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


OBJECTIVE
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.
Portland Alcohol Research Center, Portland, OR 97201, USA.
Abraham A
AA
Palmer
Michelle R
MR
Moyer
John C
JC
Crabbe
Tamara J
TJ
Phillips
D000818:Animals; D001831:Body Temperature / Q000187:drug effects* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000235:genetics; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D005838:Genotype; D012739:Gonadal Steroid Hormones / Q000494:pharmacology; D007036:Hypothermia, Induced; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011280:Pregnanolone / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D013045:Species Specificity; D013997:Time Factors
D012739:Gonadal Steroid Hormones; D000431:Ethanol; D011280:Pregnanolone