Abstract
Male mice from C57BL/6J (B6), DBA/2J (D2) and their 25 recombinant inbred (RI) strains were exposed to ethanol (EtOH) vapor (3.0–9.0 mg EtOH/liter of air) for 72 hr. Mice were selected such that each strain averaged 1.34 to 1.59 mg of EtOH/ml of blood on withdrawal. Control groups and EtOH-exposed groups were tested hourly for handling-induced convulsions (HIC) for 10 hr and at hr 24 and 25. Strain withdrawal severity was indexed as the area under the 25-hr HIC curve for the EtOH group minus that strain’s equivalent value for the control group. Genome-wide quantitative trait locus (QTL) analyses correlating strain means with allelic status at >1500 markers identified 10 chromosomal regions at P < .01. These provisionally identified QTLs were on chromosomes 1 (2 QTLs), 3, 9 (2 QTLs), 10, 12, 13, 15 and 18. Multiple regression analysis using the four most influential QTLs revealed that these loci controlled 86% of the genetic variance. A QTL mapped to distal chromosome 1 (P < .001) is in the same region as one previously definitively mapped for acute alcohol withdrawal, as well as one mapped for acute pentobarbital withdrawal. Several of the QTLs map near potential candidate genes. These provisional linkages will now be confirmed or rejected using additional genetically segregating populations.
Footnotes
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Send reprint requests to: John Crabbe, Ph.D., Portland Alcohol Research Center (R & D12), VA Medical Center, 3710 S.W. U.S. Veterans Hospital Road, Portland, OR 97201. E-mail:crabbe{at}ohsu.edu
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↵1 This work was supported by National Institute on Alcohol Abuse and Alcoholism Grants P50-AA10760 and R01-AA06243 and a Merit Review Grant from the Department of Veterans Affairs.
- Abbreviations:
- RI
- recombinant inbred
- EtOH
- ethanol
- HIC
- handling-induced convulsions
- QTL
- quantitative trait locus
- BEC
- blood ethanol concentration
- WSP
- withdrawal seizure-prone
- WSR
- withdrawal seizure-resistant
- LOD
- log of the odds of linkage
- Received December 23, 1997.
- Accepted March 20, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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