Showing papers in "Alcohol and Alcoholism in 1990"

Neuropathology of alcoholism

Abstract: Chronic alcohol consumption results in structural changes to the brain. In alcoholics without coexisting thiamine deficiency or liver disease this is largely restricted to a loss of white-matter volume. When it occurs, neuronal loss is limited in anatomic distribution and only detected with quantitative techniques. This relative paucity of neurodegeneration is reflected in studies of gene and protein expression in postmortem brain where findings are subtle and discordant between studies. In alcoholics with coexisting pathologies, neuronal loss is more marked and affects a wider range of anatomic regions, especially subcortical nuclei. Although this more widespread damage may reflect a more severe drinking history, there is evidence linking thiamine deficiency and the consequences of liver disease to the pathogenesis of alcohol-related brain damage. Furthermore, a range of other factors, such as cigarette smoking and mood disorders, that are common in alcoholics, have the potential to influence studies of brain pathology and should be considered in further studies of the neuropathology of alcoholism.

Ethanol-induced lipid peroxidation and oxidative stress in extrahepatic tissues.

Abstract: An ethanol-induced oxidative stress is not restricted to the liver, where ethanol is actively oxidized, but can affect various extrahepatic tissues as shown by experimental data obtained in the rat during acute or chronic ethanol intoxication. Most of these data concern the central nervous system, the heart and the testes. An acute ethanol load has been reported to enhance lipid peroxidation in the cerebellum. This is accompanied by an increase in the cytosolic concentration of low-molecular-weight iron derivatives which may contribute to the generation of aggressive free radicals. The ethanol-induced decrease in the main antioxidant systems (superoxide dismutase, alpha-tocopherol, ascorbate and selenium) is a likely contributor to the cerebellar oxidative stress. Most of these disturbances can be prevented by allopurinol administration. Some experimental data support also the occurrence of pro- and anti-oxidant disturbances in the cerebellum and in other regions of the central nervous system after chronic ethanol administration. Chronic ethanol administration enhances lipid peroxidation in the heart. The increased conversion of xanthine dehydrogenase into xanthine oxidase as well as the activation of peroxisomal acyl CoA-oxidase linked to ethanol administration could contribute to the oxidative stress. Chronic ethanol administration elicits in the testes an enhancement in mitochondrial lipid peroxidation and a decrease in the glutathione level, which appear to be correlated to the gross testicular atrophy observed. Vitamin A supplementation attenuates the changes in lipid peroxidation, glutathione and testicular morphology. Whether the reported disturbances are involved in the pathogenesis of the tissue disorders observed in alcoholic patients remains unanswered.(ABSTRACT TRUNCATED AT 250 WORDS)

Acamprosate appears to decrease alcohol intake in weaned alcoholics

Abstract: Five hundred and sixty-nine alcoholics were included in a double-blind placebo-controlled randomized multicenter study of the effects of Acamprosate (calcium acetylhomo-taurinate (CA), 1.3 g/day) on indicators of alcoholic relapse after withdrawal. One hundred and eighty-one patients in the CA group versus 175 in the placebo group completed the three-month study. The major efficacy criterion was plasma gamma-glutamyl transpeptidase (GGT), as an indicator of recent alcohol ingestion. This analysis was completed by criteria concordance analysis on a number of indicators of alcohol intake. Patients in both groups were similar initially. After 3 months of treatment, the patients in the CA group had significantly lower GGT (1.4±1.56 versus 2.0±3.19 times normal, P = 0.016). All significant differences ( P P > 0.05) were in favor of a superior effect of CA over placebo. The major side-effect of CA was diarrhea (present in 13% of CA patients versus 7% of placebo, P = 0.04). CA proved superior to placebo on the evolution of markers of alcohol ingestion at three months, in this large-scale multicenter study. It could be a new modality in the drug therapy of alcoholism, not involving an antabuse effect, an antidepressant action, or conditioning.

The effects of chronic ethanol consumption on hepatic mitochondrial energy metabolism.

Abstract: Chronic ethanol consumption results in a generalized depression in hepatic mitochondrial energy metabolism. Both the rate and efficiency of ATP synthesis via the oxidative phosphorylation system are decreased. Alterations in the activities of several components of the oxidative phosphorylation system contribute to the overall decrease in the capacity for ATP synthesis. There appears to be no alteration in any particular component which is rate-limiting. Although changes in membrane lipids may play a minor role, it appears that the decreased levels of mitochondria-derived polypeptide components of the oxidative phosphorylation system are primarily responsible for the depression in both the rate and efficiency of ATP synthesis. The concentrations of these mitochondrial gene products are lowered due to effects of chronic ethanol consumption on the mitochondrial translational process.

Interaction of ethanol and stress: research with experimental animals--an update.

Abstract: Research on the interaction of ethanol (ET) and stress published since 1981 is reviewed. Chronic physical stressors were found to increase the ingestion of ET compared to nonstressed animals. With foodshock, ingestion of ET decreased during the stress session but rose afterwards. The elevation of ET ingestion produced by daily immobilization was long-lasting and was related to individual initial preference for ET. Psychological stressors also increased ingestion of ET. In rat colonies, dominant rats ingested less ET, whereas submissive rats had the highest intake. Factors that modify the ingestion of ET include neonatal experience and REM sleep deprivation. Early weaning increased, while postnatal handling decreased preference for ET. The effect of postnatal handling may be influenced by genetics. Stress, applied during adult life or prenatally, modifies some, but not all, the acute effects of ET. There were marked individual differences in the interaction of ET and stress with respect to ingestion of ET. Conversely, ET may modify stress-induced behavioural and neurochemical changes. This interaction may be stressor specific. Some stressors increase the ET's effects, whereas others may decrease or not affect them. In brain, ET has been shown to lessen the stress-induced decrease in noradrenaline and 5-hydroxytryptamine (serotonin) levels and those in noradrenaline turnover and alpha 1-receptor binding. Stress-induced changes in plasma catecholamines, corticosterone, non-esterified fatty acids and amino acids, and in the decline in adrenal catecholamines are also lessened by pretreatment with ET. Possible mechanisms for the ET-stress interaction are discussed. These include mediation via the GABA-benzodiazepine-ionophore complex, endogenous opioids, the hypothalamo-pituitary-adrenocortical axis and the noradrenergic system.

Alcohol and aldehyde dehydrogenase.

Abstract: The enzymes mainly responsible for ethanol degradation in humans are liver alcohol dehydrogenases (ADH) and aldehyde dehydrogenases (ALDH). Polymorphisms occur in both enzymes, with marked differences in the steady-state kinetic constants. The Km-values for ethanol of ADH isoenzymes relevant for alcohol degradation range from 49 microM to 36 microM, and the Vmax-values from 0.6 to 10 U/mg. Expression of an inactive form of the ALDH2 isoenzyme, the so-called Oriental variant, results in impaired acetaldehyde metabolizing capacity. The differences in ethanol and acetaldehyde metabolizing activities of allelic enzyme forms may be responsible in part for the large variation in the alcohol metabolism rate in humans. Interindividual differences in the isoenzyme pattern may contribute to the genetically determined predisposition for excessive alcohol intake.

Genetic serotonin deficiency and alcohol preference in the fawn hooded rats.

Abstract: The fact that Fawn Hooded rats exhibit a genetic impairment in their normal central nervous system serotonin function suggests that they should drink significant amounts of ethanol, relative to the parent Wistar strain. In the present study we summarize our findings with respect to ethanol preference using these rats

Alcohol and membrane-associated signal transduction.

Abstract: In recent years, ethanol has been shown to interact with membrane-associated signal transduction mechanisms which rely on the reaction of phospholipases with their phospholipid substrates in the membrane. In several cell and membrane preparations, ethanol activates the polyphosphoinositide-specific phospholipase C and triggers the complete battery of intracellular signalling responses that are characteristic for hormones acting through this pathway, including the formation of inositol-1,4,5-trisphosphate, the release of Ca2+ from intracellular storage sites with the consequent activation of cytosolic Ca2+ enzymes, and the formation of diacylglycerol leading to the stimulation of protein kinase C. The activation of phospholipase C appears to be due to an interaction of ethanol with the intramembrane complex of receptor-G protein-phospholipase C, presumably promoting the release of bound GDP and the binding of GTP to activate the G-protein which controls phospholipase C activity. In many intact cells, the phospholipase C is subject to a feedback inhibitory control by protein kinase C. In liver cells, ethanol also triggers this feedback inhibition, leading to a rapid decline in the phospholipase C activation; at the same time, ethanol also causes the desensitization of the response to vasopressin and other phospholipase C-linked agonists. At hormone concentrations in the physiological range, the heterologous desensitization by ethanol of the agonist-mediated phospholipase C activation may be a significant factor at ethanol concentrations that are readily attained in vivo . Further interaction of ethanol with the intracellular second messenger system is mediated through a hormone-sensitive phospholipase D. This enzyme uses phosphatidylcholine to generate phosphatidic acid which can be further converted to diacylglycerol. In the presence of ethanol the enzyme catalyzes the transphosphatidylation to phosphatidylethanol. It is not clear, however, under what conditions this process could affect the normal pattern of formation of second messenger molecules. After chronic ethanol intake, a tolerance can develop at the cellular level to the effects of ethanol on agonist-induced signal transduction processes. However, the mechanism by which this tolerance develops is currently a matter of conjecture. Studies on liver cells indicate that the activity of protein kinase C may play a role in the development of this type of tolerance to ethanol. A better understanding of the interaction of ethanol with these phospholipid-dependent signal transduction processes could point to mechanisms by which ethanol could interfere with physiological control mechanism in a variety of cells and tissues.

The genesis of alcoholic brain tissue injury

Abstract: 1. Acetaldehyde has been implicated in the pathogenesis of alcohol-related liver damage by two mechanisms. Adduct formation with many tissue constituents, especially proteins, makes them immunologically foreign or reduces enzyme activity and formation of cytotoxic free radicals from acetaldehyde metabolism. Adduct formation damage to microtubule associated proteins and to hepatocyte membranes impedes protein movement into, out of and around the cell. 2. Evidence that these mechanisms also have a role in alcoholic brain damage includes raised blood acetaldehyde in alcoholics, especially in those chemically dependent, or in other abnormal states; effects of extra-hepatic free radical toxicity, including induction of superoxide dismutase activity and damaged, abnormal variants of the thiamin-dependent enzyme transketolase and extrahepatic acetaldehyde-adduct formation with haemoglobin. That acetaldehyde-mediated impairment of microtubule systems also damages the brain is suggested by its importance for the maintenance by protein transport of often greatly extended brain cell processes. 3. Oxygen-derived free radicals can damage brain tissue, the effects including cerebral oedema, neuronal loss and damage to the blood-brain barrier, all changes also reported in the brains from alcoholic patients. Alcohol-related pathology in the brain differing from that in the liver, shows sharper regional variations in vulnerability and adverse effects due to nutritional deficiencies, especially of B-group vitamins. Even though some such deficits are capable of causing encephalopathy in the non-alcoholic, the strong association between them and chronic alcoholism points to possible aggravation by metabolic interactions at various levels between acetaldehyde and thiamin or other B-vitamins. Selective regional vulnerability may reflect differences in ease of acetaldehyde access or to important metabolic differences. Alteration of animal behaviour by acetaldehyde points to a need to correlate clinical evidence of acetaldehyde central nervous cytotoxicity with the incidence of different types of cognitive defect.

Interaction of ethanol with drugs, hepatotoxic agents, carcinogens and vitamins

Abstract: Ethanol has been shown to have a multitude of acute and chronic interactions with xenobiotic agents, many of which can now be explained on the basis of the existence of a newly recognized microsomal ethanol oxidizing system (MEOS) involving a specific cytochrome P-450 (P450IIE1). Although such a system was proposed already two decades ago, its role was viewed with skepticism; until recently, it was commonly believed that the primary pathway for hepatic ethanol metabolism is due almost exclusively to the activity of cytosolic alcohol dehydrogenase, with a minor contribution from peroxisomal catalase. It is now recognized, however, that liver microsomes (through MEOS) participate in ethanol metabolism. The existence of this system and its inducibility contribute to the metabolic tolerance to ethanol in the alcoholic. Cross induction of other microsomal enzymes also explains the tolerance to many commonly used drugs. Most importantly, the alcohol-inducible form (P450IIE1) has a unique capacity to activate xenobiotic agents to toxic metabolites, thereby explaining the unusual susceptibility of the alcoholic to the adverse effects of other drugs, hepatotoxic agents, carcinogens and even vitamins.

Effects of a moderate dose of alcohol on blood lipids and lipoproteins postprandially and in the fasting state.

Abstract: Effects of a moderate dose of alcohol on blood lipids and lipoproteins were studied in volunteers of two age groups (20–30 and 45–55 years), each consisting of eight healthy men. The alcohol (30 g in red port and wine) was consumed during a standard dinner. Two blood samples were drawn: one in the postprandial phase, and one the next morning after fasting overnight. In the postprandial phase, one hour after intake, alcohol increased high-density lipoprotein cholesterol (HDL-C) by 11.5%, triglycerides (TG) by 15.3% and apolipoprotein A2 (Apo-A2) by 7.3% ( P = 0.002, P = 0.044 and P = 0.024, respectively). The increase in HDL-C appeared to be mainly attributed to the HDL2-C subfraction which increased by 15.3% ( P = 0.066). Furthermore, the increases in HDL-C, HDL2-C and TG were more pronounced in the middle-aged men then in the young men. After fasting overnight the effects of alcohol had disappeared.

Alcohol and bone disease.

Abstract: Alcohol is considered to be an important risk factor for various bone diseases but recent studies have shown that moderate alcohol intake can be beneficial to bone structure. Alcohol decreases osteoblastic activity, leading to decreased bone formation and defective mineralization. The changes reported in calciotropic hormones, mainly vitamin D and parathyroid hormone, are observed due in part to a deficient intestinal absorption of vitamin D and an inadequate synthesis of its hepatic metabolite, although greater emphasis has been given to dietary deficiencies or lack of exposure to sun. The changes in parathyroid hormone are not consistent and since there is no greater incidence of hyperparathyroidism in alcoholic patients, it suggests that alcohol does not have a long-term effect on the parathyroid glands. Alcohol increases calcitonin secretion acutely; calcitonin is an inhibitor of bone resorption and may be the mechanism by which moderate alcohol intake protects bone structure. Alcohol increases urinary calcium, magnesium and zinc excretion. Zinc deficiency has been postulated as a cause of oesteoporisis because it causes hypogonadism. The decrease in the levels of the gonadal hormones and the increase of cortisol, observed in chronic alcoholics, may indirectly cause osteopenia and aseptic necrosis. To these actions must be added the acidosis due to alcohol and the greater tendency of the alcoholic to fall, all of which influence bone changes and increase the incidence of bone fractures.

Alcohol and skeletal muscle disease.

Abstract: Skeletal muscle myopathy is caused by prolonged ethanol misuse and affects between half and two-thirds of chronic alcohol misusers. This chronic myopathy is characterized by a selective reduction in Type II (fast twitch) fibre area; Type I (slow twitch) fibres are relatively unaffected. The myopathy is not mediated by the patients' corticosteroid and nutritional status, liver dysfunction or neurological changes, and there is little correlation between alcoholic myopathy and alcohol intake. However, plasma alpha-tocopherol and selenium levels in myopathic alcoholics are reduced. The myopathy may in some way be related to the reduced fractional rates of skeletal muscle protein synthesis that occur in alcohol misusers and implicates free radical reactions in the pathogenesis of the myopathy. We have established a rat model of chronic alcoholic myopathy. In this model anatomically distinct skeletal muscles were taken to represent Type I (i.e. soleus) or Type II (i.e. plantaris) fibres. There were selective losses of Type II muscle protein at the end of 6 weeks of ethanol feeding. These changes were also not apparently mediated by nutritional limitations, neurological changes or liver dysfunction. Skeletal muscle protein synthesis was also reduced, as was plasma alpha tocopherol and selenium levels. Thus the rat model is amendable for further work to elucidate the molecular mechanisms responsible for alcohol-induced muscle loss.

Psychoactive substance use disorder in youth suicide.

Abstract: Fifty-eight consecutive suicides committed between 1984 and 1987 by adolescents and young adults (age 15-29 years) from an urban community were the subject of retrospective investigations through interviews with survivors and analyses of registers and medical records. Psychoactive substance use disorder in accordance with DSM-III-R was present in 47% of the youth suicides investigated, predominantly as alcohol dependence. Substance use disorder often coexisted with a borderline personality disorder or schizophrenia. Secondary depression was a frequent final factor. Dependence had developed in all females and most males. The median duration of substance use was 9 years. Substance use preceded suicidal behaviour by two years. Exposure to parental substance misuse during childhood, early parental divorce and parasuicide in the family were more frequent among subjects with substance use disorder than among other subjects. The social situation was often characterized by unemployment and legal problems. Previous inpatient care was more common than among other subjects. Language: en

The effect of interrupted alcohol supply on spontaneous alcohol consumption by rhesus monkeys.

Abstract: The alcohol supply (a 16% and a 32%, v/v, ethanol-in-water solution) for eight male rhesus monkeys, who already have had free access to water and ethanol solutions concurrently for about one year, was interrupted for 1, 2 or 7 days. The previously acquired ethanol consuming behaviour appeared very resistant to extinction, because ethanol consumption was immediately resumed after renewed access, even at a temporarily increased level. Since physical withdrawal distress was not observed and the increase was higher when interruption lasted longer, the observed behaviour could be attributed to the reinforcing effects of ethanol, leading to specific ethanol-directed behaviour.

The effects of alcohol on the female brain: a neuropathological study

Abstract: This quantitative neuropathological study compared the brains of seventeen alcoholic females with twenty non-alcoholic female controls. There was a significant (P less than 0.001) increase in the pericerebral space value (control 9.5; alcoholic 16.3) indicating shrinkage of the brain. Cerebral grey and white matter volumes were determined morphometrically. There was a significant decrease in the cerebral white matter volume (P less than .02) in the alcoholics. The cerebral grey matter volume was unchanged. These changes parallel those described previously in male alcoholics. Further studies will be necessary to establish the relative severity of the brain damage in males and females.

Effects of acute and chronic ethanol administration on thiamine metabolizing enzymes in some brain areas and in other organs of the rat

Abstract: The effect of ethanol (4.7 g/kg body wt intragastrically as a single dose or once daily for 35 days) on the levels of the thiamine metabolizing enzymes (thiamine pyrophosphokinase, TPKase; thiamine pyrophosphatase, TPPase; and monophosphatase, TMPase) was studied in different organs (liver, kidney, small intestine, heart and skeletal muscle) and nervous regions (cerebral cortex, cerebellum, medulla oblongata, pons, corpus callosum, hypothalamus and sciatic nerve) of the rat. In order to evaluate the non-specific effects of the stress of gastric gavage and of the additional caloric intake, appropriate control groups of animals were treated intragastrically with water or with a saccharose solution isoenergetic with ethanol respectively. All animals were reared on a nutritionally adequate diet supplying amounts of thiamine higher than the recommended daily requirement. Enzymatic activities were determined quantitatively by biochemical methods. Tissue TPKase levels were generally reduced by both acute and chronic ethanol administration. TPPase levels were generally reduced after acute and increased after chronic ethanol treatment. Changes in brain TMPase levels were similar to those observed for TPPase. In visceral organs and skeletal muscle TMPase activity was increased by chronic ethanol treatment as compared to acute ethanol administration. In conclusion, ethanol exerts a marked influence on the tissue levels of the thiamine metabolizing enzymes: the activity of the enzymes dephosphorylating thiamine phosphates is increased whereas the activity of the thiamine pyrophosphate synthesizing enzyme is reduced. These changes may contribute to an important extent to the disturbances in thiamine cellular uptake and metabolism observed in alcoholism.

Alcohol, sex and AIDS

Abstract: The association between alcohol consumption and AIDS risks is examined. It is concluded that chronic heavy drinking or alcohol consumption levels consistent with alcohol dependence or alcohol-related liver disease does damage the immune system. In addition alcohol consumption influences sexual behaviour for a variety of psychological, social and physical reasons. Attention is focused on the disinhibiting effects of alcohol and the popular belief that drinking may be used to facilitate or excuse otherwise unacceptable behaviour. Several studies indicate that alcohol consumption is associated with 'high risk' sexual behaviour. Accordingly drinking appears to be a risk factor for potential exposure to HIV infection and for relapse into 'high risk' sexual activities. Evidence does not support the conclusion that alcohol is a cofactor in the course of AIDS-related illnesses.

Genotyping study of alcohol dehydrogenase class i polymorphism in french patients with alcoholic cirrhosis

Abstract: Comparison of alcohol dehydrogenase polymorphism at the loci ADH2 and ADH3 is made in France between 46 alcoholic cirrhotic patients and 39 controls, by genotyping technique using polymerase chain reaction on blood microsample collected on blotting paper. The genotype distributions are similar, with low frequency of the ADH22 allele. Polymorphism at the ADH3 locus is not a genetic factor for alcoholic cirrhosis in France.

The effect of maternal ethanol infusion on placental blood flow and fetal glucose metabolism in sheep.

Abstract: Intravenous infusion of 1 g ethanol/min over 1 hr to seven catheterised pregnant ewes decreased blood flow on both sides of the placenta. The reductions in blood flow were maintained for at least 2 hr after the infusion of ethanol had ceased. Although blood flow was reduced, fetal blood gases were unchanged. Plasma glucose concentrations were unchanged by ethanol, but fetal glucose supply and consumption were both decreased following maternal ethanol infusions. If maintained by chronic alcohol consumption these changes could contribute to the growth retardation seen in the Fetal Alcohol Syndrome.

Antibodies against acetaldehyde-modified epitopes: Presence in alcoholic, non-alcoholic liver disease and control subjects

Abstract: Several studies have recently shown the presence of antibodies against acetaldehyde-modifications in the sera of alcoholic patients. To assess the specificity of this immune response, plasma immunoreactivity with proteins modified in vitro by acetaldehyde was measured using an enzyme-linked immunosorbent assay in 97 alcoholic patients with varying degrees of alcoholic liver disease, in 35 patients with non-alcoholic liver diseases and in 33 control subjects who were social drinkers. All three groups showed some response against acetaldehyde-modified epitopes. The highest plasma reactivities were found in alcoholics, especially those with steatosis and alcoholic hepatitis. Plasma from patients with non-alcoholic liver disease and control subjects also reacted with the acetaldehyde conjugates, but to a lesser extent than plasma from alcoholics. The reliability of these antibodies as markers of either alcohol abuse or alcoholic liver disease therefore appears to be low. However, further studies using more precisely modified proteins or elucidation of the classes of immunoglobulin involved in the immune response against the modified proteins may give clearer differences between the three groups.

Validity of post-mortem alcohol reports.

Abstract: The drinking behaviour of 95 consecutive men subjected to medicolegal autopsy in Helsinki was studied by interviewing a relative or friend of the deceased. Sufficient data for estimating the daily alcohol dose were obtained in 61 (64%) of the cases. Of these men, 21 (34%) were reported to drink at least an average of 80 g of alcohol daily. The validity of post-mortem alcohol reports was assessed by comparing the occurrence of alcohol-related diseases, toxicological data as well as the cause and manner of death with the reported alcohol consumption. Men whose reported daily alcohol consumption exceeded 80 g (mean 230 g) differed from men reported to drink less than 10 g (mean 3 g) in their more common incidence of positive post-mortem alcohol test (P less than 0.0005), fatty liver (P less than 0.001), enlarged liver (P less than 0.01), alcoholic hepatitis (P less than 0.05), chronic pancreatitis (P less than 0.01), and in their lower rate of death from cardiovascular diseases (P less than 0.05). The present results indicate that interviews with relatives or friends provide reliable data on the drinking behaviour of the deceased. At autopsy, the most sensitive tests coinciding with high consumption of alcohol in post-mortem alcohol reports but not with each other were positive post-mortem blood alcohol and the occurrence of fatty liver.

Teenage heavy drinkers: alcohol-related knowledge, beliefs, experiences, motivation and the social context of drinking

Abstract: During 1988 and 1989 a survey was conducted of the drinking habits and alcohol-related beliefs of a national sample of teenagers in England. Data were obtained from 6,244 respondents virtually all aged 14–16. Heavy drinkers were significantly more likely to report drinking in a mixed sex group than were other teenagers. They were also more likely than others to have drunk illegally in licensed premises, and were distinctive from other teenagers in relation to their self-reported reasons for drinking and their alcohol-related beliefs.

Endocrine consequences of alcohol abuse

Abstract: The recognized endocrine consequences of alcohol abuse are reviewed on an organ by organ basis. The organ systems for which the most information is available (liver, heart, brain) are presented first followed by those where the information base is less.

Neuroelectric processes in individuals at risk for alcoholism

Abstract: The literature dealing with electrophysiologic research in alcoholics and individuals at risk for alcoholism is reviewed. Event-related potential (ERP) differences between family history positive (FHP) and family history negative (FHN) males have been reported both prior to the ingestion of alcohol and following alcohol challenge doses. At present, the most robust of these electrophysiological findings is the lower P3 amplitude of the ERP, which has now been replicated in several laboratories. This perhaps provides a phenotypic marker, distinguishing those at risk for alcoholism.

Ro 19-4603, a benzodiazepine receptor inverse agonist, attenuates voluntary ethanol consumption in rats selectively bred for high ethanol preference.

Abstract: The effect of Ro 19-4603, a novel potent partial inverse agonist of benzodiazepine (BZ) receptors, on voluntary ethanol intake was examined in a rat line selectively bred for ethanol preference (Sardinian ethanol preferring, sP, rats). Ro 19-4603, 1 mg/kg i.p., three times daily, reduced voluntary ethanol consumption by about 40% during 7 days of treatment, but failed to reduce water intake. The results suggest that the GABA/BZ receptor complex may play a role in the reinforcing property of ethanol.

Effects of ethanol on hepatic protein trafficking: impairment of receptor-mediated endocytosis.

Abstract: Ethanol administration disorders protein trafficking in the liver. The protein secretory and plasma membrane assembly pathways have been shown to be impaired in the liver of ethanol-treated animals; however, traffic along the receptor-mediated endocytosis pathway appears to be especially susceptible to alterations by ethanol. Using asialoglycoproteins as model ligands for studying receptor-mediated endocytosis, we have identified at least three steps of this multi-step pathway that are affected by ethanol treatment. These altered steps are recycling of the receptor, internalization of the receptor-ligand complex and dissociation of the ligand from its receptor in endosomes. Ethanol-induced derangements of endocytosis are more severe in the perivenule region, where alcoholic liver injury starts and predominates, than in the periportal region of the liver. In addition, recent studies have shown that the endocytosis of other ligands, including epidermal growth factor and insulin, are also altered by ethanol treatment. Mechanisms which have been proposed to explain faulty endocytosis include: acetaldehyde adducts to tubulin resulting in impaired microtubule function, improper acidification of endosomes and defective receptor clustering in coated pits. Since receptor-mediated endocytosis by the liver represents an important process by which levels of various hormones, growth factors and other ligands are regulated, and since endocytosis may also be an integral process by which the biological effects of various ligands are elicited, changes in this important process could disrupt numerous metabolic and homeostatic events in the liver and total organism.

In vivo accelerated acetaldehyde metabolism using acetaldehyde dehydrogenase-loaded erythrocytes.

Abstract: Human erythrocytes were loaded with homogeneous acetaldehyde dehydrogenase (AcDH) purified from Alcaligenes Eutrophus (an enzyme species with an apparent Km for acetaldehyde similar to the mitochondrial enzyme), using an encapsulation procedure based on hypotonic haemolysis, isotonic reseating and reannealing. The AcDH-overloaded erythrocytes contained 1.55±0.25 I.U. of AcDH activity per ml of packed erythrocytes, a value 12–15 times higher than that of corresponding unloaded or native red cells. The AcDH-loaded erythrocytes were found to metabolize 4 ± 0.8 μmol of acetaldehyde/hr/ml of red blood cells, whereas the glycolytic activity was almost unmodified. Estimates of intracellular adenine nucleotides showed 50% ATP decay in the AcDH-loaded cells when incubated in the presence of acetaldehyde concentrations higher than 50 μM, whereas the [NAD+]/[NADH] ratio was strongly decreased but to the same extent as in control cells, suggesting that this was due to the acetaldehyde itself and not to the presence of encapsulated AcDH. Similar results were obtained using mouse erythrocytes. AcDH-overloaded mouse red blood cells from donor animals were also injected intraperitoneally into compatible recipients (Balb/C) and 80 to 85% of these were found to enter into circulation within 24 hr and to circulate with a half-life of 6–7.3 days (normal half-life 11 days). Following an acute dose of ethanol (2g/kg intraperitoneally), blood levels of acetaldehyde were significantly lower in mice receiving the AcDH-loaded erythrocytes than in controls. Blood levels of ethanol were also lower in the treated mice compared to controls. These results show that AcDH-overloaded erythrocytes can perform in vitro and in vivo as bioreactors improving alcohol and acetaldehyde metabolism, and suggest that administration of these cells to alcoholic patients could be of value in restoring to normal, or improving, alcohol and acetaldehyde metabolism.

Changes in protein, rna and dna and rates of protein synthesis in muscle-containing tissues of the mature rat in response to ethanol feeding: a comparative study of heart, small intestine and gastrocnemius muscle

Abstract: The relative sensitivity of heart, small intestine and skeletal muscle to chronic ethanol feeding was investigated in mature Wistar rats fed ethanol as 36% of total energy intake; controls were fed the same diet in which ethanol was substituted by isoenergetic glucose. 2. Chronic ethanol feeding had no apparent effect on the protein, RNA and DNA contents of heart homogenates (atria and ventricles). The ratios of RNA/protein (synthetic capacity), RNA/DNA (synthetic material per nucleus) and protein/DNA (DNA-unit or apparent cell size) were also unaltered in the hearts of alcohol-fed rats. Fractional rates of cardiac protein synthesis ( k s and synthesis relative to RNA ( k RNA) and DNA ( k DNA) and absolute rates of protein synthesis ( V s were unaffected by ethanol feeding. The total content of cardiac soluble proteins was unaltered by chronic ethanol feeding, but there were small and statistically significant decreases in the contents of the myofibrillar and stromal protein fractions. There were no differences in k s in any of the cardiac subcellular protein fractions. 3. In the small intestine, ethanol feeding had no statistically significant effect on either protein or RNA contents, but there was an apparent increase in RNA when expressed relative to either protein or DNA, though the DNA-unit was unaltered. There were also substantial decreases in k s k CRNA. K DNA and V s of approximately 15–35%. 4. In the gastrocnemius, RNA contents were significantly reduced by ethanol feeding but protein and DNA contents were unaffected. Indices of the synthetic capacity and synthetic material per nucleus were also reduced, but the DNA-unit was unaltered. These observations were accompanied by approx. 15–30% reductions in k s, k RNA, k DNA and V s in response to ethanol feeding. 5. It is concluded that various aspects of protein metabolism in the heart, small intestine and skeletal muscle are adversely affected by chronic ethanol toxicity. The characteristics and magnitude of the responses in each tissue differ. Effects in the heart may be subtle, though haemodynamic indices may ensue. The ethanol-induced alterations in the small intestine and skeletal muscle may be responsible for gastrointestinal disturbances in motility and skeletal muscle weakness, respectively.

Experimental alcoholic skeletal muscle myopathy is characterised by a rapid and sustained decrease in muscle RNA content.

Abstract: An investigation was made into the effects of ethanol feeding (36% of total calories) on skeletal muscle. From 7 to 42 days, muscle weights and protein and DNA contents of alcohol-treated rats were significantly lower (10–23%) than pair-fed controls (with glucose as 36% of total calories). Ethanol feeding markedly reduced muscle RNA content by 22–34%, when compared to controls. Muscle RNA content of ethanol-fed rats at 7, 14, 28 and 42 days of treatment was significantly lower than initial values (i.e. at 3 days) by 22–38%. Thus, ethanol feeding caused an initial net loss and thereafter a reduction in the rate of accretion of RNA. The marked and sustained loss in the muscle protein synthetic apparatus may be a precipitating event in the development of experimental skeletal muscle myopathy.