The effects of ethanol upon hydric balance and arterial pressure in rats: folic acid as a possible hypotensor

AimsChronic alcohol intake is related to hypertension. There are, however, few studies concerning the effect of ethanol upon hydric balance in relation to arterial pressure. Folic acid intake has beneficial effects upon the cardiovascular system decreasing hyperhomocysteinemia, however, more studies imply that it is related with other mechanisms. Therefore, we have studied the effects of chronic alcohol intake (30% v/v) upon hydric-saline balance and hypertension and have found that dietary supplementation with folic acid (8 mg/kg) improves the above parameters.Main methodsOur study used four experimental groups of rats: control, alcohol, alcohol with folic acid and control with folic acid. In all cases we measured the clearance of Na⁺, K⁺ and aldosterone; osmolarity in urine, liquid and solid ingestion; homocysteine levels in serum; cardiac frequency and arterial blood pressure.Key findingsThe alcohol intake increases serum aldosterone and homocysteine, which is reflected in an increase in arterial blood pressure. In addition, we have found that alcohol intake reduces both liquid and solid ingestion (causing a malnourishment status), the clearance of creatinine, aldosterone, Na⁺ and K⁺, and the ratio ClNa⁺/ClCr; it also increases urine osmolarity. Folic acid supplementation increases the clearance of Na⁺ and the ratio ClNa⁺/ClCr.SignificanceFolic acid intake improves the hypertension provoked by alcohol by increasing the aldosterone clearance, drastically reducing the serum levels of this hormone and thus its hypertensor effect.     

Effects of neonatal allopregnanolone manipulations and early maternal separation on adult alcohol intake and monoamine levels in ventral striatum of male rats

Changes in endogenous neonatal levels of the neurosteroid allopregnanolone (AlloP) as well as a single 24 h period of early maternal separation (EMS) on postnatal day (PND) 9 affect the development of the central nervous system (CNS), causing adolescent/adult alterations including systems and behavioural traits that could be related to vulnerability to drug abuse. In rats, some behavioural alterations caused by EMS can be neutralised by previous administration of AlloP. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP could increase adult alcohol consumption, and if EMS could change these effects. We administered AlloP or finasteride, a 5α-reductase inhibitor, from PND5 to PND9, followed by 24 h of EMS at PND9. At PND70 we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v) + glucose 3% (w/v), and glucose 3% (w/v)) for 15 days. Ventral striatum samples were obtained to determine monoamine levels. Results revealed that neonatal finasteride increased both ethanol and glucose consumption, and AlloP increased alcohol intake compared with neonatal vehicle-injected animals. The differences between neonatal groups in alcohol consumption were not found in EMS animals. In accordance, both finasteride and AlloP animals that did not suffer EMS showed lower levels of dopamine and serotonin in ventral striatum. Taken together, these results reveal that neonatal neurosteroids alterations affect alcohol intake; an effect which can be modified by subsequent EMS. Thus, these data corroborate the importance of the relationship between neonatal neurosteroids and neonatal stress for the correct CNS development.     

IGFR-I expression and structural analysis of the hard palatine mucosa in an ethanol-drinking rat strain (UChA and UChB)

The study analyzed the effects of chronic alcohol ingestion on the ultrastructure of the lining epithelium of the hard palatine mucosa of rats UChA and UChB (lines with voluntary alcohol consumption) in order to contribute to the understanding of the consequences of alcohol abuse for the morphology of the digestive system. Thirty female adult animals aged 120 days were divided into three experimental groups. (1) Ten UChA rats (genetically low ethanol consumer) with voluntary intake of 10% v/v (5.45 g/kg/day) ethanol solution and water. (2) Ten UChB (genetically high ethanol consumer) rats with voluntary intake of 10% v/v (7.16 g/kg/day) ethanol solution and water. (3) Ten Wistar rats with voluntary ad libitum water intake (control group). Both groups received Nuvital pellets ad libitum. The IGFR-I expression was intense in both experimental groups. The epithelial cells of the alcoholic rats UChA and UChB showed many alterations such as the presence of lipid droplets, altered nuclei, nuclei in corneum layer and disrupted mitochondria. It was concluded that ethanol intake induces ultrastructural lesions in the hard palatine mucosa.     

The role of cytochrome P450 2E1 on ethanol-mediated oxidative stress and HIV replication in human monocyte-derived macrophages

BackgroundAlcohol consumption is considered to be a major health problem among people living with HIV/AIDS. Our previous reports have shown that ethanol reduced intracellular concentrations of antiretroviral drugs elvitegravir and darunavir in the HIV-1-infected U1 cell line. Ethanol also increased HIV-1 replication despite the presence of elvitegravir. Our previous finding has also shown that the levels of cytochrome P450 enzyme 2E1 (CYP2E1) and oxidative stress in blood monocytes were induced, while the concentration of alcohol in the plasma was reduced in HIV-1-infected alcohol users compared to uninfected alcohol users. However, the role of CYP2E1 in ethanol-enhanced oxidative stress and HIV-1 replication is still unclear.MethodsThis study examined the chronic effects (14 days) of ethanol on HIV viral load, oxidative DNA damage, expression of CYP2E1, expression of antioxidant enzymes (AOEs), expression of reactive oxygen species (ROS) in human monocyte-derived macrophages (MDM). Further, to evaluate the role of CYP2E1 in mediating ethanol-induced viral replication, CYP2E1 siRNA and CYP2E1 selective inhibitor were used in the HIV-1-infected U1 cell line following ethanol treatment.ResultsChronic ethanol exposure demonstrated an increase in oxidative DNA damage and CYP2E1 expression in both non-infected and HIV-1-infected MDM. Our results showed that ethanol chronic exposure increased HIV-1 replication by ~3-fold in HIV-1-infected MDM. This ethanol-enhanced HIV-1 replication was associated with an increased oxidative DNA damage, an increased expression of CYP2E1, and a decreased expression of antioxidant enzyme PRDX6. In HIV-1-infected U1 cell line, we observed a decreased viral replication (~30%) and a decreased DNA damage (~100%) after repression of CYP2E1 by siRNA, upon ethanol exposure. We also observed a decreased viral replication (~25%) after inhibition of CYP2E1 by using selective CYP2E1 inhibitor.ConclusionsThe data suggest that chronic ethanol exposure increases HIV-1 replication in MDM, at least in part, through CYP2E1-mediated oxidative stress. These results are clinically relevant to potentially find effective treatment strategies for HIV-1-infected alcohol users.     

Consumption of alcohol over a long period and the oxidative metabolism of nervous and glandular structures associated with sexual activity

The aim of the present work is to find out whether nervous structures (hypothalamus, hypophysis, septal area, amygdala, caudate nucleus, anterior cortex (latero-frontal), posterior cortex (latero-occipital); and the glandular structures (testicles, adrenal gland, and seminal vesicle) involved in the regulation of the sexual behaviour of the male rat, are altered after an alcohol intake extending over 36 generations. The animals were killed by decapitation immediately after the sexual behaviour test was carried out. Then the oxidative metabolism (manometric technique) and the weight of the structures mentioned above were examined. The statistical analysis of the results showed that prolonged intake of alcohol over a period of 36 generations produces a significant increase in the consumption of O2 where the ventromedial hypothalamus, septal area, hypophysis, amygdala, caudate nucleus, and anterior cortex are concerned; whereas a significant decrease in the weight of testicles, hypophysis, and adrenal gland was observed. However the weight of the seminal vesicles underwent a significant increase after intake over a long period of ethanol when it was compared with its respective control. In view of these results the influence of alcohol on the oxidative metabolism of the lymbical structures is discussed, as is also the effect of alcohol on the reproductive system of these animals.     

Ethanol induction of acetaminophen toxicity and metabolism

Chronic consumption of moderate amounts of ethanol (10% solution in the drinking water) dramatically enhances the toxicity of acetaminophen in CF-1 mice as demonstrated by a significant decrease in the LD₅₀. The increased toxicity appears to result from an acceleration in the microsomal biotransformation of acetaminophen to a reactive intermediate. Accelerated acetaminophen metabolism in ethanol-treated animals, in turn, causes more rapid depletion of glutathione. These studies suggest a mechanism to account for the toxic synergism between chronic alcohol consumption and acute acetaminophen intake.     

Modulations of rabbit erythrocyte ATPase activities induced by in vitro and in vivo exposure to ethanol

Alcohol intake is associated with numerous degenerative disorders, and the detrimental effects of alcohol may be due to its influence on plasma membrane and cellular transport systems. The aim of the present study was to compare in vitro and in vivo effects of ethanol on rabbit erythrocyte ATPase activities and correlate them with ethanol-induced oxidative stress. Age-matched male rabbits were given 5% ethanol in 2% sucrose solution, for 6 weeks ad libitum; control animals were given tap water. Daily intake of ethanol was 5 g/kg body weight; this experimental regimen resulted in an average serum ethanol concentration of 16.77 ± 2.00 mM/l. After this period, blood was collected, serum ethanol concentration was determined and erythrocyte membranes were prepared according to the method of Post et al. Activities of Na⁺/K⁺- and Mg²⁺-ATPases were determined. Thiobarbituric acid-reactive substance (TBARS) assay was used to detect levels of lipid peroxidation, a major indicator of oxidative stress. In vitro ethanol inhibits both Na⁺/K⁺-ATPase and Mg²⁺-ATPase, but Na⁺/K⁺-ATPase is more sensitive to the ethanol-induced inhibition. Increasing concentration of ethanol increased TBARS production, but significant difference was attained only at 5 and 12.5 mM of ethanol. Chronic ethanol consumption induced significant increase in Na⁺/K⁺- and Mg²⁺-ATPase activity, and TBARS production. Our results suggest that increased ATPase activity induced by chronic ethanol consumption is due to oxidative, induced modification of membrane phospholipids and proteins, which are responsible for inhibition of ATPase activity. Increased production of TBARS induced by in vitro exposure to ethanol is not the only factor that influences ATPases activity. Further research is needed to elucidate this relationship.     

Low ethanol intake prevents salt-induced hypertension in WKY rats

Low alcohol intake in humans lowers the risk of coronary heart disease and may lower blood pressure. In hypertension, insulin resistance with altered glucose metabolism leads to increased formation of aldehydes. We have shown that chronic low alcohol intake decreased systolic blood pressure (SBP) and tissue aldehyde conjugates in spontaneously hypertensive rats and demonstrated a strong link between elevated tissue aldehyde conjugates and hypertension in salt-induced hypertensive Wistar-Kyoto (WKY) rats. This study investigated the antihypertensive effect of chronic low alcohol consumption in high salt-treated WKY rats and its effect on tissue aldehyde conjugates, platelet cytosolic free calcium ([Ca^{2 +}] _i )_,and renal vascular changes. Animals, aged 7 weeks, were divided into three groups of six animals each. The control group was given normal salt diet (0.7% NaCl) and regular drinking water; the high salt group was given a high salt diet (8% NaCl) and regular drinking water; the high salt + ethanol group was given a high salt diet and 0.25% ethanol in drinking water. After 10 weeks, SBP, platelet [Ca^{2 +}] _i , and tissue aldehyde conjugates were significantly higher in rats in the high salt group as compared with controls. Animals on high salt diets also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidney. Ethanol supplementation prevented the increase in SBP and platelet [Ca^{2 +}] _i and aldehyde conjugates in liver and aorta. Kidney aldehyde conjugates and renal vascular changes were attenuated. These results suggest that chronic low ethanol intake prevents salt-induced hypertension and attenuates renal vascular changes in WKY rats by preventing an increase in tissue aldehyde conjugates and cytosolic [Ca^{2 +}] _i .     

Effects of caffeine and bombesin on ethanol and food intake

The methylxanthine caffeine and ethyl alcohol are widely used and powerful psychotropic drugs, but their interactions are not well understood. Bombesin is a brain-gut neuropeptide which is thought to function as a neurochemical factor in the inhibitory control of voluntary alcohol ingestion. We assessed the effects of combinations of intraperitoneal (i.p.) doses of caffeine (CAF, 0.1-50 mg/kg) and bombesin (BBS, 1-10 micrograms/kg) on 5% w/v ethanol solution and food intake in deprived rats. Deprived male and female Wistar rats received access to 5% ethanol or Purina chow for 30 minutes after i.p. injections. In single doses, CAF and BBS significantly decreased both ethanol and food consumption, at 50 mg/kg and 10 micrograms/kg, respectively. CAF and BBS combinations produced infra-additive, or less-than-expected inhibitory effects on ethanol intake, but simple additive inhibitory effects on food intake. This experimental evidence suggests a reciprocal blocking of effects of CAF and BBS on ethanol intake but not food intake. Caffeine, when interacting with bombesin, increases alcohol consumption beyond expected values. Caffeine could affect the operation of endogenous satiety signals for alcohol consumption.     

Genetics of alcohol consumption in Drosophila melanogaster

Individual variation in alcohol consumption in human populations is determined by genetic, environmental, social and cultural factors. In contrast to humans, genetic contributions to complex behavioral phenotypes can be readily dissected in Drosophila, where both the genetic background and environment can be controlled and behaviors quantified through simple high‐throughput assays. Here, we measured voluntary consumption of ethanol in ～3000 individuals of each sex from an advanced intercross population derived from 37 lines of the Drosophila melanogaster Genetic Reference Panel. Extreme quantitative trait loci mapping identified 385 differentially segregating allelic variants located in or near 291 genes at P < 10^?8. The effects of single nucleotide polymorphisms associated with voluntary ethanol consumption are sex‐specific, as found for other alcohol‐related phenotypes. To assess causality, we used RNA interference knockdown or P{MiET1} mutants and their corresponding controls and functionally validated 86% of candidate genes in at least one sex. We constructed a genetic network comprised of 23 genes along with a separate trio and a pair of connected genes. Gene ontology analyses showed enrichment of developmental genes, including development of the nervous system. Furthermore, a network of human orthologs showed enrichment for signal transduction processes, protein metabolism and developmental processes, including nervous system development. Our results show that the genetic architecture that underlies variation in voluntary ethanol consumption is sexually dimorphic and partially overlaps with genetic factors that control variation in feeding behavior and alcohol sensitivity. This integrative genetic architecture is rooted in evolutionarily conserved features that can be extrapolated to human genetic interaction networks.     

Long-time alcohol intake modifies resistin secretion and expression of resistin gene in adipose tissue

Elevated serum resistin is implicated in insulin resistance associated with obesity and type 2 diabetes mellitus. Alcohol consumption interferes with the nutritional status, metabolic and hormonal activity of the drinker. Impact of ethanol intake on resistin level and resistin metabolic effects is unknown. Effect of long-time (28 days) ad libitum moderate alcohol (6% ethanol solution) intake on serum resistin and resistin mRNA level in adipose tissue of rats (A) was compared to control (C) and pair-fed (PF) animals. PF rats were fed the same caloric amount as A rats on previous day. Alcohol consumption resulted in reduction of food and energy intake, decreased body mass gain, epididymal fat pads mass and smaller adipocytes (vs. C rats). Alcohol intake significantly increased serum resistin and glucose, insulinemia remained unchanged. Systemic insulin resistance was not proved by HOMA, QUICKI and McAuley indexes, but impaired insulin effect on glucose transport in isolated adipocytes was present. Elevated serum resistin was positively correlated with glycemia (r = 0.88, p < 0.01) and negatively with fat cell size (r = -0.73, p < 0.05). High resistin level as the consequence of long-time alcohol intake could contribute to smaller adipocytes, higher glycemia, attenuation of insulin-stimulated glucose transport in adipocytes. Diminished resistin gene expression in adipose tissue of A and PF rats was present.     

Antihypertensive effect of low ethanol intake in spontaneously hypertensive rats

Light to moderate drinking in humans lowers the risk of coronary heart disease and may lower blood pressure. We examined the effect of chronic low daily alcohol consumption on blood pressure, platelet cytosolic free calcium [Ca²⁺]_i, tissue aldehyde conjugates and renal vascular changes in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). We also examined the effects of the same weekly amount of alcohol consumption over a one day period each week simulating weekend drinking in humans. Animals, age 7 weeks, were divided into six groups of six animals each and were treated as follows: WKY and SHR control, normal drinking water; WKY and SHR, 0.5% ethanol in drinking water; WKY and SHR, 3.5% ethanol in drinking water one day/week. After 14 weeks systolic blood pressure, platelet [Ca²⁺]_i, liver, kidney and aortic aldehyde conjugates were significantly higher (p < 0.05) in untreated SHRs as compared to untreated WKYs. Daily 0.5% ethanol consumption in SHRs significantly (p < 0.05) attenuated these changes and also attenuated smooth muscle cell hyperplasia and narrowing of the lumen in small arteries and arterioles of the kidney. WKY rats treated with 0.5% ethanol had lower aldehyde conjugates without any significant effect on blood pressure and platelet [Ca²⁺]_i as compared to WKY controls. Consumption of 3.5% ethanol one day/week did not affect blood pressure and associated changes in normotensive WKY rats or hypertensive SHRs as compared to their respective controls. These results suggest that chronic daily low ethanol intake lowers blood pressure in SHRs by lowering tissue aldehyde conjugates and cytosolic free calcium.     

S-Allyl-L-cysteine sulfoxide,a garlic odor precursor,suppresses elevation in blood ethanol concentration by accelerating ethanol metabolism and preventing ethanol absorption from gut

Abstract

Alcoholic beverages are enjoyed together with meals worldwide, but their excessive intake is associated with an increased risk of various diseases. We investigated whether S-allyl-L-cysteine sulfoxide (ACSO), a sulfuric odor precursor of garlic, suppresses elevation in plasma ethanol concentration by accelerating ethanol metabolism and preventing ethanol absorption from the gut in rats. ACSO and garlic extract with a high ACSO content (Garlic-H) suppressed elevation in concentrations of ethanol and acetaldehyde in plasma and promoted the activities of alcohol dehydrogenase and aldehyde dehydrogenase. However, ACSO and Garlic-H did not affect plasma acetate so much. Furthermore, we examined the change in plasma ethanol concentration by injecting ACSO or Garlic-H into the ligated stomach or jejunum together with ethanol solution. ACSO and Garlic-H suppressed the absorption of ethanol from the stomach and jejunum, but suppression in the jejunum was less than in the stomach. In conclusion, ACSO inhibits ethanol absorption and accelerates ethanol metabolism.     

Metabolic alterations produced in the liver by chronic ethanol administration. Increased oxidative capacity

1. Administration of ethanol (14g/day per kg) for 21–26 days to rats increases the ability of the animals to metabolize ethanol, without concomitant changes in the activities of liver alcohol dehydrogenase or catalase. 2. Liver slices from rats chronically treated with ethanol showed a significant increase (40–60%) in the rate of O₂ consumption over that of slices from control animals. The effect of uncoupling agents such as dinitrophenol and arsenate was completely lost after chronic treatment with ethanol. 3. Isolated mitochondria prepared from animals chronically treated with ethanol showed no changes in state 3 or state 4 respiration, ADP/O ratio, respiratory control ratio or in the dinitrophenol effect when succinate was used as substrate. With β-hydroxybutyrate as substrate a small but statistically significant decrease was found in the ADP/O ratio but not in the other parameters or in the dinitrophenol effect. Further, no changes in mitochondrial Mg²⁺-activated adenosine triphosphatase, dinitrophenol-activated adenosine triphosphatase or in the dinitrophenol-activated adenosine triphosphatase/Mg²⁺-activated adenosine triphosphatase ratio were found as a result of the chronic ethanol treatment. 4. Liver microsomal NADPH oxidase activity, a H₂O₂-producing system, was increased by 80–100% by chronic ethanol treatment. Oxidation of formate to CO₂ in vivo was also increased in these animals. The increase in formate metabolism could theoretically be accounted for by an increased production of H₂O₂ by the NADPH oxidase system plus formate peroxidation by catalase. However, an increased production of H₂O₂ and oxidation of ethanol by the catalase system could not account for more than 10–20% of the increased ethanol metabolism in the animals chronically treated with ethanol. 5. Results presented indicate that chronic ethanol ingestion results in a faster mitochondrial O₂ consumption in situ suggesting a faster NADH reoxidation. Although only a minor change in mitochondrial coupling was observed with isolated mitochondria, the possibility of an uncoupling in the intact cell cannot be completely discarded. Regardless of the mechanism, these changes could lead to an increased metabolism of ethanol and of other endogenous substrates.     

The effects of stress on alcohol consumption: mild acute and sub-chronic stressors differentially affect apomorphine susceptible and unsusceptible rats

The aim of this study was to investigate the effects of mild acute and mild sub-chronic challenges on alcohol intake and preference in the genetically selected ratlines of apomorphine susceptible (APO-SUS) and apomorphine unsusceptible (APO-UNSUS) animals. Animals from both lines were subjected to the 24 hr continuous alcohol vs. water paradigm under baseline conditions, after a single stressor and after multiple stressors. The intake of alcohol in ml was measured and converted to two values, namely intake in g/kg/24 hour of, and preference for, alcohol. This study shows that under baseline conditions the APO-UNSUS animals consume/prefer more alcohol than the APO-SUS animals. After an acute challenge the APO-SUS animals show a large increase in consumption, whereas the APO-UNSUS animals display only a small increase. Furthermore, sub-chronic challenges can further increase the consumption of the APO-UNSUS rat, but not that of the APO-SUS rat. The APO-SUS/ APO-UNSUS rats represent a good model to study the interaction between genetic factors and stress on directing alcohol consumption.     

Alcohol consumption and lung cancer risk: A pooled analysis from the International Lung Cancer Consortium and the SYNERGY study

BackgroundThere is inadequate evidence to determine whether there is an effect of alcohol consumption on lung cancer risk. We conducted a pooled analysis of data from the International Lung Cancer Consortium and the SYNERGY study to investigate this possible association by type of beverage with adjustment for other potential confounders.MethodsTwenty one case-control studies and one cohort study with alcohol-intake data obtained from questionnaires were included in this pooled analysis (19,149 cases and 362,340 controls). Adjusted odds ratios (OR) or hazard ratios (HR) with corresponding 95% confidence intervals (CI) were estimated for each measure of alcohol consumption. Effect estimates were combined using random or fixed-effects models where appropriate. Associations were examined for overall lung cancer and by histological type.ResultsWe observed an inverse association between overall risk of lung cancer and consumption of alcoholic beverages compared to non-drinkers, but the association was not monotonic. The lowest risk was observed for persons who consumed 10–19.9 g/day ethanol (OR vs. non-drinkers = 0.78; 95% CI: 0.67, 0.91), where 1 drink is approximately 12–15 g. This J-shaped association was most prominent for squamous cell carcinoma (SCC). The association with all lung cancer varied little by type of alcoholic beverage, but there were notable differences for SCC. We observed an association with beer intake (OR for ≥20 g/day vs nondrinker = 1.42; 95% CI: 1.06, 1.90).ConclusionsWhether the non-monotonic associations we observed or the positive association between beer drinking and squamous cell carcinoma reflect real effects await future analyses and insights about possible biological mechanisms.     

Chronic alcoholization-induced damage to astroglia and intensification of lipid peroxidation in the rat brain: Protector effect of hydrated form of fullerene C<Subscript>60</Subscript>

We studied the intensity of lipid peroxidation (LP) and the amount of a marker of astrocytes (glial fibrillary acidic protein, GFAP) in tissues of the rat brain under conditions of long-lasting consumption (12 weeks) of ethyl alcohol, as well as the protective effects of peroral administration of hydrated forms of fullerene ?₆₀ (?₆₀HyFn, FWS, fullerene water solutions). Consumption of ethanol resulted in a rise in the amount of molecular markers of oxidative stress (thiobarbiturate-active compounds) in the cerebral tissues. The level of the filamentous GFAP form in the hippocampus and cerebral cortex of alcoholized animals decreased significantly, which can be a result of death of the population of GFAP-imunnoreactive astrocytes in the brain. In the brain of rats after systematic consumption of both ethanol and an aqueous solution of hydrated fullerenes ?₆₀, the amounts of products of lipid peroxidation and of the astroglial marker did not differ significantly from the respective indices in the control animals. Our data demonstrate the efficiency of hydrated fullerenes as pathogenetic therapeutic remedies for elimination of the negative effects of ethyl alcohol on the CNS.     

Interactions between taurine and ethanol in the central nervous system

Summary.  This purpose of this review will be to summarize the interactions between the endogenous amino acid taurine and ethyl alcohol (ethanol) in the central nervous system (CNS). Taurine is one of the most abundant amino acids in the CNS and plays an integral role in physiological processes such as osmoregulation, neuroprotection and neuromodulation. Both taurine and ethanol exert positive allosteric modulatory effects on neuronal ligand-gated chloride channels (i.e., GABA_A and glycine receptors) as well as inhibitory effects on other ligand- and voltage-gated cation channels (i.e., NMDA and Ca²⁺ channels). Behavioral evidence suggests that taurine can alter the locomotor stimulatory, sedating, and motivational effects of ethanol in a strongly dose-dependent manner. Microdialysis studies have revealed that ethanol elevates extracellular levels of taurine in numerous brain regions, although the functional consequences of this phenomenon are currently unknown. Finally, taurine and several related molecules including the homotaurine derivative acamprosate (calcium acetylhomotaurinate) can reduce ethanol self-administration and relapse to drinking in both animals and humans. Taken together, these data suggest that the endogenous taurine system may be an important modulator of effects of ethanol on the nervous system, and may represent a novel therapeutic avenue for the development of medications to treat alcohol abuse and alcoholism. Received November 21, 2001 Accepted January 4, 2002 Published online August 20, 2002 Acknowledgements This work was supported by funds from the State of California for medical research on alcohol and substance abuse through the University of California at San Francisco. The author wishes to thank Drs. C. W. Hodge and P. H. Janak for their support and helpful discussions. Author's address: Dr. M. Foster Olive, Ernest Gallo Clinic and Research Center, Department of Neurology, University of California at San Francisco, 5858 Horton Street, Suite 200, Emeryville, California, U.S.A., Fax +1/510/985 3101, E-mail: folive@itsa.ucsf.edu     

Effect of the destruction of the brain serotoninergic system on the alcohol consumption by rats in the early periods of experimental alcoholism

Albino noninbred rats were divided into groups, according to the duration of alcoholic anesthesia (4.5 g/kg i.p.), of predisposed (195.6 min) and non-predisposed (69.1 min) to voluntary intake of alcohol. Another group included animals screened for 21 days according to the level of intake of 15% ethanol under the conditions of free choice between alcohol and water (6.15 and 2.62 g/kg pure ethanol per day, respectively). The animals were subjected to electro-coagulation of the dorsal or magnus raphe nucleus or were injected with 5,6-dihydroxytryptamine--DNT (75 micrograms/microliters) into the ventricles of the brain. It was established that in rats non-predisposed to alcohol intake, the destruction of the raphe nuclei, of the dorsal in particular, or injection of DOT to animals with a weak alcoholic motivation produces a dramatic increase in alcohol intake. In alcohol intake predisposed rats and in animals with a high level of alcohol use, analogous exposures do not bring about any significant differences in alcohol intake. The data obtained indicate that the reduced serotonin content in the brain is associated with an increase in the level of alcoholic motivation.