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Previous Article | Next Article
Volume 17, Number 10, Issue of May 15, 1997 pp. 3946-3955
Copyright ©1997 Society for NeuroscienceQuantitative Trait Loci Involved in Genetic Predisposition to Acute Alcohol Withdrawal in Mice
Received Oct. 21, 1996; revised Jan. 17, 1997; accepted Feb. 27, 1997.
Kari Johnson Buck1, Pamela Metten1, John K. Belknap1, 2, and John C. Crabbe1, 2 1 Portland Alcohol Research Center and Department of Behavioral Neuroscience, Oregon Health Sciences University, Portland, Oregon 97201 and 2 Department of Veterans Affairs Medical Center, Portland, Oregon 97201
Alcohol dependence (alcoholism) is accompanied by evidence of tolerance, withdrawal (physiological dependence), or compulsive behavior related to alcohol use. Studies of strain and individual differences using animal models for acute physiological dependence liability are useful means to identify potential genetic determinants of liability in humans. Behavioral and quantitative trait analyses were conducted using animal models for high risk versus resistance to acute physiological dependence. Using a two-step genetic mapping strategy, loci on mouse chromosomes 1, 4, and 11 were mapped that contain genes that influence alcohol withdrawal severity. In the aggregate, these three risk markers accounted for 68% of the genetic variability in alcohol withdrawal. Candidate genes in proximity to the chromosome 11 locus include genes encoding the
1,
2 subunits of type-A receptors for the inhibitory neurotransmitter, GABA. In addition, suggestive linkage is indicated for two loci on mouse chromosome 2, one near Gad1 encoding glutamic acid decarboxylase, and the other near the El2 locus which influences the seizure phenotype in the neurological mutant strain El. The present analyses detect and map some of the loci that increase risk to develop physiological dependence and may facilitate identification of genes related to the development of alcoholism. Syntenic conservation between human and mouse chromosomes suggests that human homologs of genes that increase risk for physiological dependence may localize to 1q21-q32, 2q24-q37/11p13, 9p21-p23/1p32-p22.1, and 5q32-q35.
Key words: ethanol; QTL; quantitative trait locus; recombinant inbred strain; selective breeding; GABAA receptor; glutamic acid decarboxylase; physiological dependence; withdrawal; seizure; handling-induced convulsions
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