Sensitivity and tolerance to ethanol in mice bred to be genetically prone or resistant to ethanol withdrawal seizures

Mice genetically susceptible (withdrawal seizure prone; WSP) and resistant (withdrawal seizure resistant; WSR) to ethanol (EtOH) withdrawal convulsions have been developed by selective breeding. WSP mice show much more severe EtOH withdrawal than WSR mice after equal intensities of exposure to EtOH. The present experiments report a systematic comparison between WSP and WSR mice with respect to their neurosensitivity to two effects of EtOH, EtOH-induced hypothermia (HT) and loss of righting reflex (RR). The degree of tolerance developed to these effects was also compared between the lines. WSP and WSR mice did not differ in sensitivity to EtOH-induced HT. When EtOH was administered daily for 3 days, both lines developed tolerance as evidenced by attenuated HT, but there was no line difference. Because blood EtOH concentrations did not change, the tolerance was functional rather than pharmacokinetic. When twice-daily injections were given for 4 days before testing on the 5th day in an effort to increase the degree of tolerance achieved, functional tolerance was slightly greater in the WSR line than in the WSP line 90 to 120 min, but not 30 to 60 min, after EtOH. In similar experiments, WSP and WSR mice were found to have the same ED₅₀ to EtOH-induced loss of RR. The brain EtOH concentrations of WSP and WSR mice were the same at the time RR was lost and at the time RR was regained. Thus, neither line developed acute functional tolerance to this effect of EtOH. WSR mice lost RR more quickly than WSP mice. Chronic daily injections of EtOH for 3 days revealed that tolerance to this measure of EtOH sensitivity developed equally in both lines. No tolerance was seen in duration of loss of RR or in blood EtOH concentration at time of regaining RR. Increasing the intensity of the tolerance-inducing regimen to twice-daily injections for 4 days succeeded in inducing significant tolerance in duration of loss of RR in both lines. Because blood EtOH concentration at time of regaining RR did not change, this tolerance was presumed to be pharmacokinetic. Tolerance in both lines in latency to lose RR was seen to an equal degree. The authors conclude that intense selection of EtOH withdrawal severity differences has produced mouse lines that do not differ markedly in neurosensitivity to two effects of EtOH. Furthermore, the lines do not differ in degree of functional tolerance to EtOH-induced HT. Finally, the lines do not differ in tolerance to EtOH-induced loss of RR.