bluuebunny/crossref_metadata_2025 huggingface dataset:
Microdialysis of Dopamine in the Nucleus Accumbens of Alcohol‐Preferring (P) Rats During Anticipation and Operant Self‐Administration of Ethanol
Authors: Melendez Roberto I. , Rodd‐Henricks Zachary A. , Engleman Eric A. , Li Ting‐Kai , McBride William J. , Murphy James M.
Published: April 2006

Background: The present study was designed to test directly whether a contextual stimulus for access to ethanol would acquire the ability to enhance locomotor activity and dopamine efflux in the nucleus accumbens (NAc) of alcohol‐preferring (P) rats. The study also explored the association between elevated locomotor activity and NAc dopamine efflux during operant self‐administration of ethanol.

Methods: Adult female P rats were randomly assigned to operantly self‐administer either 15% (v/v) ethanol or 0.0125% (w/v) saccharin. Both groups were trained in a daily 30‐min two‐lever concurrent operant task (FR‐3) to orally self‐administer ethanol or saccharin, with water on the alternate lever. A third (control) group was trained to self‐administer water on both levers. All groups were also acclimated in the operant chambers to periods of habituation, anticipation, and postadministration.

Results: Compared with controls, the ethanol group, but not the saccharin group, showed significant increases in locomotor activity as well as increased NAc dopamine efflux during the first 10 min of the anticipation period. During the first 10 min of the self‐administration period, locomotor activity was significantly increased in both the ethanol and saccharin groups compared with control values. The ethanol group, but not the saccharin group, showed significant increases in NAc dopamine efflux during the 20th and 30th min of the self‐administration period and during the first 10 min of the postadministration period.

Conclusions: The findings suggest that acquisition of signal‐induced anticipation of self‐administered ethanol is associated with increases in locomotor activity and extracellular levels of dopamine in the NAc of P rats. Such associations may be important to the development and maintenance of ethanol‐seeking behaviors. The findings also indicate that operant self‐administration of ethanol is associated with increases in extracellular levels of dopamine in the NAc of P rats.
Inhibitory Effects of Ethanol on Rat Mesangial Cell Proliferation via Protein Kinase C Pathway
Authors: Segawa Kayoko , Minami Kouichiro , Uezono Yasuhito , Shiraishi Munehiro , Shigematsu Akio
Published: April 2006

A large body of evidence has shown that ethanol inhibits the cell growth and cell proliferation in a variety of cell types. However, it has not been studied whether ethanol inhibits the proliferation of mesangial cells (MC) in the kidney. We examined the effects of ethanol on cell proliferation in cultured rat MC. Treatment with ethanol (10–200 mM) for 48 hr inhibited [3H]thymidine incorporation into MC in a concentration‐dependent manner. The same concentrations of ethanol also inhibited the increase in cell number of MC. GF109203X and chelerythrine chloride, inhibitors for protein kinase C, eliminated the inhibitory effects of ethanol; and protein kinase C activator, PMA, mimicked the effects of ethanol. In contrast, neither the protein kinase A inhibitor H‐89 nor the protein kinase G inhibitor KT5823 had any effect. These findings suggest that ethanol has inhibitory effects on the proliferation of MC, probably via activation of the protein kinase C pathway.
Ethanol Enhances Activation‐Induced Caspase‐3 Dependent Cell Death in T Lymphocytes
Authors: Kelkar Sujata , Dong Qing , Xiao Yinghua , Joshi‐Barve Swati , McClain Craig J. , Barve Shirish S.
Published: April 2006

Background: Clinical and experimental studies have shown that an important deleterious consequence of excessive alcohol consumption is immunosuppression, specifically, a depletion in the mature CD4+ T‐cell population. A predominant mechanism involved in T‐cell depletion is activation‐induced cell death (AICD). Although it is well documented that ethanol intake can cause depletion of CD4+ T cells, the mechanism of how alcohol mediates its effects is unclear.

Methods: The results were based on data from three separate experiments presented as mean ± standard deviation (SD). Jurkat CD4+ T cells and peripheral blood lymphocytes were treated with 25 mM of ethanol (12–18 hr), followed by stimulation with mitogens Conconavalin A (5 μg/ml) and Phytohemmaglutinin (1 μg/ml) or T‐cell receptor ligation (anti‐CD3 antibody (5 μg/ml)) for 6 hr, and then harvested for measurement. The apoptotic cell death markers measured include cell viability, Caspase‐3‐like activity, and DNA fragmentation.

Results: We demonstrate that alcohol pretreatment enhances AICD of Jurkat CD4+ T cells and peripheral blood lymphocytes upon activation by CD3‐crosslinking or stimulation with Conconavalin A and Phytohemmaglutinin. Furthermore, we find that the ethanol‐mediated enhancement of T cells to apoptosis involves increased activation of Caspase‐3 and can be abrogated by treatment with a specific inhibitor of Caspase‐3.

Conclusions: Our data indicate that ethanol can sensitize CD4+ T cells to enhanced stimulation‐induced Caspase‐3 activation and to subsequent AICD. This is, perhaps, an important mechanism in alcohol‐induced immunosuppression.
Corpus Callosum, Pons, and Cortical White Matter in Alcoholic Women
Authors: Pfefferbaum Adolf , Rosenbloom Margaret , Serventi Kathleen L. , Sullivan Edith V.
Published: April 2006

Background:To measure the effect of alcohol abuse on white matter brain macrostructure in women with alcoholism and to determine whether observed abnormalities interact with age.

Methods:Quantitative measures of corpus callosum area, cortical white matter volume, and pons volume were derived from magnetic resonance imaging scans obtained from 34 women with DSM‐III‐R alcoholism (aged 28‐64, mean 41 years) and 35 healthy women (aged 22‐65, mean 42 years). Transverse relaxation time of the pons was also obtained.

Results:No significant group differences in any brain measures were observed. However, in alcoholics greater length of sobriety was associated with more cortical white matter, and higher lifetime levels of alcohol consumption were associated with smaller volumes and prolonged transverse relaxation time in the pons.

Conclusions:Despite a lack of overall deficits in white matter macrostructural size in alcoholic women, certain white matter structures showed alcohol exposure vulnerability whereas others showed evidence of recovery with abstinence.
Ethanol‐Induced Translocation of Protein Kinase A Occurs in Two Phases: Control by Different Molecular Mechanisms
Authors: Dohrman Douglas P. , Chen Hui‐min , Gordon Adrienne S. , Diamond Ivan
Published: April 2006

Background: Cyclic adenosine monophosphate (cAMP)‐dependent protein kinase A (PKA) regulates cellular functions. The specificity of PKA‐mediated phosphorylation is determined primarily by PKA localization to sub‐cellular sites. Chronic exposure to ethanol causes sustained translocation of the PKA catalytic subunit (C) from the Golgi to the nucleus in NG108‐15 cells. Here we find that this is preceded by a transient short‐term ethanol‐induced translocation of PKA C. Different molecular mechanisms appear to underlie early and late phases of ethanol‐induced translocation of PKA subunits.

Methods: The time course and localization of PKA C and regulatory (RII) subunits was assessed by immunocytochemistry in NG108‐15 cells in the presence of ethanol, adenosine receptor (A2) blockade, and inhibitors of PKA activity and RNA and protein synthesis.

Results: Ethanol induces an early phase (<30 min) of C translocation to the cytoplasm and nucleus. This requires cAMP via adenosine A2 receptor activation. C then returns to the Golgi area after 60 min. A second phase of C translocation occurs during continuing exposure to ethanol (>12 hr). Re‐accumulation of nuclear C no longer requires A2 or cAMP. RII also translocates to the nucleus during chronic treatment with ethanol. Both C and RII remain in the nucleus as long as ethanol is present. Unlike the early phase of ethanol induced translocation, the second phase of PKA subunit translocation requires protein and RNA synthesis.

Conclusions: We identify two distinct phases of ethanol‐induced PKA translocation which appear to be regulated by different molecular mechanisms. The first requires A2 signaling and cAMP; the later phase requires RNA and protein synthesis. The two phases of ethanol‐induced PKA translocation observed in cell lines may contribute to changes in PKA signaling, cAMP‐dependent gene expression, and the initiation and maintenance of sustained drinking behavior in experimental animals.
Effects of Managed Care on Alcohol and Other Drug (AOD) Treatment
Authors: Magura Stephen , Horgan Constance M. , Mertens Jennifer R. , Shepard Donald S.
Published: April 2006

The article represents the proceedings of a symposium at the 2001 RSA Meeting in Montreal, Canada. The organizer/chair was Stephen Magura. The presentations examined: (1) How managed care organization policies may affect enrollees’ use of alcohol and other drug (AOD) treatment, by Constance Horgan and associates; (2) The determinants of patients’ access to and utilization of AOD treatment in a large health maintenance organization, by Jennifer R. Mertens and Constance Weisner; (3) The impact on treatment access and costs of a statewide carve‐out for AOD treatment for Medicaid, by Donald Shepard and associates; and (4) The predictive validity of a new patient assessment technology developed, in part, to better justify AOD treatment in response to the demands of managed care, by Stephen Magura and associates.
The Effects of NMDA and GABAA Pharmacological Manipulations on Ethanol Sensitivity in Immature and Mature Animals
Authors: Silveri M. M. , Spear L. P.
Published: April 2006

Background: Sensitivity to the hypnotic effects of ethanol dramatically increases with age (Silveri and Spears, 1998). Little is known regarding the neural mechanisms that might underlie this relative resistance of young animals to ethanol. The present study used a psychopharmacological approach to examine the influence of NMDA (N‐methyl‐D‐aspartate) and GABA (γ‐Aminobutyric acid) receptor systems in modulating age differences in ethanol responsiveness between young [postnatal day (P26)] and mature (P70) female and male Sprague‐Dawley rats.

Method: Dose response curves were established for the effects of intraperitoneal (ip) administration of the NMDA antagonist (+)MK‐801 (0.75, 1.0, or 1.25 mg/kg), the GABAA agonist muscimol (0.75, 1.25, or 1.75 mg/kg), or saline on loss and regain of the righting reflex and trunk blood alcohol levels following 3.5 g/kg of ethanol.

Results: (+)MK‐801 increased time to regain the righting reflex at both ages, maintaining the age‐related increase in ethanol sensitivity typically observed, although a gender effect also emerged at P70, with females being more sensitive than males to (+)MK‐801‐induced increases in duration of loss of the righting reflex. In contrast to the across‐age similarity in responsiveness to (+)MK‐801, P26 animals were considerably more sensitive to muscimol's enhancing effect on ethanol sedation than mature animals.

Conclusion: Although modulation of either the NMDA or GABA system enhances the sedative effects of ethanol at both ages, stimulation of the GABAA receptor is a more effective means of prolonging ethanol sedation in immature than mature animals.
Free‐Choice Ethanol Consumption Under the Influence of GABAergic Drugs in Rats
Authors: Schmitt Ulrich , Waldhofer Susanna , Weigelt Tamara , Hiemke Christoph
Published: April 2006

Background: Neurobiological mechanisms leading from controlled alcohol consumption to addiction are poorly understood. Among multiple neurotransmitters γ‐amino‐butyric acid (GABA) is suggested to play a role. The present investigation studied effects of drugs interacting with the GABAergic system on the motivation of ethanol consumption.

Methods: Fifty male PVG/OlaHsd rats were analyzed for free‐choice ethanol drinking behavior without and with pre‐exposure to drugs acting on the GABAergic system. For pretreatment, animals received the benzodiazepine agonists or antagonists diazepam, flumazenil, or Ro15‐4513, or the GABA uptake inhibitor tiagabine via the drinking water for 4 weeks (day −21 until day 7). On day 0, two bottles containing 5% and 12% ethanol were added. On day 7, GABAergic drug exposure was discontinued and drug solutions were replaced by water. Between days 8 and 35, three alcohol deprivation periods of 1 to 3 days were randomly implemented.

Results: The animals ingested substantial amounts of ethanol that was differentially affected by the GABAergic drugs. Diazepam increased and flumazenil decreased ethanol consumption significantly by about 30%. Without GABAergic drug pretreatment, a significant alcohol deprivation effect indicated by enhanced ethanol consumption after re‐exposure to alcohol was observed after the third deprivation phase. The deprivation effect was prevented by pretreatment with diazepam or flumazenil, unaffected by Ro15‐4513, and advanced by tiagabine.

Conclusions: Modulation of GABAergic neurotransmission affects subsequent ethanol consumption and deprivation effects. Because enhancing of the GABAergic tone by the GABA uptake inhibitor tiagabine or by the benzodiazepine diazepam had different behavioral consequences, it seemed likely that the two drugs induce differential adaptive changes leading to distinct alterations in the motivation to consume alcohol.
Testing Hypothesized Predictors of Change in Conjoint Behavioral Alcoholism Treatment for Men
Authors: McCrady Barbara S. , Hayaki Jumi , Epstein Elizabeth E. , Hirsch Linda S.
Published: April 2006

Background: The model on which alcohol‐related Behavioral Couples Therapy (ABCT) is based posits three primary domains related to alcohol consumption: individual factors, the quality and nature of the spouse's response to alcohol‐related situations, and the nature and quality of the couple's marital interactions.

Methods: This study tested the model underlying ABCT in a sample of 68 male alcoholics and their partners, who completed at least five sessions of a 15‐session outpatient treatment study in which they received ABCT. Couples were assessed at baseline, during treatment, and for 6 months after treatment completion. Stepwise multiple regression was used to test specific predictors derived from the ABCT model.

Results: Some support was provided for each component of the ABCT model. Individual drinker variables predicted drinking outcomes, both during and after treatment. Specifically, greater drinking severity and drinking frequency at baseline predicted poorer drinking outcomes. Older client age and more education predicted less frequent but more intense drinking. Spouse coping was related primarily to measures of drinking intensity, rather than drinking frequency. Less intense drinking during treatment was predicted by greater spousal use of problem solving and social support to deal with problems and less use of self‐blame, wishful thinking, and avoidance. After treatment, however, spouse coping had a less consistent relationship to drinking intensity. In the marital domain, drinking during treatment was unrelated to pretreatment marital satisfaction measures. However, in the 6 months after treatment, men's ability to remain abstinent was predicted by the quality of the pretreatment marital relationship, and the intensity of their drinking was predicted by the degree of their marital happiness immediately after treatment.

Conclusions: Results provided substantial support for the ABCT model, particularly in relationship to the role of the spouse in affecting heavy drinking.
Concurrent and Discriminant Validity of DSM‐IV Symptoms of Impaired Control Over Alcohol Consumption in Adolescents
Authors: Chung Tammy , Martin Christopher S.
Published: April 2006

Background: Little research has examined impaired control over alcohol consumption in adolescents. This study examined the concurrent and discriminant validity of two DSM‐IV dependence criteria that reflect impaired control over drinking: “using more or longer than intended” (Larger/Longer) and “persistent desire or unsuccessful efforts to quit or cut down” (Quit/Cut Down).

Methods: Adolescent drinkers, ages 13–19 (N= 173), were recruited from addictions treatment (76%) and community sources (24%). A modified SCID that included assessment of alcohol craving and questionnaires measuring dependence severity, attempts to limit drinking, and impulsivity were administered.

Results: Larger/Longer had higher prevalence and an earlier onset than Quit/Cut Down, suggesting that the symptoms respectively represent milder and more severe manifestations of impaired control over drinking. Both symptoms were associated with drinking frequency, dependence severity, episodes of passing out, and an independent measure of unsuccessful attempts to limit drinking. Alcohol craving was associated with both Larger/Longer and Quit/Cut Down. Impulsivity was correlated with Larger/Longer but not Quit/Cut Down.

Conclusions: Larger/Longer and Quit/Cut Down demonstrated adequate concurrent validity. The two symptoms were distinguished by severity and differential relations with impulsivity, suggesting that Larger/Longer and Quit/Cut Down reflect different types of impaired control over alcohol consumption. Results suggest the need for improved description and scaling of the impaired control construct in adolescents.
Alcohol‐Related Problems, Drug Use, and Male Intimate Partner Violence Severity Among US Couples
Authors: Cunradi Carol B. , Caetano Raul , Schafer John
Published: April 2006

Background: Particularly for women, level of intimate partner violence (IPV) severity is associated with risk of injury. Previous research suggests that male drinking problems and drug use are key risk factors. Few studies, however, have examined the associations between male and female alcohol problems and drug use and risk of moderate and severe male IPV in general household population samples.

Methods: A multiethnic sample of 1615 married and cohabiting couples was obtained from the 1995 National Study of Couples, a cross‐sectional study on alcohol and IPV. We assessed the contribution of past year male and female alcohol‐related problems (i.e., drinking consequences and alcohol‐dependence symptoms) and illicit drug use to the risk of moderate and severe male IPV. A series of generalized multinomial logit models, with adjustment for sociodemographic and psychosocial covariates, was constructed to assess these associations.

Results: Female and male alcohol‐related problems and female drug use, were associated with increased risk of moderate and severe male IPV. Contrary to our expectation, male drug use was not associated with elevated risk for either type of male IPV. Compared with couples residing in low‐unemployment neighborhoods, couples residing in high‐unemployment neighborhoods were at greater risk for severe, but not moderate, male IPV.

Conclusions: Alcohol‐related problems among men and women and drug use among women, appear to be important correlates of male IPV severity among couples in the general population. These findings can aid in IPV screening efforts, the formulation of prevention strategies, and help inform batterer and victim treatment programs.
Phosphatidylethanol in Rat Organs After Ethanol Exposure
Authors: Aradottir Steina , Lundqvist Christofer , Alling Christer
Published: April 2006

Background: Phosphatidylethanol (PEth) is an abnormal phospholipid formed in mammalian cells that have been exposed to ethanol. It has been suggested that PEth mediates some of the damaging effects of ethanol on cells. This study was performed to investigate the level of PEth in organs of rats after in vivo alcohol exposure.

Methods: Three exposure models were studied: (1) acute, intraperitoneal injection of ethanol (n= 3 × 3); (2) chronic, forced ethanol drinking (n= 6); and (3) chronic, free choice of ethanol (n= 20). PEth was analyzed by high‐performance liquid chromatography after lipid extraction of the organs.

Results: One acute injection gave detectable PEth levels in most organs analyzed, with maximal levels reached after 2 hr. The highest levels were reached in intestines, stomach, and lung. No PEth was detected in skeletal muscle, pancreas, or testis. The two exposure models for oral intake of ethanol also gave detectable PEth levels in most organs. The highest levels were reached in stomach, lung, and spleen. PEth was detected in muscle only in animals with heavy total alcohol intake.

Conclusions: PEth is formed in most organs of rats exposed to ethanol acutely or chronically. Variations in PEth level and rates of PEth formation and PEth degradation are organ specific.
Interleukin‐4 Treatment Restores Cellular Immunity After Ethanol Exposure and Burn Injury
Authors: Messingham Kelly A. N. , Heinrich Scott A. , Schilling Eric M. , Kovacs Elizabeth J.
Published: April 2006

Background: Previous studies from this laboratory showed that the suppression of cell‐mediated immunity after the combined injury of ethanol exposure and burn is mediated by increased presence of the proinflammatory cytokine interleukin (IL)‐6. IL‐4 is a T‐helper cell type 2 lymphocyte‐derived cytokine that serves to down‐regulate the inflammatory response. Therefore, the goal of this study was to evaluate the effects of ethanol exposure and burn injury on lymphocyte production of IL‐4 and to determine whether administration of IL‐4 could improve cellular immunity after ethanol exposure and burn injury through modulation of IL‐6 levels.

Methods: Mice were subjected to a 15% total body‐surface area burn (or sham) injury 30 min after being given a single dose of alcohol (or saline) designed to achieve a blood alcohol level of 100 mg/dl. Thirty minutes after burn, mice were treated with IL‐4 (or vehicle) and were killed 24 hr later.

Results: Lymphocytes from ethanol/burn mice secreted significantly less IL‐4 in comparison to all other groups of mice (p < 0.05). Administration of IL‐4 resulted in a complete restoration of the delayed‐type hypersensitivity (p < 0.01) and splenocyte proliferative responses (p < 0.05) and a significant reduction in circulating and splenic macrophage‐derived IL‐6 (p < 0.05). Addition of IL‐4 (100 or 300 pg/ml) to cultures generated from ethanol/burn and vehicle mice resulted in a complete restoration of splenocyte proliferation and a concomitant attenuation of macrophage IL‐6 production.

Conclusions: These studies suggest that the loss of lymphocyte production of IL‐4 after ethanol exposure and burn injury may contribute to the exaggerated production of IL‐6, a known mediator of immune suppression after injury. Moreover, the administration of IL‐4 may be beneficial for patients with injuries that are characterized by a dysregulated inflammatory response.
Potential Neuroprotective Effects of Acamprosate
Authors: Koob George F. , Mason Barbara J. , de Witte Philippe , Littleton John , Siggins George R.
Published: April 2006

This article represents the proceedings of a symposium at the 2001 RSA Meeting in Montreal, Canada. The organizers were Barbara J. Mason and George F. Koob. Anita M. Goodman served as chair. The presentations were (1) Acamprosate inhibits alcohol withdrawal‐induced neurotoxicity in organotypic hippocampal cultures, by John Littleton; (2) Acamprosate alteration of NMDA receptor‐dependent synaptic transmission and synaptic plasticity, by George R. Siggins; (3) Acamprosate and glutamate during ethanol withdrawal, by Philippe De Witte; (4) Clinical evidence of protective CNS effects of acamprosate in alcohol‐dependent individuals, by Barbara J. Mason.
Mapping of Quantitative Trait Loci Underlying Ethanol Metabolism in BXD Recombinant Inbred Mouse Strains
Authors: Grisel Judith E. , Metten Pamela , Wenger Charlotte D. , Merrill Catherine M. , Crabbe John C.
Published: April 2006

Background: Genetic factors are well known to play an important role in determining individual differences in the metabolism of ethanol (EtOH), and several specific polymorphic loci have been identified that significantly contribute to the variability of EtOH metabolism in humans. However, these variant genes are either alcohol or aldehyde dehydrogenases, and the identification of new gene products that contribute to variation in alcohol metabolism would be useful.

Methods: To identify quantitative trait loci (QTLs), we correlated variation in polymorphic markers with blood EtOH concentration and the rate of EtOH metabolism (β) in C57BL/6J and DBA/2J strains and in 25 of their recombinant inbred strains after 2 and 3 g/kg of EtOH intraperitoneally.

Results: A QTL associated with β values for both doses was definitively mapped to the proximal region of chromosome 17, syntenic with human chromosome 6q25–27. Seven to 12 chromosomal regions were provisionally identified for each phenotype; several were associated with 2 or more phenotypes. Each QTL suggests the location of a gene or genes affecting EtOH pharmacokinetics. Candidate genes suggested by these analyses included several whose gene products are known to be induced by EtOH (e.g., superoxide dismutase, glutathione transferase, and cytochrome P450 2E1), as well as several whose gene products have signaling functions likely to contribute to this induction.

Conclusions: These studies provide evidence for the existence of genes affecting EtOH metabolism in multiple chromosomal regions. Future studies will be required to identify the chromosome 17 gene product. Use of other genetic populations, such as B6D2F2 crosses, will be required to determine which of the provisional loci represent true and which represent false‐positive associations.
Alcohol Consumption Promotes Body Weight Loss in Melanoma‐Bearing Mice
Authors: Núñnez Nomelí P. , Carter Patrick A. , Meadows Gary G.
Published: April 2006

Background: Alcohol consumption is an important risk factor for cancer. Little is known about its effects on cancer progression. Previously, we showed that high ethanol consumption inhibited metastasis of B16BL6 melanoma‐bearing mice without affecting primary tumor growth. On the other hand, ethanol‐consuming tumor‐bearing (TE) mice exhibited decreased survival and decreased body weight as compared to water‐drinking, tumor‐bearing (TW) mice. The focus of this study was to determine how alcohol promotes weight loss in melanoma‐bearing mice.

Methods: Female, C57BL/6 mice were given water or 20% w/v ethanol in the drinking water for 3 weeks to 6 months before subcutaneous inoculation of 1 × 106 B16BL6 melanoma cells. Mice continued to receive the same fluids. Biochemical parameters were evaluated at various times after tumor inoculation. Body weight, water content, tumor weight and carcass fat content were determined at necropsy.

Results: TW mice elicted a modest weight loss. This response was magnified 2‐fold by alcohol consumption. The weight loss in TE mice is not caused by dehydration, decreased energy intake, or loss of skeletal muscle mass. It resulted specifically from loss in body fat. Other alterations associated with the fat loss in TE mice were: (1) decreased glucose, (2) elevated fatty acids, (3) elevated β‐hydroxybutyrate, (4) elevated glucagon, and (5) increased leptin levels in plasma. Body temperature decreased about 2.9°C in TE mice. Metabolic rate increased in TW mice. The fat loss due to alcohol consumption in tumor‐bearing mice was not due to increased metabolic rate.

Conclusions: The response elicited by alcohol consumption in tumor‐bearing mice is complex and associated with alterations in metabolism and hormones. These findings suggest that alcohol abuse could be a risk factor for cancer patients because it invokes a strong depletion of body fat. This could facilitate wasting and shorten survival time.
Microanalysis of Ethanol Self‐Administration: Estrous Cycle Phase‐Related Changes in Consumption Patterns
Authors: Ford Matthew M. , Eldridge J. C. , Samson Herman H.
Published: April 2006

Background: Female rodent and reproductive cycle‐related patterns in ethanol consumption have been identified grossly, but the regulatory processes that underlie these patterns remain to be clarified. The evaluation of consummatory bout dynamics may be useful in determining the effects of a changing endogenous state (ovarian hormone fluctuations) on ethanol consumption patterns. This study assessed the microstructural components of ethanol intake patterns across the estrus cycle.

Methods: Cumulative licking of 13 female Long‐Evans rats was recorded during continuous access (22 hr/day) to 10% ethanol and tap water solutions throughout a 10 week period. Drinking bouts were defined as 20 or more successive licks separated by less than a 60 sec pause. Vaginal smears were obtained daily from each rat between 1100 and 1130 hr to assess estrus cycle phase. ANOVAs were conducted to evaluate estrus cycle effects on consumption pattern parameters.

Results: Total daily ethanol intakes were unaffected by estrus cycle phase. Ethanol bout frequency was significantly greater during proestrus compared with all other phases, whereas ethanol bout sizes were significantly attenuated during proestrus compared with estrus and diestrus. Experience with ethanol was associated with a significant decline in bout frequency and a significant elevation in bout size across all cycle phases, which indicated that initiation of ethanol self‐administration occurred over time. A significant main effect of hour and a cycle phase by hour interaction were found for the temporal distribution of ethanol lick responses throughout the estrus cycle, and a progressive shift in lick patterns evolved between estrus and the subsequent proestrus.

Conclusions: The estrus cycle phase‐related changes in the microstructural components of ethanol intake suggest that female rats experience periods of altered sensitivity to the neurobiological and reinforcing effects of ethanol. Furthermore, these findings implicate cyclical fluctuations in ovarian hormones and other neuromodulators in the regulation of ethanol consumption patterns throughout the estrus cycle of the female rat.
Beer Congener Stimulates Gastrointestinal Motility Via the Muscarinic Acetylcholine Receptors
Authors: Fujii Wataru , Hori Hisako , Yokoo Yoshiaki , Suwa Yoshihide , Nukaya Haruo , Taniyama Kohtaro
Published: April 2006

Background: Ethanol and alcoholic beverages are known to affect upper gastrointestinal motility in humans. Beer has been reported to accelerate gastric emptying compared with other beverages that contain the same ethanol concentrations. In this study, we investigated the mechanism that underlies the effects of beer congener on gastrointestinal motility.

Methods: Gastric emptying activity was measured by means of movement of a semisolid test meal (0.05% phenol red/1.5% methylcellulose) in mice. To elucidate the mechanism for the effect of beer congener on gastrointestinal motility, we conducted receptor binding assays and contraction study by using longitudinal muscle from guinea pig ileum.

Results: Beer congener (1 g/kg orally) enhanced gastric emptying of a semisolid meal in mice. The receptor binding assay revealed that beer congener bound to dopamine D2 receptor and 5‐hydroxytryptamine (5‐HT)3 receptor. These IC50 values were more than 5 mg/ml. However, beer congener bound to 5‐HT2 receptor, 5‐HT4 receptor, and muscarinic M3 receptor with IC50 values of 2, 0.9, and 2 mg/ml, respectively. Beer congener (0.05–2 mg/ml) induced the contraction of longitudinal muscle from guinea pig ileum in a dose‐dependent manner. This effect was not affected by either tetrodotoxin (10−6M) or ketanserin (10−7‐10−5M), an antagonist for the 5‐HT2 receptor. On the other hand, 4‐DAMP (10−8−10−5M), an antagonist for the muscarinic M3 receptor, inhibited the contraction of the longitudinal muscle induced by beer congener (2 mg/ml) dose dependently.

Conclusions: Beer congener stimulates gastrointestinal motility via the muscarinic M3 receptor.
Expectancy and Risk for Alcoholism: The Unfortunate Exploitation of a Fundamental Characteristic of Neurobehavioral Adaptation
Authors: Goldman Mark S.
Published: April 2006

Psychological investigations of alcohol expectancies over the last 20 years, using primarily verbal techniques, have strongly supported expectancies as an important mediator of biological and environmental antecedent variables that influence risk for alcohol use and abuse. At the same time, rapid developments in neuroscience, cognitive science, affective science, computer science, and genetics proved to be compatible with the concept of expectancy and, in some cases, used this concept directly. By using four principles that bear on the integration of knowledge in the biological and behavioral sciences—consilience, conservation, contingency, and emergence—these developments are merged into an integrated explanation of alcoholism and other addictions. In this framework, expectancy is seen as a functional approach to adaptation and survival that has been manifested in multiple biological systems with different structures and processes. Understood in this context, addiction is not a unique behavioral problem or special pathology distinct from the neurobehavioral substrate that governs all behavior, but is rather a natural (albeit unfortunate) consequence of these same processes. The ultimate intent is to weave a working heuristic that ties together findings from molecular and molar levels of inquiry and thereby might help direct future research. Such integration is critical in the multifaceted study of addictions.
The Decreased Cellular Expression of Neuropeptide Y Protein in Rat Brain Structures During Ethanol Withdrawal After Chronic Ethanol Exposure
Authors: Roy Adip , Pandey Subhash C.
Published: April 2006

Background: Neuropeptide Y (NPY) has been implicated in the alcohol‐drinking behaviors of rodents. This study investigated the possible involvement of NPY in the neuroadaptational mechanisms to chronic ethanol exposure and its withdrawal.

Methods: Male Sprague‐Dawley rats were treated either with Lieber‐DeCarli ethanol diet or control diet for 15 days, and ethanol‐fed rats were withdrawn for 0 and 24 hr. The protein expression of NPY was determined in cortical, hippocampal, amygdaloid, striatal, and hypothalamic structures by using the gold‐immunolabeling histochemical procedure.

Results: It was found that ethanol withdrawal, but not ethanol treatment, produced significant reductions in NPY protein levels in (1) layers IV and V of the frontal and parietal cortex, (2) layer II of the piriform cortex, (3) the central and medial nuclei of the amygdala, and (4) the paraventricular nucleus of the hypothalamus in rat brain. Chronic ethanol exposure and its withdrawal had no effect on the NPY protein levels in layers II, III, and VI of the frontal and parietal cortex or cingulate gyrus, in hippocampal (CA1, CA2, CA3, and dentate gyrus) and striatal (caudate putamen and globus pallidus) structures, or in the ventro‐medial hypothalamus and basolateral amygdala. However, chronic ethanol exposure and its withdrawal produced significant reductions in NPY protein levels in the arcuate nucleus of the hypothalamus and in layers IV and V of the cingulate gyrus.

Conclusions: These results suggest that the decreased protein levels of NPY in the central and medial nuclei of the amygdala, as well as in the cortical and hypothalamic structures, during ethanol withdrawal may play an important role in the neuromechanisms of some ethanol withdrawal symptoms.
Attenuated Heart Rate Responses to Public Speaking in Individuals With Alcohol Dependence
Authors: Panknin Tera L. , Dickensheets Stacey L. , Nixon Sara J. , Lovallo William R.
Published: April 2006

Background: Because individuals with alcohol dependence (AD) have shown blunted cortisol responses to psychological stress, we assessed whether they also show attenuated cardiovascular responses. This study examined the cardiovascular responses of people meeting DSM‐IV criteria for AD to orthostasis and public speaking.

Methods: Heart rate (HR), stroke volume, cardiac output, total peripheral resistance, mean arterial pressure, systolic blood pressure, and diastolic blood pressure during orthostasis and public speaking were assessed by use of impedance cardiography and Dinamap blood pressure monitoring in 20 AD subjects abstinent for 21 to 28 days and in 10 age‐matched controls. Orthostasis consisted of standing, whereas public speaking involved preparing and presenting two speeches. Self‐reported mood state was also assessed during the tasks.

Results: AD subjects had significantly lower resting BP compared with controls. Cardiovascular responses to orthostasis were similar between groups. AD subjects had attenuated HR during public speaking but reported similar anxiety responses to controls.

Conclusions: Comparable cardiovascular responses to orthostasis in controls and AD subjects suggest intact reflex control of circulation. AD subjects had blunted HR responses to public speaking; this is consistent with the attenuated cortisol responses observed in this sample and in previous studies. This suggests a possible alteration in limbic system regulation of hypothalamic and brainstem responses to psychological stress. Cardiovascular responses of AD subjects that are inconsistent with subjective accounts of tension and anxiety suggest a disconnection between perception of threat and resulting physiologic responses in AD subjects.
Alcohol Advertising and Youth
Authors: Martin Susan E. , Snyder Leslie B. , Hamilton Mark , Fleming‐Milici Fran , Slater Michael D. , Stacy Alan , Chen Meng‐Jinn , Grube Joel W.
Published: April 2006

This article presents the proceedings of a symposium at the 2001 Research Society on Alcoholism meeting in Montreal, Canada. The symposium was organized and chaired by Joel W. Grube. The presentations and presenters were (1) Introduction and background, by Susan E. Martin; (2) The effect of alcohol ads on youth 15–26 years old, by Leslie Snyder, Mark Hamilton, Fran Fleming‐Milici, and Michael D. Slater; (3) A comparison of exposure to alcohol advertising and drinking behavior in elementary versus middle school children, by Phyllis L. Ellickson and Rebecca L. Collins; (4) USC health and advertising project: assessment study on alcohol advertisement memory and exposure, by Alan Stacy; and (5) TV beer and soft drink advertising: what young people like and what effects? by Meng‐Jinn Chen and Joel W. Grube.
Effects of Alcohol and Oxidative Stress on Liver Pathology: The Role of the Mitochondrion
Authors: Cahill Alan , Cunningham Carol C. , Adachi Masayuki , Ishii Hiromasa , Bailey Shannon M. , Fromenty Bernard , Davies Adrian
Published: April 2006

This article represents the proceedings of a symposium at the 2001 Research Society on Alcoholism meeting in Montreal, Canada. The chairs were Alan Cahill and Carol C. Cunningham. The presentations were (1) Mitochondrial regulation of ethanol‐induced hepatocyte apoptosis: possible involvement of proapoptotic Bcl‐2 family protein Bax, by Masayuki Adachi and Hiromasa Ishii; (2) Effects of ethanol on mitochondrial reactive oxygen species production and oxidative protein modification, by Shannon M. Bailey; (3) Acute ethanol binges elicit widespread oxidative mitochondrial DNA damage and depletion: protective effects of antioxidants and inhibitors of ethanol metabolism, by Bernard Fromenty; and (4) Effects of chronic ethanol consumption upon hepatic mtDNA oxidative modification and depletion, by Alan Cahill and Adrian Davies.
Alcohol and Benzodiazepines in Fatal Poisonings
Authors: Koski Anna , Ojanperä Ilkka , Vuori Erkki
Published: April 2006

Background Postmortem forensic toxicology frequently finds alcohol both alone and in combination with drugs. Although benzodiazepines are generally considered safe, they are considered dangerous with alcohol.

Methods A retrospective statistical analysis of alcohol and benzodiazepine concentrations in postmortem blood samples included 808 cases diagnosed as fatal alcohol or drug intoxication involving (1) ethanol alone; (2) ethanol with temazepam; or (3) ethanol with any combination of diazepam, chlordiazepoxide, and nordazepam.

Results The median concentration of ethanol was 3.3‰ in cases with ethanol alone and 3.5‰ when diazepam was present, but it was significantly lower, only 2.5‰, when temazepam was present in the blood. Furthermore, the median concentration of ethanol was 2.2‰ in cases with high concentrations (>0.9 mg/liter) of temazepam and 2.7‰ in cases with therapeutic (≤0.9 mg/liter) concentrations.

Conclusions Diazepam and chlordiazepoxide pose a smaller risk of death by poisoning than does temazepam when given as a hypnotic to patients suffering from alcoholism.
Biological Markers of Alcohol Consumption in Nondrinkers, Drinkers, and Alcohol‐Dependent Brazilian Patients
Authors: Figlie N. B. , Benedito‐Silva A. A. , Monteiro M. G. , Souza‐Formigoni M. L. O.
Published: April 2006

Background The purpose of this study was to compare the sensitivity and specificity of some new and traditional biological markers and indicators of health among Brazilian nondrinkers, drinkers, and alcohol‐dependent patients.

Material and Methods We evaluated 130 nondrinkers, 167 drinkers, and 183 alcohol‐dependent drinkers from Brazil who participated in the WHO/ISBRA Study on State and Trait Markers of Alcohol Use and Dependence. A standardized WHO/ISBRA Interview Schedule provided background information on the subjects’ characteristics including reported health problems and alcohol consumption. Blood samples were analyzed for aspartate aminotransferase (AST), carbohydrate deficient transferrin (CDT), γ‐glutamyltransferase (GGT), blood alcohol levels (BAL), and platelet adenylate cyclase activity (basal levels [AC] and levels after stimulation with Gpp(NH)p, cesium fluoride, and forskolin).

Results The alcohol‐dependent drinkers presented higher levels of AST, GGT, AC, CDT, and BAL than the nondrinkers and drinkers, whose levels were similar. Sex differences in the sensitivity of CDT and AC were found. The alcohol‐dependent women presented a lower prevalence of abnormal values of CDT and Gpp(NH)p‐stimulated AC than the alcohol‐dependent men, despite the fact that they presented similar alcohol consumption levels. The alcohol‐dependent drinkers presented a higher prevalence of clinical disorders than the nondrinkers and drinkers. The drinkers and alcohol‐dependent patients presented significantly higher rates of gastritis than the nondrinkers.

Conclusions Sex differences in the sensitivity of CDT and AC suggest that these markers are not as sensitive at detecting excessive alcohol use in women as they are in men. If data from this Brazilian sample are compared with those reported for international samples, relevant differences are detected, which suggests that genetic and cultural differences should be considered in the selection of biological markers of heavy alcohol consumption.
The Ethanol Conjugate Ethyl Glucuronide Is a Useful Marker of Recent Alcohol Consumption
Authors: Martin Wurst Friedrich , Metzger Joerg
Published: April 2006

Background Current biological state markers remain suboptimal with regard to sensitivity and specificity for monitoring alcohol consumption. The currently used state markers can be influenced by age, sex, and a variety of substances and non‐alcohol‐associated diseases and do not fully cover the time axis for alcohol intake. Ethyl glucuronide (EtG) is a promising, nonvolatile, water‐soluble marker of recent alcohol consumption that is stable during storage and can be detected for an extended time period (up to 80 hr) after alcohol is completely eliminated from the body.

Patients and Methods In the WHO/ISBRA Study of State and Trait Markers of Alcohol Use and Dependence, EtG was determined in urine samples from 304 patients with an liquid chromotography, electrospray ionization double mass spectrometry (ESI‐LC/MS‐MS) method. Deuterium labeled EtG was used as internal standard. Determination limit was 0.1 mg/liter. All measurements were performed in duplicate. A calibration solution was measured after each 10 samples.

Results The following significant correlations were found for the Spearman rank correlation for the total sample between EtG and other variables: sobriety in days (r=−0.6), 5‐hydroxytryptophol to 5‐hydroxyindole‐3‐acetic acid (HTOL/HIAA) ratio (r= 0.58), ethanol level (r= 0.433), methanol level (r= 0.198), carbohydrate‐deficient transferrin (r= 0.458), γ‐glutamyltransferase (r= 0.428), aspartate aminotransferase (r= 0.260), age (r= 0.264), and total grams of ethanol consumed in the previous month (r= 0.467). In a subsample of 277 subjects in whom no ethanol was detectable in urine, the following correlations with EtG levels were found: sobriety (days;r=−0.597), HTOL/HIAA ratio (r= 0.478), γ‐glutamyltransferase (r= 0.422), total grams of ethanol consumed last month (r= 0.395), and carbohydrate‐deficient transferrin (r= 0.366; all significant at p < 0.05). When we compared results between EtG levels and the HTOL/HIAA ratio, 68.8% (n= 119) of those positive for EtG did not have elevated values for the HTOL/HIAA ratio. Thirty‐one percent (31.2%) of these 119 subjects were positive for both parameters, but of those negative for EtG, only 4.4% had an elevated HTOL/HIAA ratio.

Conclusions EtG is a good candidate for a sensitive, specific, and reliable marker of recent alcohol intake. The complementary use of this marker with other biological state markers should significantly improve treatment outcome and therapy effectiveness and reduce costs.
Alcohol‐Induced Up‐Regulation of Fibrinolytic Activity and Plasminogen Activators in Human Monocytes
Authors: Tabengwa Edlue M. , Wheeler Crystal G. , Yancey Dwana A. , Grenett Hernan E. , Booyse Francois M.
Published: April 2006

Background Moderate alcohol consumption is associated with reduced risk for coronary heart disease. This may due, in part to increased fibrinolysis. Monocytes synthesize fibrinolytic proteins, tissue plasminogen activator (t‐PA), urokinase plasminogen activator (u‐PA), and their receptors. These studies were carried out to determine the effect of low alcohol on monocyte fibrinolytic activity and PA messenger RNA (mRNA) synthesis.

Methods Peripheral blood monocytes and U937 cells were incubated in absence/presence of low alcohol (0.1%, v/v) for various times (0–1 hr), followed by incubations in the absence of alcohol (0–24 hr) before measurement of fibrinolytic activity and PA mRNA levels (reverse transcriptase polymerase chain reaction).

Results Brief exposure (15 min, 4°C) of U937 cells to low alcohol resulted in an approximately 2‐ to 3‐fold increase (269.0 ± 5.6 fmol/1 × 106 cells versus 656.0 ± 94.0 fmol/1 × 106 cells) in fibrinolytic activity. Preincubation of U937 cells and peripheral blood monocytes in low alcohol (1 hr, 37°C) followed by incubation in the absence of alcohol (24 hr) resulted in a sustained approximately 4‐ to 5‐fold increase (414.0 ± 174.7 vs. 965.33.0 ± 104.8 fmol/1 × 106 cells) and an approximately 3‐ to 4‐fold (20.5 ± 2.14 vs. 74 ± 2.28 fmol/2 × 106 cells, respectively) increase in fibrinolytic activity. Preincubation of monocytes with low alcohol (1 hr, 37°C) followed by incubation in the absence of alcohol (6 hr) resulted in an approximately 5‐ to 6‐fold (0.06 ± 0.02 vs. 0.42 ± 0.02) and an approximately 2‐ to 3‐fold (0.89 ± 0.04 vs. 2.07 ± 0.29) increase in t‐PA and u‐PA mRNA (reverse transcriptase polymerase chain reaction; PA/glyceraldehyde‐3‐phosphate dehydrogenase ratio), respectively.

Conclusions These data suggest that low alcohol exerts a rapid, direct, and sustained effect on monocyte fibrinolytic activity, which may be, due in part, to increased monocyte t‐PA/u‐PA expression. These data provide a feasible molecular mechanism by which alcohol effects on monocyte fibrinolysis may contribute to the cardioprotective benefit associated with moderate alcohol consumption.