bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethanol Modulation of γ‐Aminobutyric Acid (GABA)‐Mediated Inhibition of Cerebellar Purkinje Neurons: Relationship to GABAb Receptor Input
Authors: Yang Xiaohong , Criswell Hugh E. , Breese George R.
Published: April 2006

Background: Electrophysiological recording reveals that only a portion of cerebellar Purkinje neurons are sensitive to ethanol enhancement of γ‐aminobutyric acid (GABA) responses. Although activation of beta‐adrenergic receptors permits ethanol enhancement of GABA function from some cerebellar Purkinje neurons, other neurons remain insensitive to ethanol. These findings are consistent with the finding that other external neural inputs are required to allow ethanol enhancement of GABA responses from Purkinje neurons. Because of a high expression of GABAB receptors on Purkinje cells, we tested whether activation of GABAB receptors might modulate the action of ethanol on GABA responsiveness.

Methods: Extracellular single‐unit electrophysiological recording was used to investigate the effects of ethanol on responses to GABA and muscimol (a GABAA agonist) from cerebellar Purkinje neurons. Drugs tested were baclophen (a GABAB agonist) and CGP35348 (a GABAB antagonist).

Results: Ethanol did not enhance responses to GABA and muscimol from all Purkinje neurons. Systemic administration of the GABAB agonist, baclophen (3 mg/kg intravenously), permitted ethanol to enhance GABA inhibition from ∼75% of cerebellar Purkinje neurons not initially enhanced by ethanol. Local iontophoretic application of baclophen to Purkinje neurons also allowed ethanol to enhance GABA and muscimol responsiveness from a portion of neurons in which ethanol initially did not affect their actions. An inhibitory action of ethanol on responses to GABA and muscimol, which was also influenced by baclophen, was observed from some Purkinje neurons. From Purkinje neurons initially sensitive to ethanol enhancement of GABA and muscimol function, administration of CGP35348, a GABAB antagonist, diminished the effect of ethanol on the responsiveness of these agonists from the majority (9/15) of neurons.

Conclusions: The present findings demonstrated that baclophen allows ethanol enhancement of GABA and muscimol responsiveness from some, but not all, cerebellar Purkinje neurons initially not sensitive to ethanol. Likewise, a GABAB antagonist can diminish ethanol enhancement of GABA and muscimol responses from some ethanol‐sensitive neurons. Thus, these results emphasize that GABAB receptors on a portion of Purkinje neurons act as an auxiliary neural input that allows ethanol enhancement of GABA responses. Consequently, receptor structure alone does not account for the action of ethanol on GABAA receptor function on this cell type.
A Review of the Effects of Prenatal or Early Postnatal Ethanol Exposure on Brain Ligand‐Gated Ion Channels
Authors: Costa Edmar T. , Savage Daniel D. , Valenzuela C. Fernando
Published: April 2006

Background: Ligand‐gated ion channels mediate fast excitatory and inhibitory synaptic transmission in the developing central nervous system. These channels have been shown to have roles in neuronal proliferation, differentiation, and programmed cell death. Numerous studies over the past 10 years indicate that prenatal and/or early postnatal ethanol exposure affects neurotransmitter‐gated ion channels.

Methods: We conducted a review of the relevant literature, identified by a computer‐assisted literature search. This review presents an overview of studies performed with experimental preparations from the brains of rodents exposed to ethanol in utero and/or during the neonatal period and summarizes some of the salient issues that have developed in the course of these investigations. Differences in ethanol exposure paradigms and blood alcohol concentrations obtained in these studies are highlighted, and directions for future research are suggested.

Results: Most studies have focused on the effects of prenatal or early postnatal ethanol exposure on NMDA receptors. These studies show that ethanol exposure affects ligand binding, subunit expression, and function of this receptor. Fewer studies have examined ethanol's effects on ligand‐gated ion channels other than NMDA receptors. For instance, a study reported changes in ligand binding to hippocampal kainate receptors. Another study found alterations in modulation of GABAA receptors by benzodiazepines and neurosteroids.

Conclusions: These studies suggest that the effects of ethanol on brain ion channels may have a role in the pathophysiology of Alcohol‐Related Neurodevelopmental Disorders and Fetal Alcohol Syndrome.
Is There a Difference Between CAGE Interviews and Written CAGE Questionnaires?
Authors: Aertgeerts Bert , Buntinx Frank , Fevery Johan , Ansoms Stan
Published: April 2006

Background: The CAGE questionnaire is a frequently studied and used instrument for screening of alcohol problems. It was developed and tested as a written questionnaire, but, clinically, it is often used as an oral interview. No comparisons have been made between the results of a written and an oral CAGE. This study attempted to (1) compare the results of a written CAGE questionnaire and a CAGE interview, and (2) compare the efficiency of using a simple open‐ended question about drinking habits before asking the CAGE and asking the CAGE without an introduction.

Methods: All patients who attended a general internal medicine, cardiology, or hepatology clinic were classified according to the week of the consultation, as follows: group I (week 1), patients completed a written CAGE and were subsequently interviewed during a normal consultation by a physician, who also asked the CAGE questions; group II (week 2), a physician first interviewed the patients, including the CAGE, and subsequently patients completed a written CAGE; and group III (week 3), patients completed a CAGE interview after an open‐ended introduction (“What do you drink during the day?”). Kappa values were used to compare the answers of the written and oral CAGE interviews (groups II and I). Nonparametric ANOVA was used to compare the results of group III and the oral interview of group II.

Results: Mean age was comparable between the groups, gender ratio was comparable between groups I and III, but there were fewer males in group II. Comparison of all written CAGEs with the oral CAGEs in the same patients resulted in an accuracy of 0.91 and a kappa value of 0.75 (95% CI, 0.66–0.84). No significant difference could be found between the results of the oral CAGE with or without an open‐ended introduction (p= 0.46).

Conclusions: We found no difference between the oral and the written versions of the CAGE. This is important because most research results originate from written questionnaires. Our results do not support the finding that a different approach to the CAGE questions results in an increasing number of patients in which alcohol problems were detected.
The Expression of an Alcohol Deprivation Effect in the High–Alcohol‐Drinking Replicate Rat Lines Is Dependent On Repeated Deprivations
Authors: Rodd‐Henricks Zachary A. , McKinzie David L. , Murphy James M. , McBride William J. , Lumeng Lawrence , Li Ting‐Kai
Published: April 2006

Background: The alcohol deprivation effect (ADE) is a temporary increase in the ratio of alcohol/total fluid intake and voluntary intake of ethanol (EtOH) solutions over baseline drinking conditions when EtOH access is reinstated after a period of alcohol deprivation. The ADE has been posited to be an animal model for alcohol craving. In the current study, we examined the effects of initial deprivation length and number of deprivation exposures on the ADE in the replicate lines of the high–alcohol‐drinking (HAD) rats.

Methods: Adult male HAD‐1 and HAD‐2 rats received 24 hr free‐choice access to 10% (v/v) EtOH and water for 6 weeks. Rats were then assigned to groups deprived of EtOH for 0 (control), or 2 to 8 weeks. All deprived groups were then given 24 hr access to EtOH for 2 weeks before being deprived of EtOH for another 2 weeks. This cycle of 2 weeks of access and 2 weeks of deprivation was carried out for a total of four deprivations.

Results: After the initial EtOH deprivation period, EtOH consumption in HAD‐1 and HAD‐2 rats returned to baseline levels but failed to exhibit either an early onset ADE (initial 2 hr) or prolonged ADE (24 hr). An ADE was observed in two of the four deprived groups for the HAD‐1 rats (2 week and 6 week groups) and in all deprived groups for the HAD‐2 rats after a second deprivation, and in all deprived groups of both lines after a third deprivation. In the HAD‐2 line, but not in the HAD‐1 line, the duration of the ADE was prolonged into the second reinstatement day after the fourth deprivation.

Conclusions: The expression of an ADE was observed only after repeated deprivation periods in the HAD lines. The duration of the ADE was prolonged in the HAD‐2 line, but not in the HAD‐1 line, with repeated deprivations, which suggests a dissociation between selection for alcohol preference and the effects of repeated deprivations on the duration of the ADE.
A New Assessment of the Ability of Oral Ethanol to Function as a Reinforcing Stimulus
Authors: Samson Herman H. , Czachowski Cristine L. , Slawecki Craig J
Published: April 2006

Background: In animal studies, the ability of ethanol to function as a reinforcer has been described as weak to moderate. This is in contrast with the human condition, where the consumption of alcoholic beverages can result in a variety of unwanted drinking behaviors. However, when the ethanol self‐administration pattern is examined, animal studies over the last several years indicate that the ability of ethanol presentation to maintain behavior may be greater than originally assumed.

Methods: We reevaluated the ability of ethanol to function as a reinforcing stimulus in two paradigms by using an analysis of drinking bout characteristics. Data from previous studies that employed two self‐administration models were analyzed. With the “dipper” model, small amounts of ethanol are presented after each completion of a response requirement; with the “sipper” model, the animal is allowed access to a drinking tube that contains ethanol for an extended period after completing a single response requirement. For both models, the consumption pattern could be characterized as occurring in a bout. Each drinking bout was divided into runs within the bout, and run rates and size were analyzed. As well, in the sipper model, the data on response requirement size were reviewed to demonstrate the ability of ethanol presentation to maintain high levels of responding in this model.

Results: From this assessment, we suggest that ethanol presentation in non‐food‐ or non‐water‐restricted rats is as reinforcing as many other stimuli generally considered to be strong reinforcers (i.e., food in food‐restricted rats). Using run size, we demonstrated that intake control appears to be regulated by shifts in run size during the bout and not run rate.

Conclusions: Assessment of the pattern of ethanol consummatory bouts and the behaviors that precede them is critical in understanding how ethanol functions as a reinforcer. By using a drinking pattern analysis, the shifts in the momentary salience of the ethanol stimulus can be evaluated in these animal models. In addition, the separation of responding required to gain access to ethanol from consumption of ethanol demonstrated that ethanol presentation in this procedure can be a strong reinforcer for rats.
Reverse Microdialysis of a Dopamine Uptake Inhibitor in the Nucleus Accumbens of Alcohol‐Preferring Rats: Effects on Dialysate Dopamine Levels and Ethanol Intake
Authors: Engleman Eric A. , McBride William J. , Wilber Aaron A. , Shaikh Saame R. , Eha Renee D. , Lumeng Lawrence , Li Ting‐Kai , Murphy James M.
Published: April 2006

Background: The mesolimbic dopamine (DA) system has been implicated in mediating the reinforcing actions of ethanol (EtOH). This study examines the effects of local perfusion of the DA uptake inhibitor GBR12909 (GBR) on (1) DA levels in the nucleus accumbens (NAc) and (2) EtOH drinking in alcohol‐preferring rats.

Methods: Stable drinking of a 15% (v/v) EtOH solution (minimum of 0.75 g/kg body weight) was established in daily 1 hr limited access sessions. Rats were then implanted with bilateral guide cannulae aimed 4 mm above the NAc. After recovery from surgery, concentric microdialysis probes (2 mm dialysis membrane surface) were inserted into the NAc. Most placements were in the shell or overlapping both shell and core. Two days later, the probes were perfused at 1.0 μl/min with artificial cerebral spinal fluid (aCSF) for at least a 90 min washout period followed by collection of five basal samples over 150 min. Rats were then perfused with either aCSF alone or 10, 25, 100, or 200 μM of GBR for 240 min on the first day of microdialysis. During the last 60 min of the drug treatment phase, rats were given their scheduled access to 15% EtOH. All rats were then perfused with aCSF for the last 90 min of the experiment. The following day, the procedure was repeated, but animals that received aCSF on the first day were given a dose of GBR and rats given GBR on the first day received only aCSF.

Results: GBR perfusion increased extracellular NAc DA levels dose dependently to more than 800% of basal levels at 100 to 200 μM but failed to alter EtOH intake (p > 0.05, paired t test) at any concentration tested. Moreover, after 100 μM of GBR perfusion had terminated, the extracellular levels of DA in the NAc remained elevated for approximately 24 hr (790% of day 1 basal;p < 0.05). The increase in dialysate DA levels observed during GBR perfusion with 100 μM was significantly greater for EtOH‐experienced rats than for EtOH‐naïve rats [F (7,59) = 14.85, p < 0.0001, analysis of variance, Student‐Newman‐Keuls post hoc test].

Conclusions: The results suggest (1) that EtOH drinking experience induces neuroadaptations that increase DA release in the NAc, and (2) that additional elevation in synaptic levels of DA in the NAc does not influence the maintenance of ongoing alcohol drinking under scheduled access conditions in alcohol‐preferring animals.
4.0 T Water Proton T1 Relaxation Times in Normal Human Brain and During Acute Ethanol Intoxication
Authors: Rooney William D. , Lee Jing‐Huei , Li Xin , Wang Gene‐Jack , Franceschi Dinko , Springer Charles S. , Volkow Nora D.
Published: April 2006

Background: It has been reported that acute ethanol intoxication decreases the brain water proton magnetic resonance T1 values, an effect that has been interpreted to indicate brain dehydration during this condition. Because water macromolecular interactions largely determine tissue water T1, another possible explanation for reduced brain water proton T1 values is that the interaction between water and brain macromolecules is altered by ethanol.

Methods: A 4.0 T magnetic resonance imaging (MRI) instrument was used to measure brain water proton T1 relaxation times before, during, and after ethanol intoxication (dose, 0.75 mg/kg) in healthy controls.

Results: The T1 relaxation times as assessed with MRI were highly reproducible. The mean, paired ethanol‐induced differences in T1 were −0.004 ± 0.007 sec (mean ± standard deviation) for white matter and 0.010 ± 0.015 sec for internal gray matter structures, neither of which was significant.

Conclusions: This reasonably sensitive measurement does not support the view that tissue water content or water macromolecule interactions are significantly altered in the brain during acute alcohol intoxication in otherwise healthy subjects.
Role of Nitric Oxide in Endotoxin‐Induced Hepatic Microvascular Dysfunction in Rats Chronically Fed Ethanol
Authors: Horie Yoshinori , Kimura Hiroyuki , Kato Shinzo , Ohki Eiji , Tamai Hironao , Yamagishi Yoshiyuki , Ishii Hiromasa
Published: April 2006

Background: Nitric oxide (NO) appears to be involved in the pathogenesis of endotoxin‐induced liver injury. However, little is known about how NO acts on the hepatic microcirculation, especially in alcohol‐fed animals. We examined the roles of NO in endotoxin‐induced hepatic microvascular dysfunction in control and ethanol‐fed rats.

Methods: One lobe of the liver was observed with an intravital microscope. Flow velocity of fluorescein isothiocyanate‐labeled erythrocytes in sinusoids was measured with an off‐line velocimeter. Portal pressure and mean arterial pressure also were measured.

Results: After administration of endotoxin to control, the flow velocity decreased after 30 min. Portal pressure increased after 45 min. However, in ethanol‐fed rats, both the flow velocity and portal pressure temporarily increased in the early phase. Thereafter, the flow velocity decreased and portal pressure increased. At 30 min after administration of the endotoxin, pretreatment with 10 mg/kg of an NO synthase inhibitor, NG‐monomethyl‐L‐arginine (L‐NMMA), enhanced the endotoxin‐induced decrease in the velocity of erythrocytes in the midzonal region of both control and ethanol‐fed rats. Although 0.5 mg/kg of L‐NMMA enhanced the endotoxin‐induced reduction of erythrocyte velocity in the midzonal region of ethanol‐fed rats, L‐NMMA enhanced the endotoxin‐induced reduction of erythrocyte velocity in the pericentral region of control rats. At 60 min after the endotoxin administration, L‐NMMA did not affect the endotoxin‐induced decrease of erythrocyte velocity in either control or ethanol‐fed rats. Although 10 mg/kg of L‐NMMA increased mean arterial pressure both in control and ethanol‐fed rats, 0.5 mg/kg of L‐NMMA did not change mean arterial pressure in either control or ethanol‐fed rats.

Conclusions: These results suggest that NO is involved in endotoxin‐induced hepatic microvascular dysfunction, which may contribute to the sequential liver injury, especially in alcohol‐fed animals.
Effects of CH‐100, a Chinese Herbal Medicine, on Acute Concanavalin A‐Mediated Hepatitis in Control and Alcohol‐Fed Rats
Authors: Batey R. , Cao Q.
Published: April 2006

Background: Administration of concanavalin A (Con A) leads to acute hepatitis that involves T‐cell activation and inflammatory mediator production in mice and rats. We examined the role of CH‐100, a Chinese herbal medicine previously trialed in human hepatitis C, in the prevention of Con A‐related, T‐cell‐mediated, acute liver injury in rats.

Methods: Female Wistar rats were fed 40% ethanol, 2% sucrose, or isocaloric sucrose for 8 weeks. At the same time, these animals were fed either the Chinese herbal medicine CH‐100 (4 tablets/kg body weight/day) or placebo in chow daily. Blood from the tail vein was collected for endotoxin (lipopolysaccharide) assay at 0, 4, and 8 weeks of ethanol consumption. Twenty‐four hours after injection of Con A (20 mg/kg body weight) or phosphate‐buffered saline, blood from the tail vein was collected for alanine aminotransferase and tumor necrosis factor (TNF)‐α assays. Liver‐associated CD4+ T cells were isolated from liver perfusates and then cultured with Con A (5 μg/ml) at 37°C for 24 hr. Supernatants were harvested for TNF‐α assay. The proportion of CD4+ T cells in blood and liver perfusates was measured. Liver samples were collected for histopathological analysis.

Results: Lipopolysaccharide levels were significantly reduced in CH‐100‐treated ethanol‐fed rats compared with placebo‐treated rats. After Con A injection, alanine aminotransferase levels were lower at 12 and 24 hr in herb‐treated rats compared with placebo‐treated rats. Furthermore, serum TNF‐α levels were lower in ethanol‐fed rats on herbal treatment. A significant decrease in TNF‐α production by liver‐associated CD4+ T cells in culture was observed in CH‐100‐treated ethanol‐fed rats. CH‐100 treatment was associated with a decreased percentage of CD4+ cells in both blood and liver perfusate in all groups. Herb‐treated rats displayed markedly less hepatic necrosis and a reduced CD4+ T‐cell infiltrate in portal areas than did placebo‐fed rats.

Conclusions: The results demonstrate that CH‐100 modified the T‐cell response to Con A injection. The effect was more marked in ethanol‐fed rats, which suggests a possible role for CH‐100 in treating alcoholic liver disease.
Heart Mitochondrial Respiratory Chain Complexes Are Functionally Unaffected in Heavy Ethanol Drinkers Without Cardiomyopathy
Authors: Miró Òscar , Robert Jordi , Casademont Jordi , Alonso Josep R. , Nicolás Josep M. , Fernández‐Solá Joaquim , Urbano‐Márquez Àlvaro , Hoek Jan B. , Cardellach Francesc
Published: April 2006

Background: Harmful effects of chronic ethanol intake on liver mitochondria have been clearly demonstrated; however, mitochondria from skeletal muscle are preserved, and the effect of ethanol on heart mitochondria remains controversial. We assessed individual enzyme activity of mitochondrial respiratory chain (MRC) complexes and membrane oxidative damage of heart mitochondria in active ethanol drinkers before the development of dilated cardiomyopathy.

Patients and Methods: Heart samples were obtained from otherwise healthy organ donor individuals with a sudden death of traumatic or neurological cause in whom hearts could not be used because of absence of matched receptors or size inadequacy. Detailed history of alcohol intake was achieved from the relatives. Citrate synthase activity was spectrophotometrically assayed, as well as absolute (nmol · min−1· mg protein−1) and relative (corrected by citrate synthase) activities of complex I, II, III, and IV of the MRC. Oxidative damage of myocardium membranes was assessed measuring the degree of lipid peroxidation by fluorescence using cis‐parinaric acid as probe.

Results: We included 10 ethanol drinkers (age 53 ± 13 years, 100% males, mean lifetime intake of 15.6 ± 7.9 kg ethanol · kg body weight−1) and 12 controls (age 60 ± 10 years, 75% males). Mitochondrial content did not differ between the two groups. Absolute enzyme activities for ethanol drinkers and controls were, respectively, 145 ± 75 and 130 ± 50 for complex I (p= NS); 399 ± 193 and 376 ± 100 for complex II (p= NS); 719 ± 288 and 714 ± 308 for complex III (p= NS); and 475 ± 139 and 570 ± 160 for complex IV (p= NS). After correcting such activities by citrate synthase activity, we failed again to demonstrate differences between ethanol drinkers and controls. Lipid peroxidation of myocardium membranes was similar in both groups.

Conclusions: Chronic ethanol drinkers without cardiomyopathy exhibit normal MRC activity in the heart and do not show increased oxidative damage in myocardial membranes.
Integrating Person‐Centered and Variable‐Centered Approaches in the Study of Developmental Courses and Transitions in Alcohol Use: Introduction to the Special Section
Authors: Bates Marsha E.
Published: April 2006

This special section consists of research from the symposium “Integrating Person‐Centered and Variable‐Centered Approaches to the Study of Developmental Courses and Transitions in Alcohol Use,” presented at the 1999 Annual Meeting of the Research Society on Alcoholism. The section focuses on ways to integrate variable‐centered and person‐centered approaches to better understand longitudinal trajectories of alcohol use and associated problems. Our aim is to increase awareness and discussion of alternative conceptual and quantitative approaches that involve both a person‐centered and a variable‐centered component, and to make these methods more accessible to alcohol and other drug researchers. The first paper provides a general latent variable modeling framework within which to conceptualize developmental questions that involve the combination of continuous latent variables and categorical variables that represent classifications of individuals into meaningful subgroups. This is followed by three empirical papers that use integrative methods to examine early adult outcomes of adolescent binge drinking; potential mediators of familial alcoholism effects on alcohol and tobacco use disorder comorbidity; and the ability of psychopathology, substance use, and parental history of alcohol problems to predict individual differences in the likelihood of transitions in drinking behavior during adolescence. The section concludes with a discussion of the statistical basis for integrating person‐centered and variable‐centered methods, a comparison of study findings, and directions for future research.
Integrating Person‐Centered and Variable‐Centered Analyses: Growth Mixture Modeling With Latent Trajectory Classes
Authors: Muthén Bengt , Muthén Linda K.
Published: April 2006

Background: Many alcohol research questions require methods that take a person‐centered approach because the interest is in finding heterogeneous groups of individuals, such as those who are susceptible to alcohol dependence and those who are not. A person‐centered focus also is useful with longitudinal data to represent heterogeneity in developmental trajectories. In alcohol, drug, and mental health research the recognition of heterogeneity has led to theories of multiple developmental pathways.

Methods: This paper gives a brief overview of new methods that integrate variable‐ and person‐centered analyses. Methods discussed include latent class analysis, latent transition analysis, latent class growth analysis, growth mixture modeling, and general growth mixture modeling. These methods are presented in a general latent variable modeling framework that expands traditional latent variable modeling by including not only continuous latent variables but also categorical latent variables.

Results: Four examples that use the National Longitudinal Survey of Youth (NLSY) data are presented to illustrate latent class analysis, latent class growth analysis, growth mixture modeling, and general growth mixture modeling. Latent class analysis of antisocial behavior found four classes. Four heavy drinking trajectory classes were found. The relationship between the latent classes and background variables and consequences was studied.

Conclusions: Person‐centered and variable‐centered analyses typically have been seen as different activities that use different types of models and software. This paper gives a brief overview of new methods that integrate variable‐ and person‐centered analyses. The general framework makes it possible to combine these models and to study new models serving as a stimulus for asking research questions that have both person‐ and variable‐centered aspects.
Early Adult Outcomes of Adolescent Binge Drinking: Person‐ and Variable‐Centered Analyses of Binge Drinking Trajectories
Authors: Hill Karl G. , White Helene R. , Chung Ick‐Joong , Hawkins J. David , Catalano Richard F.
Published: April 2006

Background: Many studies of the consequences of binge drinking take a variable‐centered approach that may mask developmentally different trajectories. Recent studies have reported qualitatively different binge drinking trajectories in young adulthood. However, analyses of developmental trajectories of binge drinking have not been examined for an important period of drinking development: adolescence. The purpose of this study was to examine young adult outcomes of adolescent binge drinking using an approach that combines person‐centered and variable‐centered methods.

Methods: Data were from the Seattle Social Development Project, an ethnically diverse, gender balanced sample (n= 808) followed prospectively from age 10 to age 21. Semiparametric group‐based modeling was used to determine groups of binge drinking trajectories in adolescence. Logistic regression was used to examine how well the trajectory groups predicted young adult outcomes after demographics, childhood measures, and adolescent drug use were considered.

Results: Four distinct trajectories of binge drinking during adolescence were identified: Early Highs, Increasers, Late Onsetters, and Nonbingers. These trajectories significantly predicted positive and negative outcomes in adulthood after controlling for demographic characteristics, early proxy measures of the outcome, and adolescent drug use.

Conclusions: This integrated person‐ and variable‐centered approach provides more information about the effects of specific patterns of binge drinking than studies that employ variable‐centered methods alone.
Transitions in Drinking in Adolescent Females: Evidence From the Missouri Adolescent Female Twin Study
Authors: Bucholz K. K. , Heath A. C. , Madden P. A. F.
Published: April 2006

Background: Data from adult community samples indicate that alcohol dependence originates in late adolescence, thus marking that period as a fruitful one for the study of transitions in drinking.

Methods: Using retrospective data about the timing of alcohol symptom onset from 1799 female twins who participated in the Missouri Adolescent Female Twin Study (MOAFTS), we integrated person‐centered (PC) and variable‐centered (VC) analyses to study 1‐year transitions in alcohol symptomatology. A person‐year data set reflecting the onset of 15 alcohol dependence symptoms was constructed, with each year in the young woman's life from the year of her first drink to her current age counting as one observation. Latent class analysis—a PC technique—identified classes of alcohol symptomatology for each person‐year, and a lag function was used to identify class membership 1 year earlier. One‐year transitions in drinking—a VC analysis—were then studied.

Results: Smoking, marijuana use, and conduct problems were consistent promoters of transitions to more severe drinking classes, but depressed affect was not a significant predictor. Parental history of alcohol problems or excessive drinking, particularly maternal history, was a significant predictor of more serious transitions to moderate and dependent problem drinking.

Conclusions: These data confirm that even over a 1‐year time frame there was considerable change in drinking patterns in this adolescent sample. Smoking was as potent a risk factor as conduct problems in promoting the progression of alcohol symptomatology, and the role of familial factors was found to be influential in transitions at the more severe end of the drinking spectrum.
Use of a High‐Risk Alcohol Relapse Scale in Evaluating Liver Transplant Candidates
Authors: DiMartini Andrea , Magill Judy , Fitzgerald Mary Grace , Jain Ashok , Irish William , Khera Gagan , Yates William
Published: April 2006

Background: Methods to improve assessment, selection, and monitoring of patients with alcoholic cirrhosis who pursue liver transplantation are sought continuously. We chose to investigate the use of the High‐Risk Alcohol Relapse (HRAR) scale in our transplant population in the hope that it would improve our ability to identify and follow patients at highest risk for alcohol relapse.

Methods: Detailed alcohol histories of 207 patients evaluated for liver transplantation were collected and graded for severity by using the HRAR. The HRAR provides information on the duration of alcohol use (a measure of chronicity), daily quantity of alcohol use, and rehabilitation experiences (treatment responsiveness). Posttransplant alcohol use was monitored through clinical follow‐up in the transplant clinic.

Results: Although men and women had similar years of heavy drinking pretransplant, women's daily alcohol consumption was significantly less than men’s. HRAR scores did not distinguish those listed for transplant from those not listed or those who drank posttransplant from those who did not. Transplant patients were predominantly in the low‐risk group (83% had an HRAR score <4).

Conclusions: The HRAR did not have predictive ability in our transplant population. Few of our patients were rated as high risk, and few drank posttransplant. Nevertheless, identifying patients at high risk may improve clinical care and decrease the rate of posttransplant alcohol consumption.
Understanding Drinking During Pregnancy Among Urban American Indians and African Americans: Health Messages, Risk Beliefs, and How We Measure Consumption
Authors: Kaskutas Lee Ann
Published: April 2006

Background: Little is known about urban American Indian and African American women's drinking during pregnancy, or their beliefs about the risk of doing so. However, rates of fetal alcohol syndrome (FAS) are believed to be highest among those ethnic groups.

Methods: The Developing Effective Educational Resources (DEER) project recruited pregnant American Indian, African American, and white women from urban California areas (n= 321), to develop culturally appropriate consumption measures, to gather epidemiological data about drinking during pregnancy, and to assess exposure and reactions to health warnings intended to encourage abstinence during pregnancy.

Results: The study found high levels of exposure to health warnings among all ethnic groups, but many women were unclear about the actual consequences of FAS, about the risk of drinking even beer or wine or wine coolers, or about the value of reducing intake at any time during pregnancy. The majority of the women who drank malt liquor, fortified wine, wine, and spirits reported having larger than standard drinks, and daily drinkers had the highest levels of reporting error. When drink size was considered in the calculation of alcohol volume, average daily volume of consumption during pregnancy increased to the FAS risk level (average daily volume ≥ 1) in the overall sample and among the African American and white subjects.

Conclusions: Because some women, especially heavy drinkers, will continue drinking despite exposure to abstention‐oriented health messages, it may be prudent to develop campaigns and interventions that provide factual information to help at‐risk women reduce their drinking during pregnancy. Women could be advised of beverage equivalency, of standard drink sizes, and of how their own drinks compare with standard ones. Reliance on standard drink sizes in research can result in significant underreporting of consumption, especially among pregnant risk drinkers.
Binge Pattern Ethanol Exposure in Adolescent and Adult Rats: Differential Impact on Subsequent Responsiveness to Ethanol
Authors: White Aaron M. , Ghia Amol J. , Levin Edward D. , Swartzwelder H. Scott
Published: April 2006

Background: Recent evidence indicates that adolescent animals are more sensitive than adults to the disruptive effects of acute ethanol exposure on spatial learning. It is not yet known whether adolescent animals are also more sensitive than adults to the enduring neurobehavioral effects of repeated ethanol exposure. In this study, animals were exposed to ethanol in a binge‐pattern during either adolescence or adulthood. At a time when all subjects were adults, spatial working memory was examined in the absence and presence of an acute ethanol challenge.

Methods: Rats were exposed to ethanol (5.0 g/kg intraperitoneally) or isovolumetric saline at 48 hr intervals over 20 days. Exposure began on either postnatal day 30 (adolescent group) or 70 (adult group). Twenty days after the final injection, a time at which all animals were adults, the subjects were tested on an elevated plus maze and then were trained to perform a spatial working memory task on an eight‐arm radial maze. At the beginning of each session of training on the working memory task, subjects retrieved food rewards on four of the eight arms. After a delay, subjects were placed on the maze and allowed to retrieve food from the remaining four arms.

Results: Prior exposure to ethanol did not influence behavior on the plus maze. Performance of the groups did not differ during acquisition of the spatial working memory task with a 5 min delay or during subsequent testing with a 1 hr delay. However, animals treated with ethanol during adolescence exhibited larger working memory impairments during an ethanol challenge (1.5 g/kg intraperitoneally) than subjects in the other three groups.

Conclusions: The findings indicate that binge pattern exposure to ethanol during adolescence enhances responsiveness to the memory‐impairing effects of ethanol in adulthood.
Family Violence and Victimization: Treatment Issues for Women With Alcohol Problems
Authors: Miller Brenda A. , Wilsnack Sharon C. , Cunradi Carol B.
Published: April 2006

A brief overview of the prevalence of violence in women's lives and psychological and physical consequences of these experiences is presented, with special attention to populations of women with alcohol and other drug problems. Barriers to identification of violent victimization within health care settings are discussed. Finally, potential areas for further consideration regarding policy, practice, and research are identified. The relationships between women's experiences of violent victimization and their use of alcohol and drugs are documented, although prior research has not fully explored or explained the etiologic nature of these relationships. Of additional importance is the recognition that various forms of violence occur throughout a single life span. Women's histories of violent victimization negatively affect their children, and thus, intergenerational issues are of concern. Understanding how the combined problems of alcohol and drugs interconnect with violence is relevant to the delivery of health services for women.
Alcohol and Eating Disorders: Implications for Alcohol Treatment and Health Services Research
Authors: Sinha Rajita , O'Malley Stephanie S.
Published: April 2006

Background: This paper focuses on the co‐occurrence of alcoholism and eating disorders and the clinical implications for treating this comorbidity in women with alcohol use disorders. There is substantial literature that supports higher than expected rates of co‐occurrence of these two disorders. In addition, there is evidence that the co‐occurrence of alcoholism and eating disorders is more likely to occur in the presence of other psychiatric disorders. A critical analysis of the studies on the comorbidity of these disorders is conducted along with a review of the possible etiologic association between the two disorders. Crucial questions related to pharmacological and behavioral treatments for this subgroup of alcoholic women with eating disorders are raised from a health services research perspective.

Conclusions: There is substantial evidence that alcoholism and eating disorders co‐occur at high rates. However, as this review points out, several important research questions remain regarding both the clinical manifestations of each problem in women who are comorbid for both disorders and the treatment implications.
Role of Phosphorylation in Ethanol‐Induced Aggregation of Keratin Intermediate Filaments
Authors: Negron Gerardo , Eckert Barry S.
Published: April 2006

Background: Keratins are members of a diverse group of tissue‐specific cytoskeletal components known as intermediate filaments. Regulation of the structure and intracellular distribution of intermediate filaments is known to be related to the phosphorylation state of their structural subunits. It also is known that disruption of the keratin filaments of hepatocytes in response to chronic ethanol ingestion is characteristic of alcoholic liver disease.

Methods: To characterize the mechanism of ethanol‐induced keratin filament reorganization and dephosphorylation, cells were grown in culture with and without ethanol, and then were treated at the end of the incubation period for 1 hr with either 8‐bromo‐adenosine 3′:5′‐cyclic monophosphate (8Br), water‐soluble forskolin (ws‐forskolin), H‐89 diHCL, or okadaic acid. Morphology of the cells was examined by immunofluorescence microscopy, and keratin phosphorylation levels were determined by analysis of 32P labeling.

Results: We found that treatment of hepatoma cells with 300 mM ethanol results in disruption and aggregation of the keratin network in the vicinity of the nucleus as well as a hypophosphorylation of keratin subunits from ethanol‐treated cells compared with non‐ethanol‐treated controls. 8Br and ws‐forskolin treatment of ethanol groups restored keratin phosphorylation to control levels and reversed the ethanol‐induced aggregation of keratin filaments. When H‐89, an inhibitor of A‐kinase, was added to control cells, keratin filament disorganization and dephosphorylation was observed. H‐89 produced only a slight additional decrease in keratin phosphorylation in ethanol‐treated cells, with no change in keratin distribution. Okadaic acid treatment of control cells produced hyperphosphorylation and filament network disruption, whereas in ethanol groups a reversal of the ethanol‐mediated hypophosphorylation was observed but without reversal of the keratin filament aggregation.

Conclusions: These results suggest that site‐specific phosphorylation of keratin filaments is important in maintaining their integrity and that activation of the A‐kinase system can antagonize the effects of ethanol, whereas its inhibition results in filament dephosphorylation and reorganization, mimicking effects of ethanol treatment.
Ethanol Pharmacokinetics in White Women: Nonlinear Model Fitting Versus Zero‐Order Elimination Analyses
Authors: Mumenthaler Martin S. , Taylor Joy L. , Yesavage Jerome A.
Published: April 2006

Background: Studies have shown repeatedly that ethanol pharmacokinetics are not linear, yet most researchers still determine ethanol elimination by linear, zero‐order kinetics. The goals of the present work were to: (1) fit four nonlinear pharmacokinetic models to mean breath alcohol concentration (BrAC)‐time data of 27 women and determine the best‐fit model; (2) fit the determined best‐fit model to individual BrAC data and estimate the pharmacokinetic parameters; and (3) compare the method of nonlinear model fitting with the classical zero‐order elimination method and determine in which cases the classical approach is justified.

Methods: Twenty‐seven healthy white women ingested four drinks (total of 0.67 g·kg−1) of ethanol on two test days. Approximately 24 breath ethanol samples (for pharmacokinetic analyses) and one blood sample (for hormonal markers) were taken per day. Pharmacokinetic model evaluation was based on the coefficient of variation, the weighted residual sum of squares, and the sequence of the weighted residuals. Because hormonal changes across the menstrual cycle did not significantly influence ethanol pharmacokinetics, data from the two test days were pooled.

Results: The best‐fit model was a one‐compartment open model with first‐order absorption and sequential first‐order elimination, followed by Michaelis‐Menten elimination kinetics. Fitting this model to the individual BrAC data yielded mean ka= 0.062 hr−1, Vd= 0.457 L·kg−1, ke= 0.011 hr−1, Vmax= 0.136 g·L−1·hr−1, and Km= 0.096 g·L−1. For the classical analyses, mean time to peak BrAC = 1.83 hr, disappearance rate = 0.179 g·L−1·hr−1, and area under the blood ethanol‐time curve (AUC) = 2.884 g·L−1·hr. Correlational analyses showed that more frequent drinkers eliminated ethanol significantly faster and reached significantly lower AUC than less frequent drinkers.

Conclusions: After multiple dose ingestion in white women, classical zero‐order elimination analyses can be applied only to a limited portion of the descending BrAC‐time curve. They seem justified and practical from 0.5 hr after peak BrAC until BrAC reaches 0.2 g·L−1. To describe ethanol pharmacokinetics across the entire BrAC‐time curve, however, sophisticated nonlinear model fitting is required.
Nicotinic Receptor Pore Mutations Create a Sensitive Inhibitory Site for Ethanol
Authors: Forman Stuart A. , Zhou Qing
Published: April 2006

Background: Ethanol (EtOH) inhibition and enhancement of ligand‐gated ion channel functions may be due to direct interactions with sites on these membrane proteins. Peripheral nicotinic receptors have pore sites that long‐chain alcohols inhibit but EtOH does not, either because of weak binding (low affinity) or inability to impair ion translocation (low efficacy). We tested whether nicotinic pore mutations that increase hydrophobicity and/or size can create a site where EtOH inhibits at physiological concentrations.

Methods: We studied recombinant expressed mouse muscle receptors with patch‐clamp electrophysiology to measure EtOH effects both on single‐channel conductance and on multichannel currents elicited with rapid agonist superfusion. We studied pairs of mutants with similar residue sizes but different hydrophobicities at position α252 to determine if size or hydrophobicity determines EtOH sensitivity.

Results: Inhibition of wild‐type currents is seen at EtOH concentrations >300 mM. Receptors that contain the αS252I (serine to isoleucine) mutation are significantly inhibited by 100 mM EtOH. Adding a second homologous mutation on the β subunit (βT263I) further enhances sensitivity and creates receptors that are inhibited significantly by 50 mM EtOH. The open‐state conductance of single nicotinic channels is reduced in the presence of EtOH, which closely parallels EtOH inhibition of multichannel currents. In two isosteric mutant pairs at position α252, only hydrophobic side‐chains significantly increase receptor sensitivity to EtOH.

Conclusions: Wild‐type nicotinic receptors have a very low affinity for EtOH, but only one or two mutations in the pore site create receptors inhibited by physiological EtOH concentrations. Ethanol inhibition is due primarily to channel interactions in the open state. At amino acid α252, side‐chain hydrophobicity, not size, determines receptor sensitivity to EtOH inhibition. We propose that similar sites may exist within the pores of other EtOH‐sensitive ion channels, such as NMDA receptors and neuronal nicotinic receptors.
Anti‐Interleukin‐6 Antibody Treatment Restores Cell‐Mediated Immune Function in Mice With Acute Ethanol Exposure Before Burn Trauma
Authors: Fontanilla Christine V. , Faunce Douglas E. , Gregory Meredith S. , Messingham Kelly A. N. , Durbin Elizabeth A. , Duffner Lisa A. , Kovacs Elizabeth J.
Published: April 2006

Background: Previous studies from this laboratory reported that suppression of cell‐mediated immune function was coincident with elevated interleukin (IL)‐6 production after acute ethanol exposure before burn trauma, compared with either insult alone. The goal of this study was to investigate whether treatment with an anti‐IL‐6 antibody could restore immunocompetence in mice subjected to burn trauma with previous exposure to alcohol, as assessed by delayed‐type hypersensitivity (DTH) and mitogen‐induced splenocyte proliferative responses.

Methods: Mice given an ethanol treatment designed to reach a blood alcohol level of 100 mg/dl before a 15% total body surface area burn injury were treated with an anti‐IL‐6 antibody at 30 min and 24 hr postinjury.

Results: Burn/ethanol mice exhibited a 91% suppression of the DTH response (p < 0.01) and a 76% suppression of mitogen‐induced splenocyte proliferation (p < 0.01) at 48 hr postinjury, along with increased levels of circulating and splenic macrophage‐derived IL‐6, compared with all other treatment groups. After anti‐IL‐6 antibody administration to burn/ethanol mice, there was a 25% (p < 0.05) and 63% (p < 0.01) recovery of the DTH and splenocyte proliferative responses, respectively. Addition of exogenous IL‐6 to splenocyte cultures isolated from anti‐IL‐6 antibody‐treated burn/ethanol mice resulted in a 70% inhibition of mitogen‐induced proliferative responses (p < 0.03).

Conclusions: These data confirm previous findings that burn in combination with acute ethanol exposure suppresses cell‐mediated immune function compared with either insult alone. Furthermore, the ability of the anti‐IL‐6 antibody treatment to improve cellular immune responses in the burn/ethanol group suggests that blocking this cytokine may be beneficial for the ethanol‐exposed, thermally injured individual.