Identification of genetic markers for initial sensitivity and rapid tolerance to ethanol-induced ataxia using quantitative trait locus analysis in BXD recombinant inbred mice

Edward J. Gallaher, Guy E. Jones, John Belknap, John Jr Crabbe

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Rapid tolerance to rotarod ataxia has previously been demonstrated in mice after sequential ethanol injections. Here we tested DBA/2J and C57BL/6J mice for initial ethanol sensitivity; DBA/2J mice were more sensitive (0.40 ± 0.17 mg/g brain) than C57BL/6J mice (1.44 ± 0.12 mg/g). We then monitored the development of tolerance by quantifying blood ethanol concentrations at the recovery from ataxia over five sequential injections; tolerance reached a plateau in about 5 hr. DBA/2J mice became very tolerant (final ethanol threshold 3.47 ± 0.16 mg/ml, an increase of 3.07 mg/ml, or 8.7-fold above base line); B6 became slightly tolerant (final ethanol threshold 2.62 ± 12 mg/ml, an increase of 1.18, or 1.8-fold above base line). Therefore, by the end of the treatment regimen, the rank order of sensitivity of the two strains had reversed. We then tested 25 recombinant inbred strains from among strains representing a cross between C57BL/6J and DBA/2J inbred strains, followed by a quantitative trait locus analysis with a database of 1522 markers to identify provisional loci. This procedure identified 19 markers on 11 chromosomes for initial sensitivity, 18 markers on 9 chromosomes for tolerance (delta) and 21 markers on 11 chromosomes for tolerance (fold- increase). Of these, 17 markers were in common, which suggests that initial sensitivity and tolerance share substantial genetic codetermination. Major candidate loci will be confirmed by genotyping B6D2F2 offspring that have been tested for initial sensitivity and tolerance.

Original languageEnglish (US)
Pages (from-to)604-612
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume277
Issue number2
StatePublished - May 1996

Fingerprint

Quantitative Trait Loci
Ataxia
Genetic Markers
Ethanol
Inbred DBA Mouse
Chromosomes, Human, Pair 11
Inbred C57BL Mouse
Chromosomes, Human, Pair 9
Injections
Databases
Brain

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{c89c7592f9b54f5880597ff667a8893d,
title = "Identification of genetic markers for initial sensitivity and rapid tolerance to ethanol-induced ataxia using quantitative trait locus analysis in BXD recombinant inbred mice",
abstract = "Rapid tolerance to rotarod ataxia has previously been demonstrated in mice after sequential ethanol injections. Here we tested DBA/2J and C57BL/6J mice for initial ethanol sensitivity; DBA/2J mice were more sensitive (0.40 ± 0.17 mg/g brain) than C57BL/6J mice (1.44 ± 0.12 mg/g). We then monitored the development of tolerance by quantifying blood ethanol concentrations at the recovery from ataxia over five sequential injections; tolerance reached a plateau in about 5 hr. DBA/2J mice became very tolerant (final ethanol threshold 3.47 ± 0.16 mg/ml, an increase of 3.07 mg/ml, or 8.7-fold above base line); B6 became slightly tolerant (final ethanol threshold 2.62 ± 12 mg/ml, an increase of 1.18, or 1.8-fold above base line). Therefore, by the end of the treatment regimen, the rank order of sensitivity of the two strains had reversed. We then tested 25 recombinant inbred strains from among strains representing a cross between C57BL/6J and DBA/2J inbred strains, followed by a quantitative trait locus analysis with a database of 1522 markers to identify provisional loci. This procedure identified 19 markers on 11 chromosomes for initial sensitivity, 18 markers on 9 chromosomes for tolerance (delta) and 21 markers on 11 chromosomes for tolerance (fold- increase). Of these, 17 markers were in common, which suggests that initial sensitivity and tolerance share substantial genetic codetermination. Major candidate loci will be confirmed by genotyping B6D2F2 offspring that have been tested for initial sensitivity and tolerance.",
author = "Gallaher, {Edward J.} and Jones, {Guy E.} and John Belknap and Crabbe, {John Jr}",
year = "1996",
month = "5",
language = "English (US)",
volume = "277",
pages = "604--612",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - Identification of genetic markers for initial sensitivity and rapid tolerance to ethanol-induced ataxia using quantitative trait locus analysis in BXD recombinant inbred mice

AU - Gallaher, Edward J.

AU - Jones, Guy E.

AU - Belknap, John

AU - Crabbe, John Jr

PY - 1996/5

Y1 - 1996/5

N2 - Rapid tolerance to rotarod ataxia has previously been demonstrated in mice after sequential ethanol injections. Here we tested DBA/2J and C57BL/6J mice for initial ethanol sensitivity; DBA/2J mice were more sensitive (0.40 ± 0.17 mg/g brain) than C57BL/6J mice (1.44 ± 0.12 mg/g). We then monitored the development of tolerance by quantifying blood ethanol concentrations at the recovery from ataxia over five sequential injections; tolerance reached a plateau in about 5 hr. DBA/2J mice became very tolerant (final ethanol threshold 3.47 ± 0.16 mg/ml, an increase of 3.07 mg/ml, or 8.7-fold above base line); B6 became slightly tolerant (final ethanol threshold 2.62 ± 12 mg/ml, an increase of 1.18, or 1.8-fold above base line). Therefore, by the end of the treatment regimen, the rank order of sensitivity of the two strains had reversed. We then tested 25 recombinant inbred strains from among strains representing a cross between C57BL/6J and DBA/2J inbred strains, followed by a quantitative trait locus analysis with a database of 1522 markers to identify provisional loci. This procedure identified 19 markers on 11 chromosomes for initial sensitivity, 18 markers on 9 chromosomes for tolerance (delta) and 21 markers on 11 chromosomes for tolerance (fold- increase). Of these, 17 markers were in common, which suggests that initial sensitivity and tolerance share substantial genetic codetermination. Major candidate loci will be confirmed by genotyping B6D2F2 offspring that have been tested for initial sensitivity and tolerance.

AB - Rapid tolerance to rotarod ataxia has previously been demonstrated in mice after sequential ethanol injections. Here we tested DBA/2J and C57BL/6J mice for initial ethanol sensitivity; DBA/2J mice were more sensitive (0.40 ± 0.17 mg/g brain) than C57BL/6J mice (1.44 ± 0.12 mg/g). We then monitored the development of tolerance by quantifying blood ethanol concentrations at the recovery from ataxia over five sequential injections; tolerance reached a plateau in about 5 hr. DBA/2J mice became very tolerant (final ethanol threshold 3.47 ± 0.16 mg/ml, an increase of 3.07 mg/ml, or 8.7-fold above base line); B6 became slightly tolerant (final ethanol threshold 2.62 ± 12 mg/ml, an increase of 1.18, or 1.8-fold above base line). Therefore, by the end of the treatment regimen, the rank order of sensitivity of the two strains had reversed. We then tested 25 recombinant inbred strains from among strains representing a cross between C57BL/6J and DBA/2J inbred strains, followed by a quantitative trait locus analysis with a database of 1522 markers to identify provisional loci. This procedure identified 19 markers on 11 chromosomes for initial sensitivity, 18 markers on 9 chromosomes for tolerance (delta) and 21 markers on 11 chromosomes for tolerance (fold- increase). Of these, 17 markers were in common, which suggests that initial sensitivity and tolerance share substantial genetic codetermination. Major candidate loci will be confirmed by genotyping B6D2F2 offspring that have been tested for initial sensitivity and tolerance.

UR - http://www.scopus.com/inward/record.url?scp=0030439661&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030439661&partnerID=8YFLogxK

M3 - Article

C2 - 8627537

AN - SCOPUS:0030439661

VL - 277

SP - 604

EP - 612

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -