bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Total Body Water on the Relationship Between Alcohol Consumption and Carbohydrate‐Deficient Transferrin
Authors: Martinez L. D. , Barón A. E. , Helander A. , Conigrave K. M. , Tabakoff B.
Published: April 2006

Background Clinicians agree that alcoholism commonly is overlooked in their patients, and that treating the symptoms without directing therapy to the underlying cause at best delays an inevitable decline in the patient's general health and well‐being. The current analysis focused on carbohydrate‐deficient transferrin (CDT), a promising biological marker of dangerous alcohol consumption.

Methods Included in our study were men (730) and women (613) from study sites in Canada, Brazil, and Japan. All subjects were participants in the WHO/ISBRA Study on State and Trait Markers of Alcoholism, who completed an extensive demographic, medical, and behavioral survey and provided blood samples for determination of CDT levels. ANOVA and χ2 test for equality were used to examine the effect of total body water (TBW) on the alcohol consumption/CDT relationship. To examine whether accounting for differences in TBW improved the diagnostic properties of CDT when used as a state marker for alcohol consumption, odds ratios were calculated for men and women separately.

Results Our results show that accounting for individual differences in TBW significantly influenced the alcohol consumption/CDT dose‐response relationship. The effect of TBW was different for men compared with women. When we used a consumption cutoff value of 40 g/day and the CDTect® recommended cutoffs (20 for men; 27 for women), adjusting for differences in TBW significantly increased diagnostic performance of CDT in men but not women.

Conclusions The dependence of CDT measures on body water content needs to be taken into account to maximize the performance of CDT as an effective state marker of alcohol consumption in males.
Relationships Between Effects of Smoking, Gender, and Alcohol Dependence on Platelet Monoamine Oxidase‐B: Activity, Affinity Labeling, and Protein Measurements
Authors: Snell Lawrence D. , Glanz Jason , Tabakoff Boris
Published: April 2006

Background Many studies have reported apparent associations between platelet monoamine oxidase (MAO) activity and susceptibility to alcoholism and other psychiatric conditions. Alcohol‐dependent individuals generally exhibit lower platelet MAO activity compared with controls, and on this basis, platelet MAO has been proposed as a potential genetic marker for predisposition to alcoholism. However, several lines of evidence also suggest that MAO activity is reduced in both the brain and platelets of smokers. Many alcohol‐dependent individuals are also tobacco users, and few studies have attempted to dissociate the effect of alcohol and tobacco use on MAO activity.

Methods Platelet MAO‐B activity in 629 subjects recruited as part of the WHO/ISBRA Study of State and Trait Markers of Alcohol Use and Dependence was assayed by using a high throughput fluorescence assay. Platelet MAO‐B protein concentrations were measured by analysis of immunoblots probed with a polyclonal antibody selective for MAO. Quantitative measurements of affinity labeling of platelet MAO were made by using the selective MAO‐B catalytic site antagonist [3H]Ro 19–6327.

Results Multiple regression analysis revealed that subjects’ gender, cigarette smoking, lifetime alcohol dependence, and recruitment site each contributed independently to the variance in platelet MAO activity levels. Female subjects had significantly higher MAO activity levels than males, whereas heavy smokers had significantly lower MAO activity levels than nonsmokers. Immunoblot measurement of platelet MAO‐B protein demonstrated that females had significantly higher MAO‐B protein concentrations. Platelet MAO‐B protein concentrations did not differ significantly between smokers and nonsmokers but were lower in subjects with a diagnosis of lifetime alcohol dependence (DSM‐IV) compared with subjects who were never alcohol dependent. Measurements of affinity labeling by [3H]Ro 19–6327 of platelet MAO correlated significantly with MAO activity levels (i.e., the lower MAO‐B activity in smokers was mirrored by lower levels of [3H]Ro 19–6327 binding).

Conclusions In this international population, gender, cigarette smoking, lifetime history of alcohol dependence, and recruitment site were associated with lower platelet MAO activity levels. Differences in MAO activity associated with gender and lifetime alcohol dependence can be attributed largely to differences in MAO‐B protein concentration, whereas those associated with smoking behavior may be the result of binding of an inhibitor contained in cigarette smoke to platelet MAO‐B at catalytic site of MAO.
Heart Rate and Motor‐Activating Effects of Orally Self‐Administered Ethanol in Alcohol‐Preferring (P) Rats
Authors: Bell Richard L. , Rodd‐Henricks Zachary A. , Webster Amy A. , Lumeng Lawrence , Li Ting‐Kai , McBride William J. , Murphy James M.
Published: April 2006

Background Autonomic and behavioral arousals often accompany reinforcement. Additionally, contextual cues associated with alcohol consumption elicit increases in heart rate in alcoholics. This study examined changes in heart rate (HR) and motor activity before and during limited‐access to ethanol, saccharin, or water in adult male alcohol‐preferring (P) rats.

Methods Adult male P rats were implanted with radiotelemetric transmitters to measure HR and motor activity. The experiment involved placing the animals in a test chamber for a 90‐min pretest period, with water available. Thereafter, the animals were given a 90‐min test session with access to one of three test solutions: water, 0.0125% saccharin, or 15% (v/v) ethanol (EtOH). After a week of habituation (water served as the test solution for all three groups), the animals were given their respective test solution for 3 weeks.

Results Analyses of HR revealed that the saccharin and EtOH groups had significantly higher HR than the water group during the pretest period of the third test week. Both the saccharin and EtOH groups had significantly higher HR than the water group during the test period of all three test weeks. Analyses of motor activity revealed that the EtOH group displayed higher motor activity than the water and saccharin groups during the pretest period of the third test week.

Conclusions The data indicate that oral self‐administration of EtOH enhances behavioral and autonomic activation, compared with saccharin or water, in adult male P rats and support previous observations that changes in HR can be used as an index of reinforcement. Additionally, it seems that the behavioral and autonomic activation elicited by EtOH self‐administration can be conditioned to the environment in which EtOH was self‐administered. These findings parallel reports on cued reactivity (behavioral and autonomic activation) in alcoholics exposed to alcohol‐associated stimuli.
Executive Dysfunction and Clinical Outcome in Chronic Alcoholics
Authors: Moriyama Yasushi , Mimura Masaru , Kato Motoichiro , Yoshino Aihide , Hara Tsunekatsu , Kashima Haruo , Kato Akinobu , Watanabe Akiharu
Published: April 2006

Background The purpose of this study was to investigate which of 12 neuropsychological tests predict alcoholic patients’ alcohol‐specific and/or alcoholic‐nonspecific outcome. Our hypothesis was that the ecologically valid neuropsychological tests that measure executive function are better predictors of alcoholics’ functional outcome.

Methods We administered 12 neuropsychological tests to chronic alcoholics. Included in the tests were tasks of Reaction Time, Symbol Digit Modalities, Figure Position, Digit Span, Block Design, Trail Making, and six subtests of a battery called the Behavioral Assessment of the Dysexecutive Syndrome (BADS). Previous investigators have suggested that the BADS has ecological validity. Twenty‐two male alcoholics were compared with 15 nonalcoholic control subjects on these neuropsychological measures 7 weeks after detoxification. Two functional outcome indices, i.e., resumption of drinking and occupation, were evaluated 18 months after discharge.

Results The total profile score and the score on three of the six subtests of the BADS were lower in alcoholics than in nonalcoholic controls. Alcoholics’ performance on the BADS predicted alcohol‐nonspecific outcome (occupation) but not alcohol‐specific (drinking) outcome. In contrast, other neuropsychological tests did not predict either of the two outcome indices.

Conclusions The BADS total profile score is related to alcohol‐nonspecific outcome but not to alcohol‐specific outcome.
4‐Hydroxynonenal Detoxification by Mitochondrial Glutathione S‐Transferase Is Compromised by Short‐Term Ethanol Consumption in Rats
Authors: Chen Juanjuan , Schenker Steven , Henderson George I.
Published: April 2006

Background 4‐Hydroxynonenal (HNE), a toxic lipid peroxidation product, has been implicated in mitochondrial damage in rat liver by ethanol consumption. The present study assessed the effects of short‐term in vivo ethanol exposure on HNE detoxification by mitochondrial glutathione S‐transferase (GST).

Methods Male Sprague Dawley® rats were administered 5 doses of ethanol (4 g/kg) at 12 hr intervals by gavage. Pair‐fed rats that received isocaloric dextrose instead of ethanol served as controls. Mitochondrial and submitochondrial fractions were prepared from the livers. Mitochondrial contents of HNE and HNE‐glutathione conjugate were measured by high‐performance liquid chromatography. GST isoforms were identified by Western blots in submitochondrial fractions.

Results Whereas there was an 80% increase in mitochondrial HNE content after ethanol consumption, there was a 42% decrease in the content of HNE‐glutathione conjugate, compared with controls (p < 0.05). After ethanol exposure, the GST activities toward HNE in intact mitochondria and in the membranous fraction were decreased by 37% and 45% (p < 0.05), respectively, whereas that in the aqueous fraction was unchanged. Kinetic analysis of HNE conjugation by the membrane‐associated GST showed that ethanol decreased the Vmax nearly by half (p < 0.05), whereas it did not affect the Km. HNE conjugation by the aqueous GST demonstrated a higher Km than that of the membrane‐associated GST, although its kinetics were not significantly altered by ethanol. Immunochemical analysis with Western blots demonstrated that both the membranous and the aqueous fractions of mitochondria contain GST‐α and GST‐μ isoforms, whereas GST‐π was absent.

Conclusions HNE detoxification by mitochondrial GST is compromised by short‐term ethanol consumption, which may contribute to elevated mitochondrial HNE content and hence its toxicity in the ethanol‐exposed liver.
Effects of Ethanol and Transforming Growth Factor β (TGFβ) on Neuronal Proliferation and nCAM Expression
Authors: Miller Michael W. , Luo Jia
Published: April 2006

Background Developmental events targeted by ethanol are cell proliferation, neuronal migration, and neurite outgrowth; the latter processes being mediated by neural cell adhesion molecule (nCAM). TGFβ1 affects all three of these events. Therefore, the effects of ethanol on transforming growth factor (TGF) β1 mediated activities in neocortical neurons in vitro were examined.

Methods Primary cultures of cortical neurons were obtained from 16‐day‐old fetuses and were treated with TGFβ1 (0 or 10 ng/ml) and ethanol (0 or 400 mg/dl) for 48 hr. The effects of these substances on cell numbers, [3H]thymidine incorporation, and the expression of nCAM were determined.

Results Both cell growth (the change in cell numbers over time) and cell proliferation were inhibited by TGFβ1 and ethanol. The action of these two anti‐mitogenic factors was additive. In contrast, TGFβ1 also promoted the expression of three isoforms of nCAM. Likewise, ethanol also up‐regulated nCAM expression. On the other hand, ethanol blocked TGFβ1‐mediated nCAM expression, particularly of the 120 and 180 kDa isoforms.

Conclusions TGFβ ligands inhibit neuronal proliferation and stimulate the expression of cell adhesion proteins that promote the movement of postmitotic neurons and process outgrowth. Ethanol alters these phenomena as well. Thus, in neurons, as in astrocytes, TGFβ1 and ethanol may interact.
Self‐Reported Subjective Perception of Intoxication Reflects Family History of Alcoholism When Breath Alcohol Levels Are Constant
Authors: Morzorati S. L. , Ramchandani V. A. , Flury L. , Li T.‐K. , O'Connor S.
Published: April 2006

Background The premise of this study is that the increased familial risk for alcoholism is associated with genetic determinants of the response to alcohol, characterized by sensitivity and adaptation. Following a single administration, sensitivity is the initial response to alcohol, expressed as the change in dependent measures from baseline. Adaptation of dependent measures within a single exposure to alcohol can be expressed as acute tolerance (recovery of dependent measures toward baseline values) or sensitization (movement of dependent measure further away from baseline values). This study tested the hypothesis that family history‐positive (FHP) subjects are more sensitive and more adaptive to alcohol compared with family history‐negative (FHN) subjects.

Methods The initial response and development of adaptation to alcohol were assessed by using self‐reported subjective perceptions during a breath alcohol concentration (BrAC) clamp of 60 mg%. The Biphasic Alcohol Effects Scale, the Sensation Scale and a visual analog scale of intoxication were acquired at baseline, after the BrAC clamp was established, and after maintenance of the clamp for 105 min.

Results FHP subjects were more sensitive to alcohol compared with FHNs, as evidenced by greater changes in feelings of intoxication when the BrAC clamp was initially achieved. While the clamp was maintained, the FHP subjects adapted to the effects of alcohol and their perceptions of intoxication became indistinguishable from those of the FHN subjects. The FHP subjects had developed acute tolerance to alcohol, whereas the FHN subjects did not. Other self‐reported perceptions of alcohol's effects did not distinguish between the groups.

Conclusions A differential family history of alcoholism was reflected in self‐reported subjective perceptions of intoxication when the brain's exposure to a specified concentration of alcohol was held constant (BrAC of 60 mg%). FHP subjects reported greater intoxication after alcohol and subsequently developed acute tolerance to alcohol compared with FHN subjects.
Administration of Low Doses of MK‐801 During Ethanol Withdrawal in the Developing Rat Pup Attenuates Alcohol's Teratogenic Effects
Authors: Thomas J. D. , Fleming S. L. , Riley E. P.
Published: April 2006

Background Alcohol exposure during development can produce severe and long‐lasting central nervous system damage and consequent behavioral alterations. Recent evidence suggests that NMDA receptor‐mediated excitotoxicity during periods of withdrawal may contribute to this damage. We have demonstrated that blocking the NMDA receptor with MK‐801 during alcohol withdrawal can attenuate ethanol's adverse effects on behavioral development in the rat. This study examined the dose dependency of MK‐801's ability to mitigate ethanol's teratogenic effects.

Methods Neonatal rat pups were exposed to 6.0 g/kg of ethanol in a binge‐like manner on postnatal day (PD) 6, a period of brain development equivalent to a portion of the human third trimester. Alcohol administration was accomplished with an artificial rearing procedure. Twenty‐one hours after ethanol treatment, pups were injected intraperitoneally with one of four doses of MK‐801 (0.05, 0.1, 0.5, or 1.0 mg/kg) or saline vehicle. An artificially reared control and a normally reared control group were included. On PD 18–19, activity level was monitored, and on PD 40–42, serial spatial discrimination reversal learning was assessed.

Results Alcohol exposure on PD 6 produced significant increases in activity level and deficits in reversal learning. These alcohol‐induced behavioral alterations were significantly attenuated in subjects treated with one of the three lower doses (0.05–0.5 mg/kg) of MK‐801 during withdrawal. The performance of ethanol‐exposed subjects treated with the high dose of MK‐801 (1.0 mg/kg) did not differ from that of the Ethanol Only group.

Conclusions These data suggest that alterations in NMDA receptor activation during alcohol withdrawal contribute to the neuropathology and consequent behavioral alterations associated with developmental alcohol exposure. These data have important implications for pregnant women and newborns undergoing ethanol withdrawal.
Alcohol Dependence Symptoms and Alcohol Dehydrogenase 2 Polymorphism: Israeli Ashkenazis, Sephardics, and Recent Russian Immigrants
Authors: Hasin Deborah , Aharonovich Efrat , Liu Xinhua , Mamman Ziona , Matseoane Karen , Carr Lucinda G. , Li Ting‐Kai
Published: April 2006

Background Jews have lower rates of alcohol‐related problems than other Caucasians. The ADH2*2 allele of the alcohol dehydrogenase 2 (ADH2) gene protects against alcoholism in Asians and is found in approximately 20% of Jews. We studied the relationship of ADH2*2 to DSM‐IV dependence severity in a random community sample of Israeli Ashkenazis, recent Russian immigrants (also Ashkenazis), and Sephardics.

Methods Subjects participated in a structured interview that included highly reliable questions on DSM‐IV alcohol dependence symptoms. ADH2 genotype was determined for 68 subjects.

Results Recent Russian immigrants had more past and lifetime DSM‐IV dependence symptoms. Sephardics had a higher prevalence of ADH2*2 than Ashkenazis. Controlling for group and other potentially confounding factors, ADH2*2 was associated with a lower lifetime DSM‐IV alcohol dependence severity, although this differed somewhat within groups.

Conclusions ADH2*2 protects against dependence severity in Jewish samples. Future work in larger samples should address genetic and environmental factors that affect the relationship of ADH2*2 to alcohol consumption and dependence.
Association Study of Alcoholism Subtypes with a Functional Promoter Polymorphism in the Serotonin Transporter Protein Gene
Authors: Kranzler Henry , Lappalainen Jaakko , Nellissery Maggie , Gelernter Joel
Published: April 2006

Background Association studies of a reportedly functional polymorphism in the promoter region (5′‐HTTLPR) of the gene encoding the serotonin transporter protein (genetic locus SLC6A4) in alcoholics have yielded conflicting results. The most frequently observed alleles of the 5′‐HTTLPR polymorphism are the short and long variants; the short variant is associated with lower transcriptional activity of the SLC6A4 gene than is the long variant. To reduce the heterogeneity that may confound association studies of alcohol dependence, we examined the association of 5′‐HTTLPR alleles with three dichotomous typologies of alcoholism based on sex, comorbid drug dependence, or age of onset of alcohol dependence.

Methods A sample of 471 alcohol‐dependent subjects [363 European Americans (EAs) and 108 African Americans (AAs)] and 235 control subjects (192 EAs and 43 AAs) were included in the analyses. Alcohol dependence diagnoses were made using a structured interview. DNA isolated from whole blood was PCR‐amplified, and genotypes were assigned on the basis of agarose gel size fractionation.

Results Although allele frequencies differed significantly by population, there was no evidence of differences by diagnosis or as a function of any of the three subtypes.

Conclusions Variable findings in the literature in relation to the association of 5′‐HTTLPR alleles to alcohol dependence seem to be due to factors other than the composition of study samples in terms of univariate typologies based on sex, comorbid drug dependence, or age of onset of alcohol dependence.
The Influence of Trait Anger on the Alcohol‐Aggression Relation in Men and Women
Authors: Giancola Peter R.
Published: April 2006

Background The purpose of this study was to investigate the influence of trait anger on alcohol‐related aggression in men and women.

Methods Subjects were 204 healthy social drinkers (111 men and 93 women) between 21 and 35 years of age. Trait anger was measured using the Spielberger Trait Anger Scale. After the consumption of either an alcohol or a placebo beverage, subjects were tested on a modified version of the Taylor Aggression Paradigm in which mild electric shocks were received from and administered to a fictitious opponent during a competitive task. Aggressive behavior was operationalized as the shock intensities administered to the fictitious opponent under conditions of low and high provocation.

Results Of all of the variables, provocation was the strongest elicitor of aggression. Overall, anger was positively related to aggression for all subjects. However, the central finding of this study was that alcohol was more likely to increase aggression for persons, particularly men, with higher, as opposed to lower, levels of trait anger.

Conclusions The results show that alcohol consumption does not increase aggression for all persons and in all situations. A continuing goal for future research in this area is to identify which individual difference and which contextual factors are most important in determining who will and who will not behave in an aggressive manner when intoxicated.
Longitudinal Brain Metabolic Characterization of Chronic Alcoholics With Proton Magnetic Resonance Spectroscopy
Authors: Parks Mitchell H. , Dawant Benoit M. , Riddle William R. , Hartmann Steven L. , Dietrich Mary S. , Nickel Mark K. , Price Ronald R. , Martin Peter R.
Published: April 2006

BackgroundProton magnetic resonance spectroscopy may elucidate the molecular underpinnings of alcoholism‐associated brain shrinkage and the progression of alcohol dependence.

MethodsUsing proton magnetic resonance spectroscopy, we determined absolute concentrations ofN‐acetylaspartate (NAA), creatine/phosphocreatine (Cr), and choline (Cho)‐containing compounds andmyo‐inositol (mI) in the anterior superior cerebellar vermis and frontal lobe white matter in 31 alcoholics and 12 normal controls. All patients were examined within 3 to 5 days of their last drink. Patients who did not relapse were again studied after 3 weeks and 3 months of abstinence by using an on‐line repositioning technique that allows reliable localization of volumes of interest (VOIs).

ResultsAt 3 to 5 days after the last drink, frontal white matter metabolite concentrations were not significantly different from those of normal controls, whereas brain tissue in the VOI was reduced. Cerebellar [NAA] and [Cho] and brain and cerebellar volumes were decreased, but [Cr], [mI], and VOI brain tissue volume were not significantly different. Eight patients relapsed before 3 weeks (ER), 12 relapsed between 3 weeks and 3 months (LR), and 11 did not relapse (NR) during 3 months. Cerebellar [NAA] was reduced only in ER patients, despite the fact that ER patients drank for significantly fewer years and earlier in life than LR or NR patients. After 3 months, in the 11 continuously abstinent patients, cerebellar [NAA] and brain and cerebellar volumes increased; cerebellar [Cho], [Cr], and [mI] and VOI brain tissue did not change significantly.

ConclusionsDecreased [NAA] and [Cho] in cerebellar vermis indicate a unique sensitivity to alcohol‐induced brain injury. Cerebellar [NAA] increased with abstinence, but reduced [Cho] persisted beyond 3 months. Further studies are needed to determine whether low cerebellar [NAA] is a risk factor for, or consequence of, malignant, early‐onset alcoholism.
Ethanol‐Induced Modulation of Inducible Nitric‐Oxide Synthase Activity in Human A172 Astrocytoma Cells
Authors: Davis Randall L. , Dertien Janet , Syapin Peter J.
Published: April 2006

Background Glial cells are critical in the functioning of the central nervous system (CNS), including responsiveness to injury and immunocompetence. The immune and inflammatory response involves the inducible form of nitric‐oxide synthase (iNOS), and subsequent nitric oxide (NO) production. Previously, we have demonstrated that ethanol inhibits cytokine‐induced iNOS expression and activity in rat glial cells. Evidence of ethanol‐induced effects on iNOS in human glial cells is nonexistent. Herein, the conditions necessary for significant iNOS induction in human A172 astrocytoma cells have been characterized, and subsequently, the effects of ethanol on iNOS expression have been investigated.

Methods A172 cells were analyzed immunohistochemically for the astrocyte markers, glial fibrillary acidic protein (GFAP) and S‐100β. The ability of A172 cells to express iNOS was assessed by stimulating cells with interferon‐γ (IFNγ), tumor necrosis factor‐α (TNFα), interleukin‐1β (IL‐1β), bacterial lipopolysaccharide (LPS), L‐arginine, and tetrahydrobiopterin (BH4) in various combinations. Following stimulation, iNOS induction was monitored via measurement of nitrite production and in vitro iNOS enzyme activity. Time‐course (6–24 hr) studies assessed the effects of ethanol (50–200 mM) on iNOS induction.

Results Immunohistochemistry analysis confirmed that A172 cells were phenotypically, astrocytic. Induction of nitrite production by a cytomix [IFNγ (100 ng/ml) + TNFα (30 ng/ml) + IL‐1β (5 ng/ml)] was differentially enhanced by exposure to supplemental factors including LPS, L‐arginine, and BH4. Nitrite production was greatest over the initial 24 hr of stimulation with iNOS enzyme activity peaking at 12 hr. Acute (6–24 hr) exposure of activated cells to 50 mM ethanol enhanced iNOS activity recovered from the cytosol, whereas 200 mM ethanol decreased it. Ethanol had no direct effect on the catalytic activity of the enzyme.

Conclusions The present study is the first published report of ethanol‐induced modulation of iNOS expression in human glial cells. The data suggest that ethanol is influencing iNOS enzyme levels most profoundly. Altered astrocyte function may be a point of ethanol‐induced perturbation in CNS immune function. These findings should lend insight into the role of ethanol on human CNS immunity and brain injury.
Increase of Rat Alcohol Drinking Behavior Depends on the Age of Drinking Onset
Authors: Yoshimoto Kanji , Hori Masafumi , Sorimachi Yoshihide , Watanabe Tetsushi , Yano Tadashi , Yasuhara Masahiro
Published: April 2006

Background Although alcohol drinking onset in younger people is associated with an increased risk of alcohol‐related injuries, other factors, such as habituation and susceptibility to alcohol, in the process of aging have not been adequately examined in animal models. In the present study, we determined whether age of drinking onset affected alcohol drinking behavior and led to alcohol tolerance in experimental animals, and extrapolated some of the findings to human alcohol drinking patterns.

Methods In the first experiment, 18 rats that were naive to alcohol were tested at the age of 1, 4, and 10 months with 4 hr of access to 10% (v/v) alcohol. After the time access tests, these animals (1, 4, and 10 months of age) were housed individually and given free access to 10% alcohol solution and tap water. At 3 and 6 months later, all rats that had experienced alcohol drinking were studied for the voluntary consumption of the alcohol solution, alcohol preference, under the two‐bottle method in a second experiment.

Results In the 4‐hr alcohol‐access test, alcohol intake (g/kg/hr) was significantly increased at 0.5 and 1 hr in 1‐ and 4‐month‐old naive rats compared with 10‐month‐old naive rats. The daily alcohol intake (g/kg/day) of rats with drinking onset at 1 month of age was significantly increased at 3 and 6 months after the voluntary alcohol consumption. The daily alcohol intake in the rats with drinking onset at 4 months of age was significantly increased at 6 months only. However, the daily alcohol intake did not change in the rats with drinking onset at 10 months of age through the alcohol preference test.

Conclusions Alcohol drinking behavior in experimental animals depends on the age of alcohol drinking onset.
Dopamine D2 Receptor Binding, Drd2 Expression and the Number of Dopamine Neurons in the BXD Recombinant Inbred Series: Genetic Relationships to Alcohol and Other Drug Associated Phenotypes
Authors: Hitzemann Robert , Hitzemann Barbara , Rivera Seth , Gatley John , Thanos Peter , Siming Shou Lu Lu , Williams Robert W.
Published: April 2006

Background: It has not been established to what extent the natural variation in dopamine systems contribute to the variation in ethanol response. The current study addresses this issue by measuring D2 dopamine (DA) receptor binding, the expression of Drd2, the number of midbrain DA neurons in the BXD recombinant inbred (RI) series and then compares these strain means with those previously reported for a variety of ethanol and other drug‐related phenotypes.

Methods: Data were collected for 21 to 23 of the BXD RI strains and the parental strains. D2 DA receptor autoradiography was performed using 125I‐epidepride as the ligand [Kanes S, Dains K, Cipp L, Gatley J, Hitzemann B, Rasmussen E, Sanderson S, Silverman S, Hitzemann R (1996) Mapping the genes for haloperidol‐induced catalepsy. J Pharmacol Exp Ther 277:1016–1025]. Drd2 expression was measured using the Affymetrix oligoarray system. Immunocytochemical techniques were used to determine the number of midbrain DA neurons [Hitzemann B, Dains K, Hitzemann R (1994) Further studies on the relationship between dopamine cell density and haloperidol response. J Pharmacol Exp Ther 271:969–976].

Results and Conclusions: The range of difference in receptor binding for the RI strains was approximately 2‐fold in all regions examined, the core, the shell of the nucleus accumbens (NAc) and the dorsomedial caudate‐putamen (CPu); heritability in all regions was moderate—(h 2∼0.35). Drd2 expression in forebrain samples from the RI and parental strains ranged 1.5‐ to 2‐fold and h2 was moderate—0.47. Variation in the number of tyrosine hydroxylase (TH) positive neurons was moderate, 41% and 26% and h2 was low—0.19 and 0.15 for the ventral tegmental area (VTA) and substantia nigra compacta (SNc), respectively. Significant correlations were found between D2 DA receptor binding and the low dose (1.33 g/kg) ethanol stimulant response. (p < 0.002) and between Drd2 expression and conditioned place preference (CPP) (p < 0.0005). No significant correlations were detected between ethanol preference and either receptor binding or Drd2 expression; however, a significant correlation was found between preference and Ncam expression. Ncam is approximately 0.2 Mb from Drd2. Overall, the data suggest ethanol preference and CPP are associated with the expression of Drd2 or closely linked genetic loci.
High– and Low–Alcohol‐Preferring Mice Show Differences in Conditioned Taste Aversion to Alcohol
Authors: Chester Julia A. , Lumeng Lawrence , Li Ting‐Kai , Grahame Nicholas J.
Published: April 2006

Background: Genetic differences in sensitivity to the aversive effects of alcohol may contribute to alcohol drinking behavior. The present study examined the development of conditioned taste aversion (CTA) to various doses of alcohol in two pairs of mouse lines selectively bred for high (HAP) and low (LAP) alcohol preference.

Methods: Alcohol‐naïve, male and female HAP and LAP mice from both replicate 1 (HAP n= 29; LAP n= 28) and replicate 2 (HAP n= 34; LAP n= 35) were adapted to a 2‐hr per day water restriction regimen. During five conditioning trials at 48 hr intervals, mice received an intraperitoneal injection of saline or 2 g/kg or 4 g/kg alcohol immediately following 1 hr of access to a 0.20 M NaCl solution.

Results: LAP mice of both replicates showed a significantly greater magnitude of CTA to both 2 g/kg and 4 g/kg alcohol compared with HAP mice of both replicates. There were no line differences in consumption of the NaCl solution in the saline control groups.

Conclusions: These data suggest that mice selectively bred for low alcohol preference are more sensitive to the development of alcohol CTA than mice selectively bred for high alcohol preference. The present findings indicate that common genes mediate both alcohol preference and the aversive effects of alcohol as measured in the CTA paradigm.
Acutely Administered Ethanol Participates in Testosterone Synthesis and Increases Testosterone in Rat Brain
Authors: Alomary Ahmed A. , Vallée Monique , O'Dell Laura E. , Koob George F. , Purdy Robert H. , Fitzgerald Robert L.
Published: April 2006

Background: The interaction of alcohol and testosterone has long been of interest, mainly due to the effect of alcohol on aggression and sexual behavior. To date, there have been very few, if any, studies examining the effect of acute alcohol administration on testosterone concentrations in the brain. The administration of 1,1‐dideuteroethanol ([1,1‐2H2]ethanol) provided the opportunity to trace the deuterium label into newly synthesized deuterotestosterone in brain samples to determine whether ethanol oxidation was directly linked to testosterone synthesis.

Methods: Unoperated and adrenalectomized‐gonadectomized (ADX/GDX) rats were given either ethanol or [1,1‐2H2]ethanol in a single intraperitoneal dose of 2 g/kg body weight. We used gas chromatography/mass spectrometry to accurately determine both the amount of steroids present and the degree of deuterium incorporation into specific steroids isolated from brain samples.

Results: Thirty minutes after alcohol administration, the level of total testosterone increased 4‐fold in the frontal cortex and 3‐fold in the plasma of unoperated male Wistar rats. The relative increase in the abundance of monodeuterated testosterone 30 min after [1,1‐2H2]ethanol administration was significant (p < 0.05) in both brain and plasma. ADX/GDX animals treated with alcohol had testosterone concentrations that were 5% of those found in unoperated animals dosed with ethanol.

Conclusions: Acutely administered ethanol increased brain concentrations of testosterone 4‐fold in male Wistar rats. ADX/GDX surgery reduced brain concentrations of testosterone in response to alcohol by 95%. The deuterium labeling of testosterone after [1,1‐2H2]ethanol showed that ethanol oxidation is directly linked to testosterone biosynthesis and that the deuterium‐labeled testosterone is present in the central nervous system. These results demonstrate that peripherally administered ethanol directly contributes to the concentrations of testosterone in the central nervous system and that the testosterone found in brain samples is primarily synthesized in the periphery. These findings may be important for understanding the behavioral changes associated with acute alcohol consumption.
General Practitioners and Alcohol Use Disorders: Quantity Without Quality
Authors: Malet Laurent , Llorca Pierre‐Michel , Boussiron Didier , Schwan Raymund , Facy Françoise , Reynaud Michel
Published: April 2006

Background: General medical practitioners are essential for the prevention, diagnosis, and management of alcohol use disorders. Studies to examine medical practice in this field, however, are very rare.

Method: A cross‐sectional study involving 2010 patients seen by a sample of 145 general practitioners in the Auvergne region of central France was conducted on a given day in May 1998. The purpose of the study was to evaluate the prevalence of alcohol use disorders (using the DSM‐IV diagnostic criteria for alcohol abuse or dependence and the CAGE questionnaire) and so to estimate the proportion of nonsomatic alcohol‐related care dispensed.

Results: Sixteen percent of patients consulting their general practitioner had an alcohol problem, 27% of men and 5% of women. On average, a quarter of these patients had not been previously identified by the physician. Diagnosis seemed particularly difficult in women: 11% of women aged between 36 and 45 had an alcohol‐related problem that went unidentified in 60% of cases. Care for alcohol‐related health problems was therefore seriously inadequate. In one third of cases, patients with a diagnosed alcohol‐related problem were not followed up by the physician for that problem. Two thirds received no medication, and in more than 80% of cases the physician did not refer to a specialist or prescribe admission to a specialized hospital ward.

Conclusions: These results underline the diagnostic and therapeutic difficulties experienced by general practitioners. This study has led to the establishment of a pilot health care network for patients suffering from alcohol use disorders. This network involves voluntary doctors who have been trained and are better paid for their services. Care protocols have been established to which these practitioners have to adhere.
Age and Birth Cohort Effects on Rates of Alcohol Dependence
Authors: Rice John P. , Neuman Rosalind J. , Saccone Nancy L. , Corbett Jonathan , Rochberg Nanette , Hesselbrock Victor , Bucholz Kathleen K. , McGuffin Peter , Reich Theodore
Published: April 2006

Background: Epidemiological studies of traits such as alcohol dependence and depression have often found lifetime rates in younger individuals exceeding those found in older individuals. This suggests additional influences of birth cohort or period effects so that individuals in later‐born cohorts have an increased lifetime risk.

Methods: Data from the Collaborative Study on the Genetics of Alcoholism were used to investigate secular trends for alcoholism and related conditions and to examine risk predictors while taking the cohort effect into account. We used data on 4099 interviewed parents and siblings of alcohol‐dependent subjects and 1054 members of control families. We used survival analysis techniques and the Cox proportional hazards regression model to estimate the relative risk for demographic covariates. We used the relative sample to predict risk in the sibling of the proband and family history information to determine whether there was a bias when deceased individuals were excluded from analysis.

Results: In the control sample, we observed a 1.8% lifetime rate of DSM‐III‐R alcohol dependence in women born before 1940, as contrasted to a 13% rate in women born after 1960, and a 15% lifetime rate in men born before 1940, contrasted with a 28% rate in men born after 1960. As expected, lifetime rates in relatives were increased when compared with controls. Highly significant risk ratios (RR) were observed for gender (RR, 2.3), cohort of birth (RR, 1.5 over a decade), daily smoking (RR, 2.0), heavy smoking (RR, 3.0), and comorbid diagnoses of antisocial personality (RR, 2.2) and depression (RR, 1.6). Analysis of the family history data indicated higher rates of alcohol dependence in relatives who were deceased compared to those who were living.

Conclusions: Marked cohort differences were observed and may reflect real changes over time, or artifacts of memory recall, differential mortality, or public awareness. The analysis of all relatives (living or deceased) indicates that associated mortality may, in part, explain the secular trends seen when analyses are restricted to living, personally interviewed individuals.
Role of Apoptosis in Alcoholic Liver Injury
Authors: Ishii Hiromasa , Adachi Masayuki , Fernández‐Checa Jose C. , Cederbaum Arthur I. , Deaciuc Ion V. , Nanji Amin A.
Published: April 2006

This article represents the proceedings of a symposium at the 2002 ISBRA/RSA meeting in San Francisco, USA. The organizer and chair was H. Ishii and co‐chair was A.A. Nanji. The presentations were (1) Introduction: Apoptosis in alcoholic liver disease, by A. A. Nanji; (2) Mitochondria, oxidative stress and apoptosis in alcoholic liver disease, by M. Adachi; (3) Regulation of cell death by mitochondrial glutathione, by J.C. Fernández‐Checa; (4) Toxicity of ethanol in HepG2 cells that express CYP2E1, by A.I. Cederbaum; (5) Is alcohol‐enhanced liver apoptosis a pathogenic factor in alcoholic liver disease? by I.V. Deaciuc.
Ethanol Inhibition of Neural Stem Cell Differentiation Is Reduced by Neurotrophic Factors
Authors: Tateno Masaru , Ukai Wataru , Ozawa Hiroki , Yamamoto Megumi , Toki Sadamu , Ikeda Hiroshi , Saito Toshikazu
Published: April 2006

Background: Ethanol exposure during development leads to various forms of neuronal damage. Because neural stem cells (NSCs) play a pivotal role in the development and maturation of the central nervous system, it is important to understand the effect of ethanol on NSC differentiation. In this study, we investigated the effect of ethanol on differentiation of cultured NSCs in the presence and absence of neurotrophic factors.

Methods: NSCs were derived from rat embryos on embryonic day 14. Cells were exposed to ethanol with or without neurotrophic factors, insulin‐like growth factor‐1 (IGF‐1), or brain‐derived neurotrophic factor (BDNF). The effect of ethanol on differentiation was quantified by measurement of optical density of each sample following to microtubule‐associated protein 2 enzyme‐linked immunosorbent assay and counting of the number of microtubule‐associated protein 2–positive cells microscopically. In addition, cell viability of cultured cortical neurons that were exposed to similar concentrations of ethanol was evaluated by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay.

Results: Ethanol (20–100 mM) inhibited NSC differentiation induced by basic fibroblast growth factor removal, whereas those concentrations of ethanol did not affect neuronal survival. Both IGF‐1 and BDNF promoted generation of neurons in the absence of ethanol. Moreover, they suppressed the inhibitory effect of ethanol on NSC differentiation.

Conclusions: Ethanol inhibited NSC differentiation at concentrations much lower than what compromised neuronal survival. Ethanol‐induced differential inhibition was reduced by both IGF‐1 and BDNF. These results suggest that ethanol inhibits stem cell differentiation through alteration of cellular pathways related to neurotrophic factor signaling.
Investigation of Liver Parenchymal Flow Using Contrast‐Enhanced Ultrasound in Patients With Alcoholic Liver Disease
Authors: Fujita Yasuko , Watanabe Manabu , Sasao Kanami , Wakui Noritaka , Shinohara Masao , Ishii Koji , Sumino Yasukiyo
Published: April 2006

Background: Peripheral hepatic blood flow has not been investigated using contrast‐enhanced ultrasound. The aim of this study was to assess the characteristics of peripheral blood flow within the liver parenchyma using Levovist in patients with alcoholic liver disease (ALD).

Methods: The study population comprised 160 patients: 7 normal control subjects (NC), 89 with chronic viral hepatitis (CVH), 8 with alcoholic liver injury (ALI), 18 with viral liver cirrhosis without portosystemic shunting (VLCwoPSS) plus 11 with PSS (VLCwPSS), and 12 with alcoholic liver cirrhosis without PSS (ALCwoPSS) plus 15 with PSS (ALCwPSS). First, continuous spectral Doppler ultrasound was performed to assess peripheral blood flow within the liver parenchyma. We defined the arrival time (AT) as the time when signals began to increase in the region of interest after the injection of Levovist, whereas the peak time (PT) was the time between the AT and the maximum signal. Second, stimulated acoustic emission imaging was compared between the liver parenchyma and the right kidney at 20 sec, 90 sec, and 5 min after injection of Levovist.

Results: The average AT was as follows: NC, 18.4 sec; CVH, 18.7 sec; ALI, 15.5 sec; VLCwoPSS, 18.2 sec; VLCwPSS, 12.5 sec; ALCwoPSS, 13.5 sec; and ALCwPSS, 12.7 sec. In patients with ALI and cirrhosis (excluding VLCwoPSS), the AT was earlier than in NC and CVH. The average PT was as follows: NC, 18.3 sec; CVH, 19.4 sec; ALI, 20.3 sec; VLCwoPSS, 19.3 sec; VLCwPSS, 9.0 sec; ALCwoPSS, 10.7 sec; and ALCwPSS, 4.9 sec. In patients with cirrhosis (excluding VLCwoPSS), the PT was earlier than in the other groups. As PSS developed, the PT of ALC became much earlier. In NC, the stimulated acoustic emission study showed no enhancement of the liver parenchyma at 20 sec. However, most of the patients with ALD showed marked enhancement of the liver at 20 sec. It is interesting that only slight enhancement of the liver was seen in ALCwPSS, although NC showed marked liver enhancement at 5 min.

Conclusions: Our results suggest that ALD is accompanied by regional hepatic and systemic hemodynamic changes, such as hyperdynamic circulation and arterialization of the liver, before progression to cirrhosis.
Role of Alcohol in Late‐Life Suicide
Authors: Blow Frederic C. , Brockmann Laurie M. , Barry Kristen Lawton
Published: April 2006

Abstract: Suicide is among the leading causes of death in the United States, ranking 10th to 12th annually, depending on the year. Rates of suicide increase markedly among Americans over age 75, especially among white men. After age 85, rates are >5‐fold higher in this group than in the general population. The relationship between alcohol use and later‐life suicide is complex and currently ill defined. Substance use disorders, particularly alcohol abuse and dependence, are the second most common category of axis I disorders associated with completed suicide among adults aged 65 and older, following only depression. The co‐occurrence of alcohol use disorders and depression heightens suicide risk. Most studies that have evaluated the effects of alcohol in geriatric suicide have focused on older adults who met DSM criteria for abuse and/or dependence. However, the majority of older adults who are experiencing problems related to their alcohol use do not meet alcohol abuse/dependence criteria. Therefore, the role of at‐risk and problem alcohol use in geriatric suicide may be underestimated. Drinking among elders elevates suicide risk through interactions with other factors that are more prevalent in this age group, such as depressive symptoms, medical illness, negatively perceived health status, and low social support. This article reviews the literature related to alcohol use and suicide among older adults. Clinical and research recommendations for addressing this problem are also presented.
The Subjective Valuation of Indexed Stock Options and Their Incentive Effects
Authors: Calvet A. Louis , Rahman Abdul H.
Published: April 2006

We analyze the potential role of indexed stock options in future pay‐for‐performance executive compensation contracts. We present a unified framework for index‐linked stock options, discuss their incentive effects, argue that indexation schemes based on the capital‐asset pricing model (CAPM) are the most suitable for executive compensation, and derive a subjective pricing model for the class of CAPM‐based indexed stock options. Contrary to earlier work, executives would not be motivated to take on investment projects with high idiosyncratic risk once their lack of wealth diversification and degree of risk aversion are factored into the analysis.
The Impact of Pennies on the Market Quality of the Toronto Stock Exchange
Authors: Smith Brian F. , Turnbull D. Alasdair S. , White Robert W.
Published: April 2006

Using detailed order flow data from the Toronto Stock Exchange, this paper finds no evidence that a smaller tick size lessens market liquidity for either small or large traders. Rather, there is evidence of lower trading costs, faster time to order execution, and greater price continuity. Consistent with a penny tick allowing a finer pricing grid search, there is an increase in the number of Change Former Orders and cancellations.