bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Acetaldehyde Production by Mouthwashings from Patients with Oral Cavity, Laryngeal, or Pharyngeal Cancer
Authors: Jokelainen K. , Heikkonen E. , Roine R. , Lehtonen H. , Salaspuro M.
Published: April 2006

Excessive ethanol consumption is associated with an increased risk of oral cavity, laryngeal, and pharyngeal cancer. Ethanol has been shown to be oxidized to acetaldehyde by microflora of the upper respiratory tract. As a highly toxic and reactive compound, acetaldehyde of microbial origin has been incriminated as a possible carcinogenic factor behind alcohol‐associated malignancies of the upper respiratory tract. The aim of the present in vitro study was to compare the acetaldehyde producing capacity of mouthwashings obtained from patients with oral cavity, laryngeal, or pharyngeal cancer to that of mouthwashings from controls. The ability of mouthwashings to produce acetaldehyde from ethanol in vitro was determined by incubating them in closed vials containing various concentrations of ethanol (0–44 mM) at 37°C for 1 hr. Acetaldehyde formed during the incubation was then analyzed by head space gas chromatography. Acetaldehyde production by mouthwashings increased with raising ethanol concentration in both groups. Acetaldehyde production by mouthwashings from patients with oral cavity, laryngeal, or pharyngeal cancer was significantly (p < 0.01) higher than that of the controls. Increased acetaldehyde formation from ethanol in the upper respiratory tract could thus contribute to the pathogenesis of alcohol‐associated oral cavity, laryngeal, and pharyngeal cancers.
Discriminative Stimulus Function of Ethanol: Role of GABA, Receptors in the Nucleus Accumbens
Authors: Hodge Clyde W. , Aiken Amy S.
Published: April 2006

Because the subjective effects of drugs may be related to abuse potential, this study was conducted to assess the involvement of GABAA receptor systems in the nucleus accumbens (N Acc) in the discriminative stimulus effects of ethanol. Male Long‐Evans rats were trained to discriminate between intraperitoneal (IP) injections of ethanol (1 g/kg) and saline under a fixed‐ratio 10 schedule of sucrose (10% w/v) reinforcement. When performance during training sessions met the accuracy criteria (>80%0 correct responding for five consecutive days), an ethanol generalization curve was determined. The rats were then surgically implanted with bilateral stainless‐steel guide cannulae aimed at the N ACC. Intra‐accumbens (IA) substitution test sessions were conducted during which the direct GABAAagonist muscimol (0.01, 0.04, 0.10, and 0.40 μg/μl; IA) was administered in combination with saline (IP). The direct GABAA, antagonist bicuculline (0.03,0.10, and 0.30 μg/μl; IA) was administered in combination with the training dose of ethanol (1 g/kg, ip). At 10‐min postinjection, IA muscimol partially substituted for IP ethanol. However, at 15‐min postinjection, muscimol (0.10 μg/μl; IA) fully substituted for IP ethanol. Bicuculline attenuated the discriminative stimulus properties of IP ethanol, but only at doses that significantly decreased response rate. At 10‐min postinjection, muscimol (0.01 and 0.04 μg/μl) potentiated (>80%0 ethanol lever responding) the discriminative stimulus properties of a dose of ethanol (0.5 g/kg) that alone produced only partial generalization. These data suggest that ethanol discrimination is mediated centrally and demonstrate that infusions of the GABAA, agonist muscimol in the N Acc are sufficient to produce the stimulus effects corresponding to a 1.0 g/kg training dose of ethanol. When taken together with data showing that GABAA receptor activation in the N Acc potentiates the termination of ethanol self‐administration, these data suggest that ethanol's discriminative stimulus function may influence its reinforcement function.
Serotonin Modulates Ethanol‐Induced Depression in Cerebellar Purkinje Neurons
Authors: Wang Yun , Jeng Chun‐Hueih , Lin Jiann‐Chyun , Wang Jia‐Yi
Published: April 2006

In the present study, we found that local application of serotonin (5‐HT) potentiated ethanol‐induced depressions of the spontaneous activity of Purkinje neurons in urethane‐anesthetized rats. 5‐HT also potentiated depressions induced by γ‐aminobutyric acid; however, this modulatory response was quantitatively smaller than 5‐HT‐induced potentiation of ethanol depression. Previous reports suggested that the release of 5HT can be regulated by presynaptic 5‐HT autoreceptors. We found that local application of methiothepin, which may induce 5‐HT overflow through the inhibition of presynaptic autoreceptors, facilited ethanol‐mediated responses. This methiothepin effect was greatly diminished in neonatally 5,7‐dihydroxyhyptamine‐lesioned animals, suggesting a presynaptic mechanism was involved. We also found that the 5‐HTIAantagonist UH301 did not attenuate 5‐HT‐facilitated ethanol reactions. On the other hand, local application of SHTIB agonist CGS12066B potentiated ethanol‐induced depression. Taken together, our data suggest that 5‐HT can modulate ethanol‐mediated electrophysiological depression, possibly mediated through CHT, receptors in the cerebellum.
Ethanol Suppresses Endotoxin But Not Platelet Activating Factor‐Induced Hypotension and Nitric Oxide
Authors: Greenberg Stan S. , Xie Jianming , Powers David R , Giles Thomas D.
Published: April 2006

Ethanol (ETOH) inhibits the immune response to endotoxemia. The early stage of endotoxin (LPS)‐induced shock is associated with an acute phase cardiovascular depression (APCD). Release of platelet activating factor (PAF) and tumor necrosis factor alpha (TNFa) with upregulation of nitric oxide (NO) production may initiate the APCD. Since ETOH inhibits induction of NO synthase (iNOS) mNRA by LPS, we postulate that ETOH may mask the APCD associated with endotoxemia. To test this, Sprague‐Dawley rats (280–320 g, n = 5–6/group) were given LPS [0.75 mg/kg, intravenously (iv)] or PAF (10 to 150 pg/kg, iv) 30 min after administration of sterile saline (PBS), BN‐5073 a mixed PAF antagonist (0.50 μg/kg, iv), or ETOH t2.2‐5.5 g/kg, intra‐peritoneally (ip)]. Cardiovascular parameters and plasma concentrations of nitrate and nitrite (RNI), ETOH, TNFα, and neutrophil (PMN) generation of RNI were measured. LPS and PAF both produced APCD. LPS‐induced APCD was associated with tachycardia, elevated plasma TNFα and RNI, and ex wivo generation of RNI by PMNs. ETOH and EN‐50730 prevented LPS‐induced APCD and increases in RNI and TNFα. ETOH, however, increased the mortality associated with APCD. PAF produced only hypotension, bradycardia and elevated plasma levels of TNFα. ETOH and LNMMA did not affect PAF‐induced APCD. EN‐50730 inhibited PAF‐induced APCD and plasma TNFα. We conclude that 1) ETOH inhibits the APCD and induction of NO characteristic of endotoxemia and 2) ETOH‐induced suppression of LPS‐mediated APCD may be mediated in part by suppression of release of intracellular PAF. Ethanol may increase the morbidity and mortality of endotoxemia by masking the hypotension and humoral changes characteristic of early endotoxemia thereby delaying appropriate therapy and by diminution of the protective effects of endogenous NO.
Effects of Ethanol and Temperature on NMDA Receptor Function in Different Mouse Genotypes
Authors: Musleh Wael , Alvarez Susana , Baudry Michel , Alkana Ronald L.
Published: April 2006

The present study investigated whether temperature‐related changes in NMDA receptor sensitivity to ethanol might play a role in mediating the effects of body temperature on behavioral sensitivity to ethanol or in determining genotypic differences in sensitivity to ethanol. We accomplished this by determining the effects of ethanol on three different mouse genotypes (C57, LS, and SS) on two types of NMDA receptor‐mediated responses at 30° and 35°C (i) extracellularly recorded synaptic potentials elicited in the CA1 region of the in vitro hippocampal slice preparation by stimulation of the Schaffer‐commisural pathway in the presence of the cu‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor blocker, 6,7‐dinitroqui‐noxaline‐2,3‐dione, and low magnesium concentration; and (ii) increase in [3H]MK‐801 binding elicited by glutamate in telencephalic membrane preparations. Ethanol significantly decreased NMDA receptor‐mediated excitatory postsynaptic potential (EPSP) amplitude and area in the three genotypes. In C57, the effect of ethanol on NMDA receptor‐mediated EPSP amplitude and area was more pronounced at 30°C, compared with that at 35°C. In most cases, there was a good correlation between the effects of ethanol on EPSP amplitude and area. The order of sensitivity between the three genotypes was C57 = LS > SS at 35°C and C57 > LS = SS at 30°C. Similarly, ethanol significantly decreased glutamate‐stimulated [3H]MK‐801 binding in membrane fractions. The effect of ethanol was temperature‐dependent, because ethanol produced more inhibition at 30°C than at 35°C in all genotypes. The effect of ethanol on MK‐801 binding was concentration‐dependent, and the sensitivity to 100 mM ethanol of the genotypes at 35°C was LS > SS = C57, whereas it was SS > LS = C57 at 30°C. Collectively, the results demonstrate that temperature is an important variable that can influence NMDA receptor sensitivity to ethanol measured via electro‐physiological and binding techniques, and that temperature can influence relative sensitivity of NMDA receptors to ethanol between mouse genotypes. Furthermore, the findings indicate that temperature‐induced changes in sensitivity of NMDA receptors to ethanol may play a role in mediating the effects of body temperature on behavioral sensitivity to ethanol in LS, but not C57 and SS mice.
Effect of Maternal Ethanol Consumption on Maternal and Fetal Calcium Metabolism
Authors: Keiver K. , Herbert L. , Weinberg J.
Published: April 2006

Alcohol consumption can have deleterious effects on both adult and developing bone. The mechanism(s) by which alcohol affects bone, however, is unknown. This study investigated the possibility that alcohol affects bone by alterations in calcium (Ca) metabolism. Female rats were fed lab chow ad libitum (C, Control) or a liquid diet with (E, Ethanol) or without (PF, Pair‐Fed) ethanol. After 2 weeks on their respective diets, the rats were bred and the experimental diets continued throughout gestation. Blood (dams only) and tissue were collected on day 21 of gestation. The Ca content of maternal bone showed a trend toward a decrease in E and PF compared with C dams. Ionic Ca (iCa) levels were decreased in the blood of the E compared with PF and C dams. Serum parathyroid hormone levels were elevated in the E compared with C dams, consistent with the low iCa levels. Serum levels of 1,25(OH)2D, however, were elevated only in the PF dams. Mean fetal body weight and fetal skeletal ossification were reduced in the E compared with PF and C groups, but no group differences were found in fetal Ca content. These results indicate that maternal ethanol consumption compromised the ability of the dam to regulate her blood iCa levels, possibly partly due to a failure to increase 1,25(OH)2D levels. The delays in skeletal development observed in the ethanol exposed fetuses, however, do not appear to result from impaired placental Ca transfer.
Modulation of GABAA Receptor Function by Alcohols: Effects of Subunit Composition and Differential Effects of Ethanol
Authors: Whitten R. J. , Maitra R. , Reynolds J. N.
Published: April 2006

We sought to test the hypotheses that closely related alcohols would have effects on GABAA receptor function that were not predicted by differences in lipid solubility, and that the subunit structure of the GABAA receptor would significantly affect the actions of different alcohols. Cloned subunits of human GABAA receptors were expressed in Xenopus oocytes, and two‐electrode voltage‐clamp recording was used to quantify the membrane current response to GABAA in the presence and absence of different alcohols. 1‐Butanol and 2‐butanol differentially potentiated the response to 20 μM GABA in oocytes expressing the α1β2γ2L and α2β2γ2L, receptor isoforms. In the α1β2γ2L receptor construct, 1‐butanol was more potent than 2‐butanol to potentiate GABA, receptor function, but 2‐butanol had a greater efficacy. In the α2β2 receptor construct, 1‐butanol and 2‐butanol were equipotent, but 2‐butanol again had a greater efficacy. In the a2p2 receptor construct, both 1‐butanol and 2‐butanol produced large potentiations of the current response to 3 μM GABA. The efficacy for butanol potentiation of GABA responses in the absence of a γ2L subunit was greater, but the potency was greatly reduced. Low concentrations (20 mM) of ethanol potentiated GABA responses in the α1β2γ2L receptor construct. Ethanol potentiation of GABAA receptor function was completely blocked by the benrodiazepine receptor partial inverse agonist R015‐4513 at a concentration (0.5 μM) that did not alter the control GABA response. In contrast, R015‐4513 did not block potentiation of GABAA receptor activity induced by npropanol, 1‐butanol, 2‐butanol, 1‐heptanol, or propofol (2,0‐diisopropylphenol). These results suggest that alcohols have specific interactions with GABAA receptors, and that ethanol may have unique effects not shared by other longer chain alcohols.
Increase in Vasoactive Prostaglandin E Production after Ethanol Perfusion in Human Placental Cotyledons
Authors: Randall Carrie L. , Ekblad Ulla , White Nancy M. , Cook Jocelynn L.
Published: April 2006

Studies from our laboratory indicate that prostaglandins may be mediators of at least some of the teratogenic actions of ethanol in both mouse and human tissue model systems. The present studies were designed to evaluate the relationship between ethanol and prostaglandin E (PGE) production in isolated human placental cotyledons. Placentas were obtained immediately after cesarean section delivery. A fetal artery supplying a single cotyledon was identified and cannulated, and the isolated cotyledon was placed in a perfusion chamber where maternal circulation was established and dual circulation continued throughout the perfusion procedure. Antipyrine clearance, oxygen consumption, and placental production of human chorionic gonadotropin were measured to verify tissue viability. PGE levels of the perfusate were measured by radioimmunoassay. Study 1 evaluates the effect of perfusion with 25 and 100 mM ethanol on placental PGE production. It was found that PGE production increased affer perfusion with 25 mM ethanol, but not during the perfusion period per se. The paradigm for study 2 was identical to that of study 1, with the addition of a buffer washout period after 100‐mM ethanol perfusion. Again, results indicate that perfusate PGE levels were increased in the buffer washout periods after the 25‐mM and the 100‐mM ethanol perfusions. The effect was not concentration dependent. An increase in circulating PGE associated with ethanol administration may have teratogenic actions and represent a potential mechanism underlying at least some aspects of fetal alcohol syndrome.
Periodic Naltrexone and Propensity To Take Alcoholic Beverage
Authors: Reid Larry D. , Gardell Luis R. , Chattopadhyay Soma , Hubbell Christopher L.
Published: April 2006

For over 2 months, 45 rats were maintained on a daily regimen involving 2 hr a day of access to both water and a palatable alcoholic beverage. At first, they took little ethanol. As days progressed, they eventually took over 2 g/kg of ethanol during the 2 hr. Previous research indicates that, without intervention, they would maintain this level of intake indefinitely. All rats were taken off the daily regimen for 30 days and then returned to it, i.e., rats received 30 days of “abstinence.” For 35 days following abstinence, one‐third of the subjects received placebos daily, one‐third received naltrexone (NTX), 10 mg/ kg, daily, and the one‐third received NTX on days l‐5, ll‐15,21‐25, and 3135 and placebos on the other days. Abstinence reduced all rats' intakes of alcohol compared with pre‐abstinence levels. Rats that received only placebos quickly returned to taking alcohol at pre‐abstinence levels. Rats that received NTX daily increased their intakes up to the level normally expected for receiving NTX and no abstinence. Because rats receiving daily NTX always drank a fraction of the alcohol consumed by those receiving placebos, NTX's effects did not diminish. As rats sampled alcoholic beverage, however, the effects of abstinence did diminish. The rats of periodic NTX drank as rats getting NTX when they were given NTX and as rats getting placebos when they were given placebos. Furthermore, the rats of periodic NTX showed no carry‐over effects from periods of NTX to no NTX. Abstinence and NTX together, apparently, reduce propensity to take alcoholic beverage more than either alone.
Glutathione‐S‐Transferase GST M1 “Null” Genotype and the Risk of Alcoholic Liver Disease
Authors: Savolainen V. T. , Pajarinen J. , Perola M. , Penttilä A. , Karhunen P. J.
Published: April 2006

The present study was conducted to investigate possible association between the occurrence of glutathione‐S‐transferase GST M1 “null” genotype and alcoholic liver disease (ALD). The “null” genotype indicating absent activity of class p glutathione transferase was assessed in 33 abstainers, 43 moderate alcohol consumers, and 313 heavy alcohol consumers by polymerase chain reaction. The genotypes were compared with occurrence of alcoholic fatty liver, alcoholic hepatitis, and alcoholic liver fibrosis. The “null” genotype was found among 44.7% of patients in the series, with no significant differences between different consumption groups: controls, 36.4%; moderate consumers, 39.5%; and heavy consumers, 46.3%. Occurrence of GST M1 “null” genotype was not associated with occurrence ALD among moderate alcohol consumers. Frequency of the “null” genotype was, however, statistically nearly significantly Cp = 0.07, odds ratio (OR) = 1.751 lower among heavy consumers with normal liver histology than in alcoholics with ALD. Furthermore, when compared with heavy consumers without ALD, the “null” genotype was nearly significantly more frequent among heavy consumers with at least slight liver fibrosis (p = 0.05, OR = 1.8) and statistically significantly more frequent among alcoholics with advanced liver fibrosis (p < 0.025, OR = 2.3). Results of the present Finnish association study suggest that homozygous deletion of the GST M1 gene may indicate increased susceptibility to develop irreversible liver damage in response to the toxic effects of ethanol. Significant association was found between the occurrence of the “null” genotype and the occurrence of alcoholic liver cirrhosis.
Cross‐Tolerance Between Acute Alcohol Intoxication and Endotoxemia
Authors: Bautista Abraham P. , Spitzer John J.
Published: April 2006

This study tests two hypotheses: (1) prior exposure to LPS induces cross‐tolerance for the hepatic effects of subsequent short‐term alcohol intoxication; and (2) short‐term alcohol intoxication renders the liver resistant to the effects of acute endotoxemia, resulting in reduced production of superoxide and tumor necrosis factor. In the first group of experiments, male Sprague‐Dawley rats were treated intravenously with E. coli lipopolysaccharide (LPS) (0.5 mg/kg) 48 hr before they were given an intravenous bolus of ethanol (1.75 g/kg), followed by 250–300 mg/kg/hr) for 3–5 hr. Superoxide release in the perfused liver was measured after the 3‐hr ethanol infusion. Pre‐treatment with LPS attenuated ethanol‐mediated superoxide anion release by the perfused liver. The stimulatory effect of phorbol myristate acetate on hepatic release of superoxide was also decreased. In the second group of experiments, rats previously treated with ethanol for 5 hr, received an intravenous injection of LPS (1 mg/kg). At 90 min after LPS, sera were collected for tumor necrosis factor a assay. Hepatic release of superoxide anion was determined 3 hr after LPS. Acute ethanol intoxication for 5 hr significantly reduced LPS‐induced serum tumor necrosis factor activity and free radical release by the perfused liver. LPS‐induced mortality was also decreased. In both groups of experiments serum corticosteroid levels were reduced during cross‐tolerance. These results demonstrate that cross‐tolerance develops between acute alcohol intoxication and endotoxemia manifesting in reduced hepatic production of cytotoxic cytokines and superoxide anions.
Issues in Genetic Testing for Susceptibility to Alcoholism: Lessons from Alzheimer's Disease and Huntington's Disease
Authors: Quaid Kimberly A. , Dinwiddie Stephen H. , Conneally P. Michael , Nurnberger John I.
Published: April 2006

Evidence from family, twin, and adoption studies suggests a heritable basis for alcoholism. However, alcoholism is likely to be genetically heterogeneous, and any genetic connection is likely to be in the form of genes conferring an increased risk or susceptibility. In this study, we present the evidence for a genetic component for alcoholism, and examine the precedent for genetic testing and screening for genetic susceptibility using Huntington's disease and Alzheimer's disease as examples. Finally, we discuss the preparations that need to be made before taking any findings about the genetics of alcoholism from the research laboratory into the clinic.
Alcohol Expectancies in a Native American Population
Authors: Garcia‐Andrade Consuelo , Wall Tamara L. , Ehlers Cindy L.
Published: April 2006

Native Americans, as a group, have a high prevalence of alcohol abuse and alcohol dependence, although specific risk factors for alcoholism among this population have yet to be clearly identified. One set of factors that may contribute to the development of alcoholism are expectations of alcohol's effects. Previous research has shown that heavy drinkers and alcoholics have higher alcohol‐related expectancies. Some studies have also shown an association between alcohol expectancies and a positive familial history of alcoholism. To examine factors that are related to expectations of alcohol's effects in a Native American population, this study evaluated healthy, nonalcoholic Mission Indian men between the ages of 18 and 25 years using the short form of the Alcohol Expectancy Questionnaire (AEQ). The influence of recent drinking history, family history of alcoholism, and degree of Native American heritage on alcohol‐related expectancies was determined using regression analyses for the total AEQ score and for each of the six AEQ subscales. Recent drinking history accounted for a significant proportion of the variance in the total score, as well as scale I (global positive changes) and scale VI (arousal and power) of the AEQ. Degree of Native American heritage and family history of alcoholism did not account for a significant amount of variability in alcohol expectancies. These results suggest that, consistent with findings in other populations, alcohol expectancies are related to drinking patterns in Mission Indians. However, no association with two other potential risk factors were found in this sample of Native Americans.
Screening for Problem Drinking and Counseling by the Primary Care Physician‐Nurse Team
Authors: Israel Yedy , Hollander Oscar , Sanchez‐Craig Martha , Booker Suzanne , Miller Virginia , Gingrich Ronald , Rankin James G.
Published: April 2006

Present methods to screen for alcohol abuse are generally obtrusive and result in referral to services that deal mainly with alcoholics. These factors deter physicians from identifying alcohol abuse patients at an early stage. In the present study, 81% of all primary care physicians of a single city evaluated (i) the efficiency and the acceptability of a nonobtrusive screening method for the identification of problem drinkers and (ii) the effectiveness of brief cognitive behavioral counseling given by a nurse in a lifestyle context. Patients (n = 15,686) attending the private practices of 42 primary–care physicians were asked four alcohol–neutral trauma questions in the reception area. Physicians asked about alcohol use and alcohol‐related problems only to patients with previous trauma. Problem drinkers by defined criteria were offered an appointment with a nurse who, by random assignment, gave either 3‐hr of cognitive behavioral counseling over 1 year or simply advised patients to reduce their alcohol intake. The screening method identified 62–85% of expected number of problem drinkers in this population. Following the application of exclusion criteria, 105 problem drinkers were entered in the intervention part of the study. After 1 year, patients who received counseling showed significant reductions in reported alcohol consumption (‐70%; p < 0.001), psychosocial problems (‐85%; p < 0.001) and serum gamma glutamyl transferase (‐32%h to ‐58%; p < 0.02). Physician visits were reduced (‐34%; p < 0.02) following counseling. Patients receiving only advice showed neither reductions in psycho‐social problems nor in serum gamma glutamyl transferase or physician visits, but reported a 46% reduction (p < 0.01) in alcohol consumption. Data indicate that asking patients about recent trauma is efficient and is well accepted as the first screening instrument in the identification of the problem drinker. Cost of screening per patient is under one dollar. Counseling of 3 hr given by a nurse is markedly superior (p < 0.05) to simple advice in reducing alcohol consumption, objective indicators of alcohol‐related morbidity, and the frequency of physician visits.
Can We Subtype Alcoholism? A Latent Class Analysis of Data from Relatives of Alcoholics in a Multicenter Family Study of Alcoholism
Authors: Bucholz Kathleen K. , Heath Andrew C. , Reich Theodore , Hesselbrock Victor M. , Krarner John R. , Nurnberger John I. , Schuckit Marc A.
Published: April 2006

We attempted to identify distinctive subtypes of alcoholics using latent class analysis with data from 2551 relatives of alcoholic pro‐bands, all participants in the Collaborative Study of the Genetics of Alcoholism. Latent class analysis is a multivariate technique using cross‐classified data to identify unobserved (“latent”) classes that explain the relationships among observed variables. Data on 37 lifetime symptoms of alcohol dependence from 1360 female and 1191 male relatives were analyzed, with a 4 class solution selected as the best fitting among the 2 through 6 class solutions that were examined. We observed the following classes: class 1, nonproblem drinkers (39.6% male, 50% female); class 2, mild alcoholics (persistent desire to stop, tolerance, and blackouts) (31.8% male, 28.7% female); class 3, moderate alcoholics (social, health, and emotional problems) (18.9% male, 14.6% female); and class 4, severely alfected alcoholics (withdrawal, inability to stop drinking, craving, health, and emotional problems) (9.7% male, 6.7% female). There was little evidence for the construct of alcohol abuse; endorsement probabilities for abuse symptoms (e.g., arrests and DWIs) were very low for all classes, whereas hazardous use was common among men in class 1. In addition to those in class 3 and class 4, a majority of men in class 2 qualified for DSM‐Ill‐R alcohol dependence, suggesting a bimodal distribution of drinkers and alcoholics, with little nondependent problem drinking among men in this high‐risk sample. We conclude that, in this sample, alcoholism is not differentiated by symptom profiles but rather lies on a continuum of severity, with the possible exception of withdrawal, which characterized only class 4 individuals.
Subtypes of Alcohol‐Dependent Men: A Typology Based on Relative Genetic and Environmental Loading
Authors: Johnson Eric O. , van den Bree M. B. M. , Pickens Roy W.
Published: April 2006

Using scales that distinguish between relative genetic and environmental loading, cluster analysis was used to identify three subtypes of alcohol dependence in Caucasian men from the Epidemiologic Catchment Area study (n = 911). Although all subjects met DSM‐III criteria for alcohol dependence, only the severe subtype showed evidence of substantial genetic influence. When compared on a range of clinical characteristics, the mild subtype (53% of the sample) was typically least adversely affected and the severe subtype (17%) most affected, with the dyssocial subtype (30%) falling between. Severe subtype subjects had significantly greater comorbid drug dependence and were at least four times more likely than mild subjects to have sought treatment for alcohol problems. Ratio of genetic scale score to total symptom count (genetic ratio) was highest for the severe subtype (mean = 0.37). and negatively correlated with age of first alcohol problem (rs= ‐0.16) and years between first intoxication and first problem (rs= ‐0.19). No significant correlations were found between these clinical features and genetic ratio for the mild or dyssocial subtypes. Use of these scales and subtypes may improve our ability to detect specific gene effects in genetic linkage studies and to identify environmental influences in behavioral and epidemiological studies.
DSM‐IV, DSM‐III‐R, and ICD‐10 Alcohol and Drug Abuse/Harmful Use and Dependence, United States, 1992: A Nosological Comparison
Authors: Grant Bridget F.
Published: April 2006

This study assessed agreement between DSM‐IV, DSM‐III‐R, and ICD‐10 diagnoses of alcohol and drug use disorders using data from a large representative sample of the United States population. Agreement between the three diagnostic systems for dependence was good to excellent for past year, prior to the past year, and lifetime diagnoses, for both genders, each ethnic group, and younger and older respondents. Cross‐system comparisons between DSM‐IV and DSM‐III‐R abuse were good to excellent, but concordance was consistently poor when ICD‐10 harmful use diagnoses were compared with DSM‐IV and DSM‐III‐R abuse diagnoses. Implications of these results are discussed in terms of the degree to which future research findings could be integrated with one another and the results from earlier studies using older versions of the DSM, to advance scientific knowledge in the drug and alcohol fields.
Mammillary Body and Cerebellar Shrinkage in Chronic Alcoholics with and without Amnesia
Authors: Shear Paula K. , Sullivan Edith V. , Lane Barton , Pfefferbaurn Adolf
Published: April 2006

Mammillary body and cerebellar atrophy have been described as postmortem neuropathologic markers of Korsakoff's syndrome. This study examined whether shrinkage in the mammillary bodies and cerebellum is present consistently in amnesic chronic alcoholics during lie and whether the degree of abnormality in these patients differs from that in nonamnesic alcoholics and healthy controls. The severity of shrinkage in the mammillary bodies, cerebellar hemispheres, and cerebellar vermis visualizable on MRI scans was rated on a three‐point scale in 33 chronic nonamnesic alcoholics, 9 amnesic alcoholics, and 20 healthy controls. Although both alcoholic groups showed significant mammillary body and cerebellar shrinkage relative to controls, the two patient groups did not differ from each other. Furthermore, four of eight amnesic patients in our sample did not demonstrate clinically significant mammillary body atrophy. These results suggest that alcoholism is associated with mammillary body and cerebellar tissue volume loss but do not provide evidence that these markers distinguish accurately between amnesic and nonamnesic patients. In addition, they suggest that visualizable mammillary body atrophy is not necessary for the development of amnesia in alcoholic patients.
Psychotherapeutic Considerations in Pharmacological Trials
Authors: O'Malley Stephanie S. , Carroll Kathleen M.
Published: April 2006

Recent studies have demonstrated the favorable influence of psychotherapy on trials of pharmacological agents for the treatment of patients with alcohol abuse or dependence. When appropriate psychosocial therapies are used, the effects of pharmacotherapy can be more thoroughly evaluated because the use of psychosocial therapy can increase patient retention, enhance medication compliance, and foster the acquisition of new skills that reinforce the effects of the medication. Therefore, psychosocial therapy should be included in studies designed to evaluate the efficacy of pharmacological agents for the treatment of alcohol abuse or dependence.
Ethanol Consumption and Taste Preferences in C57BL/6ByJ and 129/J Mice
Authors: Bachmanov Alexander A. , Tordoff Michael G. , Beauchamp Gary K.
Published: April 2006

Mice of the C57BL/6ByJ (B6) and 129/J (129) strains were offered different concentrations of taste solutions in 48‐hr, two‐bottle choice tests. In comparison with the 129 strain, the B6 strain had higher preferences for ethanol, sucrose, and citric acid. They had lower preferences for NaCl and similar preferences for capsaicin and quinine hydrochloride. These data are consistent with the hypothesis that the higher ethanol intake by B6 mice depends, in part, on higher hedonic attractiveness of its sweet taste component.
Induction of Cytochrome P‐4502E1 by Ethanol in Rat Kupffer Cells
Authors: Koivisto Tiina , Mishin Vladimir M. , Mak Ki M. , Cohen P. Aryeh , Lieber Charles S.
Published: April 2006

Ethanol has been shown to affect several Kupffer cell functions, but the mechanisms underlying these changes are unknown. One possible mediator is cytochrome P‐4502E1 (CYP2E1), an ethanol‐inducible enzyme that has been associated with toxic effects in the liver, as well as in many extrahepatic organs. To assess whether CYP2E1 can be induced by ethanol in Kupffer cells, male rats pair‐fed ethanol‐containing or control Lieber‐DeCarli diets for 3 weeks were studied. Immunoblotting experiments showed that ethanol‐treatment caused a 7‐fold increase in CYP2E1 content both in Kupffer cells and hepatocytes. When expressed per milligram of S9 protein, the content of CYP2E1 in Kupffer cells was, however, 10 times lower than in hepatocytes. Immunohistochemical studies revealed that CYP2E1 is located in the endoplasmic reticulum of Kupffer cells in vivo and that it is also present in isolated Kupffer cells. In both Kupffer cells and hepatocytes, ethanol feeding increased the hydroxylation of p‐nitrophenol, a relatively specific substrate for CYP2E1, demonstrating that the induced CYP2E1 was catalytically active. This reaction was significantly inhibited by anti‐CYP2E1 IgG in both types of cells. Although CYP2E1 may not be the predominant pathway for ethanol metabolism in hepatocytes, it is possibly the major one in Kupffer cells. Thus, the induction of CYP2E1 by ethanol in these cells could cause significant changes in intracellular acetaldehyde concentrations which, together with increased lipid peroxidation, may contribute to the development of alcoholic liver injury.
Suppression of Alcohol Intake after Administration of the Chinese Herbal Medicine, NPI‐028, and Its Derivatives
Authors: Overstreet David H. , Lee Yue‐Wei , Rezvani Amir H. , Pei Yue‐Hu , Criswell Hugh E. , Janowsky David S.
Published: April 2006

The Chinese herbal medicine, NPI‐028, has been used for centuries in China to counteract alcohol intoxication. The present study used a number of different experimental conditions to determine whether NPI‐028 and its derivatives might selectively influence alcohol intake in rodents that naturally exhibit high alcohol intakes. It was determined that intraperitoneal (IP) injections of NPI‐028 (0.5, 0.75, and 1.0 g/kg) suppressed alcohol intake by up to 30% in both alcohol‐preferring P and Fawn‐Hooded (FH) rats during a continuous access schedule. These injections did not significantly affect food or water intakes, nor did the highest dose of NPI‐028 (1 g/kg) alter blood ethanol levels after an IP injection of 2.5 g/kg of ethanol. In P rats, it was found that NPI‐028 was orally active with the dose of 1.5 g/kg having a greater effect on ethanol intake than the 1.0 g/kg dose; once again, food and water intakes were not significantly altered. In FH rats maintained on a limited access schedule (1 hr/day), alcohol intake was completely abolished by 1.5 g/kg of NPI‐028. Chronic IP administration of NPI‐028 (0.75 g/kg) for four consecutive days in FH rats maintained on a continuous access schedule did not lead to any diminution of its alcohol‐suppressant effects. Thus, NPI‐028 has significant effects on alcohol intake without much effect on water and food intake, and tolerance does not readily develop to these effects. The IP administration of a partially purified extract (NPI‐031) of NPI‐028, obtained by countercurrent chromatography, also dose‐dependently suppressed ethanol intake in FH rats, but the highest dose (200 mg/kg) also significantly decreased food intake. Finally, the IP administration of puerarin (NPI‐31G), an isoflavone isolated from NPI‐031 by countercurrent chromatography, significantly reduced ethanol intake in FH rats without affecting food or water intake. Therefore, NPI‐028 and one of its pure components, NPI‐031G, selectively reduced ethanol intake in alcohol‐preferring rats.
Human Neutrophil Functions Are Inhibited In Vitro by Clinically Relevant Ethanol Concentrations
Authors: Patel Mrunal , Keshavarzian Ali , Kottapalli Venkata , Badie Bahman , Winship Daniel , Fields Jeremy Z.
Published: April 2006

Neutrophils [polymorphonuclear neutrophils (PMNs)] play a pivotal role in host defense in man. These defenses may be compromised, however, in alcohol users and abusers. We therefore evaluated the effect of ethanol levels (12.5 to 500 mg/dl), on key functions of human PMNs—chemotaxis and production of reactive oxygen species—and on changes in cytosolic‐free calcium ([Ca2+]i), a pivotal intracellular mechanism of PMN activation. Ethanol significantly inhibited chemotaxis as evaluated by formyl‐methionyl‐leucyl‐phenylalanine (fMLP)‐induced upregulation of surface adhesion molecules (CD11b), fMLP‐induced PMN elongation was only inhibited by a very high ethanol concentration of 500 mg/dl. Production of reactive oxygen species by normal PMNs was assessed by either chemiluminescence (CL) for hypochlorous acid or ferricytochrome c reduction (FCR) for superoxide anions. For PMN stimulated by fMLP, ethanol inhibited CL but not FCR. For PMNs activated by phorbol myristate acetate, ethanol inhibited both CL and FCR. Ethanol did not alter baseline [Ca2+]i, as assessed by videomicroscopy using the Ca2+‐sensing fluorescent dye Fura‐2‐AM, but did significantly potentiate the increase in peak [Ca2+]i, levels that occurs in response to stimulation by fMLP. Calcium channel blockers attenuated ethanol's inhibition of CL. Thus, acute in vitro ethanol, at clinically relevant concentrations, can inhibit several critical aspects of PMN functions. But, in PMNs, unlike neural cells, these inhibitory effects do not seem to be mediated by decreases in Ca2+ influx or in [Ca2+]i.
Interleukin‐6 and Tumor Necrosis Factor‐α Clearance and Metabolism In Vivo and by the Isolated, Perfused Liver in the Rat: Effect of Acute Alcohol Administration
Authors: Deaciuc Ion V. , Alappat Julie M. , McDonough Kathleen H. , D'Souza Nympha B.
Published: April 2006

Plasma clearance and organ distribution of intravenously injected human recombinant [125I]interleukin (IL)‐6 and [125I]tumor necrosis factor (TNF)‐α were studied in male rats, 2 hr after intravenous alcohol (ethanol) administration (single dose, 2.2 g · kg‐1 body weight). Also, the rate of uptake and degradation of the two cytokines by the isolated, perfused rat liver was studied in the absence or in the presence of ethanol (35 mM) in the perfusate. Acute ethanol administration significantly increased plasma clearance rate for both cytokines (36% and 72%, for IL‐6 and TNF‐α, respectively), decreased the t1/2α (30% and 11%, for IL‐6 and TNF‐α, respectively), abolished the slow (β)‐phase component for TNF‐α, and increased t1/2β for IL‐6 (31%). Although alcohol did not affect organ distribution of TNF‐α, it increased the IL‐6 content in the liver, kidney, and blood. IL‐6 uptake rate by the isolated, perfused rat liver was 2‐fold higher than TNF‐α uptake, whereas the rate of degradation was larger for TNF‐α than for IL‐6, despite the fact that both cyokines were presented to the liver at the same concentration (6 nM). Ethanol addition to the perfusate (35 mM, final concentration) significantly increased TNF‐α uptake (24%), without affecting IL‐6 uptake or the degradation rate of either cytokine. Also, the kinetics of degradation by the isolated, perfused rat liver was linear for TNF‐α, but exponential for IL‐6. Data presented in this study demonstrate that: (1) acute alcohol consumption can alter the kinetic behavior of IL‐6 and TNF‐α in the bloodstream, mainly by accelerating their clearance which, in turn, may counteract the outcome of cytokine secretion and delivery to the blood; and (2) short exposure of liver to ethanol levels commonly seen in humans after binge drinking may alter its capacity to take up cytokines.
Alcohol in Fatal and Nonfatal Injuries: A Comparison of Coroner and Emergency Room Data from the Same County
Authors: Cherpitel Cheryl J.
Published: April 2006

Although alcohol is thought to be associated with severity of injury, relatively little data are available that compares alcohol's involvement in injury cases treated in the emergency room (ER) with coroner cases of injury fatality, both coming from the same county. Data from a probability sample of casualty patients 18 years and older treated at the University of Mississippi Medical Center ER in Jackson during a 6‐month period (n= 275) are compared with data from coroner reports of all fatalities from unnatural causes among those 18 and older in the same county during a 1‐year period surrounding the 6 months of data collection in the ER (n= 222). The two samples are compared on demographic characteristics, cause of injury, place of injury, and alcohol use before the event. A significantly larger proportion of the coroner sample was positive for alcohol (57%) and intoxicated (36%), compared with the proportion of those in the ER sample breathalyzed within 6 hr of injury, and reporting no drinking after the event who were positive (15%) and intoxicated (6%). Differences were most pronounced for motor vehicle accidents and fires. Violence‐related injuries were more likely in the coroner sample (32%) than in the ER sample (l6%), and they were more likely to involve alcohol at levels of intoxication. Those in the coroner sample were also more likely to be alcohol‐positive for injuries occurring in all places except the home of another and the workplace. Using logistic regression, gender (male) and site (coroner) were predictive of a positive blood alcohol across all causes of injury combined. Gender (female), being alcohol‐positive and site (coroner) were significantly predictive of motor vehicle accidents. Alcohol was not found to be a significant predictor for falls, other accidents, or injuries resulting from violence. Data suggest that alcohol's association with severity of injury varies by cause of injury.
Effect of Diazepam on Plasma γ‐Aminobutyric Acid in Sons of Alcoholic Fathers
Authors: Cowley Deborah S. , Roy‐Byrne Peter P. , Greenblatt David J. , Kramer Gerald L. , Petty Frederick
Published: April 2006

A subgroup of abstinent alcoholics display low levels of plasma γ‐aminobutyric acid (GABA). Two previous studies of plasma GABA in sons of alcoholic fathers (SOAs) have yielded conflicting results. The aim of the current study was to measure plasma GABA both at baseline and after challenge with diazepam, a GABAA receptor agonist, in a group of SOAs already shown to display decreased eye movement, memory, and sedative effects of diazepam. Twenty‐seven SOAs and 23 male control subjects received four logarithmically increasing doses of diazepam or placebo in randomized order on 2 days at least 1 week apart. Plasma GABA was measured at baseline and after the last dose. There were no significant differences between SOAs and controls in baseline plasma GABA levels. In the whole sample, there were significant correlations between baseline plasma GABA and both high novelty‐seeking and low‐harm avoidance scores on the Tridimensional Personality Questionnaire. Both SOAs and controls displayed decreases in plasma GABA over time on both testing days, but there was no effect of diazepam on plasma GABA and no significant difference between groups in plasma GABA response to diazepam. These results suggest that neither low plasma GABA at baseline nor altered plasma GABA response to diazepam is associated with increased genetic risk for alcoholism.
Alcohol and Substance Use among Japanese High School Students
Authors: Matsushita Sachio , Suzuki Kenji , Higuchi Susumu , Takeda Aya , Takagi Satoshi , Hayashida Motoi
Published: April 2006

In the first large‐scale survey on the use of alcohol and tobacco and the inhalation of paint thinner by Japanese high school students, a higher percentage of respondents reported past or regular use of these substances than in a 1978 survey. The survey was conducted in 44 high schools. The 14,438 respondents (ages 15–18 years) represented 9 of Japan's 47 geographically distinct urban and rural prefectures. Most (76%) reported that they had consumed alcohol at some time, and 50% reported drinking on a regular basis. Alcohol consumption, drinking partners, and motivation for drinking were compared by student gender, geographic region, and years of education. Fewer students reported smoking cigarettes: 32% had smoked at some time, and 14% smoked regularly. Inhalation of paint thinner was rare: 3% had purposely inhaled it, and 1% had abused it. A significant percentage of the alcohol drinkers also used tobacco and/or thinner, a tendency that was the same despite differences in gender, grade in high school, and urban or rural geographic region. A tendency toward polysubstance use was evident among these high school students.
DSM‐IV Alcohol Dependence in a Treatment Sample of White, Black, and Mexican‐American Men
Authors: Caetano Raul , Schafer John
Published: April 2006

This study examines the presentation, correlates, and factor structure of DSM‐IV alcohol dependence among 256 White, 263 Black, and 212 Mexican‐American men admitted consecutively to five alcohol treatment programs in San Jose, CA. Interviews of ˜1 hr were conducted to the programs' facilities by trained interviewers using a standardized questionnaire. The response rate was 87%. Results show that the proportion of Black respondents who are alcohol‐dependent according to the DSM‐IV criteria is lower (63%) than the proportion of Whites (86%) and Mexican Americans (76%). However, the proportion of respondents reporting each criterion of dependence was similar across groups. The most powerful predictor of the number of dependence indicators reported by respondents was level of alcohol consumption, independent of ethnicity. A unidimensional model of dependence combining all seven indicators of DSM‐IV alcohol dependence fit well across men in all three ethnic groups. These results indicate that both the presentation and factorial structure of DSM‐IV alcohol dependence were uniform across White, Black and Mexican‐American men in treatment for alcohol problems.