Sensitivity and tolerance to ethanol in mouse lines selected for ethanol-induced hypothermia

Within-family selective breeding techniques have been used to create two li nes of mice to be insensitive (HOT) and two lines to be sensitive (COLD) to the hypothermic effects of an acute 3.0-g/kg ethanol (EtOH) injection. Pre vious studies have found HOT mice to be relatively resistant to the develop ment of tolerance to this effect, whereas COLD mice readily develop toleran ce. The breeding program is currently in selected Generation 52, and the HO T and COLD mice differ by about 10 degreesC (average of both replicates) in their selected hypothermic response. Starting with selection Generation 20 , separate lines of mice were inbred from the HOT-2 and COLD-2 selected lin es, while selection continued for the original two replicate lines of HOT a nd COLD mice. To assess whether different dose treatments would produce dif ferential tolerance development in the HOT and COLD selected lines, we admi nistered different dose regimens across 5 days to HOT and COLD mice. The CO LD mice developed tolerance while the HOT mice did not, regardless of total EtOH administered. In a separate study, we administered EtOH (3.0 g/kg) to mice for 3 days to assess a shorter tolerance paradigm. We also present he re responses to the selection dose of 3.0-g/kg EtOH in the inbred HOT (IHOT -2) and COLD (ICOLD-2) mice tested after 41 generations of brother-sister m ating. In addition, we report recent attempts to find doses of EtOH that wo uld produce an equivalent initial hypothermic response in each of the six l ines (HOT-1, COLD-1 HOT-2, COLD-2, ICOLD-2, and IHOT-2). When doses were se lected to produce similar initial hypothermic sensitivity, tolerance was te sted by giving three daily doses and examining the attenuation of the hypot hermic response on the third day. All three COLD lines developed significan t tolerance, while the HOT lines did not. The HOT and COLD mice provide a g enetic model to study mechanisms mediating acute EtOH-induced hypothermia a s well as tolerance development. (C) 2001 Elsevier Science Inc. All rights reserved.