SELECTION OF LINES FOR ETHANOL THERMAL SENSITIVITY

The major long-term goal of the proposed selective breeding study is to
shed light on an ubiquitous, easily assessed response to ethanol
(hypothermia) that is useful as an index of sensitivity, tolerance and
withdrawal from physical dependence on EtOH. We have been developing an
animal model of genetic susceptibility to EtOH-induced HT. Using
within-family selective breeding, lines and replicates have been selected
for susceptibility (COLD) and resistance (HOT) to acute HT after 3 g/kg
EtOH. The continued successful selection of the proposed lines could
provide a much-needed genetic marker for predicting the susceptibility to
develop ethanol physical dependence. The first goal of the proposed experiments is to continue to develop the
HOT and COLD selected lines until response to selection has apparently
reached its maximum. At this point, genes predisposing for alcohol
sensitivity will presumably have been fixed in the homozygous state. The
second goal is to determine genetic correlates of the HT response. A
number of behavioral response to EtOH other than EtOH-induced HT, and
hypothermic response to other agents postulated to share, or not to share,
ethanol's mechanism of action will be compared in the HOT and COLD lines
each 4 generations throughout selection. As a second method for verifying
correlated response to selection, embryos from the lines will be frozen to
preserve the genetic stock at regular intervals during the course of
selection. The existence of cryopreserved embryos from each 4 generations
of selection will allow subsequent testing for correlated responses to
selection. In effect, a cross-sectional experiment can be done which
recapitulates the developmental progress of the selection program.
Cryopreservation will also provide an essential insurance policy against
the possibility of loss of the COLD and HOT lines due to fire, infectious
disease, "animal rights" activism, or other catastrophic loss. Additional
stock of the lines will be bred and be made available for researchers who
wish to perform mechanism-oriented experiments to elucidate the
physiological and/or biochemical basis for alcoholism.