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

Abstract

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.The physical action of ethanol on cell membranes can be demonstrated in vitro by a change in the order parameter, S, ofspinlabeled biomembranes. The order parameter represents the degree of restraint imposed on molecular motion by the membrane structure in the environment of the probe. We have previously shown that addition of ethanol to spin-labeled mouse synaptosomal and erythrocyte plasma membranes in vitro disorders the membranes. This effect is concentration-related over the range 10-350 mM (1) and is stronger in the membrane core than near the surface (2). To address the question of whether the disordering is directly related to the behavioral effects of ethanol, we seek pharmacological, temporal, and genetic correlations between in vivo and in vitro responsiveness to ethanol. Pharmacological correlations are studied by comparing potencies ofdrugs in vivo and in vitro. We have shown that the membrane-disordering action of a series of aliphatic alcohols correlates well with their potency in vivo as measured by the ED50 for loss of righting reflex in mice (3). Temporal correlations are studied by comparing the time courses of altered drug sensitivity (e.g., during chronic administration) and of the in vitro effect. We have reported that membranes isolated from mice that had been treated chronically with ethanol were resistant to ethanol added in vitro, indicating that mice and membranes had developed tolerance in parallel (4).Here we report a genetic correlation. We measured the in vivo and in vitro effects of ethanol in genetically different populations of animals. We used the "long-sleep" (LS) and "shortsleep" (SS) lines of mice (5) (Boulder, CO). They were tested at age 7-9 weeks.Test of Ataxia. HS mice were randomly assigned to groups of 18 for testing on three different days. The mice were injected intraperitoneally with ethanol, 2.5 g/kg given as 25% (wt/vol) in saline. This dose produced obvious ataxia. When the mice appeared to be recovering, they were tested repeatedly by placing them on a horizontal dowel. ...

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