Search

It is well known that ethanol preexposure sensitizes the liver to LPS hepatotoxicity. The mechanisms by which ethanol enhances LPS-induced liver injury are not completely elucidated but are known to involve an enhanced inflammatory response. Ethanol exposure also increases the metabolic rate of the liver, and this effect of ethanol on liver is mediated, at least in part, by the sympathetic hormone, epinephrine. However, whether or not the sympathetic nervous system also contributes to the sensitizing effect of ethanol preexposure on LPSinduced liver damage has not been determined. The purpose of this study was therefore to test the hypotheses that 1) epinephrine pre-exposure enhances LPS-induced liver damage (comparable to that of ethanol preexposure) and that 2) the sympathetic nervous system contributes to the sensitizing effect of ethanol. Accordingly, male C57BL/6J mice were administered epinephrine for 5 days (2 mg/kg per day) via osmotic pumps or bolus ethanol for 3 days (6 g/kg per day) by gavage. Twenty-four hours later, mice were injected with LPS (10 mg/kg ip). Both epinephrine and ethanol preexposure exacerbated LPS-induced liver damage and inflammation. Concomitant administration of propranolol with ethanol significantly attenuated the sensitizing effect of ethanol on LPS-induced liver damage. These data support the hypothesis that the sympathetic nervous system contributes, at least in part, to the mechanism of the sensitizing effect of ethanol. These results also suggest that sympathetic tone may contribute to the initiation and progression of alcoholic liver disease. adrenaline; endotoxemia; two-hit model; hepatotoxicity

The ad hoc genetic correlation between ethanol sensitivity and learning mechanisms in Drosophila could overemphasize a common process supporting both behaviors. To challenge directly the hypothesis that these mechanisms are singular, we examined the learning phenotypes of 10 new strains. Five of these have increased ethanol sensitivity, and the other 5 do not. We tested place and olfactory memory in each of these lines and found two new learning mutations. In one case, altering the tribbles gene, flies have a significantly reduced place memory, elevated olfactory memory, and normal ethanol response. In the second case, mutation of a gene we name ethanol sensitive with low memory (elm), place memory was not altered, olfactory memory was sharply reduced, and sensitivity to ethanol was increased. In sum, however, we found no overall correlation between ethanol sensitivity and place memory in the 10 lines tested. Furthermore, there was a weak but nonsignificant correlation between ethanol sensitivity and olfactory learning. Thus, mutations that alter learning and sensitivity to ethanol can occur independently of each other and this implies that the set of genes important for both ethanol sensitivity and learning is likely a subset of the genes important for either process.

Prostaglandin (PG)E derivatives are widely used for treating gastric mucosal injury. PGE receptors are classified into four subtypes, [EP.sub.1] [EP.sub.2], [EP.sub.3], and [EP.sub.4]. We have tested which EP receptor subtypes participate in gastric mucosal protection against ethanol-induced gastric mucosal injury and clarified the mechanisms of such protection. The gastric mucosa of anesthetized rats was perfused at 2 ml/min with physiological saline, agonists for [EP.sub.1], [EP.sub.2], [EP.sub.3], and [EP.sub.4], or 50% ethanol, using a constant-rate pump connected to a cannula placed in the esophagus. The gastric microcirculation of the mucosal base of anesthetized rats was observed by transillumination through a window made by removal of the adventitia and muscularis externa. [PGE.sub.2] and subtypespecific EP agonists were applied to the muscularis mucosae at the window. Application of 50% ethanol dilated the mucosal arterioles and constricted the collecting venules. Collecting venule constriction by ethanol was completely inhibited by [PGE.sub.2] and by [EP.sub.2] and [EP.sub.4] agonists (100 nM) but not by an [EP.sub.1] or an [EP.sub.3] agonist. Ethanolinduced mucosal injury was also inhibited by [EP.sub.2] and [EP.sub.4] agonists. When leukotriene (LT)[C.sub.4] levels in the perfusate of the gastric mucosa were determined by ELISA, intragastric ethanol administration elevated the [LTC.sub.4] levels sixfold from the basal levels. These elevated levels were significantly (60%) reduced by both [EP.sub.2] and [EP.sub.4] agonists but not by other EP agonists. Since [LTC.sub.4] application at the window constricted collecting venules strongly, and an LTC antagonist reduced ethanol-induced mucosal injury, reductions in LTC4 generation in response to [EP.sub.2] and [EP.sub.4] receptor signaling may be relevant to the protective action of [PGE.sub.2]. The present results indicate that [EP.sub.2] and [EP.sub.4] receptor signaling inhibits ethanol-induced gastric mucosal injury through cancellation of collecting venule constriction by reducing [LTC.sub.4] production. prostaglandin [E.sub.2]; EP receptor; gastric microcirculation; gastric perfusion

Ethanol treatment increases gene expression in the liver through mechanisms that are not clearly understood. Histone acetylation has been shown to induce transcriptional activation. We have investigated the characteristics and mechanisms of ethanol-induced histone H3 acetylation in rat hepatocytes. Immunocytochemical and immunoblot analysis revealed that ethanol treatment significantly increased H3 acetylation at Lys9 with negligible effects at Lys14, -18, and -23. Acute in vivo administration of alcohol in rats produced the same results as in vitro observations. Nuclear extracts from ethanol-treated hepatocytes increased acetylation in H3 peptide to a greater extent than extracts from untreated cells, suggesting that ethanol either increased the expression level or the specific activity of histone acetyltransferases (HAT). Use of different H3 peptides indicated that ethanol selectively modulated HAT(s) targeting H3-Lys9. Treatment with acetate, an ethanol metabolite, also increased acetylation of H3-Lys9 and modulated HAT(s) in the same manner as ethanol, suggesting that acetate mediates the ethanol-induced effect on HAT. Inhibitors of MEK (U0126) and JNK (SP600125), but not p38 MAPK inhibitor (SB203580), suppressed ethanol-induced H3 acetylation. However, U0126 and SP600125 did not significantly affect ethanol-induced effect on HAT, suggesting that ERK and JNK regulate histone acetylation through a separate pathway(s) that does not involve modulation of HAT. Chromatin immunoprecipitation assay demonstrated that ethanol treatment increased the association of the class I alcohol dehydrogenase (ADH I) gene with acetylated H3-Lys9. These data provide first evidence that ethanol increases acetylation of H3-Lys9 through modulation of HAT(s) and that histone acetylation may underlie the mechanism for ethanol-induced ADH I gene expression. ethanol metabolism; selective acetylation; extracellular signal-regulated kinase; c-Jun N[H.sub.2]-terminal kinase stimulates reactive oxygen species production and increases pancreatic

Alcohol has long been thought to cause fatty liver by way of altered NADH/NA[D.sup.+] redox potential in the liver, which, in turn, inhibits fatty acid oxidation and the activity of tricarboxylic acid cycle reactions. More recent studies indicate that additional effects of ethanol both impair fat oxidation and stimulate lipogenesis. Ethanol interferes with DNA binding and transcription-activating properties of peroxisome proliferator-activated receptor-[alpha] (PPAR[alpha]), as demonstrated with cultured cells and in ethanol-fed mice. Treatment of ethanol-fed mice with a PPAR[alpha] agonist can reverse fatty liver even in the face of continued ethanol consumption. Ethanol also activated sterol regulatory element binding protein 1, inducing a battery of lipogenic enzymes. These effects may be due in pan to inhibition of AMP-dependent protein kinase, reduction in plasma adiponectin, or increased levels of TNF-[alpha] in the liver. The understanding of these ethanol effects provides new therapeutic targets to reverse alcoholic fatty liver. triglyceride; lipid; transcription factor; ethanol

Experiments were designed to determine whether ethanol influenced aggression in honey bees. Two experiments are reported. In Exp. 1, harnessed honey bees were fed a 1%, 5%, 10%, or 20% ethanol solution. Two control groups received either a sucrose solution only or no pretreatment, respectively. The dependent variable was the number of sting extensions over 10 min. Analysis showed that aggression in harnessed bees was not influenced by prior ethanol consumption. Because there was some suspicion that the extension of the sting apparatus may be hindered by harnessing, and the authors wanted to use a design that increased ecological validity, Exp. 2 was conducted with free-flying bees. Sucrose or 20% ethanol solutions were placed in front of beehives, and the number of stings on a leather patch dangled in front of the hive served as the dependent variable. The experiment was terminated after 5 hr. because bees exposed to ethanol became dangerously aggressive. A unique aspect of the study was that Africanized honey bees were used.

We examined the interaction of ethanol with the [gamma]-aminobutyric acid (GABA)ergic system in neurons of slices of the rat central amygdala nucleus (CEA), a brain region thought to be critical for the reinforcing effects of ethanol. Brief superfusion of 11-66 mM ethanol significantly increased GABA type A (GAB[A.sub.A]) receptor-mediated inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) in most CeA neurons, with a low apparent E[C.sub.50] of 20 mM. Acute superfusion of 44 mM ethanol increased the amplitude of evoked GABAA IPSPs and IPSCs in 70% of CeA neurons. The ethanol enhancement of IPSPs and IPSCs occurred to a similar extent in the presence of the GABA type B (GAB[A.sub.B]) receptor antagonist CGP 55845A, suggesting that this receptor is not involved in the ethanol effect on CeA neurons. Ethanol superfusion also decreased paired-pulse facilitation of evoked GAB[A.sub.A] IPSPs and IPSCs and always increased the frequency and sometimes the amplitude of spontaneous miniature GAB[A.sub.A] IPSCs as well as responses to local GABA application, indicating both presynaptic and postsynaptic sites of action for ethanol. Thus, the CeA is the first brain region to reveal, without conditional treatments such as GAB[A.sub.B] antagonists, consistent, low-dose ethanol enhancement of GABAergic transmission at both pre- and postsynaptic sites. These findings add further support to the contention that the ethanoI-GABA interaction in CeA plays an important role in the reinforcing effects of ethanol. alcohol | GABA IPSP/Cs | paired-pulse facilitation | miniature synaptic current | electrophysiology

Lipid composition can influence the effect of ethanol binding on bilayer properties, which can alter the lipid-protein interactions and membrane protein functions. This was tested on lipid bilayers containing cholesterol, gangliosides and sphingomyelin. The cholesterol and gangliosides in bilayers was found to altered the response of the hydrocarbon interior to ethanol binding in the lipid-water interface.

Exhibiting photographic slides of various types to students reveals the suppression of emotional response to the slides by doses of alcohol. An analysis of the psychophysiological responses shown by these students reveals that the effective modulation of startle does not vary with alcohol consumption. This implies a nonspecific attenuation of arousal reactions during 'stress-response dampening' by alcohol.

Use of the Taylor aggression paradigm on 36 occasional male drinkers aged between 18 and 40 years revealed that large scale alcohol consumption caused major changes in their behavior. In this method, shock treatment was used twice on a sober and a drunk group. The sober group exhibited a defensive reaction the second time but the drunk group could not use the knowledge acquired to show defiance to the shock treatment, proving that intoxication dulls responses to feelings such as pain.

A study conducted to analyze the effect of alcohol on managerial performance revealed that performance was limited with regard to improvement at a lower intoxication level due to myopia and motivated 'strain.' The effects of alcohol intoxication were studied on many managers, measured over reliable indicators of managerial performance. Speed and frequency of managerial action were influenced by intoxication at 0.10 level and not 0.05 level breath alcohol concentration.

Single-cell extracellular recordings from dopaminergic neurons of the ventrotegmental region, coupled with antidromic identification from the nucleus accumbens, and microdialysis technique studies in the muscles accumbens were used to examine the activity of the mesolimbic dopaminergic system in rats withdrawn from chronic ethanol administration. The reduction of mesolimbic dopaminergic activity in the ethanol withdrawal syndrome is induced by the sudden stoppage of chronic ethanol administration.

An analysis of the impact of graded alcohol intake on glucose, insulin and free fatty acids levels in non-insulin-dependent diabetes mellitus, NIDDM, patients includes evaluation of blood glucose responses, insulin responses and quantitative evaluation of serum free fatty acids. The study involves the administration of non-alcohol beer in three doses, with of 0%, 2.7% and 5.4% of alcohol. Glycaemic regulation in NIDMM patients is unaffected by small percentages of alcoholic content. It is suggested that drastic changes in carbohydrate metabolism can occur due to increased amounts of ethanol intake over a period of time.

A study on the relation between physical aggression, alcohol and drugs reveals that alcohol-mediated aggression is influenced by the character of the consumer, characteristics of the drug and the circumstance under which alcohol is consumed. Cognitive nature and motivational states also are important for understanding the relation. Increased level of alcohol consumption and other drugs with anxiolytic/sedative effects increases the aggressiveness in human beings. Situational factors such as provocation and social pressure also increase alcohol-mediated aggression.

The rats defeated in territorial aggression have decreased responses to the 5-HT2/IC receptor agonist, DOI, but if treated with ethanol (ET), the 5-HT2 receptor mediated responses are not desensitized. Anxiety-like effects are noted after the rats are defeated in territorial aggression.

The intake of tryptophan decreases the aggressive behavior in rats, and monoaminergic agonist such as tyramine increases the aggression induced by alcohol. Low doses of alcohol cause an increase in offensive or defensive aggression, irrespective of whether the rat is made to eat a diet rich in tryptophan. The serotonergic agonists such as fluoxitine and fenfluramini decrease the aggression caused by alcohol consumption.

Two experiments were conducted on laboratory mice to find the link between alcohol and aggression. The mice exhibited a similar battered alcoholic syndrome, in which the treated mice were prone to becoming victims of violence. The treated animal had reduced perception of social signals from the environment due to the intake of alcohol. The alcohol treated mice indulges in defensive aggression. The variety of behavioral changes are due to the different effects of alcohol on neurophysiology and endocrine functioning.

The study of the effects of alcohol on agonistic behavior in mice reveals that, unlike human beings, no increase in defensive or aggressive behavior is seen after alcohol administration. Alcohol does not decrease anxiety or fear in rats and, therefore, animal models are not appropriate for studying the effects of alcohol on human aggressive behavior. The only similarity between rat and human behavior is that, in both cases, alcohol changes the normal behavior.

A study of the influence of acute low alcohol doses on aggressive behavior in rodent and primate species reveals a relation between alcohol, aggression and the GABA benzodiazepine receptor complex. The effects of alcohol on aggressive behavior is different for each individual. Alcohol acts on the benzodiazepine-GABAA chloride ionophore receptor complex to control the aggressive behavior. The benzodiazepine receptor antagonists such as benzodiazepine and the beta-carboline derivatives curb the aggression heightening effects of alcohol, while benzodiazepine agonists increase the aggression heightening effects of alcohol. The GABAA-benzodiazepine receptor complex is an important site for distinguishing between less aggressive and more aggressive animals.

The behavior of laboratory rats, living in colonies and subordinated, is studied to analyze the effect of alcohol on the social aggressive and defensive behaviors. Rats living in colonies are prone to be more aggressive as a result of alcohol consumption. The rats that are subordinated by the other members of the group become more defensive and also die sooner. The subordinated rats, who are highly stressed, also voluntarily consume more alcohol than the dominant rats, and the anxiolytic effect of alcohol plays an important role in the behavioral pattern of these rats. Alcohol reduces the threat related inhibition of these rats and induces them to behave defensively.

A study of 96 male and 86 female social drinkers reveals the relation between alcohol consumption and responses to violent pornography. In both males and females, consumption of alcohol induces them to behave in a sexually aggressive way, as described in the pornographic story. Men high in hypermasculinity are prone to reacting in a more sexually aggressive way after consuming alcohol, as they feel that violent sexual advance is the only right way of behaving.

Alcohol increases aggressive behavior due to its anxiolytic property, which decreases threat-related inhibition. As a psychomotor stimulant, alcohol induces a person to be aggressive, even if there is little provocation. As alcohol increases one's sensitivity to pain, defensive aggression is likely to increase. Alcohol also affects the higher order cognitive function, as a result of which, behavior cannot be planned or controlled.

The Malmo-modification of the Michigan Alcoholism Screening Test (Mm-MAST), a test dealing with cutting down, annoyance by criticism, guilty feeling and eye-openers (CAGE), and a trauma test were given to 2,370 male and female first year Finnish students, with an average age of 22, to determine the effects of alcohol intake on their lives. Heavy drinking was determined by the quantity of alcohol consumed, the type of alcohol consumed and the interval of consumption. Males had higher scores on the combined test than females, and high level consumption was attributed to drinking being a part of Finnish culture. The Mm-MAST alone is sufficient to identify problem drinkers and is more reliable than CAGE and the trauma questionnaires.

A survey of 607 couples, aged 18 to 20, reveals a relation between premarital aggression and heavy alcohol consumption by the husband. Heavy drinkers are more prone to displaying violence, and the young, newly wed couples are at a high risk of experiencing alcohol-related problems. Lesser hostile men, who believe that alcohol induces aggressive behavior, become violent after alcohol intake, as they make alcohol an excuse for their aggressive behavior. Alcohol intake and aggression due to marital dissatisfaction are also indicated. However, even those who do not believe that alcohol leads to aggression are associated with premarital aggression after a heavy intake of alcohol.

The free-operant aggression methodology, developed from the experimental tradition of behavioral pharmacology, can be used to explore the relation between alcohol and aggressive behavior. The relation between alcohol use and aggressive behavior cannot be easily explained, because violence does not always result after the consumption of alcohol, and violence can occur in the absence of alcohol, too. As the alcohol dose is increased, the aggressive response also increases, and the intensity varies in each individual. The aggressive response, however, is influenced mainly by the social context under which alcohol is consumed and the period of provocation.

One of the four treatments of alprazolam and alcohol, alprozolam and placebo drink, placebo capsule and alcohol and placebo capsule and placebo drink were administered to forty eight moderate social drinkers. A combination of alcohol and alprazolam was found to increase the aggressive behavior in human beings. The psychophysiological measures were recorded when, after some time, the individuals were made to compete in a competitive reaction time task. The feelings of anxiety and hostility were increased by the task. Alprazolam decreased anxiety but not hostility, immediately after the task.

Astudy on the effects of alcohol reveals that alcohol decreases anxiety but increases the tendency of defensive attack. Alcohol and diazepam decrease a person's capacity to avoid dangerous situations. A low alcohol dose can also enhance the defensive attack, which is categorized under aggression. Thus, people under the influence of alcohol tend to indulge in violent fights, and the victims, if also under the influence of alcohol, do not avoid the fight and strike back defensively.

A moderate dose of alcohol has the capacity to increase the aggressiveness of the person, when provoked, though, if left alone there is no evidence of aggression. Taylor and Leonard explained, in 1983, that alcohol decreases a person's capacity to concentrate, and so the attention is directed at the most prominent external factor. Aggression increases if the aggression-instigative factors such as threat and frustration are prominent, and no aggression is exhibited if aggression-inhibitory factors are prominent.

Cells of Schizosaccharomyces pombe and Saccharomyces cerevisiae reveal an intracellular catalase activity and an intracellular cryptic activity. Both the cells were found to catalase into the medium. A study of the relationship between the two types of activities shows that both are influenced by prolonged aeration and are affected by the membrane permeability characteristic of the patent catalase activity. The catalase activities of substrates influencing catabolite repression, in activation or energizing cells, affect membrane permeability.

Researchers used the 1986 NMFS (National Mortality Followback Survey) conducted by the NCHS (National Center for Health Statistics) to sample 1% of deaths in the US, and to investigate the connection between alcohol consumption and cirrhosis mortality. The rising number of deaths per day resulted in a steep rise in the percentage of decedents with cirrhosis.

A study was conducted to investigate the relationship between chronic consumption of ethanol and structural modification of the memberanous (M) cells in rats. Rats in a control group were kept on liquid-only diet for 45 days while the experimental group rats were maintained on ethanol and a liquid diet. Subsequent comparison of the liver tissue of the two groups revealed that the rats in the experimental group showed ultrastructural changes, such as mitochondrial swelling and vacuolization of the cytoplasm, in the Ileal M cells. These changes, however, were found to be reversible after ethanol withdrawal.