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.