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

Abstract：

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.

journal_name

Psychopharmacology (Berl)

journal_title

Psychopharmacology

authors

Palmer AA,Moyer MR,Crabbe JC,Phillips TJ

doi

10.1007/s00213-002-1106-2

subject

Has Abstract

pub_date

2002-07-01 00:00:00

pages

313-22

issue

eissn

0033-3158

issn

1432-2072

journal_volume

162

pub_type

杂志文章

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