Characterization of acute functional tolerance to the hypnotic effects of ethanol in mice

Background: Acute functional tolerance (AFT) to ethanol-induced hypnosis is one of the main factors that affect the duration of ethanol-induced loss of righting reflex (LRR: sleep time). Investigators who use duration of LRR as a measure of ethanol-induced sedation should consider the potential magnitude and time course of this neuroadaptation when interpreting their results. However, AFT to the hypnotic effects of ethanol has not been well characterized. The present study explored this form of AFT using a novel method of monitoring LRR in mice. Methods: Genetically heterogeneous mice were used to study effects of dose and time on the development of AFT. Mice were treated with different dose regimens and tested for LRR after hypnotic doses using a cylindrical restrainer. Measures of initial sensitivity and AFT to ethanol-induced hypnosis were calculated and analyzed. Inbred strains of mice were then characterized for AFT magnitude after a single ethanol dose. Results: Results showed that (a) AFT developed in a dose-dependent fashion but attained an apparent maximum value; (b) AFT to ethanol-induced hypnosis could develop partially after a small, subhypnotic dose; (c) AFT developed very rapidly and approached its maximum for a given dose by the 10th min after injection of ethanol; and (d) AFT has a strong genetic component. Conclusion: Although specific for AFT to the hypnotic effects of ethanol, the present findings expand general knowledge about acute tolerance and should also be useful for investigators who use loss of righting reflex as a measure of ethanol sensitivity.