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.
D000438:Alcohols / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D006993:Hypnotics and Sedatives; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D012995:Solubility; D013329:Structure-Activity Relationship; D013570:Synaptic Membranes / Q000187:drug effects*; D013574:Synaptosomes / Q000187:drug effects
D000438:Alcohols; D006993:Hypnotics and Sedatives