Quantitative trait loci (QTLs) are chromosomal regions containing genes that influence a complex trait such as drug withdrawal severity. We have established that there is a great deal of common genetic influence on withdrawal from barbiturates, benzodiazepines, nitrous oxide, and alcohol. During the current period, we have mapped several QTLs that jointly have a major influence on the severity of pentobarbital (PB) withdrawal. The three largest QTLs are on mouse chrs 1, 4 and 11. QTLs in each of these regions have also been provisionally mapped for diazepam withdrawal, and definitively mapped for ethanol withdrawal: the chr 1 QTL was also provisionally mapped for nitrous oxide withdrawal. Using congenic strains to isolate each of the three QTLs against a uniform (inbred) genetic background, we propose to continue toward the eventual identification of the genes that underlie each PB withdrawal QTL. We propose to: (1) Test congenics for the strongest PB QTLs for their pleiotropic effects on withdrawal from other drugs of abuse; (2) Produce polycongenics in different combinations to determine whether gene-gene (epistatic) interactions are additive, potentiating in some combinations, or epistatic in some other way; (3) Narrow each QTL interval from our present approximately 20 cM to approximately 1 cM using interval specific congenic strains (ISCS); (4) Scan promising candidate genes for cDNA differences between B6 and D2 genotypes by SSCP; (5) Produce polycongenics from specific donor segment (SDS) congenics produced from appropriate interval specific congenic strains, and test for epistatic interactions among QTLs, as well as QTL pleiotropisms for withdrawal from other drugs, and for other drug-related responses known to be genetically correlated with PB withdrawal severity; and (6) Start with an F2 population, screen for additional QTLs not previously ascertained and produce additional congenics to facilitate eventual cloning of the genes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA005228-11
Application #
6175045
Study Section
Special Emphasis Panel (ZRG1-ALTX-3 (01))
Program Officer
Satterlee, John S
Project Start
1989-08-01
Project End
2004-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
11
Fiscal Year
2000
Total Cost
$361,173
Indirect Cost
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Buck, Kari J; Chen, Gang; Kozell, Laura B (2017) Limbic circuitry activation in ethanol withdrawal is regulated by a chromosome 1 locus. Alcohol 58:153-160
Walter, Nicole A R; Denmark, DeAunne L; Kozell, Laura B et al. (2016) A Systems Approach Implicates a Brain Mitochondrial Oxidative Homeostasis Co-expression Network in Genetic Vulnerability to Alcohol Withdrawal. Front Genet 7:218
Tipps, Megan E; Raybuck, Jonathan D; Kozell, Laura B et al. (2016) G Protein-Gated Inwardly Rectifying Potassium Channel Subunit 3 Knock-Out Mice Show Enhanced Ethanol Reward. Alcohol Clin Exp Res 40:857-64
Milner, Lauren C; Shirley, Renee L; Kozell, Laura B et al. (2015) Novel MPDZ/MUPP1 transgenic and knockdown models confirm Mpdz's role in ethanol withdrawal and support its role in voluntary ethanol consumption. Addict Biol 20:143-7
Iancu, Ovidiu D; Colville, Alexandre; Oberbeck, Denesa et al. (2015) Cosplicing network analysis of mammalian brain RNA-Seq data utilizing WGCNA and Mantel correlations. Front Genet 6:174
Tipps, Megan E; Raybuck, Jonathan D; Buck, Kari J et al. (2015) Acute ethanol withdrawal impairs contextual learning and enhances cued learning. Alcohol Clin Exp Res 39:282-90
Tipps, Megan E; Buck, Kari J (2015) GIRK Channels: A Potential Link Between Learning and Addiction. Int Rev Neurobiol 123:239-77
Kruse, L C; Walter, N A R; Buck, K J (2014) Mpdz expression in the caudolateral substantia nigra pars reticulata is crucially involved in alcohol withdrawal. Genes Brain Behav 13:769-76
Tipps, Megan E; Raybuck, Jonathan D; Buck, Kari J et al. (2014) Delay and trace fear conditioning in C57BL/6 and DBA/2 mice: issues of measurement and performance. Learn Mem 21:380-93
Hitzemann, Robert; Bottomly, Daniel; Iancu, Ovidiu et al. (2014) The genetics of gene expression in complex mouse crosses as a tool to study the molecular underpinnings of behavior traits. Mamm Genome 25:12-22

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