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Results for “ethanol tolerance”

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PubMed1991

The ability of chlordiazepoxide to maintain ethanol tolerance and dependence.

Two criteria need to be satisfied in the demonstration of cross-dependence to chlordiazepoxide (CDP) in ethanol-dependent mice. These are the ability of CDP to suppress ethanol withdrawal and to maintain the dependent state. In this study, mice which had been fed chronically an ethanol diet followed by two days of CDP diet treatment had more severe CDP withdrawal signs induced by Ro15-1788 than drug-naive mice which were similarly exposed to the CDP diet treatment. The data indicate that CDP can maintain the dependent state acquired from the prior ethanol treatment. Alternatively, the prior ethanol treatment would have facilitated the development of CDP dependence, but it was not deemed likely. Three behavioral tests, namely, runway, sleep time, and drug-induced hypothermia, were used to test whether CDP could maintain the ethanol tolerance acquired from the prior ethanol treatment. The runway test showed that CDP could maintain the previously acquired ethanol tolerance. However, interpretations of the data from the sleep time and hypothermia tests are more equivocal because of factors such as peak tolerance, differential rates of development and dissipation of ethanol (or CDP) tolerance as determined by different behavioral tests.

Animals↗
PubMed2000

Phenotypic and genotypic relationships between ethanol tolerance and sensitivity in mice selectively bred for initial sensitivity to ethanol (SS and LS) or development of acute tolerance (HAFT and LAFT).

BACKGROUND: Genetically based risk for development of alcoholism in humans seems to be related to initial sensitivity and/or acute tolerance to ethanol. The genetic basis for the development of tolerance has received less attention than other ethanol-related behaviors. We have selected lines of mice, according to genetics, which are differentially sensitive to the initial hypnotic effect of ethanol (Short Sleep and Long Sleep, SS and LS) and other lines that differentially develop acute functional tolerance to ethanol (High and Low Acute Functional Tolerance, HAFT and LAFT). We review reports of the relationship between initial sensitivity and two forms of tolerance as measured using different behavioral measures and different time scales. The goal of the study was to investigate alcohol tolerance as measured by different behavioral tests conducted over different time periods and relate these variables to hypnotic sensitivity. METHODS: We investigated the phenotypic and genotypic relationships between different measures of tolerance to ethanol in the SS and LS mice. We used two measures of tolerance: (a) The time an animal can remain on a stationary dowel or roto-rod at 5-min intervals up to 30 minutes after a single low dose of ethanol (Acute Single Dose Tolerance, ASDT-dowel or ASDT-roto-rod); and (b) The difference in blood ethanol levels taken when a mouse could repeatedly regain balance on a stationary dowel or roto-rod after successive doses of ethanol (Acute Functional tolerance, AFT-dowel or AFT-roto-rod). The time course in AFT was much longer, up to 2 hours. We carried out the same studies on the High and Low Acute Functional Tolerance (HAFT and LAFT) mice. RESULTS: SS and LS mice differ in hypnotic sensitivity as measured by sleep time, and they differ in all forms of acute tolerance that were measured except in AFT-dowel. Although there were phenotypic correlations between AFT-dowel and ASDT-roto-rod in the Heterogeneous Stock (HS) of mice, provisional Quantitative Trait Loci (determined with Recombinant Inbred mice from a SS X LS cross) for the two phenotypes did not overlap, which indicated that there was little or no genetic correlation between the measures. HAFT and LAFT mice do not differ in hypnotic sensitivity as measured by sleep time measurements nor in ataxic sensitivity as measured on the dowel. The HAFT and LAFT mice both developed tolerance when tested in the 30-minute time frame, but the differences between the lines was largely in the rate of development of tolerance and not the amount developed. On the other hand, when tolerance was measured over 2 hr on the dowel or roto-rod, the HAFT and LAFT animals developed different levels of tolerance. CONCLUSIONS: We concluded that measures of tolerance depended on both the time of ethanol's action and the behavioral task used. It seemed that the measures of tolerance used in this study had different genetic bases in mice. Presumably, tolerance will also vary in humans depending on the behavioral measure, and tolerance will also have different genetic bases for the different behavioral measures in humans.

Alleles↗
PubMed2005

The slowpoke gene is necessary for rapid ethanol tolerance in Drosophila.

BACKGROUND: Ethanol is one of the most commonly used drugs in the world. We are interested in the compensatory mechanisms used by the nervous system to counter the effects of ethanol intoxication. Recently, the slowpoke BK-type calcium-activated potassium channel gene has been shown to be involved in ethanol sensitivity in Caenorhabditis elegans and in rapid tolerance to the anesthetic benzyl alcohol in Drosophila. METHODS: We used Drosophila mutants to investigate the role of slowpoke in rapid tolerance to sedation with ethanol vapor. Rapid tolerance was defined as a reduction in the sedative phase caused by a single previous sedation. The ethanol and water contents of flies were measured to determine if pharmacodynamic changes could account for tolerance. RESULTS: A saturated ethanol air stream caused sedation in <20 min and resulted in rapid tolerance that was apparent 4 hr after sedation. Two independently isolated null mutations in the slowpoke gene eliminated the capacity for tolerance. In addition, a third mutation that blocked expression specifically in the nervous system also blocked rapid tolerance. Water measurements showed that both ethanol and mock sedation caused equivalent dehydration. Furthermore, a single prior exposure to ethanol did not cause a change in the ethanol clearance rate. CONCLUSIONS: Rapid tolerance, measured as a reduction in the duration of sedation, is a pharmacokinetic response to ethanol that does not occur without slowpoke expression in the nervous system in Drosophila. The slowpoke channel must be involved in triggering or producing a homeostatic mechanism that opposes the sedative effects of ethanol.

Alleles↗
PubMed1984

Intraventricular arginine vasopressin maintains ethanol tolerance.

Tolerance to the hypnotic effect of ethanol in mice is prolonged by once daily intraventricular injections of arginine vasopressin. This action is similar to that reported previously when vasopressin was administered subcutaneously. The results indicate that maintenance of ethanol tolerance by vasopressin is a centrally mediated action of the peptide, and is not due to possible aversive properties of peripherally administered vasopressin.

Analysis of Variance↗
PubMed1998

High ethanol tolerance in young adults is associated with the low-activity variant of the promoter of the human serotonin transporter gene.

Central serotonergic neurotransmission has been implicated in the aetiology of ethanol tolerance and dependence. Cellular expression of the serotonin transporter and serotonin reuptake is modulated via a polymorphic, repetitive element in the 5'-flanking regulatory region of the serotonin transporter gene (5-HTTLPR). We report the association of the low-activity, short variant of the 5-HTTLPR with high ethanol tolerance among young adults in a case-control association study (n = 713). The low-activity 5-HTTLPR showed a significantly increased allele frequency (chi2 = 7.30; df = 2; P = 0.007) and genotype frequency among young adults (< or =26 years) with high ethanol tolerance homozygous for the short allele (chi2 = 7.58; df = 1; P = 0.02). The estimated odds ratio for the homozygous short variant compared to the homozygous long variant was 2.82 (95% CI 1.30-6.11). This indicates that the low-activity 5-HTTLPR may be involved in the neuronal mechanisms responsible for ethanol tolerance and dependence.

Adult↗
PubMed1995

Very long-chain fatty acids change the ethanol tolerance of Drosophila melanogaster larvae.

This research tested the hypothesis that long-chain saturated fatty acids increase the order of cell membranes of an organism and minimize the detrimental fluidizing effects of ethanol. Unsaturated fatty acids increase membrane fluidity and are unlikely to increase the ethanol tolerance of the organism. Both a fatty acid-free medium and media supplemented with very long-chain fatty acids (20 or more carbons) were fed to wild-type larvae of Drosophila melanogaster; larvae were then transferred to media with or without ethanol to test for effects of the fatty acids on ethanol tolerance. Ethanol decreased the percent of larvae to pupate, and lengthened larval development time. However, the percentage of pupae to reach the adult stage and the weight of adult males increased when the larvae were fed ethanol. The very long-chain, unsaturated fatty acids, arachidonic acid [20:4(n-6)] and docosatetraenoic acid [22:4(n-6)], were associated with increased larval mortality when administered in a medium supplemented with ethanol. Arachidic acid (20:0) increased the percentage of larvae to pupate under ethanol stress, decreased the development time and increased the adult weight in the presence and absence of ethanol. Behenic acid (22:0) was not effectively incorporated into phospholipids and had little effect on growth traits. Thus, the experimental results were consistent with the hypothesis.

Alcohol Dehydrogenase↗
PubMed2003

Ethanol tolerance in the yeast Saccharomyces cerevisiae is dependent on cellular oleic acid content.

In this investigation, we examined the effects of different unsaturated fatty acid compositions of Saccharomyces cerevisiae on the growth-inhibiting effects of ethanol. The unsaturated fatty acid (UFA) composition of S. cerevisiae is relatively simple, consisting almost exclusively of the mono-UFAs palmitoleic acid (Delta(9)Z-C(16:1)) and oleic acid (Delta(9)Z-C(18:1)), with the former predominating. Both UFAs are formed in S. cerevisiae by the oxygen- and NADH-dependent desaturation of palmitic acid (C(16:0)) and stearic acid (C(18:0)), respectively, catalyzed by a single integral membrane desaturase encoded by the OLE1 gene. We systematically altered the UFA composition of yeast cells in a uniform genetic background (i) by genetic complementation of a desaturase-deficient ole1 knockout strain with cDNA expression constructs encoding insect desaturases with distinct regioselectivities (i.e., Delta(9) and Delta(11)) and substrate chain-length preferences (i.e., C(16:0) and C(18:0)); and, (ii) by supplementation of the same strain with synthetic mono-UFAs. Both experimental approaches demonstrated that oleic acid is the most efficacious UFA in overcoming the toxic effects of ethanol in growing yeast cells. Furthermore, the only other UFA tested that conferred a nominal degree of ethanol tolerance is cis-vaccenic acid (Delta(11)Z-C(18:1)), whereas neither Delta(11)Z-C(16:1) nor palmitoleic acid (Delta(9)Z-C(16:1)) conferred any ethanol tolerance. We also showed that the most ethanol-tolerant transformant, which expresses the insect desaturase TniNPVE, produces twice as much oleic acid as palmitoleic acid in the absence of ethanol and undergoes a fourfold increase in the ratio of oleic acid to palmitoleic acid in response to exposure to 5% ethanol. These findings are consistent with the hypothesis that ethanol tolerance in yeast results from incorporation of oleic acid into lipid membranes, effecting a compensatory decrease in membrane fluidity that counteracts the fluidizing effects of ethanol.

Animals↗
PubMed2004

Effect of cellular inositol content on ethanol tolerance of Saccharomyces cerevisiae in sake brewing.

The effect of cellular inositol content on the ethanol tolerance of sake yeast was investigated. In a static culture of strain K901 in a synthetic medium, when cells were grown in the presence of inositol in limited amount (L-cells), the inositol content of cells decreased by one-third that of cells grown in the presence of inositol in sufficient amount (H-cells). L-cells exhibited a higher death rate constant than H-cells in the presence of 12-20% ethanol, while no difference in specific ethanol production rate in the presence of 0-18% ethanol between the two cell types was observed. L-cells leaked more intracellular components, such as nucleotides, phosphate and potassium, in the presence of ethanol than H-cells. L-cells exhibited a lower intracellular pH value than H-cells, which represented the lowering of cell vitality by the decrease in H(+) extrusion activity. Furthermore, the plasma membrane H(+)-ATPase activity of L-cells was approximately one-half of that of H-cells. Therefore, it was considered that the decrease in viability in the presence of ethanol due to inositol limitation results from the lowering of H(+)-ATPase activity, which maintains the permeability barrier of the yeast membrane, ensuring the homeostasis of ions in the cytoplasm of yeast cells. It is assumed that the lowering of H(+)-ATPase activity due to inositol limitation is caused by the change in lipid environment of the enzyme, which is affected by inositol-containing glycerophospholipids such as phosphatidylinositol (PI), because in the PI-saturated mixed micellar assay system, the difference in H(+)-ATPase activity between L- and H-cells disappeared. In the early stage of sake mash, inositol limitation lowers the ethanol tolerance due to the decrease in H(+)-ATPase activity as in static culture. In the final stage of sake mash, the disruption of the ino1 gene responsible for inositol synthesis, resulted in a decrease in cell density. Furthermore, the ino1 disruptant, which was not capable of increasing the cellular inositol level in the final stage, exhibited a significantly higher methylene blue-staining ratio than the parental strain. It was suggested that the yeast cellular inositol level is one of the important factors which contribute to the high ethanol tolerance implied by the increased cell viability in the presence of ethanol.

Journal Article↗
PubMed1993

Acquisition of ethanol tolerance in Saccharomyces cerevisiae: the key role of the mitochondrial superoxide dismutase.

Saccharomyces cerevisiae aBR10 cells are able to develop resistance to lethal ethanol concentrations (14%, v/v), by preexposure to a sublethal heat shock (37 degrees C) or ethanol stress (8%, v/v). Heat shock and 8% ethanol stress had no effect on the concentrations of glutathione [reduced (GSH) and oxidized (GSSG) forms] and on glutathione reductase and CuZn superoxide dismutase (SOD) activities, suggesting that the development of resistance to lethal ethanol concentrations is independent of these antioxidant defenses. In fact, a S. cerevisiae mutant, deficient in CuZnSOD, had an even higher ethanol tolerance, compared to the wild-type strain, and this mutation did not impair a further acquisition of ethanol tolerance. In contrast to CuZnSOD, the MnSOD activity seems to play a more important role in ethanol resistance. The MnSOD activity of the S. cerevisiae aBR10 cells increased upon exposure to heat shock or 8% ethanol. The higher tolerance to 14% ethanol in CuZnSOD deficient cells was also associated to a higher MnSOD activity, as compared to the aBR10 cells; this activity decreased during both stress pretreatments (while still higher than that observed in the wild-type strain). The results obtained suggest that maximum ethanol tolerance is attained with a MnSOD activity close to 1.0 U/mg protein. On either side of this value, the increased sensitivity of S. cerevisiae cells to 14% ethanol might be due to an inability to prevent either superoxide radical- or hydrogen peroxide-induced damages, respectively. These results are supported by the fact that a MnSOD deficiency renders yeast cells more ethanol sensitive.

Drug Resistance, Microbial↗
PubMed1980

Ethanol tolerance measured electrophysiologically in hippocampal slices and not in neuromuscular junctions from chronically ethanol-fed rats.

The electrophysiologically measured effects of perfused ethanol were examined in neuromuscular junctions and hippocampal slices removed concurrently from naive and ethanol-tolerant rats. At the neuromuscular junction, ethanol augmented the frequency height, and half-width of spontaneous miniature endplate potentials (Mepp). No tolerance was noted to these effects in junctions from ethanol-fed animals. Ethanol depressed the stratum radiatum evoked hippocampal CA1 population spike. Clearcut tolerance to this effect was noted in slices from chronically ethanol-fed animals.

Alcoholism↗
PubMed1999

Ethanol tolerance and alcohol dehydrogenase (ADH; EC 1.1.1.1) activity in species of the cardini group of Drosophila.

Ethanol tolerance, alcohol dehydrogenase (ADH; EC 1.1.1.1) activity, and tissue-specific expression were examined in species of the cardini group of Drosophila using D. melanogaster as a standard of comparison. In contrast to most fruit-breeding species, all cardini species examined, two from the cardini subgroup and five from the dunni subgroup, were ethanol sensitive (LC50 < or = 2.05%) and the mean ADH activity of males ranges from only 8 to 16% that of D. melanogaster AdhFF. Among all seven cardini species, there were small but significant differences in ethanol tolerance and ADH activity. Differences in enzyme mobility were in accordance with the proposed phylogeny for the dunni-subgroup species. ADH is expressed in the fat body and midgut. Males of D. acutilabella and of D. belladunni have significantly less ethanol tolerance and express less ADH activity than females in zymograms and histological preparations.

Adaptation, Physiological↗
PubMedDate not supplied

Genetics and ethanol tolerance.

This paper reviews some of the research on genetic bases of individual differences in ethanol tolerance of mice conducted at the Institute for Behavioral Genetics and at its predecessor laboratory at the University of California, Berkeley. Tolerance is, of course, a complex concept. Theoretical distinctions are made between tachyphylaxis and more slowly acquired tolerance and between dispositional and tissue tolerance. Pragmatically, a variety of measures (such as locomotor activity, sleep time, hypothermia) can be used to define these processes, and the different indices may yield quite different results even when they presumably indicate the same process. It is clear that an understanding of genetic influence in "ethanol tolerance" will require wide sampling of this complex domain. The work described here represents only a beginning, but it may illustrate the general approaches that are available for addressing the issue.

Alcohol Drinking↗
PubMed2005

The hangover gene defines a stress pathway required for ethanol tolerance development.

Repeated alcohol consumption leads to the development of tolerance, simply defined as an acquired resistance to the physiological and behavioural effects of the drug. This tolerance allows increased alcohol consumption, which over time leads to physical dependence and possibly addiction. Previous studies have shown that Drosophila develop ethanol tolerance, with kinetics of acquisition and dissipation that mimic those seen in mammals. This tolerance requires the catecholamine octopamine, the functional analogue of mammalian noradrenaline. Here we describe a new gene, hangover, which is required for normal development of ethanol tolerance. hangover flies are also defective in responses to environmental stressors, such as heat and the free-radical-generating agent paraquat. Using genetic epistasis tests, we show that ethanol tolerance in Drosophila relies on two distinct molecular pathways: a cellular stress pathway defined by hangover, and a parallel pathway requiring octopamine. hangover encodes a large nuclear zinc-finger protein, suggesting a role in nucleic acid binding. There is growing recognition that stress, at both the cellular and systemic levels, contributes to drug- and addiction-related behaviours in mammals. Our studies suggest that this role may be conserved across evolution.

Alcoholism↗
PubMed1992

Tolerance to adenosine's accentuation of ethanol-induced motor incoordination in ethanol-tolerant mice.

Our previously published reports have provided data that have supported a functional correlation between ethanol-induced changes in the characteristics of adenosine receptor, adenosine uptake and release in the brain, and ethanol-induced motor incoordination. The present data demonstrated a cross-tolerance between ethanol and adenosine further supporting the hypothesis that brain adenosine modulates the motor impairing effects of ethanol. Mice that received (-)-N6-cyclohexyladenosine (CHA) [0.25 mg/kg/day, intraperitoneally (ip)] for 10 days exhibited marked attenuation (cross-tolerance) to acute ethanol-induced motor incoordination compared with chronic saline (ip) controls. The attenuation of acute ethanol-induced motor incoordination was essentially same in animals that received CHA (25 ng/5 microliters/day for 10 days) by the intracerebroventricular (icv) route as opposed to the controls that chronically received artificial cerebral spinal fluid by the same route. Similarly, tolerance was exhibited to acute CHA (0.125 mg/kg ip and 12.5 ng/5 microliters icv) by animals fed liquid ethanol (19.5 g/kg/24 hr) for 10 days compared with none in the pair-fed sucrose controls. Scatchard plots using cerebellar tissue homogenates from animals given chronic CHA or chronic ethanol indicated no change in Bmax and/or Kd values for CHA binding when compared with CHA binding in tissues from their respective controls. However, a lack of any change in the binding characteristics cannot rule out the involvement of adenosine receptors in the observed cross-tolerance between ethanol and CHA. The results may suggest desensitization of adenosine A1 receptors due to chronic CHA and ethanol as an alternate possible explanation in the development of cross-tolerance between adenosine (CHA) and ethanol.

Adenosine↗