bluuebunny/crossref_metadata_2025 huggingface dataset:
Oral Ethanol‐Reinforced Responding in Rhesus Monkeys: Effects of Opioid Antagonists Selective for the μ‐,κ‐, or δ‐Receptor
Authors: Williams Keith L. , Woods James H.
Published: May 2006

To determine the mechanism by which naltrexone (NTX) reduces oral ethanol‐reinforced responding, opioid antagonists that show μ‐, κ‐, or δ‐selectivity were evaluated. Rhesus monkeys (n= 6) were given opportunities to respond and receive ethanol (1 % or 2%) or water during daily 3‐hr drinking sessions. Before some drinking sessions, the monkeys received intramuscular injections of saline or the following drugs: the μ‐selective irreversible antagonist clocinnamox (CCAM), the κ‐selective long‐lasting antagonist nor‐binaltorphimine (nor‐BNI), or the δ‐selective antagonist naltrindole. Also, NTX was administered along with either CCAM or nor‐BNI. When given alone, CCAM (0.1 mg/kg) had no effect on ethanol‐reinforced responding. When NTX (0.32 mg/kg) was given with CCAM, responding maintained by ethanol was decreased. Nor‐BNI (3 mg/kg) reduced ethanol‐reinforced responding only on the day of injection. On subsequent days, when other studies report continued κ‐antagonism, responding maintained by ethanol returned to control levels. Also, NTX (0.32 mg/kg), administered in the presence of nor‐BNI, was still able to reduce ethanol‐reinforced responding. Naltrindole failed to alter responding maintained by ethanol. Because selective antagonism at the μ‐, κ‐, or δ‐receptor did not reduce ethanol‐reinforced responding, NTX's ability to reduce ethanol consumption may not be mediated by these previously characterized opioid receptors. NTX may exert its effects through an uncharacterized opioid binding site or through a nonopioid mechanism.
Repeated Alcohol Administration Differentially Affects c‐Fos and FosB Protein Immunoreactivity in DBA/2J Mice
Authors: Ryabinin Andrey E. , Wang Yuan‐Mei
Published: May 2006

To identify alcohol‐responsive brain areas, we have immunohisto‐chemically analyzed expression of c‐Fos, FosB, and other Fos‐related antigens in the brain of inbred DBN/2J mice after a single or repeated injection of alcohol (4 g/kg). We observed increased expression of c‐Fos after alcohol administration in the central nucleus of amygdala, paraventricular nuclei of hypothalamus and thalamus, and several other brain areas. Although increased expression of c‐Fos in the nucleus accumbens was also observed, this increase was not statistically significant. Repeated administration of alcohol had the tendency to reduce alcohol‐induced c‐Fos expression in these areas. Immunohistochemical analysis using an antibody recognizing most Fos‐related antigens revealed increases of expression of these proteins in a partially overlapping set of brain regions. In contrast to c‐Fos, FosB expression was found to be elevated significantly higher after repeated than after acute treatment with alcohol in several brain areas, including the shell of nucleus accumbens. In contrast to previous c‐Fos studies, our studies confirm that alcohol administration indeed activates the reward circuits, including the basal ganglia, and suggest that FosB could serve as a more sensitive marker for this activation.
Action of Ethanol and Zolpidem on γ‐Aminobutyric Acid Responses from Cerebellar Purkinje Neurons: Relationship to β‐Adrenergic Receptor Input
Authors: Yang Xiaohong , Knapp Darin J. , Criswell Hugh E. , Breese George R.
Published: May 2006

The observation that cerebellar Purkinje cells contain type‐I benzodiazepine‐sensitive GABAA, receptors is consistent with findings in the present work that the majority of Purkinje neurons are sensitive to enhancement of GABA by the type‐1 benzodiazepine agonist, zolpidem. Previous work has demonstrated a relation between zolpidem and ethanol enhancement of GABA responses in several brain regions, but had not tested Purkinje neurons. Therefore, given that a majority of Purkinje neurons were found to be sensitive to zolpidem, ethanol would have been expected to enhance GABA responses from this cell type. However, in agreement with earlier electrophysiological studies, ethanol enhanced GABA inhibitory responses from only a small proportion of these cerebellar Purkinje neurons. Rather than enhancement of GABA, local application of ethanol either inhibited or did not affect responses to GABA from a majority of cerebellar‐Purkinje neurons. Nonetheless, as previously reported, a portion of the Purkinje neurons initially insensitive to ethanol enhancement of GABA became sensitive to this action of ethanol with co‐application of the β‐adrenergic agonist, isoproterenol. Thus, these results collectively implicate a β‐adrenergic input dependency for ethanol enhancement of GABA from some, but not all, cerebellar Purkinje neurons sensitive to zolpidem. Because a β‐adrenergic input did not allow ethanol enhancement of GABA from all Purkinje neurons, future studies should explore the possibility that other auxiliary neural inputs to zolpidem‐sensitive cerebellar Purkinje neurons may be required for ethanol enhancement of GABA responsiveness when a β‐adrenergic input does not have this action. Likewise, knowing that the action of zolpidem can predict ethanol enhancement of GABA in other brain regions, the present findings suggest that a future determination be made concerning whether zolpidem‐sensitive neurons in these other regions of brain require a β‐adrenergic or an alternative neural input for ethanol enhancement of GABA responses.
Acute Functional Tolerance to Ethanol and Fear Conditioning Are Genetically Correlated in Mice
Authors: Radcliffe Richard A. , Erwin V. Gene , Wehner Jeanne M.
Published: May 2006

It has been speculated that tolerance to alcohol involves some form of neuronal plasticity that is similar to or the same as that mediating learning and memory. To investigate this possibility further, we tested the hypothesis that acute functional tolerance (AFT) to alcohol is genetically correlated to a Pavlovian learning task fear conditioning. Mice selectively bred for differences in ability to acquire AFT were tested for fear conditioning. Subjects received a mild footshock paired to a broadband clicker and were tested 24 hr later for their freezing response to the conditioning chamber (context), to an altered chamber, and to the clicker. Both the original and replicate lines selected for high AFT (HAFT) were found to freeze significantly more than those selected for low AFT (HAFT) in response to the context and to the clicker. In a second experiment, an F2 Population derived from the C57BL/6 (B6) and DBA/2 (D2) mouse strains were tested first for fear conditioning, followed 3 weeks later by AFT testing. AFT was defined as the difference between blood alcohol levels determined at the time of regain balance on a dowel rod first after 1.75 g/kg of ethanol and again after a subsequent dose of 2.0 g/kg. Consistent with results from HAFT and LAFT, freezing to context was found to be significantly positively correlated to AFT (r= 0.38, p= 0.04) in the F2 mice. The results suggest that co‐variation in fear conditioning and AFT may be mediated by one or more of the Same or at least tightly linked genes. Further dissection of this correlation may reveal neuronal mechanisms common to both AFT and fear conditioning.
Use of a Two‐Compartment Model to Assess the Pharmacokinetics of Human Ethanol Metabolism
Authors: Levitt Michael D. , Levitt David G.
Published: May 2006

The relationship between blood ethanol concentration and hepatic ethanol metabolism commonly is calculated using the Michaelis‐Menten equation and a one‐compartment model that assumes equality of blood and hepatic ethanol concentrations. However, at low blood concentrations, most of the ethanol arriving at the liver is metabolized, and hepatic ethanol concentrations may fall far below that of the entering blood. We have developed a two‐compartment model of ethanol metabolism that accounts for the fall in ethanol concentration that may occur as blood traverses the liver and used this model to make predictions concerning ethanol metabolism at various blood ethanol concentrations. The two‐compartment model predicts that near‐complete saturation will occur more abruptly and at a lower blood concentration (˜3 mM) than is the case with the one‐compartment model. Thus, the two‐compartment model predicts a near‐constant ethanol elimination rate for blood ethanol concentrations above 3 mM (as commonly observed in human subjects), whereas the one‐compartment model predicts an increasing elimination rate over the range of concentrations observed in experimental studies. In agreement with observed data, the two‐compartment model predicts that first‐pass metabolism should be extremely sensitive to the rate of ethanol absorption. Application of this model to previously published data indicated that, when absorption was slowed via concomitant food ingestion, first‐pass metabolism accounts for ˜50% and 10% of ethanol dosages of 0.15 g/kg and 0.3 g/kg, respectively. When ingested without food, there is negligible first‐pass metabolism of even very small ethanol dosages (0.15 g/kg). These findings suggest that first‐pass metabolism is an unimportant determinant of the blood ethanol response to ingestion of potentially inebriating doses of ethanol.
Direct Antagonism of Ethanol's Effects On GABAA Receptors by Increased Atmospheric Pressure
Authors: Davies Daryl L. , Alkana Ronald L.
Published: May 2006

Previous studies have shown that exposure to 12 times normal atmospheric pressure of helium‐oxygen gas (heliox) directly antagonizes a range of ethanol's acute and chronic behavioral effects. The present study extends the investigation to the biochemical level by investigating the effects of pressure on ethanol‐induced potentiation of GABAA receptor function in mouse membrane vesicles (micro‐sacs). Exposure to 12 atmospheric pressure heliox significantly antagonized ethanol (25 to 100 mM) potentiation of GABA‐activated 36Cl‐ uptake, but did not significantly alter baseline GABAA receptor function measured by the response of the system to GABA (10 to 100 μM), bicuculline (3 and 100 μM), or picrotoxin (100 μM). These findings add essential support for the hypothesis that hyperbaric exposure is a direct ethanol antagonist that can be used as a tool to help identify ethanol's initial cellular and molecular sites of action that cause its behavioral effects. Taken in context with previous behavioral studies, the present results also provide important new evidence for a cause‐effect relationship between ethanol potentiation of GABAA receptor function and ethanol's anesthetic and behavioral effects.
Suppression of the Granulocyte Colony‐Stimulating Factor Response to Escherichia coli Challenge by Alcohol Intoxication
Authors: Bagby Gregory J. , Zhang Ping , Stoltz David A. , Nelson Steve
Published: May 2006

Alcohol's suppressive effects on polymorphonuclear leukocyte (PMN) production and function increases host susceptibility to a wide variety of infections and impairs the ability of these effector cells to seek and destroy invading pathogens. Granulocyte colony‐stimulating factor (G‐CSF), an important regulator of PMN production and function, is known to be increased in the plasma during infectious episodes. In previous studies we found acute alcohol intoxication to suppress the tumor necrosis factor‐α (TNFα) response to in vivo challenges with bacteria or lipopolysaccharide. The present study was initiated to determine the impact of alcohol intoxication on the plasma G‐CSF response to Gram‐negative infection. For this purpose, rats received an intravenous challenge of Escherichia coli (106 CFU) 30 min after an intraperitoneal injection of ethanol (5.5 g/kg) or an equivalent volume of saline (control). Ethanol‐intoxicated rats had a greater 48 hr mortality to live E. coli injection than did unintoxicated animals (45% vs. 8%). Despite an increased bacterial burden in both the lung and liver at 24 hr after initiating E. coli infection in alcohol‐intoxicated animals, PMN tissue recruitment, indexed as myeloperoxidase activity, did not differ between control and alcohol‐treated rats. Moreover, alcohol suppressed blood PMN phagocytic capacity to a greater extent in animals given alcohol than controls at 5 and 24 hr after initiating infection. In control animals after intravenous E. coli injection, bioactive G‐CSF increased in plasma and peaked near 300 ng/ml at 8 hr. In rats pretreated with alcohol, the plasma G‐CSF response was markedly suppressed in response to intravenous E. coli (p 0.05). In a second experiment, neutralization of the E. coli‐induced plasma TNFα response by pretreatment with anti‐TNFα antibody similarly inhibited the plasma G‐CSF response. These results support the postulate that alcohol‐induced inhibition of TNFα directly contributes to the adverse effects of alcohol on PMN function by suppressing the normal autocrine amplification pathway responsible for G‐CSF production.
Effect of Nitric Oxide Synthase Inhibitors on Preventing Ethanol‐Induced Suppression of the Hypothalamic‐Pituitary‐Gonadal Axis in the Male Rat
Authors: Shi Qin , Emanuele Nicholas V. , Emanuele Mary Ann
Published: May 2006

Ethanol (EtOH) suppression of the hypothalamic‐pituitary‐gonadal (HPG) axis results in broad reproductive malfunction. In the HPG axis, the suppressive effects of EtOH are manifested by decreased serum testosterone, reduced testicular luteinizing hormone (LH) receptor numbers, lowered serum LH and pituitary β‐LH mRNA levels (in castrated animals), and impaired luteiniring hormone releasing hormone (LHRH) release from the hypothalamus. Increasing evidence has suggested that nitric oxide (NO) plays a role in regulation of the HPG axis. NO was shown to stimulate LHRH secretion from the hypothalamus and to have variable effects on LH release from the pituitary. At the gonadal level, NO is inhibitory to testosterone production. NO may directly inhibit some testicular steroidogenic enzymes. To investigate the effect of EtOH, NO, and their interaction on the male HPG axis, three NO synthase (NOS) inhibitors, NQ‐nitro‐l‐arginine methyl ester, NQ‐nitro‐l‐arginine, and 7‐nitro indazole were used to study overall HPG function in the presence and absence of EtOH. Animals were given intraperitoneal injections of saline, EtOH, various NOS inhibitors, or EtOH, along with NOS inhibitors 2 hr before sacrifice. Serum testosterone and LH concentrations, pituiiry βLH mRNA levels, hypothalamic LHRH mRNA levels, and LHRH content were determined. It was found that blocking NOS by these NOS inhibitors prevented EtOH‐induced suppression of testosterone and, in some cases, serum LH. However, this was not accompanied by concurrent changes with NOS blockade on LHRH mRNA, hypothalamic pro‐LHRH or LHRH content or pituitary LH β mRNA levels. It appears that the protective effect of NOS blockade was largely, although not completely, due to a direct effect at the gonadal level.
The Sleep of Abstinent Pure Primary Alcoholic Patients: Natural Course and Relationship to Relapse
Authors: Drummond Sean P.A. , Gillin J. Christian , Smith Tom L. , DeModena Anna
Published: May 2006

Sleep in male pure primary alcoholic inpatients was examined at a mean of 16 days (n= 29), 19 weeks (n= 29), 14 months (n= 9), and 27 months (n= 4) of abstinence. Results were as follows: (1) the sleep of abstinent alcoholic patients is short, fragmented, and shallow early in abstinence; (2) a patient's sleep improves slowly over at least the first year of abstinence; however, (3) some facets of a patient's sleep remain abnormal even after 27 months of abstinence; (4) insomnia and sleep fragmentation after approximately 5 months of abstinence may be related to relapse by 14 months. The mechanism underlying the relationship between sleep and withdrawal in alcoholic patients is not well understood, and the issue of treating sleep problems as an adjunct to prevention of relapse warrants further investigation. Key Words: Alcoholism, Sleep, Abstinence, Relapse.
Carbohydrate‐Deficient Transferrin: Diagnostic Efficiency Among Patients with End‐Stage Liver Disease Before and After Liver Transplantation
Authors: Heinernann A. , Sterneck M. , Kuhlencordt R. , Rogiers X. , Schulz K. H. , Queen B. , Wischhusen F. , Puschel K.
Published: May 2006

We tested the diagnostic validity of carbohydrate‐deficient transferrin (CDT) as an indicator for relapse into elevated alcohol consumption among patients who were examined under follow‐up treatment before (n= 147) and after (n= 102) orthotopic liver transplantation (OLT) in the outpatient‐department of the University Hospital Department of Surgery in Hamburg‐Eppendorf. CDT measurements were performed with two commercial kits in parallel (CDTect‐RIA and CDT%‐RIA). Short‐term parameters of alcohol consumption (ethanol, methanol) indicated relapses into elevated alcohol consumption in 11.4% of the evaluated patients with alcoholic liver disease (ALD) before transplantation. Before OLT, median CDT values were determined to be elevated among patients with alcoholic as well as nonalcoholic end‐stage liver diseases (NALD). Among patients with ALD, we found elevated CDT medians even in those who were successfully scheduled for OLT after long‐term evidence of abstinence proved by biochemical short‐term parameters and psychological tests. Both CDTect and CDT% assays had comparable low specificities in selected patient groups before transplantation. CDT% and CDTect were negatively correlated with the albumin level. Before the study ended, CDT was no longer implemented in the evaluation of whether an OLT should be administered. This was due to inconsistent results of CDT in ALD as well as NALD. After OLT, patients with ALD, as well as NALD, had statistically significant lower CDT medians than before OLT, which ranged within reference levels. We determined, according to CDT, elevated alcohol consumption subsequent to OLT in 4 of 13 patients with ALD who underwent transplantation during the study (median observation period: 10 months). CDT does not appear to be useful in evaluating patients before OLT. With regained specificity and high sensitivity in patients after OLT, CDT could be recommended as a standard instrument for quality control in patients with ALD after liver transplantation.
Evaluation of Acetaldehyde‐Modified Hemoglobin and Other Markers of Chronic Heavy Alcohol Use: Effects of Gender and Hemoglobin Concentration
Authors: Hazelett S. E. , Liebelt R. A. , Brown W. J. , Androulakakis V. , Jarjoura D. , Truitt E. B.
Published: May 2006

The present study examined whether measurement of hemoglobin‐acetaldehyde (HbA1‐AcH) using an improved methodology may be useful as a biological marker of alcohol abuse. Red blood cell hemolysates of 182 patients consecutively admitted to the drug and alcohol treatment unit of our institution were analyzed for HbA1‐AcH concentration using cation exchange HPLC. Mean HbA1‐AcH of those who claimed to drink ≥6 drinks/day [mean = 0.055 (% total hemoglobin), SD = 0.051] was significantly higher than the mean of those who drank < 6 drinks/day (mean = 0.026, SD = 0.0174). The greatest sum of sensitivity (67%) and specificity (77%) came with a cut‐score of 0.030 area% of total hemoglobin. A cut‐score of 0.080 produced a 100% specificity, but lowered the sensitivity to 20%. The Pearson product moment correlation (r) between HbA1‐AcH and reported drinks per day was r= 0.30 (p < 0.001). There was no significant difference in the association of HbA1‐AcH and reported drinking between males and females, and the small difference observed was shown to be entirely associated with differences in hemoglobin levels between the sexes. Cocaine use did not significantly alter the correlation between reported drinking and HbAl‐AcH levels. Hemoglobin levels were shown to have a significant correlation with HbA1‐AcH independent of drinking. HbA1‐AcH was shown to have a better sensitivity and specificity than γ‐glutamyltransferase, ALT, AST, or mean corpuscular volume in this population. The results suggest that HbA1‐AcH may be a useful marker to help detect alcohol abuse, especially in populations where other markers have been shown to fail.
Physical and Mental Comorbidity of Substance Use Disorders in Psychiatric Consultations
Authors: Alaja Riitta , Seppä Kaija , Sillanaukee Pekka , Tienari Pekka , Huyse Frits J. , Herzog Thomas , Malt Ulrik F. ,   Antonio Lobo, and the European Consultation‐Liaison Workgroup
Published: May 2006

Comorbidity of substance use disorders with physical and mental disorders was investigated among 1249 consecutive psychiatric consultation patients admitted to six general hospitals in Finland. Of the patients 354 (28%) were diagnosed with substance use disorders (ICD‐10), of which 22% were due to use of at least two different types of psychoactive substances. Alcohol dependence (117/226) in male patients and acute drug intoxication (49/128) at a similar rate as alcohol dependence (44/128) in female patients were the most common clinical conditions. With few exceptions, all substance use disorders were comorbid and in 63% of affected patients comprised a “triple diagnosis” (i.e., physical, mental, and substance use diagnoses concurrently). Poisonings and personality disorders in both sexes, digestive system diseases in men, and injuries in women were related to substance use disorders. Conclusions for service provision were: (1) the high level of co‐occurrence of physical and mental disorders with substance use disorders calls for comprehensive, multi‐disciplinary assessment of any substance use problems ascertained in psychiatric consultations; (2) poisoning with substance use involvement and mental comorbidity was the most common combined clinical condition justifying provision of addiction psychiatric emergency consultations in general hospitals; (3) polydrug use indicating severe problems and complex treatment needs should be identified; and (4) psychiatric referrals of patients with physical alcohol‐related disorders should be ensured in general hospitals.
Regional Cerebral Metabolism in Female Alcoholics of Moderate Severity Does Not Differ From That of Controls
Authors: Wang Gene‐Jack , Volkow Nora D. , Fowler Joanna S. , Pappas Naomi R. , Wong Christopher T. , Pascani Kathleen , Felder Christoph A. , Hitzernann Robert J.
Published: May 2006

It is generally believed that women are more vulnerable to alcohol's toxic effects than men. Studies in male alcoholics have consistently shown reductions in brain glucose metabolism. However, such studies have not been done in female alcoholics. The purpose of this study was to evaluate if similar or worse brain metabolic abnormalities occurred in female alcoholics. For this purpose, we measured regional brain metabolism with positron emission tomography and [18F]fluorodeoxyglucose in 10 recently detoxified female alcoholics and compared it with that in 12 age‐matched female controls. There were no differences between alcoholics and control females in regional brain glucose metabolism whether we used regions of interest analysis or statistical parameter maps methods. These results do not support a higher toxicity for the effects of alcohol in the female brain, as assessed with regional brain glucose metabolism, because metabolic values in female alcoholics did not differ from those of controls, whereas metabolic values in male alcoholics are generally lower than those in controls. However, this study is confounded by the fact that the severity of alcohol use in these female alcoholics was less than that of the male alcoholics previously investigated in positron emission tomography studies. Future studies in male subjects with alcoholism of moderate severity are required to address gender differences in sensitivity to alcohol effects in brain metabolism.
Monocytes, Alcohol Use, and Altered Immunity
Authors: Szabo Gyongyi
Published: May 2006

The immunomodulatory capacity of acute, moderate alcohol consumption was investigated in this study in nonalcoholic volunteers after 2 ml of vodka/kg body weight of alcohol consumption. There was a significant, transient increase in interleukin‐12 and interferon‐γ (IFN γ) levels in whole blood samples collected 4 hr after alcohol consumption in response to an ex vivo bacterial challenge with lipopolysaccharide (p < 0.02). However, decreased IFN γ levels were produced by mononuclear cells collected later after alcohol consumption (16 hr), suggesting that acute alcohol consumption has a biphasic effect on IFN γ inducibility. Furthermore, isolated blood monocytes collected 16 hr after alcohol consumption showed significantly decreased IL‐1β production in response to subsequent bacterial stimulation, implying that in vivo alcohol consumption affects monocyte‐derived inflammatory cytokine production. These results demonstrate that even acute, moderate alcohol consumption has a modulating capacity on immune functions that may contribute to decreased immunity and host defense.
Mechanisms Mediating the Influence of Alcohol on the Hypothalamic‐Pituitary‐Adrenal Axis Responses to Immune and Nonimmune Signals
Authors: Ogilvie Kathleen , Lee Soon , Weiss Burt , Rivier Catherine
Published: May 2006

In the rat, the acute administration of alcohol induces dose‐related increases in plasma ACTH and corticosterone levels. This response depends on the delivery of the hypothalamic peptides corticotropin‐releasing factor and vasopressin (VP) to the pituitary. On the other hand, exposure to an alcohol diet for 7 to 10 days significantly blunts the hypothalamic‐pituitary‐adrenal (HPA) axis in response to other homeostatic threats, such as mild electroshocks or immune signals. This decreased response is at least in part due to an attenuated ability of VP to increase ACTH secretion. We have previously shown that nitric oxide (NO) inhibits the pituitary response to VP. We therefore hypothesized that chronic alcohol treatment might increase levels of this gas within the HPA axis, and tested this possibility by determining whether blockade of NO formation might restore a normal pituitary response to VP. We observed that such was the case, and therefore propose that NO participates in the blunted activity of the HPA axis during prolonged exposure to alcohol. Finally, we determined whether alcohol would exert neuroendocrine effects that extended beyond the initial drug treatment. To explore this possibility, we injected rats with alcohol intragastrically for 3 days, then re‐exposed them to the drug 3 to 12 days later. Rats pretreated with the vehicle and injected with alcohol several days later showed the expected significant rise in plasma ACTH and corticosterone levels, as well as a marked increase in immediate early genes mRNA levels in the paraventricular nucleus (PVN) of their hypothalamus. In contrast, animals pretreated with alcohol exhibited a blunted hormonal and hypothalamic response during the second drug exposure but, interestingly, retained a normal endocrine response to other signals, such as exposure to electro‐footshocks or cytokine injection. We originally thought that this phenomenon of selective endocrine tolerance might be explained by decreased serotonin levels in the PVN. Whereas alcohol indeed decreased concentrations of this neurotransmitter in the PVN, exposure to electroshocks induced similar changes. However, an initial exposure to shocks did not blunt the ability of the HPA axis to be activated by a second shock session, by alcohol or by immune signals (delivered several days later). These results do not support the hypothesis that the decreased HPA axis response to a second alcohol challenge is mediated via decreased serotonin afferents to corticotropin‐releasing factor neurons in the PVN.
Combined Efficacy of Acamprosate and Disulfiram in the Treatment of Alcoholism: A Controlled Study
Authors: Besson Jacques , Aeby François , Kasas Antoine , Lehert Philippe , Potgieter Adriaan
Published: May 2006

This study presents the results of a multicenter investigation of the efficacy of acamprosate in the treatment of patients with chronic or episodic alcohol dependence. One hundred eighteen patients were randomly assigned to either placebo or acamprosate, and both groups were stratified for concomitant voluntary use of disulfiram. Treatment lasted for 380 days, with an additional 360‐day follow‐up period. The primary efficacy parameters evaluated were: relapse rate and cumulative abstinence duration (CAD). Results were analyzed according to Intention‐To‐Treat principles using χ2, t, and multiple regression analyses where appropriate. After 30 days on study medication, 40 of 55 (73%) acamprosate‐treated patients were abstinent, compared with 26 of 55 (43%) placebo‐treated patients (p= 0.019). The treatment advantage remained throughout the study medication period and was statistically significant until day 270 (p= 0.028). Twenty‐seven percent of patients on acamprosate and 53% of patients on placebo had a first drink within the first 30 days of the study. The mean CAD was 137 days (40% abstinent days) for the patients treated with acamprosate and 75 days (21% abstinent days) for the placebo group (p= 0.013). No adverse interaction between acamprosate and disulfiram occurred, and the subgroup who received both medications had a better outcome on CAD than the those on only one or no medication. Acamprosate was well tolerated. Diarrhea was the only significant treatment‐induced effect. It was concluded that acamprosate was a useful and safe pharmacotherapy in the long‐term treatment of alcoholism. Concomitant administration of disulfiram improved the effectiveness of acamprosate.
Difficulties with Questions on Usual Drinking and the Measurement of Alcohol Consumption
Authors: Hasin Deborah , Carpenter Kenneth M.
Published: May 2006

Questions about usual drinking play an important role in the construction of alcohol consumption measures. However, little is known about difficulties in answering these questions for respondents with variability in their drinking patterns. We investigated this in a community sample of 945 drinkers and in a clinical sample of 400 patients treated for alcohol and/or drug problems. Demographic variables were not consistently related to self‐reported difficulty in answering, but a diagnosis of current DSM‐IV alcohol dependence was significantly related in both samples. In modeling the relationship between alcohol consumption and DSM‐IV alcohol dependence, the fit of the model to the data was significantly improved by the addition of a variable indicating respondents'difficulty answering the usual drinking questions. Using this information in the development of alcohol consumption questions may provide more precise estimates of the risk from alcohol consumption to outcomes such as alcohol dependence.
Moderate, Long‐Term, Alcohol Consumption Potentiates Normal, Age‐Related Spatial Memory Deficits in Rats
Authors: Baird T. J. , Vanecek S. A. , Briscoe R. J. , Vallett M. , Carl K. L. , Gauvin D. V.
Published: May 2006

A modified “Samson” sucrose fading procedure was used to establish voluntary consumption of a 20% ethanol (EtOH) solution in male Sprague‐Dawley rats for 18 consecutive months. Intakes were stable over the life span, and corresponded to the moderate to high levels of intake typically observed in human “social” drinkers and alcoholics. The Morris Water Maze (WM), Olton Radial Arm Maze (RM), and a “balance beam” test were used to assess the effects of alcohol and aging on spatial memory and motor function. Aged EtOH‐consuming rats (AGED/ALC) demonstrated impaired task acquisition, relative to aged controls (AGED), not reaching criterion performance in either spatial memory task even when given four additional days of training. AGED/ALC rats scored significantly lower on percent correct out of the first eight arm entries, and committed more perseverative errors in the RM. There were no significant performance differences between AGED and AGED/ALC rats on a balance beam test of fine motor coordination and equilibrium, suggesting that deficits observed in the RM and WM were not related to differential motor functioning. These results demonstrated that long‐term, moderate, oral self‐administration of EtOH, within the range typically consumed by humans, had adverse effects on spatial memory in rats, and that such a pattern of EtOH consumption seemed to exacerbate the decline in cognitive functioning associated with normal aging.
Analysis of the 5‐HT2 Receptor Ligands Dimethoxy‐4‐indophenyl‐2‐aminopropane and Ketanserin in Ethanol Discriminations
Authors: Szeliga Kendall T. , Grant Kathleen A.
Published: May 2006

Previous studies have suggested a modulatory role of the 5‐HT2 receptor system in the behavioral effects of ethanol. The present study examined the discriminative stimulus effects of the 5‐HT2A/2C agonist (–)‐dimethoxy‐4‐indophenly‐2‐aminopropane (DOI) and the 5‐HT2A antagonist ketanserin in rats trained to discriminate either 1.5 g/kg of ethanol from water (intragastrically, n= 7) or 2.0 g/kg of ethanol from water (intragastrically, n= 8). In substitution tests, neither DOI (0.3 to 1.0 mg/kg, ip) nor ketanserin (3.0 to 17.0 mg/kg, ip) produced discriminative stimulus effects similar to either training dose of ethanol, although decreases in rates of responding were significant at the highest doses tested. Likewise, when given in combination with ethanol, neither 5‐HT2 ligand shifted the ethanol‐dose response determination in either the 1.5 or 2.0 g/kg ethanol training groups. DOI in combination with ethanol did not alter rates of responding, whereas ketanserin in combination with ethanol significantly decreased response rates. Thus, the 5‐HT2A receptor ligands do not appreciably affect the discriminative stimulus effects of ethanol, in contrast to previous results with 5‐HT1B ligands.
Mouse Strain Differences in Oral Operant Ethanol Reinforcement under Continuous Access Conditions
Authors: Risinger Fred O. , Brown Miriam M. , Doan Angela M. , Oakes Roger A.
Published: May 2006

The present experiment examined ethanol setf‐administration in C57BL/6J (C57) and DBA/2J (DBA) mice using a continuous access operant procedure. Adult male C57 and DBA mice were initially trained to perform a lever press response to obtain access to 10% w/v sucrose solution. Subsequently, the mice were placed in operant chambers on a continuous (23 hr/day) basis with access to food (FR1), 10% v/v ethanol (FR4), and water from a sipper tube. C57 mice displayed greater rates of responding on the ethanol‐associated lever compared with DBA mice. Responding on the food lever was the same in both strains, but DBA mice consumed greater amounts of water. C57 mice consistently displayed both prandial and nonprandial episodes (bouts) of ethanol responding. DBA mice did not respond for ethanol in bouts. Following 50 consecutive sessions, ethanol concentration was altered every 5 days. Response patterns were determined using 0, 5, 10, 20, and 30% v/v ethanol concentrations. C57 mice displayed concentration‐dependent responding on the ethanol lever showing that ethanol was functioning as an effective reinforcer in this strain. In contrast, responding on the ethanol lever by DBA mice did not change as a function of ethanol concentration. Saccharin (0.2% w/v) was subsequently added to the ethanol mixture, and responding was examined at 0, 5, 10, and 20% ethanol concentrations. Overall, ethanol lever responding was increased in both strains. As before, C57 mice showed higher levels of ethanol responding, compared with DBA mice. C57 mice also showed higher responding for saccharin alone. These results are consistent with findings that suggest orally administered ethanol is a more effective reinforcer in C57 mice than in DBA mice. Furthermore, C57 mice engage in ethanol‐reinforced responding over a broader range of conditions than DBA mice.
Ethanol Induced Changes in Superoxide Anion and Nitric Oxide in Cultured Microglia
Authors: Colton Carol A. , Snell‐Callanan Julie , Chernyshev Olga N.
Published: May 2006

Induction of oxidative stress has been implicated as a causative factor in fetal alcohol syndrome although the source of reactive oxygen species is not clear. One potential source is the microglia, the CNS macrophage, which generate superoxide anion as part of their normal immune function. Our data indicate that chronic exposure to ethanol alters the function of cultured neonatal hamster microglia by inducing superoxide anion production in resting (nonstimulated) cells. An increase in superoxide anion was seen at 24 or 48 hr of ethanol treatment but was not seen during acute exposures of up to 3 hr. This effect was dose dependent and was maximal at 20 mM ethanol. Treatment with ethanol did not directly activate the respiratory burst seen in microglia and did not act as a priming agent to enhance phorbol‐ester‐stimulated superoxide anion production. Lipopolysaccharide‐mediated priming of microglial superoxide anion production was also not affected by exposure to 20 mM ethanol for 24 hr. Ethanol treatment, however, did depress nitric oxide (NO) levels in hamster microglia which had been stimulated to produce NO by polyinosinic:polycytidylic acid (poly I:C). Uptake of latex beads was increased by 24 hr of exposure to ethanol. The overall action of ethanol on neonatal hamster microglia is to shift the balance between the production of superoxide anion and NO. Because NO is protective to mammalian cells, these changes predict that oxidative stress in the CNS would be enhanced.
Methods for Health Risk Assessment of Chemicals: Are They Relevant for Alcohol?
Authors: Victorin Katarina , Haag‐Grönlund Marie , Skerfving Staffan
Published: May 2006

A description is given of the principles used for toxicological risk assessment of food additives and environmental contaminants. The terminology is not generally accepted. Hazard identification is to identi whether a substance may cause toxic effects in man. Dose‐response assessment is to understand the relationship between exposure and various toxic effects. The shape of dose‐response curves is discussed. For most effects (including nongenotoxic carcinogens), a threshold is assumed, under which there is no risk. For genotoxic compounds, no such threshold is assumed. For substances with a threshold, an uncertainty factor is applied to the no‐observed‐adverse‐effect level or the lowest‐observed‐adverse‐effect level, to arrive at an acceptable or tolerable daily intake. In the case of ethanol, some of these principles of toxicological risk assessment may be used and based on epidemiological dose‐response data. The critical effects are liver effects, fetal damage, and cancer. All of these effects may be assumed to have thresholds. Possible uncertainty factors are discussed. However, because of the decreased risk of cardiovascular effects at low/moderate intakes and the fact that alcohol intake is a lifestyle factor, it is doubtful whether the application of a no‐observed‐adverse‐effect level/uncertainty factor approach—as used for food additives and environmental pollutants, to which there is unavoidable exposure—is really applicable or meaningful for ethanol.
Risk Perception of Alcohol Consumption
Authors: Sjöberg Lennart
Published: May 2006

A review is given of general principles of risk perception, with some historical highlights of the field. It is pointed out that the risk target is of great importance (i.e., that personal risks are almost always perceived as smaller than risks to others). The implications of perceived personal and general risks are different, with general risks being more important for policy attitudes. The concepts needed to investigate risk perception are different, depending on what kind of risk is studied. Alcohol consumption risks give rise to uniquely strong risk denial, closely tied to control notions. Consumption of alcohol is found to be related to personal alcohol risk in a positive manner; the larger the consumption, the larger is the perceived risk. However, no such relationship is found for general risk. At the societal level, alcohol was the most common explanation that people gave for the prevalence of violence.
The Significance of Alcohol for Violence and Accidents
Authors: Brismar Bo , Bergman Bo
Published: May 2006

For almost all types of accidents and violence, there is a causal relationship with alcohol intoxication or alcohol abuse. Alcohol may have significance as a risk factor for the perpetrator (culprit, car driver, etc.), as well as for the victim. This is especially clear in cases of violence and assault. Younger males are overrepresented in much of the data that shows causal relationships. A clear dose‐response association can be seen in many accident cases concerning both accident risk and severity. The correlation is not as clear in cases of violence. However, the causal relationships between alcohol and accidents or violence may be difficult to evaluate. Factors such as the abuse of other drugs, unemployment, and other sociodemo‐graphic factors must be taken into account. The populations studied are often selected, e.g., from emergency departments, pathology units (postmortem data), or related to those epidemiological studies based on interviews. There is often a lack of relevant control data.
Longitudinal Changes in Predictor Profiles of Abstinence from Alcohol Use Among Male Veterans
Authors: Curran Geoffrey M. , Booth Brenda M.
Published: May 2006

We examined variations in predictors of abstinence depending on the timing of follow‐up after alcohol treatment using data from 298 males who completed inpatient treatment at a Midwestern VA Alcoholism Treatment Unit. Our findings indicate fluidity of abstinence and relapse across subjects in the 12 months posttreatment. We also found substantial shifts in the salience of predictors even across short periods of continued abstinence. Methodologically, these findings demonstrate the importance of multiple and closely spaced follow‐up points in outcomes research. Substantively, our data support previous findings concerning the impact of increased medical severity, positive employment history, and depression on treatment outcomes.
Glial Cell Loss in the Hippocampus of Alcoholics
Authors: Korbo Lise
Published: May 2006

Alcohol abuse is often accompanied by cognitive impairment. Memory and concentration problems, especially, are described in neuropsychologically tested abstinent alcoholics. This impairment seems to be reversible, because a neuropsychological study has reported that after >5 years of abstinence, former alcoholics performed normally compared with a control group. The neuropathological correlate to the cognitive impairment associated with alcoholism is still under debate. Hippocampus is an area of the brain primarily involved in learning and memory, and the hippocampus is affected in several demential diseases. Over recent years, it has become evident that the glial cells in the brain, especially the astrocytes, play a central part in many activities that are critical to the normal functions of the brain. The total number of neuron and glial cells in the hippocampus was estimated in five severely affected alcoholics and five controls with an unbiased stereological technique: the optical fractionator. A statistically significant loss of 37% of the glial cells was found globally in the hippocampus of the alcoholics compared with controls. A reduction of astrocytes and oligodendrocytes and, to a lesser degree, microglial cells accounted for this loss. No loss of neurons was found in the hippocampus from alcoholics. The loss of glial cells and the potential for regeneration of these cells after cessation of alcohol abuse is discussed in the light of the results of clinical studies of former alcoholics.
Gamma‐Hydroxybutyric Acid (GHB) in the Treatment of Alcohol Withdrawal Syndrome: A Randomized Comparative Study Versus Benzodiazepine
Authors: Addolorato Giovanni , Balducci Giuseppe , Capristo Esmeralda , Attilia Maria L. , Taggi Franco , Gasbarrini Giovanni , Ceccanti Mauro
Published: May 2006

Background: Benzodiazepine has been shown to be one of the most effective class of drugs in the management of alcohol withdrawal syndrome (AWS). Gamma‐hydroxybutyric acid (GHB) has recently been introduced in the treatment of alcohol problems, including AWS. At present there are no comparative studies between benzodiazepines and GHB in AWS treatment. The aim of the present randomized, controlled, single‐blind study was to evaluate the efficacy and safety of GHB compared with diazepam in the treatment of AWS.

Methods: Sixty alcoholics affected by AWS were enrolled in the study. Diazepam (0.5–0.75 mg/kg body weight for 6 days, tapering the dose 25% daily until day 10) was administered orally to 30 patients (25 males, 5 females; mean age 44.3 ± 10.9 years); GHB (50 mg/kg body weight for 10 days) was administered orally to 30 patients (26 males, 4 females; mean age 41.7 ± 10.4 years). The Clinical Institute Withdrawal Assessment for Alcohol‐revised scale (CIWA‐Ar) was used to evaluate the AWS physical symptoms. The State Anxiety Inventory test for current anxiety assessment and the Zung self‐rating Depression Scale for current depression assessment were performed.

Results: Eight patients (26.6%) in the diazepam group and 4 patients (13.3%) in the GHB group dropped out. Both treatments were effective in reducing AWS. No significant difference was found between the groups in CIWA‐Ar total score at baseline and at the different times of observation. Considering the CIWA‐Ar subscore and Zung scale, a significant reduction of anxiety on day 4 (p< 0.02), agitation on day 5 (p< 0.02) and time of recovery of depression on day 5 (p< 0.02) was observed in the GHB group with respect to the diazepam group. Drowsiness and vertigo developed after initial drug administration in the GHB (19.2%) and diazepam (36.4%) groups and quickly resolved in both groups.

Conclusions: GHB is as effective in the management of AWS as benzodiazepine and it seems to be quicker in reducing anxiety, agitation, and depression. Both drugs are safe and well‐tolerated in AWS management.
Ethanol‐Induced Alterations in Neurotrophin Expression in Developing Cerebellum: Relationship to Periods of Temporal Susceptibility
Authors: Heaton Marieta Barrow , Mitchell J. Jean , Paiva Michael
Published: May 2006

Background: The developing cerebellum has been shown to be profoundly affected by exposure to ethanol and to exhibit a temporal pattern of vulnerability. Cerebellar Purkinje cells are particularly susceptible to ethanol on postnatal day 4 or day 5 (P4‐5), whereas this population is much less vulnerable to similar ethanol insult slightly later in the postnatal period (P7‐9). The purpose of the study was to determine whether differential alterations in neurotrophic factors might be associated with this differential susceptibility.

Methods: Neonatal rats were exposed to ethanol via vapor inhalation, and enzyme‐linked immunoabsorbent assays were subsequently conducted to assess cerebellar nerve growth factor, brain‐derived neurotrophic factor, and neurotrophin‐3 protein content. These analyses were made after ethanol exposure during the period of maximal cerebellar ethanol sensitivity (postnatal days 4‐5 [P4‐5]), during a period of much lower sensitivity (P7‐8), and during the entire “brain growth spurt” (P4‐10).

Results: These determinations revealed a significant ethanol‐induced decrease in cerebellar nerve growth factor after exposure on P4‐5 but not after exposure on P7‐8 or P4‐10. No significant changes in brain‐derived neurotrophic factor or neurotrophin‐3 were found with any of the exposure paradigms.

Conclusions: These results suggest that alterations in nerve growth factor, which has previously been shown to support cerebellar Purkinje and granule cells, may be a mechanism contributing to the early ethanol susceptibility within these neuronal populations.