Initial sensitivity, tolerance and cross-tolerance to allopregnanolone- and ethanol-induced hypothermia in selected mouse lines

Rationale: Acute ethanol administration induces hypothermia in genetically susceptible animals. Tolerance to this effect may develop with repeated administration. Allopregnanolone is an endogenously produced neuroactive steroid that acts at the GABA-A receptor. We postulated that allopregnanolone would induce hypothermia, and that lines of mice selectively bred for high (COLD-1 and COLD-2) or low (HOT-1 and HOT-2) sensitivity to ethanol's hypothermic effects would also be differentially sensitive to allopregnanolone-induced hypothermia. We also postulated that tolerance would develop to these two drugs by similar mechanisms, such that tolerance to one would impart cross-tolerance to the other. Objectives: To assess sensitivity, tolerance and cross-tolerance to allopregnanolone's and ethanol's hypothermic effects in HOT-1 and 2, and COLD-1 and 2 mice. Methods: Mice were administered one of several doses of allopregnanolone each day, for 4 days, and initial sensitivity and tolerance to allopregnanolone-induced hypothermia were assessed. On day 5, ethanol was administered to assess cross-tolerance. In a separate experiment, COLD-1 and 2 mice were made tolerant to ethanol's hypothermic effects, and challenged with allopregnanolone to assess cross-tolerance. Results: COLD mice exhibited greater initial sensitivity to the hypothermic effect of allopregnanolone, as compared to HOT mice. Tolerance to allopregnanolone-induced hypothermia was greater in COLD mice than in HOT mice, but only COLD-1 mice showed cross-tolerance to ethanol. Both replicate lines of COLD mice developed tolerance following repeated administration of ethanol, but only COLD-2 mice showed cross-tolerance to allopregnanolone. Conclusions: These results demonstrate shared genetic influence over allopregnanolone and ethanol's initial hypothermic effects. They also suggest genotype-dependent differences in the mechanisms for tolerance to these two compounds.