Dynamics of redistribution of blood serum lipoproteins in patients with alcoholism during alcohol intoxication and its abolition

In the patients with alcoholism at intoxication and different periods of alcohol abolition the blood serum lipoproteins were investigated by a method of gradient gel-electrophoresis using the computer program for qualitative definition. It was found out that change of the total sum of all lipoprotein fractions was approximated to parabolic dependence with maximum in the 3rd day after alcohol abolition. Under intoxication disturbances the individual apoB-containing fractions were minimal as compared with the control, while at the initial stages of alcohol abolition their redistribution was noticed as reflecting the growth of the processes of cholesterol transportation from liver to peripheral tissues. The 14th day after alcohol abolition was characterized by tendency to normalization of these disturbances, but at the 30th day of soberness a recurrence growing the changes of apoA-containing lipoproteins transformation was observed. In the patients under intoxication period and first 3 days after alcohol abolition a significant increase of quantity of all the apoA-containing lipoprotein populations took place which was restored completely in remission. On the base of both the own results and data from literature sources we suppose that these changes are the results of direct influence of ethanol and but they are not a pathogenic indication of a chronic alcoholism.     

The activity of 2',5'-oligoadenylate-synthetase in rat spleen lymphocytes in the chronic ethanol intoxication and administration of zinc acetate

It was shown that the activity of interferon-induced enzyme 2',5'-oligoadenylate-synthetase is suppressed in rat spleen lymphocytes under the chronic alcohol intoxication. The values of enzyme activity were minimal under the long-term action of etanol (21 day). The combined administration of zinc acetate and etanol to rats causes the increase of enzyme activity, the effect is most expressed on the late stages of alcohol intoxication development.     

Lesions of skeletal muscles in rats with acute alcoholic intoxication

Histological and histochemical studies of the rat skeletal muscles in acute alcohol intoxication have revealed metabolic disturbances, characterized by a decreased glycogen level, small-drop fatty infiltration, decreased activity of aerobic and enhanced activity of anaerobic enzyme glycolysis, dystrophic and focal necrotic myocyte changes. Acute alcohol intoxication in fasting animals is accompanied by more pronounced dystrophic and necrotic myocyte changes, decreased glycogen and lipid content.     

Effects of inmecarb on alcohol intake and the state of hepatic cytochrome P-450 system during various stages of experimental alcoholism in rats

The influence of the new anti-alcohol drug Inmecarb on the alcohol consumption as well as on activity of the liver cytochrome P-450 system was studied in rats during chronic alcohol intoxication in the free choice situation between water and 15% ethanol solution. It was shown that voluntary alcohol consumption of different duration (10 days to 8 months) does not change the activity of liver cytochrome P-450 system. Inmecarb treatment (40 mg/kg, i.p. twice a day) during 14 days resulted in decrease of alcohol consumption in rats. This effect was most pronounced in late stages of experimental alcoholism. Inmecarb decreases the cytochrome P-450 content and suppresses the activity of aniline hydroxylase in rats with different duration of voluntary alcohol intoxication, but most pronounced effect was observed during the late stages of experimental alcoholism.     

The effect of ethanol upon early development in mice and rats. I. In vivo effect upon preimplantation and early postimplantation stages

The preimplantation and early postimplantation effect of chronic alcohol consumption (at least a month before mating and during pregnancy until killing) and of acute ethanol intoxication during the preimplantation period (i.v. infection of ethanol) was studied on albino rats (Wistar) and albino mice (RAP). The main results were as follows: Chronic alcoholization. Rats: significant retardation of preimplantation development and in early postimplantation stages; a tendency of lowering of the mean litter size. Mice: significant increase of the number of preimplantation pathological forms; a tendency of lowering of the mean litter size. Pathological changes show, both in rats and mice, an obvious "litter effect". Acute ethanol intoxication. Rats: significant retardation in some litters, normal or even advanced development in others. This effect differs from the previously reported effect of acute ethanol intoxication during early postimplantation stages. The results obtained attest the prenatal noxious effect of chronic ethanol consumption in both species used and of acute ethanol intoxication during preimplantation development upon early postimplantation development in rats. Within the limits of extrapolation possibilities, they represent a risk signal for other species (including human).     

Effect of alcohol intoxication on ascorbic and dehydroascorbic acid levels in rat tissue. and human blood

It is found that acute ethanol intoxication is accompanied by a decrease in the ascorbic acid content in the brain, liver and kidneys. The content of dehydroascorbic acid in kidneys in this case increases and in the brain tends to decrease. The chronic alcohol intoxication of rats has an opposite (as compared to the acute intoxication) effect on changes in the content of ascorbic and dehydroascorbic acids in the studied organs. People with chronic alcohol intoxication have the lower content of ascorbic acid in blood plasma and the higher content in erythrocytes, the content of dehydroascorbic acid being increased.     

Effect of prolonged alcoholization on the cerebral electical activity and emotional behavior of rats

Two stages of alcohol intoxication were detected in an experiment on 21 rats during formation of addiction to alcohol. It has been shown that the emotiogenic hypothalamic zones may play the part of trigger mechanisms with infolvement of limbic and neocortical apparatuses. At the same time a different type of integration of addiction to alcohol food is possible, in which the emotiogenic zones do not play the principal part. The late stages of formation of addiction to alcohol are characterized by EEG hypersynchronia with a qualitatively different structure in the periods of abstinence and "saturation" with alcohol. A close connection has been recorded between the mechanisms of emotion, hypersynchronia and behavioral epileptic phenomena.     

Experimental alcohol blastopathy

Experimental data are presented with respect to "experimental alcohol blastopathy" performed in our laboratory. As in our interpretation the notion of blastopathy involves both pathological changes during preimplantation development due to previous, preconceptional or preimplantation influences and later, pre- or postnatal effects induced by factors active during the preimplantation period, up to now the following experimental models were applied (on rats and mice): chronic and acute maternal, biparental or paternal ethanol alcoholization; preimplantation treatment with acetaldehyde or disulfiram followed by ethanol administration; acute ethanol intoxication before implantation on the background of chronic maternal ethanol intake; chronic maternal intake of various beverages. The main components of experimental alcohol blastopathy detected (by using a complex control methodology) were: pathological changes during the preimplantation developmental stages (lower mean number of embryos/animal, retardation of development, lowered migration rate of the embryos from the oviduct to the uterus, higher number of pathological morphological features), delayed implantation, disturbances of the early postimplantation development, retarded late foetal and placental growth. The effect of ethanol may be direct (ethanol being detectable in the oviductal and uterine fluid after both acute and chronic alcoholization) or indirect, via changes of the maternal macro- or microenvironment. The increase of the maternal blood acetaldehyde level may contribute to the appearance of alcohol blastopathy. Chronic beer and wine intake and acute intoxication with cognac suggest - up to now - the enhancing effect of beverage congeners. The noxious effect of acute ethanol intoxication superposed to chronic alcoholization is more marked that the separate effect of the two kinds of treatment. The chronic ethanol intake of fertilizing males (in mice) leads, both in the case of treated or untreated females, to lowered fertilization efficiency, to retardation of development (not occurring in the experimental model with chronic alcoholization of females) and to an enhanced increase of the number of pathological features. The cytogenetic control of preimplantation embryos (after chronic, acute or combined treatment with ethanol) does not reveal significant chromosomal changes. A possible alcohol blastopathy in humans must be taken into account (i.e. a noxious effect during the very early period of pregnancy when it is ignored).     

Concentrations of protein sulfhydryl and amino groups in the brain during acute and chronic alcoholic intoxication

The content of sulphydryl and amine groups in water- and salt- soluble proteins of different areas of the rat brain was studied as affected by acute and chronic alcohol intoxication. With a relatively unchanged content of sulphydryl groups, noticeable variations are observed in the level of amine groups, most pronounced in proteins of the intermediate and middle areas of the brain. Under chronic intoxication the greatest changes in the content of the functional groups occur on the fourth day after cessation of the alcohol administration, when changes in the clinical state of the animals are most pronounced. It is supposed that the found shifts are caused by an acetaldehyde reversible blockade of amino groups and by the conformation rearrangement of protein molecules.     

Electroencephalographic study of naloxone effects in the recovery of an acute alcoholic intoxication

Experimental assays analysing EEG changes during the recovery of an acute alcoholic intoxication were carried out in three groups of cats: 1) Recovery of acute alcoholic intoxication produced by continuous intravenous perfusion of ethanol, 0.06 g/kg/min, during 20 minutes. 2) Recovery of acute alcoholic intoxication by injecting naloxone (400 micrograms/kg), just after finishing alcohol perfusion. 3) Recovery of acute alcoholic intoxication by injecting naloxone (400 micrograms/kg), 15 min after finishing perfusion. Naloxone administered after an acute alcoholic intoxication worsens the recovery of EEG parameters; 1-2 (p less than 0.05), 1-3 (p less than 0.05).     

Hemispheric lateralization of the visual-spatial function in chronic alcoholic intoxication in humans

A series of behavioural and electrophysiological parameters was recorded in subjects with chronic alcohol intoxication during solving of visual-spatial nonverbalized task. It is shown that in comparison with the healthy subjects, their reaction time (RT) of correct decisions was increased; it was more expressed when stimuli were presented in the left visual field, i.e., directly to the right hemisphere, and the number of correct reactions decreased at stimuli presentation directly to the left hemisphere. During repeated tests there were no changes in the number of correct reactions and RT value in the group with chronic alcohol intoxication. It is found that long-term taking of alcohol produces an increase of latency and decrease of the amplitude of the late positive wave P300, more pronounced in the right cerebral hemisphere.     

Role of phospholipids in changes in lysosomal membrane stability in conditions of chronic alcoholic intoxication

Pronounced destabilization of liver lysosomal membranes has been revealed in rats in conditions of 30-day-long alcohol intoxication. Noticeable fractional changes in phospholipid composition of lysosomal membranes have been found. Significant increase in lysophosphatidylethanolamine and lysophosphatidylcholine levels have been observed. Type A2 phospholipase activity was found in lysosomal fractions, with the enzyme activity Ca2+-dependent, optimal at pH 8 and increasing many-fold following alcohol intoxication. The changes in lysosomal membrane phospholipids appear to be related to phospholipase A2 activation.     

Theta oscillations are sensitive to both early and late conflict processing stages: effects of alcohol intoxication

Prior neuroimaging evidence indicates that decision conflict activates medial and lateral prefrontal and parietal cortices. Theoretical accounts of cognitive control highlight anterior cingulate cortex (ACC) as a central node in this network. However, a better understanding of the relative primacy and functional contributions of these areas to decision conflict requires insight into the neural dynamics of successive processing stages including conflict detection, response selection and execution. Moderate alcohol intoxication impairs cognitive control as it interferes with the ability to inhibit dominant, prepotent responses when they are no longer correct. To examine the effects of moderate intoxication on successive processing stages during cognitive control, spatio-temporal changes in total event-related theta power were measured during Stroop-induced conflict. Healthy social drinkers served as their own controls by participating in both alcohol (0.6 g/kg ethanol for men, 0.55 g/kg women) and placebo conditions in a counterbalanced design. Anatomically-constrained magnetoencephalography (aMEG) approach was applied to complex power spectra for theta (4-7 Hz) frequencies. The principal generator of event-related theta power to conflict was estimated to ACC, with contributions from fronto-parietal areas. The ACC was uniquely sensitive to conflict during both early conflict detection, and later response selection and execution stages. Alcohol attenuated theta power to conflict across successive processing stages, suggesting that alcohol-induced deficits in cognitive control may result from theta suppression in the executive network. Slower RTs were associated with attenuated theta power estimated to ACC, indicating that alcohol impairs motor preparation and execution subserved by the ACC. In addition to their relevance for the currently prevailing accounts of cognitive control, our results suggest that alcohol-induced impairment of top-down strategic processing underlies poor self-control and inability to refrain from drinking.     

The level of free radical oxidation products in heart and blood plasma in diabetes mellitus combined with chronic alcohol intoxication

The level of glycemia, contents of free radical oxidation products (thiobarbituric acid reactive substances, oxidatively modified proteins) have been investigated in blood plasma and heart of rats with diabetes mellitus subjected to chronic alcohol intoxication. Preexisting diabetes mellitus had no influence on the effect of chronic alcohol consumption on the blood plasma levels of oxidatively modified proteins, thiobarbituric acid reactive substances and glucose. However, the contents of thiobarbituric acid reactive substances and products of oxidative modification of proteins were significantly higher in hearts of diabetic rats with chronic alcohol intoxication than in diabetic rats without alcohol intoxication or in rats subjected to chronic alcohol treatment. The alcohol-induced hyperactivation of free radical processes found in the heart may have additional damaging effect.     

Ultrastructure of sensorimotor cortex neurons in the progeny of rats receiving alcohol during pregnancy

Dynamics of ultrastructural changes in the sensomotor cortex neurons has been studied on the 21st, 30th and 60th days of life in offspring born by the rats given 20% alcohol (2 g/kg) during pregnancy. Moderate antenatal alcoholization produces certain disturbances in the ultrastructure of the cortical neurons and their dendrites. This is manifested as presence of retardation signs in maturation of nervous cell populations, as dystrophic changes in the neurons and their dendrites and display of reparative character with their own dynamics in the postnatal period of ontogenesis. The first two categories of the ultrastructural changes in the cortical neurons are more manifested at early stages of the postnatal development of the offspring, and the reparative processes--at the age of two months. Despite the presence of the reparative shifts, the dystrophic changes of the neurons of hypoxic character are present up to the period of sexual maturation. This demonstrates that the antenatal alcoholic intoxication in the offspring is manifested in the postnatal ontogenesis for a long time.     

Contents of aldosterone and electrolytes in blood plasma and the myocardium of rats after single physical exertion during acute alcoholic intoxication]

It was proved in experiments with male Wistar rats that acute alcohol intoxication caused significant changes in electrolytes balance in blood plasma and myocardium remaining for a long time after ethanol injection. SPL test makes it possible to reveal inadequate reaction of blood plasma aldosterone in alcohol injected rats. This fact may be considered as the fact of involving extracardiac component of compensation of myocardial functional insufficiency conditioned mainly by electrolyte unbalance. The tolerance to physical loading is significantly higher in alcohol injected rats than in intact animals.     

Neurochemical Mechanisms Underlying Alcohol Addiction: Model Experiments on Rats

We measured the activities of the main alcohol-metabolizing enzymes (alcohol dehydrogenase, AlDH, and aldehyde dehydrogenase, AdhDH) in the blood serum, comparing these indices with the contents of ethanol and its main metabolite, acetaldehyde (AcAdh), in the blood, and also measured the contents of catecholamines (adrenaline, noradrenaline, and dopamine) in the blood and in different brain structures (hypothalamus, midbrain, and neocortex) of rats in the states of acute alcohol intoxication and chronic alcohol addiction. It was shown that, because of dissimilar changes in the activities of AlDH and AdhDH under conditions of alcohol intoxication, the dynamic balance between endogenous ethanol and AcAdh existing in the norm is disturbed, which results in an increase in the level of AcAdh. Such a phenomenon probably is one of the crucial factors underlying the development of alcohol addiction.     

Acute and chronic ethanol consumption differentially impact pathways limiting hepatic protein synthesis

This review identifies the various pathways responsible for modulating hepatic protein synthesis following acute and chronic alcohol intoxication and describes the mechanism(s) responsible for these changes. Alcohol intoxication induces a defect in global protein synthetic rates that is localized to impaired translation of mRNA at the level of peptide-chain initiation. Translation initiation is regulated at two steps: formation of the 43S preinitiation complex [controlled by eukaryotic initiation factors 2 (eIF2) and 2B (eIF2B)] and the binding of mRNA to the 40S ribosome (controlled by the eIF4F complex). To date, alcohol-induced alterations in eIF2 and eIF2B content and activity are best investigated. Ethanol decreases eIF2B activity when ingested either acutely or chronically. The reduced eIF2B activity most likely is a consequence of twofold increased phosphorylation of the alpha-subunit of eIF2 on Ser(51) following acute intoxication. The increase in eIF2alpha phosphorylation after chronic alcohol consumption is the same as that induced by acute ethanol intoxication, and protein synthesis is not further reduced by long-term alcohol ingestion despite additional reduced expression of initiation factors and elongation factors. eIF2alpha phosphorylation alone appears sufficient to maximally inhibit hepatic protein synthesis. Indeed, pretreatment with Salubrinal, an inhibitor of eIF2alpha(P) phosphatase, before ethanol treatment does not further inhibit protein synthesis or increase eIF2alpha phosphorylation, suggesting that acute ethanol intoxication causes maximal eIF2alpha phosphorylation elevation and hepatic protein synthesis inhibition. Ethanol-induced inhibition of hepatic protein synthesis is not rapidly reversed by cessation of ethanol consumption. In conclusion, sustained eIF2alpha phosphorylation is a hallmark of excessive alcohol intake leading to inhibition of protein synthesis. Enhanced phosphorylation of eIF2alpha represents a unique response of liver to alcohol intoxication, because the ethanol-induced elevation of eIF2alpha(P) is not observed in skeletal muscle or heart.     

Psychopathological and hormonal manifestations of alcoholic intoxication and emotional stress in monkeys

Ethological approach to studying mature P. hamadryas and M. mulatta males has revealed a wide spectrum of changes in individual and zoosocial behaviour in response to the administration of different alcohol doses and stress stimuli. It has been established that neuroendocrine basis for the depression of psychic and locomotor activities developing in conditions of alcohol intoxication and emotional stress is an extremely high release of catecholamines and the increase of glucocorticoid secretion accompanied by a sharp decrease in androgen products. It should be noted that the exposure to stress stimuli during consumption of small alcohol doses intensifies depression-like stress-induced behaviour of monkeys.     

Acute alcohol intoxication increases atrogin-1 and MuRF1 mRNA without increasing proteolysis in skeletal muscle

Acute alcohol intoxication decreases muscle protein synthesis, but there is a paucity of data on the ability of alcohol to regulate muscle protein degradation. Furthermore, various types of atrophic stimuli appear to regulate ubiquitin-proteasome-dependent proteolysis by increasing the muscle-specific E3 ligases atrogin-1 and MuRF1 (i.e., "atrogenes"). Therefore, the present study was designed to test the hypothesis that acute alcohol intoxication increases atrogene expression leading to an elevated rate of muscle protein breakdown. In male rats, the intraperitoneal injection of alcohol dose- and time-dependently increased atrogin-1 and MuRF1 mRNA in gastrocnemius, the latter of which was most pronounced. A comparable change was absent in the soleus and heart. The ability of in vivo-administered ethanol to increase atrogene expression was independent of the route of alcohol administration (intraperitoneal vs. oral), as well as of nutritional status (fed vs. fasted) and gender (male vs. female). The increase in atrogin-1 and MuRF1 was independent of alcohol metabolism, and the overproduction of endogenous glucocorticoids and could not be prevented by maintaining the circulating concentration of insulin-like growth factor-I. Despite marked changes in atrogene expression, acute alcohol in vivo did not alter the release of either 3-methylhistidine (MH) or tyrosine from the isolated perfused hindlimb, suggesting that the rate of muscle proteolysis remains unchanged. Moreover, alcohol did not increase the directly determined rate of protein degradation in isolated epitrochlearis muscles or cultured myocytes. Finally, no increase in atrogene expression or 3-MH release was detected in muscle from rats fed an alcohol-containing diet. Our results indicate that although acute alcohol intoxication increases atrogin-1 and MuRF1 mRNA preferentially in fast-twitch skeletal muscle, this change was not associated with increased rates of muscle proteolysis. Therefore, the loss of muscle mass/protein in response to chronic alcohol abuse appears to result primarily from a decrement in muscle protein synthesis, not an increase in degradation.