Functional tolerance to ethanol in mice: relationship to lipid metabolism

Abstract

The development of functional tolerance to ethanol was studied in young adult mice of the TO Swiss and C57BL strains. Ethanol administration was by intermittent inhalation for 7 h and the development of tolerance was assessed by estimating blood ethanol concentrations at successive losses of the righting reflex. The administration of (±)α-tocopherol at a dose previously shown to inhibit the effect of ethanol on peripheral phospholipid composition (750 mg kg⁻¹ i.p.) was without effect on functional tolerance. Chronic administration of DL-carnitine, 7% w/w in diet for 10 days, a treatment previously shown to prevent ethanol-induced triglyceride accumulation, was also without effect on ethanol tolerance. Administration of the cholesterol synthesis inhibitor, diazacholesterol (30 mg kg⁻¹ i.p.) 3 times per week for 3 weeks from weaning, markedly inhibited the subsequent development of functional tolerance. Administration of the inhibitor of protein synthesis, cycloheximide (300 μg kg⁻¹ i.p.) greatly inhibited the development of ethanol tolerance whereas actinomycin D (100 μg kg⁻¹ i.p.) was without effect. The results are discussed in relation to the hypothesis that ethanol cellular tolerance results from adaptation in the composition of the lipids of neuronal membranes. It is concluded that synthesis of some protein is involved in the development of cellular tolerance and also that cholesterol plays some part in the development of tolerance.