Concentration-dependent effects of ethanol in long-sleep and short-sleep mice.

Abstract

It has been observed that responses to ethanol may be altered by varying the injection concentration while keeping the dose constant, but these concentration‐dependent effects have not been well characterized. The results of the study reported here indicate that the long‐sleep (LS) and short‐sleep (SS) mice, selectively bred for ethanol‐induced narcosis at a concentration of 30% v/v, may have been selected in large part for the concentration‐dependent peripheral toxic effects of ethanol rather than ethanol's direct effects on the central nervous system. The study was designed to assess sleep time and waking blood ethanol concentration (BEC), hypothermia, and the linear decline in BEC in LS mice following an intraperitoneal injection of 3.8 g/kg of ethanol in concentrations of 190.0, 237.5, 292.3, or 380.0 mg/ml, and in SS mice following an intraperitoneal injection of 4.1 g/kg of ethanol in concentrations of 205.0, 256.2, 315.4, or 410.0 mg/ml. LS sleep time increased as a function of concentration, and mice injected with 380.0 mg/ml never regained the righting reflex. Waking BECs were significantly different for LS mice injected with the 190.0 and 292.3 mg/ml concentrations. For the SS mice, marginally significant differences were found among sleep times, and none of the animals injected with the 410.0 mg/ml regained the righting reflex. The lack of significant concentration‐dependent differences in SS waking BECs is attributable to extreme variability in the BECs of mice injected with the 315.4 mg/ml concentration. Both the LS and SS mice showed a concentration‐dependent decrease in body temperature, with the greatest temperature change observed at the highest concentrations. Maximum temperature depression occurred at 120 to 150 min postinjection in the LS mice and at 60 to 90 min postinjection in the SS. Only SS mice injected with the 205.0 or 256.2 mg/ml concentrations reethanolgained control temperature levels. The linear decline in BEC was faster at lower concentrations than at higher concentrations for LS mice. The declines in BEC for SS mice were not found to vary as a function of concentration. Concentration‐dependent differences in sleep time and hypothermia may not be due to differences in circulating levels of ethanol, but rather to slower elimination rates and/or enhanced depressant effects on peripheral organ systems. The present study supports the notion that the LS mice are more sensitive to the peripherally mediated concentration‐dependent effects of ethanol than are the SS mice. The systemic toxic effects of high ethanol concentrations may be more important in determining narcosis than previously suspected.