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Mapping murine loci for physical dependence on ethanol.

Kari J Buck1, Brooks S Rademacher, Pamela Metten

  • 1Portland Alcohol Research Center, and Department of Behavioral Neuroscience, Oregon Health & Science University, VA Medical Center, Research Service (mailcode RD40), 3710 SW US Veteran's Hospital Road, Portland, OR 97201, USA. buckk@ohsu.edu

Psychopharmacology
|March 29, 2002
PubMed
Summary

Genetic mapping identified quantitative trait loci (QTLs) on mouse chromosomes 1 and 19 significantly associated with ethanol withdrawal severity. These findings advance understanding of genetic factors contributing to alcohol physical dependence.

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Area of Science:

  • Genetics
  • Neuroscience
  • Pharmacology

Background:

  • Alcoholism is characterized by physical dependence, tolerance, and problematic alcohol use.
  • Genetic factors significantly influence susceptibility to alcohol withdrawal.
  • The C57BL/6J and DBA/2J mouse strains exhibit differential withdrawal responses, serving as a model for genetic studies.

Purpose of the Study:

  • To conduct a genome-wide quantitative trait locus (QTL) mapping study to identify genes influencing ethanol withdrawal severity.
  • To dissect the genetic underpinnings of physical dependence on ethanol using a mouse model.

Main Methods:

  • A cohort of 400 B6D2F2 mice was utilized for the genome-wide QTL mapping.
  • Physical dependence was induced via chronic ethanol vapor exposure for 72 hours.

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  • Ethanol withdrawal severity was assessed by handling-induced convulsions (HICs) and corrected for blood ethanol concentration and baseline HIC severity.

    • Main Results:

    • Significant QTLs associated with ethanol withdrawal severity were identified on chromosomes 19 and distal 1 (P<0.00005), explaining 45% of the genetic variance.
    • A major effect QTL on distal chromosome 1 accounted for 26% of the genetic variance.
    • Supporting evidence for additional QTLs on chromosomes 13 (sex-limited), 4, and proximal 1 was found, potentially explaining another 38% of the genetic variance.

    Conclusions:

    • Identified QTLs are located near candidate genes involved in neurosteroid biosynthesis and signal transduction pathways.
    • Syntenic homology suggests potential human chromosomal regions (e.g., 10q23-q26, 1q21-q43) harboring genes related to ethanol physical dependence.