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

Abraham A. Palmer, Michelle R. Moyer, John Jr Crabbe, Tamara Phillips

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)313-322
Number of pages10
JournalPsychopharmacology
Volume162
Issue number3
DOIs
StatePublished - 2002

Fingerprint

Pregnanolone
Induced Hypothermia
Ethanol
Hypothermia
GABA-A Receptors

Keywords

  • Allopregnanolone
  • Cross-tolerance
  • Ethanol
  • Neuroactive steroids
  • Selected lines

ASJC Scopus subject areas

  • Pharmacology

Cite this

Initial sensitivity, tolerance and cross-tolerance to allopregnanolone- and ethanol-induced hypothermia in selected mouse lines. / Palmer, Abraham A.; Moyer, Michelle R.; Crabbe, John Jr; Phillips, Tamara.

In: Psychopharmacology, Vol. 162, No. 3, 2002, p. 313-322.

Research output: Contribution to journalArticle

@article{3718f22b235a4c0b86d9e55d546a2d91,
title = "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.",
keywords = "Allopregnanolone, Cross-tolerance, Ethanol, Neuroactive steroids, Selected lines",
author = "Palmer, {Abraham A.} and Moyer, {Michelle R.} and Crabbe, {John Jr} and Tamara Phillips",
year = "2002",
doi = "10.1007/s00213-002-1106-2",
language = "English (US)",
volume = "162",
pages = "313--322",
journal = "Psychopharmacology",
issn = "0033-3158",
publisher = "Springer Verlag",
number = "3",

}

TY - JOUR

T1 - Initial sensitivity, tolerance and cross-tolerance to allopregnanolone- and ethanol-induced hypothermia in selected mouse lines

AU - Palmer, Abraham A.

AU - Moyer, Michelle R.

AU - Crabbe, John Jr

AU - Phillips, Tamara

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

KW - Allopregnanolone

KW - Cross-tolerance

KW - Ethanol

KW - Neuroactive steroids

KW - Selected lines

UR - http://www.scopus.com/inward/record.url?scp=0036020325&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036020325&partnerID=8YFLogxK

U2 - 10.1007/s00213-002-1106-2

DO - 10.1007/s00213-002-1106-2

M3 - Article

C2 - 12122490

AN - SCOPUS:0036020325

VL - 162

SP - 313

EP - 322

JO - Psychopharmacology

JF - Psychopharmacology

SN - 0033-3158

IS - 3

ER -