac protein synthesis after 24 hr. Acute alcohol dosage reduced cardiac protein synthesis in mixed, myofibrillary, and sarcoplasmic protein fractions. Similar results were obtained when data were expressed relative to ribonucleic acid (i.e., kRNA). Neither acute nor chronic treatments with the calcium antagonist amlodipine ameliorated the deleterious actions of ethanol on protein synthesis.

Conclusions: Ethanol may affect cardiac protein synthesis independently of altered calcium entry.
Combining Ondansetron and Naltrexone Effectively Treats Biologically Predisposed Alcoholics: From Hypotheses to Preliminary Clinical Evidence
Authors: Johnson Bankole A. , Ait‐Daoud Nassima , Prihoda Thomas J.
Published: April 2006

Background: Individuals considered to be early onset alcoholics (EOA) are characterized by an early onset age, a broad range of antisocial behaviors, high familial loading, and presumed biological disease predisposition. Ondansetron, a 5‐HT3 antagonist, improves drinking outcomes and increases abstinence rates among EOA. Individuals with high familial loading for developing alcoholism have lower levels of β‐endorphin and demonstrate a more pronounced increase in β‐endorphin levels in response to alcohol administration compared with individuals who do not have alcoholic relatives. The propensity for naltrexone (a mu opioid antagonist) to reduce alcohol's rewarding effects and drinking in humans is greatest in individuals with high familial loading. Predicated on the added knowledge that 5‐HT3 receptors may themselves mediate alcohol reward via activation of the endogenous opioid system, we hypothesized that the combination of ondansetron and naltrexone would act synergistically and would be an effective treatment in EOA.

Methods: We conducted an 8‐week double‐blind placebo controlled clinical trial in which 20 EOA were randomized to receive ondansetron (4 μg/kg twice a day) + naltrexone (25 mg twice a day) or placebo as an adjunct to weekly standardized group Cognitive Behavioral Therapy.

Results: At endpoint, subjects who received ondansetron + naltrexone (n= 10), compared with those who received placebo (n= 10), had fewer drinks/day (covariate adjusted mean 0.99 ± 0.60 vs. 3.68 ± 0.63;F 1, 16 = 9.35, p= 0.008; effect size = 1.42), drinks/drinking day (covariate adjusted mean 3.14 ± 0.87 vs. 6.76 ± 0.71;F 1, 13 = 10.45, p= 0.007; effect size = 1.71), and a trend toward increased percent days abstinent (covariate adjusted mean 69.76 ± 8.64 vs. 48.24 ± 9.12;F 1, 16 = 3.58, p= 0.08; effect size = 0.88).

Conclusions: Ondansetron plus naltrexone seems to synergistically improve the drinking outcomes of EOA. Larger scale studies that test these medications, both alone and together, among various alcoholic subtypes are needed to establish and extend these promising findings.
An Abundant Proneurotensin Polymorphism, 479A>G, and a Test of Its Association With Alcohol Dependence in a Finnish Population
Authors: Vanakoski Jyrki , Mazzanti Chiara , Naukkarinen Hannu , Virkkunen Matti , Goldman David
Published: April 2006

Background: Neurotensin is a 13‐amino acid neuropeptide that endogenously modulates dopamine release in the central nervous system. In substance dependence, the mesolimbic dopamine system has been postulated to be a central structure that mediates rewarding and reinforcing effects. Neurotensin receptors in the neurons of the ventral tegmental area facilitate dopamine release, making the neurotensin gene an excellent candidate gene for alcohol dependence and for other behaviors that involve reinforcement.

Methods: A total of 639 psychiatrically interviewed Finns were genotyped for proneurotensin 479A>G polymorphism. We used the polymorphism as a marker to study the association between proneurotensin gene and alcohol dependence by comparing 229 unrelated Finnish healthy controls to 134 unrelated alcohol‐dependent (DSM‐III‐R criteria) subjects who were also criminal offenders. In addition, 276 relatives of the alcohol‐dependent and control subjects were genotyped.

Results: The frequencies of the genotypes in the whole sample (n= 639) were 0.84 for 479A/A, 0.16 for 479A/G, and 0.003 for 479G/G. The frequency of the rarer 479G allele was 0.07 and 0.06 in controls and alcohol‐dependent subjects, respectively, and this difference was not statistically significant (χ2= 0.264, df= 1, p= 0.61, controls vs. alcohol‐dependent subjects).

Conclusions: The results of the comparison between psychiatrically interviewed controls and alcoholics from a relatively well defined population indicate that the proneurotensin 479A>G polymorphism is not strongly associated with alcohol dependence. The results do not rule out a role for this gene in the pathogenesis of alcoholism or in differential vulnerability.
Season of Birth and Substance Abuse: Findings From a Large National Sample
Authors: Goldberg Abbie E. , Newlin David B.
Published: April 2006

Background: Season of birth is a putative etiological factor for several psychiatric illnesses. An excess of late winter and early spring births has been demonstrated repeatedly for schizophrenia, which has usually been interpreted as the result of prenatal or infant exposure to seasonally mediated “harmful effects,” such as infectious diseases. This study determined whether the seasonal birth rates of substance abusers differed from those of unaffected control groups.

Methods: The 1992 National Longitudinal Alcohol Epidemiologic Survey, an interview‐based study of 42,862 men and women, provided data to assess the association between quarter year of birth and lifetime diagnoses of substance abuse.

Results: Logistic regression revealed decreases in winter births in men with histories of alcohol dependence. The significant interaction of sex with season of birth reflected an excess of fall births among male but not female alcoholics. In contrast, there was no evidence of seasonality of birth among alcohol abusers. Men and women with histories of illicit drug use had excesses of fall birth.

Discussion: Birth rates of men with past or present alcohol dependence, and of men and women with histories of illicit drug use, implicated seasonal factors in the pathogenesis of substance abuse. The similar birth patterns of illicit drug users and male alcoholics suggest that they may share some common etiological factor, such as seasonal effects on environmental temperature, hormonal function, or susceptibility to viral infection during pregnancy or early infancy.
Subjective and Objective Responses to Ethanol in Moderate/Heavy and Light Social Drinkers
Authors: Holdstock Louis , King Andrea C. , de Wit Harriet
Published: April 2006

Background: Individuals who drink heavily are at an increased risk for adverse consequences of drinking and progression of their drinking habits to abuse or dependence. Therefore, it is important to delineate factors associated with their heavy drinking.

Methods: We examined individual differences in subjective and objective responses to ethanol associated with level of consumption by reanalyzing data from the nine heaviest and nine lightest social drinkers from each of two independently collected subject samples: Holdstock and de Wit (1998) and King et al. (1997). The light drinkers in both samples consumed five or less alcoholic drinks per week, whereas the moderate/heavy drinkers consumed eight or more drinks per week with frequent binge episodes. Acute subjective and objective responses to ethanol (0.6 or 0.8 g/kg) or placebo were compared in the two groups at baseline and during rising and falling blood alcohol concentrations.

Results: Moderate/heavy drinkers reported greater stimulant‐like and fewer sedative‐like and aversive subjective effects after ethanol than did lighter drinkers. These differences occurred in the absence of any group differences in breath alcohol levels, performance effects, or neuroendocrine changes or in overall reports of feeling any drug effects.

Conclusions: These data indicate that habitual moderate/heavy ethanol use was associated with greater stimulant‐like effects after an acute dose of alcohol. This finding is consistent with the idea (Newlin and Thomson, 1990, 1999) that individuals who experience greater stimulant‐like effects during the ascending limb and lesser sedative‐like effects on the descending limb of the blood alcohol concentration curve may be at greater risk for developing ethanol use disorders. Although we cannot determine the causality of this association, sensitivity to the stimulant effects of ethanol may play an important role in the continuation of heavy ethanol use and the increased risk of negative consequences from this use.