Effect of chronic acetaldehyde intoxication on ethanol tolerance and membrane fatty acids

Recent studies have suggested that acetaldehyde participates directly in the pathogenesis of alcoholism. Its action has been attributed mainly to its physico-chemical properties. Results of direct intoxication of laboratory animals with acetaldehyde have been reported, but only for short periods of exposure and at high doses. These are probably not representative of the conditions found during alcohol intoxication. The pulmonary route of administration described here enables long term intoxication with acetaldehyde, at levels corresponding to values measured during chronic ethanol intoxication. Chronic administration of acetaldehyde during 3 weeks induced a metabolic tolerance to ethanol as tested by the sleeping time after a challenge dose of ethanol; behavioural tolerance (measured by blood alcohol levels on waking) was not observed. At the end of the intoxication, phospholipid fatty acids of erythrocyte and synaptosome membranes were also analysed. Small changes in levels of the shorter fatty acids were observed in the phosphatidyl-choline fraction. By comparison with the effects of ethanol on the same membrane preparations, only a small part of this effect can be attributed to acetaldehyde. The first metabolite of ethanol has, however, a sure effect on the pattern of fatty acid phospholipids.     

Effect of topiramate treatment on ethanol consumption in rats

Rationale  

Results from clinical studies have shown that topiramate effectively reduces alcohol consumption in a population of heavy-drinking alcohol-dependent humans.     

Effect of various central nervous system-acting drugs on ethanol and acetaldehyde metabolism in rats

Blood ethanol levels following intravenous ethanol administration were much higher during anesthesia with diethyl ether (ether), phenobarbital and pentobarbital than in unanesthetized control rats. Blood acetaldehyde levels were significantly lower during anesthesia with ether. Ether inhibited alcohol dehydrogenase (ADH) activities in vitro in an uncompetitive fashion; Ki, ether concentration which produced 50% inhibition of NADH formation, was 9.7 mM. Pentobarbital produced slight elevations of ADH activities in vitro and phenobarbital had no effects. Acetaldehyde levels during anesthesia with phenobarbital and pentobarbital were slightly higher than in unanesthetized animals. Phenobarbital and pentobarbital inhibited aldehyde dehydrogenase (ALDH) activities in vitro in a noncompetitive fashion; Ki were 29 and 37 mM, respectively. Ether did not influence ALDH activities in vitro. Thus, pentobarbital was suggested as the most appropriate anesthetic agent in such animal experiments.     

Voluntary ethanol consumption after ethanol and acetaldehyde treatment in alcohol-preferring C57BL mice

C57BL mice normally show a preference for alcohol solutions compared with water. The effect of chronic, ethanol treatment sufficient to produce behavioural tolerance on the voluntary ethanol consumption of C57BL mice was compared with the effect of acute ethanol and acute and chronic administration of acetaldehyde. Chronic treatment with ethanol caused a loss of preference which lasted more than 12 weeks after withdrawal from the treatment. The acute ethanol treatment and the acute and chronic acetaldehyde treatments only produced a transient loss of preference which returned to normal within 1 week of cessation of treatment. The effect of these drugs on liver alcohol dehydrogenase (LAdH) was also examined. Changes in LAdH activity did not correlate with alcohol preference. Possible reasons for the different effects of the drug treatments on alcohol preference are discussed.     

Effect of acetyl-L-carnitine on ethanol consumption and alcohol abstinence syndrome in rats

The effect of acetyl-L-carnitine on alcohol consumption and its possible ability to alleviate all symptomatology of ethanol withdrawal syndrome has been investigated in rats. Alcohol-dependence was induced in animals (9-15 g/kg ethanol solution at 20% for a period of 4 days) in order to measure the effects of acetyl-L-carnitine on ethanol abstinence syndrome. The ethanol dependence phase was characterized by the onset of signs and responses of progressive severity: hyperactivity, tremors, spastic rigidity and spontaneous convulsive seizures. After 4 days, 8 h after the last ethanol administration, two groups of animals received acetyl-L-carnitine (125 mg/kg and 250 mg/kg intraperitoneally, respectively) and the intensity of the withdrawal syndrome was assessed on the basis of the appearance of tremors. The effect of acetyl-L-carnitine on voluntary alcohol consumption was investigated in a rat line selected for innate ethanol preference. For 15 days the animals could freely choose both water and/or a hydroalcoholic solution (10% p:v). Acetyl-L-carnitine was given intraperitoneally at a dose of 200 mg/kg twice daily. The water and the hydroalcoholic solution levels were checked at the same time daily. Acetyl-L-carnitine treatment significantly reduced the onset of tremors in ethanol withdrawal syndrome as well as the level of ethanol intake in alcohol-preferring rats. These results suggest a possible pharmacological role of acetyl-L-carnitine in the treatment of alcohol dependence.     

Differences in ethanol sensitivity and acute tolerance between UChA and UChB rats

OBJECTIVE: In order to learn more about the genetic factors that determine the different responses to ethanol that contribute to the voluntary consumption of ethanol, this study examines the sensitivity to a nonnarcotic dose of ethanol (2.3 g/kg IP) of rats genetically selected for their low (UChA) and high (UChB) ethanol voluntary consumption. METHOD: Sensitivity was evaluated by studying both ethanol-induced (2.3 g/kg) motor impairment in a modified tilting-plane test and hypothermia. Blood ethanol concentration obtained after the ethanol dose and the correlation between ethanol sensitivity and voluntary ethanol consumption were also studied. RESULTS: Results obtained with both tests revealed that UChB rats were less sensitive to ethanol than UChA ones. The genetic difference in motor impairment appeared not to be the result of different blood ethanol levels. Furthermore, rats of both strains recovered motor activity when blood ethanol was at the highest level, indicating the development of acute tolerance. The acute tolerance appeared to develop in shorter time in UChB than in UChA rats. In contradistinction, time course of hypothermia was significantly related to that of blood ethanol. A significant correlation between motor impairment and ethanol voluntary consumption (p<.001) was obtained. CONCLUSIONS: The difference in motor impairment reported here might be related to differences between the strains in the ability to develop acute tolerance to ethanol. Acute tolerance development appears to be positively correlated to voluntary ethanol consumption by the rat.     

Metabolism of ethanol and acetaldehyde in intact rats during pregnancy

Ethanol and acetaldehyde contents in the peripheral blood of intact non-pregnant and pregnant rats have been determined after an intraperitoneal injection of ethanol. Determinations have also been made of the ethanol and acetaldehyde contents and the lactate/pyruvate ratios in frozen, clamped livers of intact pregnant and non-pregnant rats with or without a prior injection of ethanol. The in vitro activities of the liver alcohol and acetal-dehyde dehydrogenase have also been measured. Elimination rate of ethanol in vivo was found to be equal in pregnant and non-pregnant rats, but the acetaldehyde content of the peripheral blood after ethanol administration was higher in pregnant than in non-pregnant animals. Because the ethanol and acetaldehyde contents of frozen, clamped livers were similar in magnitude in pregnant and non-pregnant rats and no differences were found in the in vitro activities of the liver alcohol and acetaldehyde dehydrogenase between the two animal groups a difference in the extrahepatic metabolism of acetaldehyde is suggested to explain the high acetaldehyde content in the peripheral blood of pregnant rats after ethanol administration. The lactate and pyruvate contents of frozen, clamped livers of pregnant rats without a prior close of ethanol were higher than those of non-pregnant animals indicating a high rate of glycolysis during pregnancy, but the lactate/pyruvate ratios of the livers were equal in the two animal groups both with and without previous ethanol loading.     

Effect of acetaldehyde on skeletogenesis in rats

Acetaldehyde (ACH), the metabolite of ethanol was administered to pregnant CF rats intraperitoneally (50 mg/kg) from day 8 through 15 of gestation and fetuses from different mothers were collected from day 16 through 21 of gestation. Fetuses were processed for alizarin skeletal staining. There was significant delay in ossification besides certain skeletal malformations such as wavy ribs. The delay in ossification may be one of the reasons for reduced birth weight and increased postnatal mortality and growth.     

Effect of ethanol on turpentine-induced acute phase response in rats

Turpentine-induced acute-phase response and its modulation by ethanol in rats at 48 hr has been studied. There was more than 2.3-5.1 fold increase in fibrinogen and seromucoids concentrations in plasma, accompanied by 28% decline in albumin concentration in turpentine-stimulated rats. The fractional synthesis rate of these two acute-phase proteins was increased by 4.1-6.4 fold, while that of albumin (non acute-phase protein) was reduced by 32.6%. Ethanol inhibited this induction of acute-phase protein synthesis at 48 hr. The inhibition of acute-phase response by ethanol was significantly more pronounced for seromucoids than for fibrinogen and appeared to be dependent on the carbohydrate content of the acute-phase glycoprotein.     

Comparative effects of chronic ethanol and acetaldehyde exposure on myocardial function in rats

This study was conducted to compare separately the chronic effects of high blood levels of ethanol and acetaldehyde on the metabolism of the heart. Levels of ethanol and acetaldehyde were altered by administration of either 4-methylpyrazole (4-MP), a potent alcohol dehydrogenase inhibitor, or pargyline (PAR), a monoamine oxidase inhibitor that markedly increases acetaldehyde levels in the blood following ethanol administration. Measurements were made in rats consuming ethanol for three to four weeks. Mitochondrial respiration, in vitro contractility of glycerinated heart muscle fibers, and myocardial protein synthesis were determined. As compared to animals receiving only ethanol, administration of either-4-methyl-pyrazole or pargyline plus ethanol resulted in more severe damage to mitochondrial respiration and myocardial protein synthesis. The data illustrate that both acetaldehyde and ethanol in high concentrations can cause severe damage to myocardial metabolism.     

Shock induced ethanol consumption in rats

Two experiments are presented which describe the temporal and volumetric changes in ethanol consumption by rats exposed to recurring schedules of inescapable random shock. The animals in Experiment 1, which had a choice between ethanol and water, increased their voluntary ethanol consumption immediately after the shock schedule. The postshock changes occurred with both 5% and 10% V/V ethanol, were specific to the presence of shock and were not reflected by measures of total daily ethanol intake. Experiment 2 exposed rats to extended 22 hr stress sessions, during which each animal had four simulataneous fluid choices available: water, saccharin 0.1% W/V, ethanol 5% V/V, and ethanol 10% V/V. Temporal intake patterns for both 5% and 10% ethanol showed pronounced peaks for the interval immediately following the shock schedule. A shift of intake from 5% to 10% ethanol was also demonstrated with increasing time under shock, while saccharin and water intake decreased. The results are interpreted as a relationship between voluntary ethanol intake and escape from the consequences of stress.     

Effect of sex on ethanol consumption and conditioned taste aversion in adolescent and adult rats

Rationale

Vulnerability to alcoholism is determined by many factors, including the balance of pleasurable vs. aversive alcohol-induced sensations: pleasurable sensations increase intake, while aversive sensations decrease it. Female sex and adolescent age are associated with lower sensitivity to intake-reducing effects and more rapid development of alcohol abuse.

Objectives

This study assessed voluntary drinking and the aversive effects of alcohol to determine whether these measures are inversely related across the sexes and development.

Methods

Voluntary drinking of 20 % ethanol in an every-other-day (EOD) availability pattern and the dose–response relationship of ethanol conditioned taste aversion (CTA) were assessed in male and female adolescent and adult rats.

Results

CTA was sex specific in adult but not adolescent rats, with adult females exhibiting less aversion. Voluntary ethanol consumption varied according to age and individual differences but was not sex specific. Adolescents initially drank more than adults, exhibited greater day-to-day variation in consumption, were more susceptible to the alcohol deprivation effect, and took longer to establish individual differences in consumption patterns.

Conclusions

These results show that the emergence of intake patterns differs between adolescents and adults. Adolescents as a group initiate drinking at high levels but decrease intake as they mature. A subset of adolescents maintained high drinking levels into adulthood. In contrast, most adults consumed at steady, low levels, but a small subset quickly established and maintained high-consumption patterns. Adolescents also showed marked deprivation-induced increases. Sex differences were not observed in EOD drinking during either adolescence or adulthood.     

Initial sensitivity and acute tolerance to ethanol in the P and NP lines of rats

We recently reported that selectively bred, alcohol-preferring (P) and alcohol-nonpreferring (NP) rats differ in sensitivity to a single sedative-hypnotic dose of ethanol, as measured by performance in the jump test. The present study examines the contributions of initial sensitivity and acute tolerance development to this difference. Initial sensitivity, assessed by brain alcohol content upon loss of the aerial righting reflex, was not significantly different between P and NP groups given 3 g ethanol/kg body weight intraperitoneally. Acute tolerance was indexed from blood alcohol concentrations (BAC) upon recovery of jumping performance following two successive ethanol doses. Practiced P and NP rats were required to jump 35 cm to a descending platform following the IP injection of 2.0 g ethanol/kg. The NP group took signiificantly longer (74 min) than the P (33 min) group whereupon BAC₁ of NP rats (234 mg%) was significantly lower than that of P rats (250 mg%). A second injection (1.0 g/kg) was given immediately after the animals reached the 35 cm criterion. Again, NP rats took significantly longer (124 min) than P rats (52 min) to jump 35 cm and BAC₂ of NP animals was lower (295 mg%) than that of P rats (343 mg%). The difference between BAC₂ and BAC₁, the measure of tolerance development, was significantly larger for P rats (90 mg%) than for NP rats (61 mg%). No significant differences in blood ethanol elimination weree observed between the groups. The data indicate no difference in initial sensitivity between P and NP animals but that P rats develop acute tolerance more rapidly and/or to a greater degree than do NP rats. The results are consistent with a relationship in these selectively bred lines of rats between alcohol preference and the development of acute tolerance.     

Initial sensitivity,acute tolerance and alcohol consumption in four inbred strains of rats

Initial sensitivity and acute tolerance to ethanol were determined in a jumping test in separate groups of spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats, and of Dahl salt-sensitive (SS) and salt-resistant (SR) rats. One week later, voluntary consumption of ethanol was studied in all groups. SH rats were found to be more sensitive than WKY, but there was no difference in acute tolerance development between these two strains. SH rats, however, drank significantly more alcohol than the WKY in both the two-bottle choice paradigm and the limited access model. Similarly, SS rats drank significantly more alcohol than the SR rats, although SS rats were found to be more sensitive to ethanol than SR. There was again no difference in acute tolerance development between these two strains. These observations suggest that difference in alcohol consumption in these strains cannot be accounted for by significant differences in acute tolerance or in initial sensitivity to ethanol.     

Effect of raphe lesions on the development of acute tolerance to ethanol and pentobarbital

The effect of electrolytic lesions in the median and dorsal raphe nuclei was tested on acute tolerance development to ethanol and pentobarbital in the rat, as measured by motor impairment on the moving belt test. Acute tolerance to ethanol (1.7 g/kg, IP) or pentobarbital (17.5 mg/kg, IP) was monitored at 12.5, 25, or 50 min in separate subgroups tested only once each. One week of recovery was allowed between ethanol and pentobarbital tests. Median raphe lesions delayed the development of acute tolerance, whereas dorsal raphe lesions produced a negligible effect. These results were seen with both ethanol and pentobarbital. The mesolimbic 5-HT pathway from the median raphe nucleus is important in the development of acute tolerance to ethanol and pentobarbital, as was shown to be the case previously for chronic tolerance.     

Metabolic and pharmacodynamic tolerance to ethanol in rats

The development of tolerance to ethanol was studied in rats fed nutritionally adequate liquid diets containing ethanol or sucrose for up to 5 weeks. Tolerance was shown to be due to both metabolic and pharmacodynamic factors. Tolerance began to develop after 3 days of ethanol intake, reached a plateau by 16 days and persisted for up to 22 days after stopping the ethanol intake. The rate of onset and decay of both components of tolerance was similar.     

Production of reactive oxygen species following acute ethanol or acetaldehyde and its reduction by acamprosate in chronically alcoholized rats

The salicylate trap method, combined with microdialysis, has been used to validate whether reactive oxygen species, particularly hydroxyl radicals, (^•OH), are generated in the hippocampus of male Wistar rats after acute intraperitoneal administration of either ethanol, 2 and 3 g/kg, or acetaldehyde, 200 mg, or during the initial stages of ethanol withdrawal after chronic ethanol intoxication. Salicylate (5 mM) was infused into the hippocampus via the microdialysis probe and the products of its metabolism by hydroxyl radical, particularly 2,3-dihydroxybenzoic acid (2,3-DHBA) as well as 2,5-dihydroxybenzoic acid (2,5-DHBA) assayed by HPLC (High Pressure Liquid Chromatography).

Acetaldehyde, 200 mg/kg, and the higher acute dose of ethanol, 3 g/kg, induced transitory increases in 2,3-DHBA and 2,5-DHBA microdialysate content. At the cessation of four weeks of chronic ethanol intoxication, (by the vapour inhalation method), the mean blood alcohol level was 1.90 g/l. Significant increases of microdialysate 2,3-DHBA and 2,5-DHBA levels were assayed 3 h after alcohol withdrawal which were sustained for a further 5 and 1 h 40 min respectively. Oral administration of Acamprosate, 400 mg/kg/day, during the chronic ethanol intoxication procedure prevented the increased formation of 2,3- and 2,5-DHBA by comparison to rats chronically ethanol intoxicated alone.     

Absence of effect of prenatal ethanol on adult emotionality and ethanol consumption in rats.

Lower peak blood ethanol concentrations after 1 and 2 g of ethanol per kg were found in pregnant rats than in virgin females. No significant differences in adult "emotionality" or ethanol consumption were found in rats exposed to prenatal alcohol and in pair-fed and untreated controls.