The ion current induced by the glutamate receptor agonist N-methyl-D-aspartate (NMDA) in voltage-clamped hippocampal neurons was inhibited by ethanol (EtOH). Inhibition increased in a concentration-dependent manner over the range 5 to 50 mM, a range that also produces intoxication. The amplitude of the NMDA-activated current was reduced 61 percent by 50 mM EtOH; in contrast, this concentration of EtOH reduced the amplitude of current activated by the glutamate receptor agonists kainate and quisqualate by only 18 and 15 percent, respectively. The potency for inhibition of the NMDA-activated current by several alcohols is linearly related to their intoxicating potency, suggesting that alcohol-induced inhibition of responses to NMDA receptor activation may contribute to the neural and cognitive impairments associated with intoxication.

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Ethanol inhibits NMDA-activated ion current in hippocampal neurons

Ethosomes — novel vesicular carriers for enhanced delivery: characterization and skin penetration properties

https://www.gastrojournal.org/article/0016-5085(95)90027-6/pdf

Antibiotics prevent liver injury in rats following long-term exposure to ethanol

Ethanol, at pharmacologically relevant concentrations of 20 to 100 mM, stimulates gamma-aminobutyric (GABA) receptor-mediated uptake of 36Cl-labeled chlorine into isolated brain vesicles. One drug that acts at GABA-benzodiazepine receptors, the imidazobenzodiazepine Ro15-4513, has been found to be a potent antagonist of ethanol-stimulated 36Cl- uptake into brain vesicles, but it fails to antagonize either pentobarbital- or muscimol-stimulated 36Cl- uptake. Pretreatment of rats with Ro15-4513 blocks the anticonflict activity of low doses of ethanol (but not pentobarbital) as well as the behavioral intoxication observed with higher doses of ethanol. The effects of Ro15-4513 in antagonizing ethanol-stimulated 36Cl- uptake and behavior are completely blocked by benzodiazepine receptor antagonists. However, other benzodiazepine receptor inverse agonists fail to antagonize the actions of ethanol in vitro or in vivo, suggesting a novel interaction of Ro15-4513 with the GABA receptor-coupled chloride ion channel complex. The identification of a selective benzodiazepine antagonist of ethanol-stimulated 36Cl- uptake in vitro that blocks the anxiolytic and intoxicating actions of ethanol suggests that many of the neuropharmacologic actions of ethanol may be mediated via central GABA receptors.

http://science.sciencemag.org/content/sci/234/4781/1243.full.pdf

A selective imidazobenzodiazepine antagonist of ethanol in the rat

Ethanol in vitro increased the fluidity of spin-labeled membranes from normal mice. Membranes from mice that had been subjected to long-term ethanol treatment were relatively resistant to this fluidizing effect. The data suggest that the membranes themselves had adapted to the drug, a novel form of drug tolerance.

https://science.sciencemag.org/content/sci/196/4290/684.full.pdf

Drug tolerance in biomembranes: a spin label study of the effects of ethanol

The effects of ethanol on membrane fluidity at 37° have been assessed by a sensitive electron paramagnetic resonance technique. Erythrocyte and brain membranes from DBA/2J mice were spin-labeled with 5-doxylstearic acid ( N -oxyl-49,49-dimethyloxazolidine derivative of 5-ketostearic acid). The molecular motion of the spin label was measured from the EPR spectrum by determining the order parameter S , an index of membrane fluidity. The fluidity of both erythrocyte and synaptosomal membranes was greater than that of myelin but less than that of mitochondrial membranes. The addition of low concentrations (0.02 or 0.04 M) of ethanol in vitro increased fluidity in erythrocyte, mitochondrial, and synaptosomal membranes. This fluidizing effect of ethanol was dose-related up to 0.35 M in all the membranes except myelin. These data suggest that nonlethal concentrations of ethanol may increase membrane fluidity in vivo .

Effects of low concentrations of ethanol on the fluidity of spin-labeled erythrocyte and brain membranes.

With the use of 5-doxylstearic acid as the spin probe, we previously found that low concentrations of ethanol in vitro reduced the order of mouse biomembranes and that similar membranes isolated from mice after 8 days of ethanol treatment had an elevated cholesterol content and were resistant to the in vitro disordering effect of ethanol. To localize the effects of ethanol, compare ethanol effects with temperature effects, and explore the relationship between cholesterol and ethanol, we have now measured order parameters of mouse synaptosomal plasma membranes and of multilayer vesicles composed of egg phosphatidylcholine and cholesterol, spin-labeled with 5-doxyl-, 12-doxyl-, or 16-doxylstearic acid. The bilayer was more ordered at the region monitored by the 5-doxyl than the 12- or 16-doxyl label, and was made less ordered by warming or by the addition of ethanol (0.35 M). The disordering effect of ethanol (decrease in order parameter) was greater at high temperatures than at low temperatures and was progressively reduced by the addition of cholesterol. In brain membranes, ethanol had a greater effect with 12- and 16-doxylstearic acid than with the 5-doxyl label. In phospholipid model membranes, incorporation of cholesterol increased the order parameter of 12-doxylstearic acid more than that of the 5-doxyl label. In general, the effect of ethanol was greater at high temperatures, low cholesterol concentrations, or in the interior of the membrane between the surface and the core. Ethanol may thus act most strongly in relatively disordered domains of neuronal membranes.

J. H. Chin

Papers

Effects of low concentrations of ethanol on the fluidity of spin-labeled erythrocyte and brain membranes.

Membrane-Disordering Action of Ethanol: Variation with Membrane Cholesterol Content and Depth of the Spin Label Probe