Search PubMed⌕ Search

Biomedical subjects

D B Goldstein

Publications and source records attributed to D B Goldstein.

At least 73 records · Page 4Linked to original sources
PubMed1983

Increased surface glycoconjugates of synaptic membranes in mice during chronic ethanol treatment.

Synaptosomal plasma membranes from mice treated chronically with ethanol were incubated with galactose oxidase and [3H]-sodium borohydride, in order to label the exposed galactose and N-acetylgalactosamine groups of glycoconjugates. The ethanol treatment approximately doubled the amount of exposed sugars. This change may be related to previously observed alterations in the physical properties of neuronal membranes in ethanol-treated mice.

Acetylgalactosamine↗
PubMed1983

Time course of functional tolerance produced in mice by inhalation of ethanol.

Continuing our characterization of the ethanol inhalation model for chronic ethanol administration, we have now measured the magnitude and time course of functional tolerance, for comparison with physical dependence and with biochemical and biophysical studies of tissues taken from alcohol-treated mice. Ethanol was administered to mice by inhalation for 1 to 9 days, using pyrazole to maintain continuously elevated blood ethanol levels. At different times after termination of the ethanol administration, a test dose of ethanol was administered by injection and the sensitivity of the mice was assessed by measuring the brain concentration of ethanol at which the animals lost their balance on a horizontal rod. Tolerance, tested at 6 hr after withdrawal and expressed as a ratio of brain ethanol concentrations of mice that had been chronically treated with ethanol and their controls, was measurable after only 1 day of ethanol treatment and increased further in experiments of 3 and 6 days duration, but did not continue to increment during 9 days of alcohol inhalation. The tolerance disappeared rapidly after withdrawal; it was maximal at the earliest test; 2 hr after withdrawal, but decayed progressively and was no longer appreciable 30 hr after withdrawal. The method is suitable for accurate measurement of ethanol sensitivity, even when residual alcohol remains from the chronic treatment.

Aerosols↗
PubMed1983

Changes in synaptic membrane order associated with chronic ethanol treatment in mice.

The fluidity of brain synaptosomal plasma membranes (SPM) from ethanol-treated mice and control mice was investigated by a sensitive EPR technique. Mice were made tolerant to and physically dependent on ethanol by 3 days of continuous exposure to ethanol vapor. Daily injections of pyrazole were used to stabilize the blood alcohol levels. At the time of withdrawal, SPM were prepared and spin-labeled with 5-, 12-, or 16-doxylstearic acid. "Baseline" order parameters were measured in the absence of added alcohol. The chronic ethanol treatment produced a significant increase in the baseline order parameter that could be detected with the 12-doxyl probe. This indicates a more rigid membrane associated with the withdrawal hyperexicitability. Baseline order parameters measured with the 5-doxyl probe (near the bilayer surface) or with the 16-doxyl probe (near the bilayer interior) were not affected by the chronic ethanol treatment. When ethanol or t-butanol was added in vitro to membranes labeled with the 5- or 12-doxyl probe, a membrane component of tolerance was revealed; that is, the SPM from ethanol-treated mice required more alcohol to reduce the membrane to a given disordered state. The SPM content of cholesterol and phospholipid was not affected by the chronic ethanol treatment.

Animals↗
PubMed1982

The rapid onset of tolerance to ataxic effects of ethanol in mice.

We have developed a precise quantal method for assessing the sensitivity to ethanol in the mouse. Mice placed on a clamped stationary horizontal dowel are scored ataxic or not ataxic depending on whether they are able to remain on the dowel during a 30-s observation period. A threshold blood ethanol concentration is determined by assaying tail blood drawn immediately upon recovery from ethanol-induced ataxia. This threshold is quite reproducible within a population of Swiss-Webster mice (coefficient of variation 9%). The precision of this method allowed us to follow the onset of rapid tolerance during a series of sequential IP ethanol doses. Tolerance persisted overnight in the absence of ethanol, and was found not to increase further with additional ethanol exposure on 2 subsequent days. The observed tolerance was shown not to be due to circadian changes in ethanol sensitivity or repeated practice on the task, indicating a true tissue tolerance.

Animals↗
PubMed1982

Ethanol disordering of spin-labeled mouse brain membranes: correlation with genetically determined ethanol sensitivity of mice.

Disordering of brain and erythrocyte membranes by ethanol in vitro was measured by ESR using 5-doxylstearic acid as spin label. Synaptosomal plasma membranes and erythrocyte membranes were isolated from two lines of mice developed, by selective breeding, for differential sensitivity to hypnotic effects of ethanol. Membranes taken from alcohol-sensitive "long-sleep" mice were more strongly disordered by ethanol in vitro than were membranes from alcohol-resistant "short-sleep" mice. Furthermore, within a population of genetically heterogeneous mice, the most ethanol-sensitive animals had the most ethanol-sensitive synaptosomal plasma membranes. In vivo sensitivity of the individual mice was evaluated by measuring brain ethanol levels at a precise behavioral end point, recovery from ataxia. The data extend our previous observations of correlations between in vitro and in vivo effects of ethanol and suggest that membrane disordering may be a primary mechanism of acute effects of ethanol.

Animals↗
PubMed1982

Movement of free cholesterol from lipoproteins or lipid vesicles into erythrocytes. Acceleration by ethanol in vitro.

Human erythrocytes were incubated with heat-inactivated plasma, and the transfer of cholesterol to the red cells was followed to equilibrium over 24 hr. When cholesterol-enriched plasma was used, there was a net flow of sterol into red cells. Ethanol, in a concentration-related manner, accelerated the cholesterol transfer without appreciably affecting the final sterol content of the erythrocytes at equilibrium. Ethanol also accelerated the exchange of tritiated cholesterol between normal or cholesterol-enriched plasma and red cells, whether or not there was a net cholesterol flow. Ethanol speeded up sterol transfer from several cholesterol donors, including prelabeled erythrocytes, low-density lipoproteins, high-density lipoproteins, and egg lecithin vesicles. Ethanol (0.35 M) increased the rate constant of the transfer by about 30-40% with different sterol donors. These observations may be related to the previously reported increase in cholesterol in the brain and red cell membranes of mice after chronic treatment with ethanol.

Cholesterol↗
PubMed1982

Rapidly developing functional tolerance to ethanol is accompanied by increased erythrocyte cholesterol in mice.

We investigated the time course for development of functional tolerance to the ataxic effects of ethanol in four genetically distinct mouse populations. Two inbred-strains (C57BL/6J and DBA/2J) and two lines of mice (long-sleep and short-sleep) selectively bred for differences in acute ethanol sensitivity were used. Mice were injected i.p. with ethanol in doses that produced ataxia and were tested repeatedly for their ability to balance on a wooden rod. When they regained their balance at threshold, brain ethanol levels were measured in some mice and booster injections of ethanol were administered to the remaining animals. This sequence was repeated for five injections, delivering a total of 6 g/kg of ethanol to the final group of animals. Functional tolerance developed in all four populations of mice as evidence by threshold brain ethanol levels that were significantly higher after two or three successive injections than after one injection. The magnitude of tolerance was not increased by practice on the dowel. To investigate whether alterations in membrane lipid composition accompanied this rapid development of tolerance, we used erythrocytes as a model system and measured the cholesterol and phospholipid content of their membranes. The erythrocyte membranes from ethanol-tolerant mice of each population contained more cholesterol than those from controls. The erythrocyte membrane phospholipid content of ethanol-tolerant animals changed only slightly in two populations.

Animals↗
PubMed1981

Interaction of ethanol with biological membranes.

Ethanol is among the drugs with anesthetic potency determined by lipid solubility, in accord with the Meyer-Overton hypothesis. Thus, it is likely that ethanol acts in a hydrophobic environment. Using electron paramagnetic resonance with 5-doxylstearic acid as spin label, we find that ethanol disorders mouse cell membranes, making the lipid matrix more fluid. We surmise that consequent disruption of the function of integral membrane proteins may be the cause of ethanol's central actions. When mice are treated for 8 days with ethanol, their membranes become tolerant to the disordering effect of ethanol. This tolerance is accompanied by an increased proportion of cholesterol in the membranes.

Animals↗
PubMed1981

A relationship between alcohol intoxication and the disordering of brain membranes by a series of short-chain alcohols.

This study has established a correlation between the hypnotic potencies of aliphatic alcohols and their abilities to disrupt the structure of neuronal membranes in vitro. The hypnotic potency was determined in mice from the ED50 for loss of righting reflex. The alcohol-induced perturbation of mouse brain synaptosomal plasma membranes was measured by a sensitive electron paramagnetic resonance technique. The membrane disordering potency was determined from the slope of the concentration-dependent decrease in order parameter observed for each alcohol. Significant reductions in the order parameter were observed at nerve blocking concentrations. The following alcohols were investigated: ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 3-methyl-1-butanol, 1-hexanol and 1-octanol. The disordering potency of each alcohol was closely related to its membrane solubility, based on published oil/water partition coefficients. Structural disorganization resulting from the incorporation of alcohols into neuronal membranes may be an integral step in the mechanism of alcohol intoxication. For a given degree of membrane disorder, intramembrane alcohol concentrations and intramembrane alcohol volumes were estimated from published partitioning and molecular volume data and compared for constancy. The data did not favor either the intramembrane drug concentration or the intramembrane drug volume as a more effectual determinant of disordering potency.

Alcohols↗
PubMed1980

Effects of aliphatic alcohols and aldehydes on fluidity of spin-labeled synaptosomal plasma membranes.

Synaptosomal plasma membranes from Swiss-Webster mice were spin-labeled with 5-doxylstearic acid. By electron paramagnetic resonance techniques an order parameter was measured. A decrease in the order parameter reflected an increase in membrane fluidity. In confirmation of our previous work, ethanol decreased membrane order. Pentanol also showed a concentration-related decrease in the order parameter in the range of 23 to 87 mM. At equimolar concentrations, pentanol was about 9 times more effective than ethanol. Acetaldehyde had no effect on membrane fluidity at concentrations that might be found in vivo during ethanol oxidation (23 or 227 microM) but a very high concentration, 2.3 mM, produced a small decrease in the order parameter comparable to the effect of an intoxicating concentration of ethanol. Valeraldehyde also had a slight fluidizing effect and appeared very roughly three times more potent than acetaldehyde. This study shows that the fluidizing effects of ethanol are not shared by its aldehyde metabolite at relevant concentrations. The fluidizing effects of aldehydes are slight but they increase with concentration and with chain length.

Alcohols↗
PubMed1979

Fluidity and lipid composition of mouse biomembranes during adaptation to ethanol.

Showing that ethanol added in vitro increased the fluidity of mouse erythrocyte and synaptosomal membranes and that the same membranes isolated from mice after chronic treatment with ethanol had increased cholesterol and were resistant to ethanol in vitro, the study suggests that the animals had adapted to the chronic presence of the drug by changing their membrane lipid composition to offset the fluidizing effects of ethanol.

Animals↗
PubMed1979

Sodium bromide and sodium valproate: effective suppressants of ethanol withdrawal reactions in mice.

Mice were made physically dependent on ethanol by a 3-day alcohol inhalation regimen, using pyrazole to stabilize blood ethanol concentrations. After withdrawal, convulsions elicited by handling were scored repeatedly for 30 hr as a measure of central nervous system hyperexcitability. Administration of sodium bromide, 0.2 to 2.0 g/kg i.p., suppressed the convulsions in a dose-related fashion. Bromide was effective at subsedative doses. However, bromide increased the postwithdrawal mortality. Bromide may act at chloride channels, as gamma-aminobutyric acid does. Valproate and its amide temporarily suppressed the withdrawal reaction at doses that caused some sedation. Muscimol and beta-alanine had no effect.

Alcoholism↗