bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethanol and Cocaine Cause Additive Inhibitory Effects on the Calcium Transients and Contraction in Single Cardiomyocytes
Authors: Nicolás Josep M. , Rubin Emanuel , Thomas Andrew P.
Published: April 2006

The heart is a major locus for the toxic actions of cocaine and ethanol, each of which has been shown to interfere with excitation‐contraction coupling in cardiac muscle cells. Because these drugs are frequently used in combination, the present study was designed to investigate how they interact to modify the Ca2+ transient and associated contraction in fura2‐loaded cardiomyocytes. A high‐speed imaging technique using a charge‐coupled device as detector and short‐term image store was used to measure cytosolic Ca2+ and contraction simultaneously from fluorescence images obtained during the contractile cycle. Ethanol (100 mM) and cocaine (50 μM) caused reversible reductions in Ca2+ transient amplitude of 24.3 ± 3.0% and 25.1 ± 3.6%, respectively. Neither agent modified basal Ca2+. Ethanol treatment decreased peak shortening by 44.3 ± 3.5%, whereas the contractile depression by cocaine was 31.4 ± 5.3%. The relatively greater effect of ethanol on contraction resulted from a Ca2+‐independent component of ethanol action on contractility. When cardiomyocytes were exposed simultaneously to ethanol and cocaine, Ca2+ transient amplitude was reduced by 38.7 ± 3.0%, and peak contraction was decreased by 55.1 ± 3.5%. These values represent a significantly greater inhibition than observed with either drug alone (p < 0.02) and are compatible with additive effects of the two drugs acting at distinct loci within the excitation‐contraction coupling pathway. Thus, simultaneous use of cocaine and ethanol leads to an enhanced depression of myocardial contractility, which is likely to contribute to the cardiotoxic actions of the combination of these two drugs.
Daidzin Decreases Ethanol Consumption in Rats
Authors: Heyman Gene M. , Keung Wing‐Ming , Vallee Bert L.
Published: April 2006

In a previous study, daidzin, a constituent of an ancient Chinese herbal treatment for alcoholism, decreased home‐cage ethanol consumption in laboratory Syrian golden hamsters. The present study tested the generality of daidzin's antidipsotropic effects. Rats served as subjects in a two‐lever choice procedure. At one lever, responses earned 10% ethanol, flavored with saccharin. At the other lever, responses earned an isocaloric starch solution. Daidzin decreased both ethanol and starch consumption, but the decreases in ethanol intake were larger. Changes in consumption were dose dependent, and differences in ethanol and food consumption increased slightly (but significantly) as dose increased. Daidzin produced a similar pattern of decreases in lever pressing. In baseline, there was an approximately equal distribution of responses between the two levers; at the highest daidzin dose, the relative number of responses at the ethanol lever decreased to 30%. These results replicate and extend earlier findings, and they encourage further research on daidzin's capacity to decrease ethanol consumption.
A Decrease in the Size of the Basal Ganglia in Children with Fetal Alcohol Syndrome
Authors: Mattson Sarah N. , Riley Edward P. , Sowell Elizabeth R. , Jernigan Terry L. , Sobel David F. , Jones Kenneth Lyons
Published: April 2006

Magnetic resonance imaging was conducted on six children and adolescents with fetal alcohol syndrome and seven matched normal controls. Detailed volumetric analyses demonstrated significant reductions in the cerebral vault, basal ganglia, and diencephalon in the children with fetal alcohol syndrome, compared with control children. In addition, the volume of the cerebellar vault was smaller than controls in 4 of the 6 children with fetal alcohol syndrome, although the group difference did not reach significance. When the basal ganglia were divided into the caudate and lenticular nuclei, both of these regions were significantly reduced in the children with fetal alcohol syndrome. Finally, when the overall reduction in brain size was controlled, the proportional volume of the basal ganglia and, more specificatly, the caudate nucleus was reduced in the children with fetal alcohol syndrome. These results may relate to behavioral findings in both humans and animals exposed to alcohol prenatally.
Relation Between Executive Cognitive Functioning and the Adverse Consequences of Alcohol Use in Social Drinkers
Authors: Giancola Peter R. , Zeichner Amos , Yarnell Jennifer E. , Dickson Kelly E.
Published: April 2006

The purpose of this study was to assess the relation between Executive Cognitive Functioning (ECF) and the adverse consequences of alcohol consumption. ECF encompasses “higher order” cognitive abilities involved in goal‐directed behavior, such as attentional control, mental flexibility, planning, and self‐monitoring. Impaired ECF has been shown to result in a variety of negative consequences, including excessive drug and alcohol use. Subjects were 79 nonalcoholic male social drinkers between 17 to 30 years of age. ECF was measured using three neuropsychological tests: the Wisconsin Card Sorting Test (WCST), the Conditional Associative Learning Test (CAT), and the Sequential Matching Memory Test (SMMT). Adverse drinking consequences were measured using the Drinker Inventory of Consequences (DrlnC). The DrlnC assesses drinking consequences in five domains: Physical, Intrapersonal, Interpersonal, Social Responsibility, and Impulse Control. Scores from the neuropsychological tests were reduced into two latent variables: one representing the WCST and the other representing the CAT and SMMT. The results indicated that errors on the CAT/SMMT variable were positively related to adverse consequences in each domain, except for physical consequences. A similar association was found between the WCST variable and impulse control consequences. These findings indicate that performance on tests measuring ECF is related to the severity of drinking consequences. Therefore, prevention and treatment outcomes may be improved by incorporating cognitive habilitation into current interventions.
Lack of Allelic Association of Dopamine D1 and D2 (TaqIA) Receptor Gene Polymorphisms with Reduced Dopaminergic Sensitivity in Alcoholism
Authors: Heinz Andreas , Sander Thomas , Harms Helmut , Finckh Ulrich , Kuhn Silke , Dufeu Peter , Dettling Michael , Gräf Klaus , Rolfs Arndt , Rommelspacher Hans , Schmidt Lutz G.
Published: April 2006

Our study tested the hypothesis of whether the sensitivity of central dopamine receptors corresponds to the genotypic constitution of DNA‐polymorphisms of the dopamine D1 and D2 receptor (DRD1, DRD2) genes and is associated with poor treatment outcome. Therefore, 97 alcohol‐dependent patients were assessed according to their sensitivity of central dopamine receptors (apomorphine‐induced secretion of growth hormone), clinical outcome during a 6‐month observation period, and genotypic constitution of the TaqIA restriction fragment length polymorphism (RFLP) at the DRD2 locus and of the Bsp12861 RFLP at the DRD1 locus. On the 1st day of detoxification, dopamine receptor hyposensitivity was found in treatment nonresponders, but not in responders. Apomorphine‐induced growth hormone release did not differ significantly in alcoholics with different genotypes of the DRD1 and DRD2 RFLPs. Neither did we find a significant allelic association with treatment response. Thus, we did not find evidence for a genetic determination of dopamine receptor hyposensitivity in alcoholics with poor treatment outcome.
Carbohydrate‐Deficient Transferrin in Healthy Women: Relation to Estrogens and Iron Status
Authors: Stauber Rudolf E. , Vollmann Heidelore , Pesserl Iris , Jauk Barbara , Lipp Rainer , Halwachs Gabriele , Wilders‐Truschnig Martie
Published: April 2006

The determination of carbohydrate‐deficient transferrin (CDT) in serum has been found useful as a marker of increased alcohol consumption of >60 g/day. It is not clear why the reference range is different for women (0 to 26 units/liter) and men (0 to 20 units/liter). We evaluated serum COT in 286 healthy subjects (209 women, 77 men) using a commercially available radioimmunoassay. Premenopausal women had higher CDT levels than postmenopausal women, whereas no age‐related difference of CDT levels was found in men. In postmenopausal women, higher CDT levels were associated with estrogen replacement therapy. In premenopausal women, however, neither the phase of the menstrual cycle nor contraceptive steroid use showed a significant association with the increase in CDT levels. No significant correlations were found between CDT and either serum estradiol or serum iron. In conclusion, both premenopausal state and postmenopausal estrogen replacement therapy seem to increase serum levels of CDT. Therefore, menopausal status and exogenous estrogens should be considered when interpreting CDT values in women.
A Prospective Study of Self‐Esteem and Alcohol Use Disorders in Early Adulthood: Evidence for Gender Differences
Authors: Walitzer Kimberly S. , Sher Kenneth J.
Published: April 2006

The relations among gender, self‐esteem, and DSM‐III alcohol use disorder diagnoses were examined in a sample of 217 men and 240 women evaluated at four annual assessments over the college years. The results support clinical observations that low self‐esteem plays a particularly important etiological role in alcohol problems in women relative to men. Women who had an alcohol use disorder during years 3 and/or 4 showed relatively low levels of self‐esteem throughout the study period. Furthermore, the study provides clear evidence for prospective prediction from year 1 self‐esteem to year 4 alcohol use disorder diagnosis for women, but not for men. There was minimal evidence to suggest that alcohol use predicts later self‐esteem.
Different Sensitivity to Ethanol in Alcohol‐Preferring sP and ‐Nonpreferring sNP Rats
Authors: Colombo Giancarlo , Agabio Roberta , Carai Mauro A.M. , Lobina Carla , Pani Marialaura , Reali Roberta , Vacca Giovanni , Luigi Gessa Gian
Published: April 2006

Background and Objectives Clinical research has proposed that initial sensitivity to ethanol may be negatively correlated with levels of subsequent ethanol intake; consistently, alcohol‐preferring P rats were found to be less sensitive to the ataxic and sedative/hypnotic effects of ethanol than ‐nonpreferring NP rats. The present study investigated the initial sensitivity to the ataxic and sedative/hypnotic effects of ethanol and to the sedative/hypnotic effects of pentobarbital and diazepam in selectively bred Sardinian alcohol‐preferring sP and ‐nonpreferring sNP rats.

Methods: In experiment 1, time to lose (onset) and regain (sleep time) the righting reflex after the acute intraperitoneal (ip) administration of 3.0 and 3.5 g/kg ethanol were measured in sP and sNP rats. In experiment 2, sP and sNP rats were required to perform a motor coordination task on a Rota‐Rod after the acute intragastric administration of 2.0, 2.5, and 3.0 g/kg ethanol. Experiment 3 assessed onset and sleep time in sP and sNP rats after the acute injection of pentobarbital (40 mg/kg; ip) and diazepam (15 and 20 mg/kg; ip).

Results: In experiment 1, sP rats took shorter times to lose the righting reflex and regained this reflex over longer periods of time and at lower blood ethanol levels than sNP rats. In experiment 2, ethanol affected motor coordination to a greater extent in sP than sNP rats. In contrast, results from experiment 3 showed that sP and sNP rats were not differentially sensitive to the sedative/hypnotic effects of pentobarbital and diazepam.

Conclusions: The results of experiments 1 and 2 suggest that sP rats possess a genetically determined, greater sensitivity to the motor impairing and sedative/hypnotic effects of ethanol than sNP rats. Although caution should be adopted before hypothesizing any comparison to humans, these results may feature sP rats as an experimental model of those subsets of human alcoholics with initial high sensitivity to ethanol challenges. Finally, the results of experiment 3 suggest a minimal involvement of the benzodiazepine and barbiturate recognition sites in the differential sensitivity to ethanol of sP and sNP rats.
Serotonin, Impulsivity, and Alcohol Use Disorders in the Older Adolescent: A Psychobiological Study
Authors: Soloff Paul H. , Lynch Kevin G. , Moss Howard B.
Published: April 2006

Background: Alcohol use disorders (AUDs) among adolescents are associated with a high prevalence of conduct disorder (CD), much as type II alcoholism in adults is associated with impulsive‐aggressive behavior and antisocial personality traits. Adults with impulsive personality disorders and AUD demonstrate diminished central serotonergic responsiveness to serotonergic agonists. Dysregulation of central serotonergic function may contribute to a vulnerability to impulsive‐aggressive behavior, CD, and AUD. We studied older adolescents, both male and female, to examine the relationships between sex, dispositional impulsivity, aggressivity, CD, and responsiveness to serotonergic challenge with d,l fenfluramine (FEN) early in the development of AUD.

Methods: Thirty‐six adolescents between the ages of 16 and 21 years were assessed for DSM‐IV AUD and other Axis I disorders by using the Psychoactive Substance Use Disorders section of the Structured Clinical Interview for DSM III‐R, the Schedule for Affective Disorders and Schizophrenia for School‐Age Children–Present and Lifetime Version, and CD interviews. Impulsivity and aggressivity were assessed by the Barratt Impulsiveness Scale, Lifetime History of Aggression, Buss‐Durkee Hostility Inventory, Eysenck Impulsiveness Questionnaire, Youth Self Report, and Multidimensional Personality Questionnaires. FEN was administered as 0.8 mg/kg to a maximum of 60 mg, and blood was sampled at fixed intervals for prolactin, cortisol, fenfluramine, and norfenfluramine levels.

Results: Eighteen adolescents (12 male, 6 female) with AUD scored significantly higher on all measures of impulsivity and aggressivity compared with 18 healthy controls (12 male, 6 female). There were no significant differences between groups in peak prolactin or cortisol responses (minus baseline), or area‐under‐the‐curve determinations (AUC); however, 9 subjects with AUD and comorbid CD had significantly elevated cortisol AUC levels compared with subjects with AUD and no CD or with normal controls. In the total sample, cortisol AUC was associated positively with measures of aggression.

Conclusions: Adolescents with early‐onset AUD are characterized by impulsivity and aggressivity compared with healthy peers but do not demonstrate the diminished prolactin or cortisol responses to FEN characteristic of adult alcoholics with impulsive‐aggression.
Nicotine Is More Reinforcing in Smokers With a Past History of Alcoholism Than in Smokers Without This History
Authors: Hughes John R. , Rose Gail L. , Callas Peter W.
Published: April 2006

Background: Whether smokers with a past history (PH) but not current history of alcohol dependence are more nicotine dependent than smokers with no such history (NH) is unclear. The present study was an experimental test of this hypothesis.

Method: Twenty PH and 10 NH smokers abstained from smoking for 16 hr on each of 4 days. On each of 3 days, participants received three doses per day of 0, 2, or 4 mg nicotine gum in a within‐subjects, randomized, double‐blind, crossover design. To examine subjective effects, participants completed the Profile of Mood States, Addiction Research Inventory, and other ratings before and after each dose. To examine nicotine reinforcement, participants reported preference among the gums, reported on money versus gum choices, and, on the 4th day, underwent a double‐blind self‐administration test.

Results: Across the 21 subjective measures, with one exception, PH and NH smokers did not differ in subjective response to nicotine. However, across all three reinforcement measures, nicotine was a more potent reinforcer in PH than NH smokers.

Conclusions: These results provide a behavioral mechanism to explain prior findings that PH smokers are more nicotine dependent than NH smokers.
Validation of Multidimensional Scaling‐Based Modeling of Alcohol Expectancies in Memory: Age and Drinking‐Related Differences in Expectancies of Children Assessed as First Associates
Authors: Dunn Michael E. , Goldman Mark S.
Published: April 2006

Background: As evidence has accumulated that alcohol expectancies mediate the effects of other drinking antecedents, attempts to understand the mechanism by which expectancies influence behavior have focused on modeling memory processes. Previous expectancy work, however, has used relatively indirect approaches to retrieve and model information stored in memory. By using the method most recommended by memory researchers for directly obtaining uncontaminated memory contents, we assessed children's expectancies and related findings to empirically modeled organization and activation of expectancies in memory based on scaled instruments.

Methods: Individual interviews were conducted with 462 children in 2nd through 5th grades, and surveys were completed by 1003 children in 3rd, 6th, 9th, and 12th grades. Interviews and surveys consisted of a measure designed to retrieve participants’ first expectancy associate to an alcohol prompt and several drinking quantity/frequency questions.

Results: Older and higher drinking children were more likely to report positive expectancies as their first associate to an alcohol prompt. Age and drinking‐based findings were consistent with organizational structure, dimension emphasis shift, and paths of association identified by prior multidimensional scaling techniques.

Conclusions: Consumption of alcohol among children corresponded to accessibility of positive expectancies in memory. In addition, the use of multidimensional scaling to study the organization and activation of alcohol expectancies in memory was validated.
Brief Intervention for Female Heavy Drinkers in Routine General Practice: A 3‐Year Randomized, Controlled Study
Authors: Aalto Mauri , Saksanen Reijo , Laine Pirkko , Forsström Raija , Raikaa Mia , Kiviluoto Markku , Seppä Kaija , Sillanaukee Pekka
Published: April 2006

Background: Today, heavy drinking is a common health hazard among women. The evidence in favor of providing some kind of brief intervention to reduce drinking is quite convincing. However, we do not know if intervention works in a natural environment of routine health care. The purpose of this study was to evaluate the effectiveness of long‐lasting, brief alcohol intervention counseling for women in a routine general practice setting.

Methods: In five primary care outpatient clinics in a Finnish town, 118 female early‐phase heavy drinkers who consulted their general practitioners for various reasons were given brief alcohol intervention counseling. Intervention groups A (n= 40) and B (n= 38) were offered seven and three brief intervention sessions, respectively, over a 3‐yr period. The control group C (n= 40) was advised to reduce drinking at baseline. Main outcome measures were self‐reported weekly alcohol consumption, carbohydrate‐deficient transferrin, mean corpuscular volume (MCV), aspartate aminotransferase, alanine aminotransferase, and gamma‐glutamyltransferase.

Results: Depending on the outcome measure and the study group, clinically meaningful reduction of drinking was found in 27% to 75% of the heavy drinkers. Within all the groups, MCV significantly decreased. However, there were no statistically significant differences between study groups A, B, and C in the mean changes between the beginning and endpoint in the main outcome measures.

Conclusions: The present study indicated that minimal advice, as offered to group C, was associated with reduced drinking as much as the brief intervention, as offered to groups A and B, given over a 3‐yr period. Furthermore, in the routine setting of the general practice office, the effectiveness of the brief intervention may not be as good as in special research conditions. The factors possibly reducing the effectiveness in a routine setting are unknown. Thus, different methods of implementing brief intervention need to be evaluated to find better ways to support general practice personnel in their efforts to help heavy‐drinking female patients to reduce their drinking.
Application of a Quality of Life Measure, the Life Situation Survey (LSS), to Alcohol‐Dependent Subjects in Relapse and Remission
Authors: Foster J. H. , Marshall E. J. , Peters T. J.
Published: April 2006

Background: Recent studies have shown that quality of life (QOL) is improved significantly when subjects do not relapse to heavy drinking, and QOL deteriorates significantly on prolonged relapse. This article further investigates these relationships using a QOL index, the Life Situation Survey (LSS).

Methods: Eighty‐two DSM‐IV alcohol‐dependent subjects admitted for alcohol detoxification were studied at baseline and 12 week follow‐up. Sociodemographic data were collected, and severity of alcohol dependence (SADQ) and General Health Questionnaire (GHQ‐12) were baseline indices only. The main outcome measure, the LSS, was administered at both time points.

Results: Two subjects were lost to follow‐up and one died during the study period. Thus, the relapse/nonrelapse analysis related to 79 subjects. Fifty subjects (63%) had relapsed to heavy drinking at 3 months follow‐up. There was a significant correlation between LSS and GHQ‐12 scores. Significant changes occurred in total LSS scores as a result of relapse and nonrelapse. The improvement in LSS scores associated with nonrelapse was larger than the deterioration that accompanied relapse. In those subjects who did not relapse to heavy drinking, the mean follow‐up score remained in the poor/borderline LSS range. Remission from heavy drinking was accompanied by significant improvements in appetite, sleep, and self‐esteem. Relapse to heavy drinking coincided with a significant deterioration in mood/affect, public support, and work/life role scores.

Conclusion: QOL as assessed by the LSS in recently detoxified alcoholics is impaired significantly. In the nonrelapse group, there was a significant improvement in LSS scores after 3 months. Relapse was accompanied by a smaller deterioration in LSS scores. The LSS can play an important role in monitoring the clinical care and progress of alcohol‐dependent subjects.
Event‐Related Potentials and Cue‐Reactivity in Alcoholism
Authors: Herrmann Martin J. , Weijers H.‐Gerd , Wiesbeck Gerhard A. , Aranda Derlis , Böning Jobst , Fallgatter Andreas J.
Published: April 2006

Background: Relapse is a major problem in the treatment of addictive behaviors. Conditioning models of alcohol addiction suggest that stimuli associated with previous drug use (cues) may initiate relapse in a definite group of alcoholics. Event‐related potentials (ERPs) might be useful to reveal the brain functional substrates of cue‐reactivity.

Methods: In a preliminary investigation, 11 alcohol‐dependent patients who did not take part in the electrophysiological study completed a structured interview to rate 80 words as to the degree of relatedness to alcohol. Based on these results, cue‐reactivity for 15 alcohol‐related and 15 unrelated word cues, each repeated eight times, was investigated in 19 alcohol‐dependent men (44.2 ± 8.5 years) and 19 healthy control men (42.5 ± 12.5 years).

Results: A cue‐reactivity that consisted of significantly higher amplitudes in the ERPs after alcohol‐related words compared with unrelated words was found in alcohol‐dependent patients, but not in controls, at the electrode location Pz [F (1,36) = 5.2, p < 0.05].

Conclusions: Consistent with the hypothesis, only alcohol‐dependent patients were characterized by signs of increased cerebral activity associated with alcohol‐related compared with unrelated cues. Therefore, the results support the concept of cue‐reactivity in alcoholism based on a neurobiological measurement. Future investigations will show whether this cue‐reactivity can be applied to assess the risk of relapse in individual alcohol‐dependent patients.
Demographic Characteristics, Life Context, and Patterns of Substance Use Among Alcohol‐Dependent Treatment Clients in a Health Maintenance Organization
Authors: Tam Tammy W. , Weisner Constance , Mertens Jennifer
Published: April 2006

Background: Although individuals dependent only on alcohol and those dependent on both alcohol and drugs typically are not studied together in clinical trials, they are treated together in most treatment programs. In this study we compared epidemiological characteristics of the alcohol‐only and alcohol‐and‐drug dependents in a treatment sample to assess differential treatment needs.

Method: Patients admitted to treatment at a health maintenance organization's chemical dependency program were sampled and interviewed by using a structured questionnaire. The sample included 491 alcohol‐only and 217 alcohol‐and‐drug dependents. Demographic characteristics, lifetime and current substance use, Addiction Severity Index composite scores, and DSM‐IV criteria for alcohol and drug dependence were assessed at admission .

Results: The odds of alcohol‐and‐drug dependence were higher among males, African Americans (when compared with whites), those who were younger, and those with less than college education. The risk was also higher among those who initiated heavy drinking or drug use before the age of 18. Increased psychiatric and family/social problems also were associated with combined dependence.

Conclusions: Even in this relatively homogeneous socioeconomic status population, demographic characteristics were important predictors of type of dependence. Treatment programs which provide services that address prevention and psychosocial problems should pay attention to age of initiation as well as psychiatric and social problems.
The Infant Rat Learns About Alcohol Through Interaction with an Intoxicated Mother
Authors: Molina Juan Carlos , Pepino Marta Yanina , Johnson Johnmarc , Spear Norman E.
Published: April 2006

Background:Infant rats detect the presence of alcohol in milk when the dam suffers a moderate state of alcohol intoxication. The present study examined when rat pups begin to show behavioral changes indicative of the interaction with an intoxicated dam. The study also attempted to determine if infantile experiences involving a moderately intoxicated dam result in alcohol‐derived memories with a particular hedonic content.

Methods:Infant rats were allowed to interact during postnatal days (PDs) 3, 5, 7, 9, 11 and 13 with alcohol‐intoxicated (EtOH dose: 2.5 g/kg) or alcohol‐free dams. After the interaction took place, some pups were tested in terms of ultrasonic vocalizations (USVs) and motor reactivity when isolated and placed on each of two distinctive tactile surfaces (sandpaper or soft fabric) presented in a counterbalanced order, and the second of which was always paired with ambient ethanol odor. At PD 14 pups were evaluated in terms of the preference for texture (sandpaper versus soft fabric) and odor (alcohol versus clove) as well as alcohol ingestion.

Results:Very early in life (PD 3) USVs and overall activity were significantly higher in pups that had previously interacted with an intoxicated dam than in those exposed to an alcohol‐free dam. Although this difference was not apparent during the following days, it was clear that a specific memory of alcohol's chemosensory cues was formed. Pups interacting with intoxicated dams followed by pairing of ethanol odor and an arousing texture (sandpaper), later avoided this texture in the preference test; pups that interacted with alcohol‐free dams did not show this effect. The former animals also exhibited less consumption of alcohol than preweanlings never exposed to alcohol in the context of nursing.

Conclusions:In conjunction with prior studies these results indicate that very early in ontogeny the infant processes the presence of ethanol, and perhaps its effect on its mother, within the nursing context. Under the present experimental circumstances infants appear to acquire alcohol‐related information that comprises an aversive hedonic component.
Acute Tyrosine Depletion and Alcohol Ingestion in Healthy Women
Authors: Leyton M. , Young S. N. , Blier P. , Baker G. B. , Pihl R. O. , Benkelfat C.
Published: April 2006

Background: Recently we reported that, in vervet monkeys, ingestion of an amino acid mixture deficient in the catecholamine precursors, phenylalanine and tyrosine, produced a decrease in alcohol self‐administration. We now report the results of a similar study in humans.

Methods: Three groups of healthy female social drinkers were administered a nutritionally balanced amino acid mixture (B, n= 13), a mixture deficient in the serotonin precursor, tryptophan (Trp‐free, n= 14), or a phenylalanine/tyrosine deficient mixture (Phe/Tyr‐free, n= 12). Six hours after administration of the amino acid mixture, alcohol ingestion was measured during a free‐choice “Taste Test.”

Results: Compared to the B mixture, Phe/Tyr‐free, but not Trp‐free, significantly decreased the ingestion of alcohol [p < 0.02]. Neither Phe/Tyr‐free nor Trp‐free significantly decreased orange juice ingestion or the self‐reported “Liking” of either substance. Some subjects experienced transient nausea and/or regurgitated the amino acid mixtures, but excluding these subjects did not change the results.

Conclusions: The results suggest that (a) Phe/Tyr‐free may be a suitable method for investigating the role of catecholamines in the self‐administration and subjective effects of alcohol, (b) acutely decreased catecholamine neurotransmission might disrupt mechanisms mediating alcohol self‐administration, and (c) acutely decreased serotonin neurotransmission seems not to alter alcohol self‐administration.
Alcohol‐Induced Brain Pathology and Behavioral Dysfunction: Using an Animal Model To Examine Sex Differences
Authors: Savage Lisa M. , Candon Paul M. , Hohmann Heather L.
Published: April 2006

Background: Human epidemiological studies suggest that the female brain may be more susceptible to the toxic effects of alcohol and that this is the reason why women show greater behavioral dysfunction after chronic alcohol exposure. This hypothesis was tested by using a rat model of chronic alcoholism [chronic ethanol treatment (CET)]. The investigation assessed sex differences in neuropathology and behavior after chronic exposure and subsequent withdrawal from alcohol.

Methods: Young male and female rats (∼3 months old) were assigned to either a CET group, which received a 20% ethanol drinking solution for 20 weeks, or a pair‐fed control group, which received ad libitum tap water and a restricted diet for 20 weeks. After the CET groups were phased off the 20% alcohol solution, learning and memory abilities were examined by using matching‐to‐position and nonmatching‐to‐position tasks. Neuropathology was assessed in the frontal cortex and medial septal region.

Results: CET was shown to cause behavioral deficits. The behavioral dysfunction was sex, task, and process dependent; i.e., CET‐female rats displayed a delay‐dependent impairment on delayed matching‐to‐position, whereas CET‐male rats displayed a delay‐independent impairment on delayed nonmatching‐to‐position. CET resulted in a significant reduction in the frontal cortical (FR1) and collosal thickness, as well as a decrease in cells staining immunopositive for choline acetyltransferase in the medial septal region. However, relative to male rats exposed to CET, female rats did not show any accelerated neuropathology after CET.

Conclusions: Chronic exposure to ethanol does result in both brain and behavior dysfunction in male and female rats. The results demonstrate that different cognitive processes are altered by chronic ethanol exposure in male and female rats. However, the neurobiological mechanisms responsible for these differences remain to be determined.
Nifedipine Alleviates Alterations in Hippocampal Kindling After Repeated Ethanol Withdrawal
Authors: Veatch Lynn M. , Gonzalez Larry P.
Published: April 2006

Background: Current clinical treatment of alcohol detoxification commonly includes pharmacotherapy to lessen the potential for seizures, especially in those patients undergoing repeated treatment. Basic research continues to study the alcohol withdrawal‐related “kindling” of seizures both to understand the mechanisms involved and to identify alternative treatments. Ethanol withdrawal has been shown to result in the delay of electrical kindling at several brain sites, which suggests a long‐lasting disruption of neuronal function.

Methods: This study focused on the participation of the l‐type voltage‐gated calcium channels in this process by the treatment of animals during withdrawal with nifedipine, an agent that blocks these channels. Animals were randomly assigned to ethanol (ethanol‐exposed/ethanol‐naive) and drug treatment (nifedipine/vehicle) groups. Subjects receiving ethanol were exposed to five cycles of 3 days’ ethanol exposure, with each exposure cycle separated by a 1‐day withdrawal period. Drug treatment was administered twice during each withdrawal period. Twenty days after completion of ethanol exposure, animals received daily kindling stimulations to hippocampal area CA3 until the kindling criterion was attained.

Results: Ethanol‐exposed animals that received vehicle treatment during ethanol withdrawal required more daily stimulations to become fully kindled than did ethanol‐naive controls. This delay in seizure development was most pronounced in the progression from focal seizure behaviors to more generalized seizures. Animals that received the same ethanol exposure but that were treated with nifedipine required significantly fewer stimulations than did ethanol‐exposed animals that received vehicle. Ethanol‐exposed/nifedipine‐treated animals did not differ from ethanol‐naive controls that received vehicle or nifedipine.

Conclusions: Alcohol withdrawal‐related alterations in seizure‐sensitive neural circuitry such as the hippocampus persist long after cessation of ethanol exposure. Furthermore, the L‐type voltage‐gated calcium channels are involved in this effect in that blockade of these channels during acute withdrawal alleviates alterations in seizure mechanisms on a long‐term basis.
Amelioration of Ethanol‐Induced Neurotoxicity in the Neonatal Rat Central Nervous System by Antioxidant Therapy
Authors: Heaton Marieta Barrow , Mitchell J. Jean , Paiva Michael
Published: April 2006

Background: The cerebellum of the neonatal rat is highly susceptible to ethanol, with profound loss of Purkinje cells resulting from even brief exposure during the first postnatal week. Developmental ethanol exposure previously has been shown to induce free radicals/oxidative stress processes and/or down‐regulate protective antioxidants. In an earlier study, we found antioxidants protected against ethanol neurotoxicity in a tissue culture environment. The present study was designed to determine whether similar protection could be manifested in the intact animal.

Methods: Neonatal rats were administered a liquid diet via intragastric intubation on postnatal days 4 and 5 (P4‐P5), the peak period of ethanol sensitivity in the developing cerebellum. The diet consisted of milk formula with 12% ethanol, the isocaloric substitution of maltose‐dextrin for ethanol, or ethanol plus the antioxidant vitamin E. Unbiased three‐dimensional counting was utilized to analyze Purkinje cell numbers and density within defined volumes from these animals on P5.

Results: These determinations revealed a substantial loss of Purkinje cells in the ethanol‐treated animals compared to controls (approximately 30–44%), but this loss was prevented by the inclusion of vitamin E (60IU/100 ml) in the diet. A lower concentration of the antioxidant (30IU/100 ml) was not effective in this regard, however.

Conclusions: These results suggest that ethanol‐related cerebellar damage during this early postnatal period may be related to oxidative stress processes or the insufficiency of protective antioxidants. Thus, antioxidant treatment may represent a possible therapy for preventing or ameliorating the central nervous system (CNS) damage seen in the fetal alcohol syndrome.
Metronidazole Increases Intracolonic but Not Peripheral Blood Acetaldehyde in Chronic Ethanol‐Treated Rats
Authors: Tillonen Jyrki , Väkeväinen Satu , Salaspuro Ville , Zhang Yong , Rautio Merja , Jousimies‐Somer Hannele , Lindros Kai , Salaspuro Mikko
Published: April 2006

Background: Metronidazole leads to the overgrowth of aerobic flora in the large intestine by reducing the number of anaerobes. According to our previous studies, this shift may increase intracolonic bacterial acetaldehyde formation if ethanol is present. Metronidazole is also reported to cause disulfiram‐like effects after alcohol intake, although the mechanism behind this is obscure. Therefore, the aim was to study the effect of long‐term metronidazole and alcohol treatment on intracolonic acetaldehyde levels and to explore the possible role of intestinal bacteria in the metronidazole related disulfiram‐like reaction.

Methods: A total of 32 rats were divided into four groups: controls (n= 6), controls receiving metronidazole (n= 6), ethanol group (n= 10), and ethanol and metronidazole group (n= 10). All rats were pair‐fed with the liquid diet for 6‐weeks, whereafter blood and intracolonic acetaldehyde levels and liver and colonic mucosal alcohol (ADH) and aldehyde dehydrogenase (ALDH) activities were analyzed.

Results: The rats receiving ethanol and metronidazole had five times higher intracolonic acetaldehyde levels than the rats receiving only ethanol (431.4 ± 163.5 μM vs. 84.7 ± 14.4 μM, p= 0.0035). In contrast, blood acetaldehyde levels were equal. Cecal cultures showed the increased growth of Enterobacteriaceae in the metronidazole groups. Metronidazole had no inhibitory effect on hepatic or colonic mucosal ADH and ALDH activities.

Conclusions: The increase in intracolonic acetaldehyde after metronidazole treatment is probably due to the replacement of intestinal anaerobes by ADH‐containing aerobes. Unlike disulfiram, metronidazole neither inhibits liver ALDH nor increases blood acetaldehyde. Thus, our findings suggested that the mechanism behind metronidazole related disulfiram‐like reaction might be located in the gut flora instead of the liver.
Changes in Microsomal Activity in Alcoholism and Obesity
Authors: de la Maza M. Pía , Hirsch Sandra , Petermann Margarita , Suazo Myriam , Ugarte Guillermo , Bunout Daniel
Published: April 2006

Background: Liver damage is more prevalent among obese alcoholics, and cytochrome P‐450–2E1(CYP2E1) induction is involved in its pathogenesis.

Objectives The study was undertaken to assess microsomal function, in alcoholic and nonalcoholic male subjects with different body compositions, through pharmacokinetics of chlorzoxazone (CLZ). We also intended to study the relationship between CLZ hydroxylation and urinary levels of 8‐hydroxydiguanosine, and between CLZ levels and liver histology.

Methods: Serial measurements of CLZ serum concentration, after a 750 mg dose, were performed in 17 alcoholics (9 normal weight and 8 obese) and 21 nonalcoholic subjects (10 normal weight and 11 obese). Concentration of 6‐hydroxy‐chlorzoxazone (6‐OH‐CLZ) was determined at the second hour. Anthropometry, clinical laboratory tests, and urinary 8‐hydroxydiguanosine concentrations were measured. Liver biopsies were performed in alcoholics.

Results: Five biopsies revealed severe lesions, one in normal‐weight and four in obese patients (p= NS). Area under the curve (AUC) of CLZ was higher in normal‐weight controls compared with the rest of the groups (ANOVA p= 0.001). This parameter correlated negatively with adiposity in nonalcoholic subjects and did not correlate with liver histology. 6‐OH‐CLZ/CLZ ratio was lower in normal‐weight controls, compared with obese subjects and normal‐weight alcoholics (p= 0.02). Both alcoholism and obesity were included as predictors of CLZ AUC in a multiple regression analysis. The two‐factor ANOVA showed an additive effect of centripetal body fat distribution and alcoholism. Urinary 8‐hydroxydiguanosine levels were extremely variable.

Conclusions: Centripetal adiposity and alcoholism are associated with induction of CYP2E1. This may explain the higher prevalence of liver damage among obese alcoholics and also nonalcoholic steatohepatitis.
An Examination of the Synergistic Interaction of Ethanol and Thiamine Deficiency in the Development of Neurological Signs and Long‐Term Cognitive and Memory Impairments
Authors: Ciccia Rosanne M. , Langlais Philip J.
Published: April 2006

Background: The prolonged and heavy consumption of ethanol has been associated with thiamine deficiency and a wide range of cognitive and memory impairments. The present study was undertaken to test the hypothesis that ethanol and thiamine deficiency act synergistically, producing more severe clinical neurological disturbances and cognitive and memory impairments than either thiamine deficiency or chronic ethanol alone.

Methods: The acute neurological and long‐term behavioral consequences of combined chronic (32 weeks) ethanol consumption (20% v/v in drinking water) and three separate 4‐week long episodes of dietary thiamine deficiency (ET/TD) versus ethanol (ET) or thiamine deficiency (TD) treatments alone were examined in male Sprague Dawley® rats aged 12 weeks at the start of treatment.

Results: The ET/TD group lost less weight than the TD group during each episode of thiamine deficiency. Contrary to expectations, the progression and severity of ataxia, impaired righting reflexes, and opisthotonic posturing were similar in the ET/TD and TD groups. None of the ET animals displayed any neurological or behavioral symptoms during treatment. After withdrawal from ethanol and a 7‐week recovery period, none of the groups differed in spontaneous activity. On subsequent testing, the ET group displayed a significant increase in perseverative responding in a spontaneous alternation task. A small but significant proportion of ET/TD (23%), ET (17%), and TD (8%) animals were unable to reach criterion on an initial nonmatching‐to‐position task (NMTP) or in two subsequent reversals of the matching and NMTP tasks, which indicated persistent learning impairments. A large proportion of animals in each of the three groups demonstrated significantly reduced accuracy compared with controls at longer delays of matching‐to‐position tasks (MTP), but only the ET group was consistently impaired at the shorter delays. There were no significant correlations between blood ethanol concentration and any of the learning and memory measures.

Conclusions: These results indicate that the interaction of chronic ethanol consumption and bouts of TD is both domain specific and not always synergistic. Learning and reference memory appear to be sensitive to a synergistic interaction of ET and TD, whereas short‐term working memory disturbances are most affected by ET and neurological symptoms are most associated with TD. Furthermore, neither the presence of neurological symptoms nor blood ethanol concentrations appear to be good predictors of learning and memory deficits.
Pharmacological Treatments for Alcoholism: Revisiting Lithium and Considering Buspirone
Authors: Fawcett Jan , Kravitz Howard M. , McGuire Marcella , Easton Michael , Ross Jeffrey , Pisani Vincent , Fogg Louis F. , Clark David , Whitney Michael , Kravitz Glenda , Javaid Javaid , Teas Gregory
Published: April 2006

Objective Previous research has suggested that both lithium and buspirone could lessen alcoholics’ desire to drink as well as reduce the actual amounts of alcohol consumed. The purpose of this study was to compare lithium and buspirone monotherapy with placebo on outcomes of abstinence, alcohol quantity consumed, treatment retention and compliance, and medication side effects.

Methods: We conducted a randomized, double‐blind, placebo‐controlled, three‐arm parallel group, clinical trial that compared lithium and buspirone with placebo in 156 alcohol‐dependent men.

Results: Study retention rates for the three treatment groups at 3 and 6 months, respectively, were 61% and 46% for lithium, 44% and 27% for buspirone, and 52% and 38% for placebo (p= NS, for 3 and 6 months). Overall abstinence rates were 28% and 19% at 3 and 6 months, respectively. However, mean daily quantities of alcohol consumed and percentage of drinking days decreased significantly (p < 0.0001) over time in all treatment groups. Differential improvement was seen only for the decrement in quantity consumed in the buspirone group, compared with the placebo group, but only at a trend level (p= 0.07). According to pill counts, compliance did not differ significantly among the treatment groups.

Conclusions: These results do not support the hypothesis that either lithium or buspirone, compared with placebo, produces differential reductions in alcohol consumption. The results suggest the need to enhance treatment retention to maximize outcomes.
Partial Rescue of Ethanol‐Induced Neuronal Apoptosis by Growth Factor Activation of Phosphoinositol‐3‐Kinase
Authors: de la Monte Suzanne M. , Ganju Neema , Banerjee Kakoli , Brown Nancy V. , Luong Tri , Wands Jack R.
Published: April 2006

Background: Ethanol inhibition of insulin signaling pathways may contribute to impaired central nervous system (CNS) development in the fetal alcohol syndrome and brain atrophy associated with alcoholic neurodegeneration. Previous studies demonstrated ethanol inhibition of insulin‐stimulated growth in PNET2 CNS‐derived proliferative (immature) neuronal cells. We now provide evidence that the growth‐inhibitory effect of ethanol in insulin‐stimulated PNET2 cells is partly due to apoptosis.

Methods: Control and ethanol‐treated PNET2 cells were stimulated with insulin and analyzed for viability, apoptosis, activation of pro‐apoptosis and survival gene expression and signaling pathways, and evidence of caspase activation.

Results: Ethanol‐treated PNET2 neuronal cells exhibited increased apoptosis mediated by increased levels of p53 and phospho‐amino‐terminal c‐jun kinase (phospho‐JNK), and reduced levels of Bcl‐2, phosphoinositol 3‐kinase (PI3 K), and intact (∼116 kD) poly (ADP ribose) polymerase (PARP), a deoxyribonucleic acid repair enzyme and important substrate for caspase 3. Partial rescue from ethanol‐induced neuronal cell death was effected by culturing the cells in medium that contained 2% fetal calf serum instead of insulin, or insulin plus either insulin‐like growth factor type 1 or nerve growth factor. The resulting enhanced viability was associated with reduced levels of p53 and phospho‐JNK and increased levels of PI3 K and intact PARP.

Conclusions: The findings suggest that ethanol‐induced apoptosis of insulin‐stimulated neuronal cells can be reduced by activating PI3 K and inhibiting pro‐apoptosis gene expression and intracellular signaling through non‐insulin‐dependent pathways.