bluuebunny/crossref_metadata_2025 huggingface dataset:
The Portacaval‐Shunted Rat: A New Model for the Study of the Mechanisms Controlling Voluntary Ethanol Consumption and Ethanol Preference?
Authors: de Waele Jean‐Pascal , Audet Robert M. , Rose Christopher , Butterworth Roger F.
Published: May 2006

Portacaval anastomosis (PCA) is a surgical procedure whereby blood from the portal vein is shunted into the inferior vena cava. PCA in the rat results in a significant increase (from 0.77 ± 0.26 to 3.51 ± 0.37 g of ethanol/kg/day) in voluntary ethanol consumption in a free‐choice paradigm between water and 5% ethanol solution. After PCA surgery, increased voluntary ethanol consumption starts abruptly at 6 to 7 days and is maintained for > 28 weeks. Voluntary ethanol consumption in rats after PCA results in blood ethanol levels up to 158 mg%. After PCA, the ethanol preference ratio (defined as the percentage of total fluid intake constituted by ethanol) increased from 19 ± 2% to 78 ± 2% (p < 0.001). Administration of the nonselective opioid receptor antagonist naloxone (5 mg/kg, sc) resulted in a significant 6‐fold attenuation of voluntary ethanol consumption by rats with PCA, an effect that was not mediated by an effect on locomotor activity. These findings, together with previous reports of widespread alterations of the μ‐ and δ‐opioid receptors in the brain after PCA, suggest that increased voluntary ethanol consumption and ethanol preference in PCA rats may result from activation of the endogenous opioid system. Preliminary studies suggest that rats with PCA manifest behavioral signs consistent with the development of dependence. The portacaval‐shunted rat may provide a useful preparation for the study of mechanisms, in particular those involving the liver, implicated in the development of increased voluntary ethanol consumption and ethanol preference.
Glycerol Increases Content and Activity of Human Cytochrome P‐4502E1 in a Transduced HepG2 Cell Line by Protein Stabilization
Authors: Yang Ming‐Xue , Cederbaum Arthur I.
Published: May 2006

Glycerol is widely used to stabilize cytochrome P‐450 and prevent its transformation to cytochrome P‐420. The effect of glycerol on the content and activity of human cytochrome P‐4502E1 (CYP2E1) in a HepG2 cell line that stably and constitutively expresses this P‐450 was evaluated by immunoassays and oxidation of P‐nitrophenol. Addition of 100 to 200 mM glycerol to the culture medium resulted in a 2½‐ to 3‐fold increase in the content and activity of CYP2E1 in microsomes isolated from the cells. Increases could be observed within 4 to 8 hr after addition of glycerol to the culture medium. Glycerol had no effect on the content of cytochrome b5 or activities of NADPH‐cytochrome P‐450 reductase or NADH‐cytochrome b5 reductase. Upon the addition of cycloheximide to stop protein synthesis, CYP2E1 content and activity decreased with apparent half‐lives of 6 and 4 hr, respectively. Glycerol prevented or decreased this loss of CYP2E1 content and activity. Labeling CYP2E1 with [35S]methionine, followed by pulse‐chase experiments with cold methionine and immunoprecipitation of CYP2E1 indicated a half‐life for CYP2E1 of ∼3 hr. Glycerol increased the half‐life to ∼11 hr. Stabilization of CYP2E1 protein by glycerol was not additive or synergistic with the increase of CYP2E1 by ethanol or 4‐methylpyrazole, suggesting that all three agents elevate CYP2E1 by a similar type of mechanism in this model. These results indicate that glycerol can interact with human CYP2E1 to stabilize it against proteolytic degradation, increasing the half‐life of the enzyme and thereby elevating the content and activity of CYP2E1.
Chronic Ethanol Downregulates Gal‐β‐l,4GlcNAc α2,6‐Sialyltransferase and Gal‐β‐l,3GlcNAc α2,3‐Sialyltransferase mRNAs in Rat Liver
Authors: Rao Manjunath N. , Lakshman M. R.
Published: May 2006

We have previously demonstrated that chronic ethanol specifically decreases the hepatic level and rate of synthesis of 2,6‐sialyltrans‐ferase (2,6‐ST). To understand its mechanism of action, effects of 8 weeks of chronic ethanol feeding on the expression of sialyltrans‐ferase (ST) genes in rat liver and kidneys were determined by North‐emblot analysis of ST mRNAs. It was found that, compared with the pair‐fed control rats, the percentage decreases in ST mRNAs in the ethanol‐fed group were as follows: liver—Gal‐β‐1,4GlcNAc α2,6‐ST (2,6‐ST): 59% (p < 0.001); liver—Gal‐β‐1,3GlcNAc α2,3‐ST (2,3‐ST): 32% (p < 0.01); and kidneys—2,6–ST: 5% (NS). In contrast, glyceral‐dehyde‐3‐phosphate dehydrogenase mRNA in both liver and kidneys was unaffected by the same ethanol treatment. Taken together, these results demonstrate that chronic ethanol downregulates the expression of 2,6‐ST and 2,3‐ST genes in rat liver.
Alcohol, Cytokines, and Estrogen in the Control of Bone Remodeling
Authors: Kimble Robert B.
Published: May 2006

Alcohol has been identified as a risk factor for the development of osteoporosis. Chronic alcohol abuse has been shown to decrease bone mass and increase the incidence of fractures. Although the exact mechanism by which alcohol influences bone metabolism is not clear, it is likely a combination of both direct and indirect effects on bone cells. Alcohol has the potential to alter bone metabolism indirectly through its effects on gonadal hormones and through the secretion of cytokines shown to be critical factors in postmeno‐pausal osteoporosis. Data are summarized here demonstrating that interleukin‐1 and tumor necrosis factor play a direct causal role in the bone loss due to estrogen deficiency. In addition, studies are cited showing that these same cytokines are produced in alcohol‐induced liver disease with the potential to enhance bone loss in post‐menopausal women and in male patients. Although there are not yet data directly supporting the role of cytokines in bone loss due to alcohol consumption, the studies presented herein are intended to stimulate further research on the role of alcohol, estrogen, and cytokines in osteoporotic bone loss.
Effects of Dihydropyridines on the Components of the Ethanol Withdrawal Syndrome: Possible Evidence for Involvement of Potassium, as Well as Calcium?
Authors: Watson W.P. , Little J.J.
Published: May 2006

Comparison was made of the ability of two dihydropyridine calcium channel antagonists, nitrendipine and felodipine, to prevent a range of signs of ethanol withdrawal. The increases in handling‐induced behavior seen in mice during withdrawal from chronic ethanol treatment were prevented by administration of nitrendipine, 50 mg/kg, but not by, felodipine, 10 mg/kg, a dose that caused a similar displacement of dihydropyridine binding in central nervous system tissue, in vivo and in vitro. A higher dose of felodipine, 20 mg/kg, also had no effects. Nitrendipine, but not felodipine, prevented audio‐genic seizures during the withdrawal phase. Similarly, nitrendipine prevented both the decrease in thresholds for N‐methyl‐dl‐aspartate seizures and the increase in thresholds for convulsions due to 4‐aminopyridine, which were seen during the withdrawal period, while felodipine did not alter either of these changes. Withdrawal from the ethanol chronic treatment increased the thresholds to seizures produced by intravenous aminophylline; this change was also prevented by nitrendipine. The significance of this increase in thresholds was lost after felodipine administration. In naive mice (not treated with ethanol) the doses of nitrendipine and felodipine used in the withdrawal studies were tested against the effects of convulsant drugs. Both dihydropyridines increased, to similar extents, the thresholds for seizures produced by bicuculline, pentylenetetrarol, and by N‐methyl‐dl‐aspartate. The thresholds for aminophylline were unaltered by either dihydropyridine. In contrast, the thresholds for seizures due to 4‐aminopyn'dine in the naive animals were not changed by felodipine, but were increased by nitrendipine. The results suggest that changes in potassium, as well as calcium, may possibly be involved in some of the stages of the ethanol withdrawal syndrome. Key Words: Ethanol Withdrawal, Dihydropyridine, Calcium, Potassium, Seizures.
Ethanol, Flunitrazepam, and Pentobarbital Modulation of GABAA Receptors Expressed in Mammalian Cells and Xenopus Oocytes
Authors: Harris R. Adron , Mihic S. John , Brozowski Susan , Hadingham Karen , Whiting Paul J.
Published: May 2006

GABAA receptors composed of human α1β2γ2L, α1β2γ2S, α1 β3γ2S, α6β3γ2S, and αβ3γ3 subunits as well as bovine α1 β1 γ2L and α1β1 subunits were stably expressed in mammalian L(tk−) cells and transiently expressed in Xenopus oocytes. Effects of muscimol, ethanol, flunitrazepam, and pentobarbital on receptor function were compared for the two expression systems using a 36CI− flux assay for cells and an electrophysiological assay for oocytes. Muscimol activated all receptors in both expression systems but was more potent for L(tk−) cells than oocytes; this difference ranged from 2.6–to 26–fold, depending upon subunit composition. The most pronounced differences between receptors and expression systems were found for ethanol. In L(tk−) cells, low (5–50 mM) concentrations of ethanol potentiated muscimol responses only with receptors containing the γ2L subunit. In oocytes, concentrations of 30–100 mM produced small enhancements for most subunit combinations. Flunitrazepam enhanced muscimol responses for all receptors except α6β3γ2S and α1β1, and this enhancement was similar for both expression systems. Pentobarbital also enhanced muscimol responses for all receptors, and this enhancement was similar for L(tk−) cells and oocytes, except for α6β3γ2S where the pentobarbital enhancement was much greater in oocytes than cells. The α6β3γ2S receptors were also distinct in that pentobarbital produced direct activation of chloride channels in both expression systems. Thus, the type of expression/assay system markedly affects the actions of ethanol on GABAA receptors and also influences the actions of muscimol and pentobarbital on this receptor. Differences between these expression systems may reflect posttranslational modifications of receptor subunits.
The Nitric Oxide Synthase Inhibitor l‐NAME (Nω‐Nitro‐L‐Arginine Methyl Ester) Does Not Produce Discriminative Stimulus Effects Similar to Ethanol
Authors: Green Kristen L. , Gatto Gregory J. , Grant Kathleen A.
Published: May 2006

N‐methyl‐d‐waspartate (NMDA) antagonists substitute for the discriminative stimulus effects of ethanol, indicating that a component of ethanol's behavioral activity is produced via blockade of NMDA receptor/channel function. Recently, it has been reported that ethanol inhibits NMDA‐stimulated nitric oxide synthase (NOS) activity in cortical neurons, thereby decreasing the formation of nitric oxide (NO) in the brain. These findings suggest that some of the behavioral effects of ethanol may be mediated by inactivation of NOS. The present study examined the role of NO formation in mediating the discriminative stimulus effects of ethanol. To address this hypothesis, an NOS inhibitor, Nω‐nitro‐L‐arginine methyl ester (l‐NAME) and an NMDA competitive antagonist, (d)‐4–(3‐phosphonoprop‐2‐enyl)piperazine‐2‐carboxylic acid (CPPene), were administered to two groups of rats trained to discriminate 1.5 g/kg of ethanol (n= 6) or 2.0 gkg (n= 7) of ethanol from water. After training, dose ranges of CPPene (3 to 17 mg/kg, ip) and l‐NAME (100 to 780 mg/kg, ip) were tested for ethanol‐like effects. l‐NAME was also tested under a range of pretreatment times (20,60,90, and 120 min). An additional group of rats trained to discriminate 2.0 g/kg (n = 7) of ethanol from water was also tested with CPPene (10 mg/kg, ip) and l‐NAME (100 and 300 mg/kg, ip) to verify data gathered from the original 2.0 gkg of ethanol group tested with l‐NAME after a 20‐minute pretreatment. Although overall, 17 of 20 animals trained to discriminate ethanol from water exhibited complete substitution of CPPene for ethanol, l‐NAME, without affecting response rates, did not consistently substitute for either 1.5 g/kg or 20 g/kg of ethanol. These results indicate that inhibition of NO formation is less effective than direct NMDA receptor antagonism in producing ethand‐like discriminative stimulus effects.
Hearing, Speech, Language, and Vestibular Disorders in the Fetal Alcohol Syndrome: A Literature Review
Authors: Church Michael W. , Kaltenbach James A.
Published: May 2006

Fetal alcohol syndrome (FAS) is characterized in part by mental impairment, as well as craniofacial and ocular anomalies. These conditions are traditionally associated with childhood hearing disorders, because they all have a common embryonic origin in malformations of the first and second branchial arches, and have similar critical periods of vulnerability to toxic insult. A review of human and animal research indicates that there are four types of hearing disorders associated with FAS. These are: (1) a developmental delay in auditory maturation, (2) sensorineural hearing loss, (3) intermittent conductive hearing loss due to recurrent serous otitis media, and (4) central hearing loss. The auditory and vestibular systems share the same peripheral apparatuses (the inner ear and eighth cranial nerve) and are embryologically and structurally similar. Consequently, vestibular disorders in FAS children might be expected. The evidence for vestibular dysfunction in FAS is ambiguous, however. Like other syndromes associated with craniofacial anomalies, hearing disorders, and mental impairment, FAS is also characterized by a high prevalence of speech and language pathology. Hearing disorders are a form of sensory deprivation. If present during early childhood, they can result in permanent hearing, language, and mental impairment. Early identification and intervention to treat hearing, language, and speech disorders could therefore result in improved outcome for the FAS child. Specific recommendations are made for intervention and future research.
Frontal Lobe Volume Loss Observed with Magnetic Resonance Imaging in Older Chronic Alcoholics
Authors: Pfefferbaum Adolf , Sullivan Edith V. , Mathalon Daniel H. , Lim Kelvin O.
Published: May 2006

This study used magnetic resonance imaging to quantify the extent and pattern of tissue volume deficit and cerebrospinal fluid volume enlargement in younger versus older chronic alcoholics relative to normal controls. In the present analysis, we divided our previously reported group of 62 alcoholic men into a younger group (n = 33, age mean = 37.5 ± 4.5, and range = 26 to 44 years) and an older group (n= 29, age mean = 52.7 ± 6.0, and range = 45 to 63 years) to examine whether, in addition to extent, the two age groups differed in pattern of tissue type and regional brain volume abnormalities quantified with magnetic resonance imaging. Brain volumes were adjusted for normal variation in head size and age established from a group of healthy controls and were expressed as Z‐scores. The younger group had significant cortical gray, but not white, matter volume deficits and sulcal and ventricular enlargement relative to age‐matched controls. The older group had volume deficits in both cortical gray and white matter and sulcal and ventricular enlargement that significantly exceeded the younger alcoholic group. An analysis of six cortical regions revealed that, although both age groups had gray matter volume deficits throughout the cortex, the older alcoholic group had a selectively more severe deficit in prefrontal gray matter relative to the younger alcoholic group. Similarly, the cortical white matter volume deficit in the older alcoholics was especially severe in the prefrontal and frontal regions. The differences in brain dysmorphology between the two alcoholic groups cannot easily be attributed to potential alcohol history differences typically related to age because the two groups had similar disease durations and amounts of lifetime alcohol consumption. These results provide in vivo evidence that the frontal lobes are especially vulnerable to chronic alcoholism in older men.
Association between Alcohol Use and Smoking in Adolescent and Young Adult Twins: A Bivariate Genetic Analysis
Authors: Koopmans Judith R. , van Doornen Lorenz J.P. , Boomsma Dorret I.
Published: May 2006

The association between alcohol use and smoking was examined in a large population‐based sample of Dutch twins consisting of three age groups; young adolescent twins aged 12–14 years (n= 650 twin pairs), 15–16‐years‐old adolescent twins (n= 705 twin pairs), and young adult twins aged 17–25 years (n= 1266 twin pairs). For all three age groups, alcohol use and smoking were correlated (r= 0.5–0.6). Adolescents and young adults who smoked were more likely to drink alcohol than nonsmokers. The relation between alcohol use and smoking was also found within a twin pair; alcohol use in one twin was correlated with smoking in the cotwin. This finding suggested that familial factors contribute to the association between alcohol and tobacco use. With a bivariate genetic model, it was examined to what extent the comorbidity was due to genetic and environmental factors that predispose to both alcohol use and smoking. The genetic analyses showed that the underlying factors that influence alcohol and tobacco use and cause their association were different for adolescent and young adult twins. Initiation of alcohol use and smoking in adolescents (aged 12–16 years) was substantially influenced by the same shared environmental features. Alcohol and tobacco use in young adults were associated due to the same genetic risk factors.
Voices of the Afflicted
Authors: Erickson Carlton K.
Published: May 2006

Over the past 10 years, I have been privileged to conduct educational forums for audiences containing many recovering alcoholics or otherwise chemically dependent persons. In these forums about the addictive diseases and their treatment and research possibilities, significant interaction with the audience members occurs. During these interactions, certain anecdotal phenomena seem to predominate. The repetitive nature of these reports suggests the need for systematic investigation. As with editorial comments in major medical journals, obsetved phenomena and unanswered questions from those afflicted can be valuable in the generation of testable hypotheses. Pehaps the ideas presented herein will be useful in the development of future research on alcohol abuse and alcohol dependence.
No Electrocortical Evidence of Automatic Mismatch Dysfunction in Children of Alcoholics
Authors: van der Stelt Odin , Gunning W. Boudewijn , Snel Jan , Kok Albert
Published: May 2006

The mismatch negativity (MMN) event‐related potential (ERP) component is an automatic, attention‐independent brain response to auditory stimulus change, which has been reported to be smaller in alcoholics relative to nonalcoholic controls. To determine whether MMN decrements might be a trait marker of alcoholism that is also present in nonalcoholic individuals at high risk for developing alcoholism, we investigated MMN in 9‐to 18‐year‐old children of alcoholics (n= 20) and control children (n= 20) in three different stimulus conditions using a passive auditory oddball paradigm. There were no statistically significant between‐group differences observed in amplitude, scalp topography, and peak latency of MMN. These findings, if replicated, suggest that reported MMN decrements in alcoholics most likely represent a state marker, and not a trait marker, of alcoholism. Also, inasmuch as another ERP component, the P300, is attention‐dependent and reported to be smaller in children of alcoholics, the present results implicate that deviations in attentive, but not in automatic, information processing are associated with alcoholism vulnerability.
Infants' Suckling Responses to the Flavor of Alcohol in Mothers' Milk
Authors: Mennella Julie A.
Published: May 2006

Contrary to medical folklore, previous research has demonstrated that alcohol consumption by lactating women diminished milk intake by their infants during breast feeding. To determine whether this decrease in milk consumption was due to the infants responding to the altered flavor of the milk that also resulted, we evaluated the infants' intake and sucking responses to alcohol‐flavored human milk outside of the context of breast feeding, thereby separating the changes due to the infants' response to the flavor from any other changes that could also result from acute maternal alcohol consumption such as alterations in milk ejection or the composition of milk. The testing procedure consisted of a two‐bottle preference test that was composed of four, 60–sec trials in which the mother's milk flavored with alcohol was alternated with the mother's milk alone in an ABBA or BAAB design. Attached to the nipple of each bottle was a transducer that responded to pressure changes produced by the infants' suckling. There was no suppression of sucking or intake in response to the ethanol‐flavored milk. Rather, the infants consumed significantly more and sucked more frequently when drinking the alcohol‐flavored milk compared with the unaltered milk. That experience with the flavor of alcohol in mothers' milk modified the infants' responses to alcohol flavor is suggested by the relationship between the reported frequency of mothers' drinking during lactation and the infants' rhythm and frequency of sucking when feeding the alcohol‐flavored milk. These findings indicate that infants can readily detect the flavor of alcohol in mother's milk but that the decrease in consumption at the breast after maternal alcohol consumption is apparently not due to the infants rejecting the flavor of alcohol in their mothers' milk.
Comparison of the Alcohol Dependence Scale and Diagnostic Interview Schedule in Homeless Women
Authors: Chantarujikapong Sunanta I. , Smith Elizabeth M. , Fox Louis W.
Published: May 2006

The Alcohol Dependence Scale (ADS) is a 25 item self‐report instrument designed to evaluate the degree of severity of alcohol dependence. Although previous studies have reported on the validity of the ADS, no studies using the ADS have been done on the homeless population, a special and rapidly growing population. To assess the utility of the ADS in a population of homeless, substance‐abusing women, the ADS questionnaire was compared with the DSM‐III‐R alcohol use disorder diagnosis as measured by the Diagnostic Interview Schedule (DIS). Both the ADS and the DIS were administered to 149 homeless, substance‐abusing women by trained, lay interviewers. There was good agreement between the ADS and the past‐year DIS diagnosis of alcohol use disorder. The level of agreement between the ADS and DIS, as well as sensitivity and specificity, for various ADS cutoff scores are reported to facilitate selection of cutoff scores by clinicians and future researchers.
Effect of Apolipoprotein E Phenotype on Plasma Lipids and Lipoproteins in Alcohol Abusers
Authors: Liinamaa M. Johanna , Kervinen Kari , Hannuksela Minna L. , Kesaniemi Y. Antero , Savolainen Markku J.
Published: May 2006

The effect of apolipoprotein (apo) E phenotype on the concentration and chemical composition of plasma lipoproteins was studied in 73 male alcohol abusers and 50 male controls. The apo E phenotype was confirmed by genotyping to avoid possible effects of posttrans‐lational modifications by alcohol or its metabolites. The lipid and protein concentrations of both intermediate density lipoprotein and low density lipoprotein were lower among the alcohol abusers than among the controls, those with E4 having the highest low density lipoprotein masses in both groups. In the alcohol abusers with E4 only the high density lipoprotein (HDL)‐2 lipid and protein concentrations were higher than in the controls with respective phenotype group, whereas both HDL2 and HDL3 were higher in alcohol abusers with other apo E phenotypes, suggesting that apo E modulates the alcohol‐effect on HDL subfractions. This effect was not explained by cholestetyl ester transfer protein activity, which was lower in the alcohol abusers (25 to 34%, p < cOm), but without significant difference between the apo E groups. In conclusion, alcohol abuse does not cause major changes in the electric charge of apo E in humans. Heavy alcohol intake seems to have a beneficial effect on plasma lipids and lipoproteins, regardless of the apo E phenotype, but the modulation of the alcohol‐induced increase in HDL by apo E phenotype should be taken into consideration in future studies. Key Words: Alcohol, Apolipoprotein E, HDL, LDL, VLDL.
Decreased Measures of Experimental Anxiety in Rats Bred for High Alcohol Preference
Authors: Möller Christian , Wiklund Lisa , Thorsell Annika , Hyytiá Petri , Heilig Markus
Published: May 2006

A prevalent notion holds that acute anti‐anxiety actions of ethanol are important for the reinforcing properties of this drug, and might predispose individuals with pre‐existing anxiety disorders for developing ethanol dependence. This notion remains controversial, and human studies have yielded conflicting results. Ethanol dependence is likely a heterogenous disorder, and the discrepancies might be explained by a different relationship between anxiety and alcohol reinforcement in different subtypes of alcoholism. Recent results in experimental animals suggest that antianxiety actions of ethanol are important reinforcers of voluntary ethanol consumption in heterogeneous rats. Here, we examined whether the relationship is different in the AA line of rats bred for high voluntary ethanol intake. Behavior was studied in two established animal models of anxiety, a punished drinking conflict test, and the elevated plus maze. In the conflict test, the AA line displayed a markedly disinhibited behavior over a range of shock intensities, compared both with their counterpart, the ANA line, and with regular Wistar rats. On the plus maze, both AA and Wistar rats showed lower measures of experimental anxiety than ANA subjects. The phenotype of the animals was confirmed using a two‐bottle free choice alcohol drinking procedure. The disinhibited behavior and spontaneous ethanol preference of the AA line differs from what has been found in heterogeneous rats, and displays similarities to genetically transmitted type II alcoholism according to the nomenclature of Cloninger.
Effect of Exogenous GM1 on Ethanol Sensitivity in Selectively Bred Mouse Lines
Authors: Ullman M. David , Ventura Robert F. , Draski Laura J. , Deitrich Richard A. , Baker Rodney C.
Published: May 2006

Ethanol sensitive long‐sleep (LS) and ethanol resistant short‐sleep (SS) mice are lines that have been genetically selected for differential central nervous system sensitivities to the hypnotic effect of ethanol. Because they were genetically selected only for differences in sensitivity to ethanol hypnosis, biochemical and physiological differences between them are likely related to their differential ethanol sensitivity. The synaptosomal and whole brain concentration of GM1 ganglioside was previously shown to differ significantly between the lines. Further, GM1 alters membrane responses to ethanol, including a differential effect on LS and SS synaptosomal membrane disordering. Therefore, GM1 was administered intracerebroventricularly (icv) with micro‐osmotic pumps, to partially bypass the blood‐brain barrier and to test its effect on CNS sensitivity to ethanol hypnosis in LS and SS mice. In the first experiment, 3 days' infusion of GM1 (20 μg/μl, 24 μl/day), saline control and treated LS and SS mice were tested for both regaining of the righting reflex and waking brain ethanol concentration. Incorporation of 3H‐GM1 into brain membranes was verified by scintillation spectroscopy. GM1 did not alter ethanol sensitivity or brain ethanol concentration at time of waking in LS mice. Conversely, SS mice treated with GM1 were significantly more sensitive to ethanol hypnosis than saline controls as measured by the time to regain the righting reflex (“sleep time”? and waking brain ethanol concentrations. In the second experiment, GM1‐treated SS mice were again significantly more sensitive to ethanol hypnosis than saline controls. GM1 incorporation into the contralateral and ipsilateral cerebral hemispheres was determined by high‐performance liquid chromatography.
Abnormalities of Peripheral Blood T Lymphocytes and Natural Killer Cells in Alcoholic Hepatitis Persist after a 3‐Month Withdrawal Period
Authors: Laso Francisco‐Javier , Madruga José lgnacio , López Antonio , Ciudad Juana , Alvarez‐Mon Melchor , San Miguel Jesús , Orfao Alberto
Published: May 2006

Present information about the behavior of the different lymphoid subsets in alcoholic hepatitis (AH), including cells displaying cyto‐toxic activity, is scanty and contradictory. The aim of this study was to gain further insight into knowledge of the immunological abnormalities involved in AH and the possible role of ethanol (EtOH) consumption in these changes. We analyzed the distribution of a wide range of peripheral blood (PB) lymphoid subsets, both during active EtOH intake and after a 3‐month withdrawal period, using multiple stainings with monoclonal antibodies and flow cytometry, as well as natural killer (NK) cytotoxic activity. AH patients entering the study were selected strictly; only those undergoing their first episode of AH with no other lesions at liver biopsy were enrolled. Regarding the alcohol intake period, the most striking finding was a significant increase of the absolute number of PB T cells affecting both CD4+ and CD8+ lymphocytes. These changes were associated with a higher expression of T‐cell activation antigens, such as HLA DR and CD11c. Simultaneously, a significant increase in both NK cells (CD3−‐/ CD56+) and the cytotoxic T cells coexpressing the CD3 and the CD56 molecules together with an increased NK cytotoxic activity were observed. By contrast, the CD19+/CD5+ B‐cell subset was significantly decreased. No significant changes were observed with EtOH withdrawal except in CD5+ B lymphocytes, which returned to normal values. Our results show that, in AH patients, a significant expansion of both activated T cells and NK lymphocytes occurs in the PB, which is associated with an increased NK cytotoxic activity. Interestingly these abnormalities persist during the withdrawal period.
Fetal Alcohol Exposure Produces Delay‐Dependent Memory Deficits in Juvenile and Adult Rats
Authors: Nagahara Alan H. , Handa Robert J.
Published: May 2006

The effects of prenatal alcohol exposure on both behavioral and neurobiological measures may be dependent, in part, on the age of the animal. Previous evidence from our laboratory has shown a delay‐dependent memory deficit in young adult fetal alcohol exposure (FAE) rats. The present study examined the effects of FAE on an alternation task at three different ages of male rats: juvenile (days 38 to 44), young adult (days 82 to 89), and adult (days 173 to 180). In the present study, subjects were three age groups of male offspring of Sprague‐Dawley rats fed 35% ethanol‐derived calories, pair‐fed with sucrose, or control‐fed with lab chow during the last week of gestation. Subjects were food‐deprived before training and then trained in the T‐maze for food reward. Rats were trained to alternate at no delay on six sessions over 3 days. On each of the next 4 days, rats were tested for two sessions at delays of 10 sec, 30 sec, 60 sec, and then a no‐delay condition. On the final day of testing, rats were tested at the 60‐sec delay for 10 trials. No FAE effect was observed at the short delay during the training sessions; however, the adult group had a lower performance on the training sessions, compared with the other groups. In the test session, the FAE groups showed a delay‐dependent memory deficit. FAE rats in all three age groups were impaired at the 30‐sec and 60‐sec delays, compared with their control groups. However, only the juvenile FAE rats were impaired at the 10‐sec delay, compared with the control groups. The FAE groups were not impaired when tested again at no delay. These findings indicate long‐term consequences of prenatal alcohol exposure in rats on memory retention that is present up to 6 months of age. In addition, the finding that only the juvenile FAE rats showed impairment at the 10‐sec delay indicates that certain deficits may decrease as the FAE rat matures.
Effect of Chronic Ethanol Exposure on Myocardial Phosphoinositide Turnover
Authors: Piano Mariann R. , Schwertz Dorie W.
Published: May 2006

The effect of chronic ethanol consumption (2 months) on atrial contractility and the myocardial phosphoinositide signaling system was examined in rat heart. Two months of ethanol consumption was not associated with changes in heart weight‐to‐body weight ratios; however, developed twitch tension was significantly lower in the ethanol atria compared with the control atria. Cytosolic and membrane‐associated phospholipase C activity in atrial and ventricular tissue was measured and ethanol consumption was only associated with changes in ventricular cytosolic phospholipase C activity. When examining α1‐adrenergic stimulated phosphoinositide turnover in [3H]inositol radiolabeled left atria, no differences in phenylephrine (10 μM)‐stimulated inositol monophosphate, inositol bisphosphate, inositol trisphosphate, and inositol tetrakisphosphate were found between groups before or at various times after the addition of phenylephrine. It is concluded that short‐term ethanol consumption is associated with depressed contractile function, but not the development of hypertrophy or changes in α1‐adrenoreceptor‐stimulated phosphoinositide turnover.
Liver Regeneration Attenuates Increased Voluntary Alcohol Intake Evoked by the Liver Damage
Authors: Fogel W. A. , Kruk A. , Kozlowska M. , Sasiak K. , Andrzejewski W. , Maslinski C.
Published: May 2006

Liver dysfunction induced in Wistar rats either surgically (by construction of portocaval anastomosis) or chemically (by chronic administration of thioacetamide) led to increased voluntary alcohol intake. Alcohol preference could be attenuated by liver regeneration that was triggered by a two‐thirds hepatectomy done on cirrhotic rats. The brain serotonin system was activated in portocaval anastomosis rats and unchanged in thioacetamide‐treated rats, thus suggesting that serotonin is not likely to be implicated in the mecha‐nism(s) underlying development of alcohol preference in these rats. Also, tetrahydro‐p‐carboline could possibly be excluded from consideration. Neither change in the brain concentration or distribution of tetrahydrobetacarboline after long‐term treatment with thioacetamide could be found.
Acute Ethanol Effects on Focal Cerebral Ischemia in Nonfasted Rats
Authors: Zhao Yong‐Jie , Yang Guo‐Yuan , Domino Edward F.
Published: May 2006

Focal cerebral ischemia was induced in a rat model of middle cerebral artery occlusion. Three groups of adult male Sprague‐Dawley rats, given food and water ad libitum, were subjected to 4 hr of middle cerebral artery occlusion. All were given vehicle control and ethanol pretreatments intraperitoneally 1 hr before. Mean ipsilateral brain water content in the control, 2 g/kg ethanol, and 2 g/kg ethanol + insulin‐treated groups showed ischemia core: 81.1%, 82.5%, and 80.9%; intermediate zone: 81.0%. 81.9%, and 80.3%; and outer zone: 80.3%, 81.3%. and 80.1%, respectively. Brain Na+and K+content in these groups paralleled the water content. In addition to significantly (p< 0.05) more brain edema, the 2 g/kg ethanol‐treated animal group also had significant hyperglycemia. In contrast, the 2 g/kg ethanol + insulin‐treated animals were normoglycemic and had ischemic, intermediate, and outer zone Na+, K+, and CI−levels comparable with the control group (p> 0.05). These results stress the importance of measuring and controlling plasma glucose levels in the in vivo studies of the neurotoxic effects of acute ethanol.
Studies on the Time‐Course of Ethanol's Acute Effects on Skeletal Muscle Protein Synthesis: Comparison with Acute Changes in Proteolytic Activity
Authors: Reilly Matthew E. , Mantle David , Richardson Peter J. , Salisbury John , Jones Jenny , Peters Timothy J. , Preedy Victor R.
Published: May 2006

A study of the effects of ethanol on skeletal muscle protein synthesis and protease activities was carried out in young male Wistar rats (150 g) for up to 24 hr after a single intraperitoneal dose of 75 mmol of ethanol/kg of body weight. At 20 min, the mean blood ethanol levels were 448 mg/dl. This level dropped steadily to zero through the following 24 hr. Compared with pair‐fed controls, significant reductions in total protein, RNA, and DNA contents were seen only after 24 hr in all skeletal muscles studied: changes were more marked in the muscles containing large proportions of type II fibers. In plantaris muscle, the fractional rate of protein synthesis (Ks, %/day) did not fall 20 min after dosage but was reduced after 1 hr by 23% (p < 0.001), and by 63% after 24 hr, compared with control saline‐injected rats (p < 0.001). This effect was independent of dietary intake because, compared with the pair‐fed group, the 24‐hr ethanol‐treated rats still showed a 52% decrease in fractional rates of protein synthesis (p < 0.001). Smaller reductions in ks were seen in soleus muscles in response to ethanol at 24 hr (‐39%, p < 0.001). The activities of a variety of lysosomal and nonlysosomal proteases in plantaris muscle of 24‐hr treated rats were not significantly affected by ethanol. Only alanyl‐ and tripeptidyl‐aminopeptidase activities were reduced significantly (26%, p < 0.05 and 39%, p < 0.01, respectively). These results suggest that the muscle compositional changes seen over acute periods of ethanol toxicity are predominantly associated with impaired synthesis of protein and that the contribution of cellular proteolytic systems may be minimal. The effects of ethanol on skeletal muscle protein metabolism are greater in muscles containing a predominance of type II fibers than in those containing mainly type I fibers. Ethanol's effects on muscle may be influenced by hormonal changes after 24 hr, because protein synthesis is still compromised and free plasma T3 and corticosterone are altered at this time‐point.
Evaluation of Lactational Parameters after Alcohol Administration for Four Days during Early or Midlactation in the Rat
Authors: Subramanian Marappa G.
Published: May 2006

This study was conducted to examine the effects of alcohol administered for 4 days during early lactational (days 5 to 8; experiment I) or midlactational (days 9 to 12; experiment II) stage in the rat on various lactational parameters. Litter size was adjusted to eight on day 2, and dams were implanted with an atrial catheter on day 3 (experiment I) or day 7 (experiment ll). From days 5 to 8 in experiment I and days 9 to 12 in experiment II, dams were infused with saline (control rats) or alcohol in saline solutions (1.0 and 2.0 g/kg body weight; experimental groups). Blood alcohol levels (BALs) achieved after infusion of the initial doses were maintained for 4 hr daily by continuing infusion. To control for the reduced food intake in the high dose alcohol group, one control group and the group given 1.0 g/kg of body weight alcohol were pair‐fed to the 2.0 g/kg body weight alcohol group. On day 8 (experiment I) or day 12 (experiment II), pups were separated from the dam at 0800 hr, and an extension was attached to the catheter. Alcohol or saline was infused, and the BALs achieved after infusion of initial doses were maintained for 4 hr. After removal of a baseline blood sample, pups were returned to dams, and additional blood samples were taken for prolactin measurement 10, 30, 60, and 120 min after suckling started. Suckling latency and milk consumed during the 120 min of suckling were measured. Litters were weighed every other day from days 2 to 21. In both studies, suckling‐induced prolactin was inhibited by alcohol. Milk consumed by the pups during the 2‐hr period was lower for alcohol groups, compared with control. The suckling latencies were comparable among groups. Litter weights showed no alcohol dose effect. In summary, based on the results from our previous and present studies, we conclude the following: alcohol administered for 1, 4, or 8 days inhibited sucklinginduced prolactin release in lactating rats. During a 2‐hr test period after alcohol administration, milk consumed by pups was not adversely affected after alcohol administration for 1 day. Whereas, 4 or 8 days of administration had a significant effect. The adverse effect of alcohol on litter growth, however, was evident only after 8 days of alcohol administration. Thus, the detrimental effects of alcohol on different lactational parameters seem to be correlated to the duration of alcohol administration to dams during lactation.
Dexmedetomidine, Diazepam, and Propranolol in the Treatment of Ethanol Withdrawal Symptoms in the Rat
Authors: Riihioja Päivi , Jaatinen Pia , Oksanen Hanna , Haapalinna Antti , Heinonen Esa , Hervonen Antti
Published: May 2006

In this study, the effects of dexmedetomidine, a selective α2‐adrenoceptor agonist, on ethanol withdrawal symptoms, were compared with those of diazepam and propranolol. The rats were given highly intoxicating doses of ethanol for 4 days. After the intoxication period, rats were divided into four equal groups: a dexmedetomidine‐treated group (30 μg/kg, sc), a diazepam‐treated group (2 mg/kg, sc), a propranolol‐treated group (5 mg/kg, sc), and a control group with no medication. Medication was given in the withdrawal phase—2, 8, 14, and 20 hr after the onset of the withdrawal symptoms. The severity of the ethanol withdrawal symptoms (rigidity, tremor, irritability, and hypoactivity) was observed up to 33 hr after the onset of the ethanol withdrawal symptoms. Both dexmedetomidine and diazepam significantly relieved tremor compared with the control group. Diazepam reduced irritability significantly, compared with the control group. When measured as the sum score of the three most specific withdrawal signs (rigidity, tremor, and irritability), dexmedetornidine and diazepam significantly relieved the ethanol withdrawal reaction. Propranolol attenuated tremor, but was inefticient against other withdrawal symptoms. Dexmedetomidine may thus represent a new effective drug in the treatment of the ethanol withdrawal syndrome.
Deposition of Cellular Fibronectin Increases before Stellate Cell Activation in Rat Liver during Ethanol Feeding
Authors: Gillis Sylvia E. , Nagy Laura E.
Published: May 2006

Cellular fibronectin (cFN)—a structural extracellular matrix protein—facilitates cell adhesion, migration, and differentiation during organ development; wound healing; tissue regeneration; and fibrogenic processes. cFN is deposited early in various fibrotic diseases and seems to function as a template for deposition of other extracellular matrix proteins, such as collagen type I and laminin, in the injured area. We have compared the relative changes in cFN levels with other pathogenic markers of alcoholic liver injury over time of ethanol feeding in the rat. Male Wistar rats were allowed free access to a liquid diet containing 36% of total energy as ethanol or pair‐fed an isocaloric control diet for 4, 8, and 12 weeks. Serum alanine arnino‐transferase activity and total liver lipid were increased in ethanol‐fed animals, compared with pair‐fed controls after 4,8, and 12 weeks of feeding. Liver lipid content was higher in ethanol‐fed rats as early as 4 weeks and was further increased by 12 weeks of feeding. Total fibronectin and cFN protein quantity was greater in liver from ethanol‐fed rats after 8 and 12 weeks (fibronectin: 2.3‐fold and 2.6‐fold; cFN: 4.3‐fold and 2.6‐fold higher than pair‐fed at 8 and 12 weeks, respectively). α‐Smooth muscle actin, an indicator of hepatic stellate cell activation, was increased in the liver of ethanol‐fed rats after 12 weeks of feeding (344% higher compared with pair‐fed), with no differences observed at any earlier time points. In summary, increases in hepatic immunoreactive cFN content were observed subsequent to increased liver lipid concentration, but before hepatic stellate cell activation in rats fed the ethanol‐based diet. These data suggest that deposition of cFN in the liver during long‐term ethanol consumption may represent an early response to injury similar to that observed in other models of liver injury and wound healing.
Ethanol Reduces Expression of the Nerve Growth Factor Receptor, But Not Nerve Growth Factor Protein Levels in the Neonatal Rat Cerebellum
Authors: Dohrman Douglas P. , West James R. , Pantazis Nicholas J.
Published: May 2006

The cerebellum is especially vulnerable to ethanol's neurotoxic effects during development, and ethanol exposure during the brain growth spurt will deplete cerebellar neurons. The mechanisms underlying this neuronal cell loss remain elusive. Nerve growth factor (NGF) is a neurotrophin that promotes cell survival in various brain areas, and there is evidence that NGF may play a role in the developing cerebellum. This study examined whether ethanol exposure of the neonatal rat cerebellum altered the levels of either NGF or the expression of p75 and trkA, which are two components of the NGF receptor. Ethanol exposure had no effect on NGF levels in the neonatal cerebellum, as determined by an NGF‐specific ELISA. Immunohistochemical labeling techniques indicated that both the p75 and trkA NGF receptors were expressed on Purkinje cell dendrites in the developing cerebellum, with posterior lobules expressing higher levels of p75 and trkA NGF receptor, compared with anterior lobules. Ethanol exposure of neonatal rats reduced the expression of both p75 and trkA NGF receptors on the Purkinje cell dendrites. These results suggest that ethanol could interfere with neurotrophic support of Purkinje cells by reducing the levels of available NGF receptor.
Binge‐Like Alcohol Exposure of Neonatal Rats Via Intragastric Intubation Induces Both Purkinje Cell Loss and Cortical Astrogliosis
Authors: Goodlett Charles R. , Peterson Stephanie D. , Lundahl Kristy R. , Pearlman Aaron D.
Published: May 2006

Binge‐like alcohol exposure in neonatal rats on postnatal days 4 to 9 via artificial rearing results in a well‐documented transient astrogliosis in the cerebral cortex. A recent study, which replicated the astrogliosis using artificial rearing, found that alcohol administered via daily exposure cycles in a vapor inhalation chamber on postnatal days 4 to 9 failed to elicit the effect, thus suggesting that the gliosis was an interactive effect of the artificial rearing administration and not specific to alcohol. The present study evaluated the effects in an intragastric intubation model that replicated the dosing parameters of the artificial rearing while avoiding the stress of surgery and extended maternal separation. In coronal frozen sections through parietal cortex labeled immunohistochemically for glial fibrillary acidic protein, the pups exposed to alcohol by intubation had a significantly greater density of glial fibrillary acidic protein‐positive astrocytes per unit volume, compared with liiermate controls intubated with a maltose‐dextrin formula; alcohol also induced fibrillary hypertrophy of the labeled astrocytes. In the cerebellum, alcohol induced a significant reduction in Purkinje cell number as determined using the optical disector method. These outcomes extend previous findings that neonatal binge alcohol exposure induces acute cortical astrogliosis and Purkinje cell loss, and confirm that the alcohol‐induced amgliosis is not an artifact of artificial rearing.