Abstract

Decreased GABAergic transmission is thought to play an important role in the development of alcohol dependence/withdrawal, but the specific genes responsible for adaptive changes in GABAergic transmission remain to be elucidated. In our studies to date, QTL analysis using three populations derived from the C57BL/6J and DBA/2J inbred mouse strains have identified several loci that contribute to genetic differences in acute alcohol withdrawal severity. One alcohol withdrawal locus (Alcw1) has been localized at a high level of significance (p<.000015, relative to the null hypothesis of no linkage to an approximate 10cM from the centromere that encodes the alpha1, alpha 6, gamma2 and beta 2 subunits of GABAA receptors. Another locus (Alcw2) has tentatively been mapped on chromosome 2, and in all three populations showed the strongest association with markers located 37 cM from the centromere (p<.002). Alcw2 maps near two genes encoding neuronal subtypes of glutamic acid decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis, located 43cM and 9 cM from the centromere.
Aims 1 and 2 of this proposal will use DBA/2J, C57BL/6J, and BXD recombinant inbred mice to test the hypothesis that genetically determined differences in acute alcohol withdrawal severity are correlated with differences in cDNA coding sequence between parental DBA/2J and C57BL/6J alleles, RNA transcriptional differences and/or different functional properties for the protein products of identified candidate genes encoding GABAA recptor subunits and/or GAD subtypes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AA011114-03
Application #
2894142
Study Section
Special Emphasis Panel (ZRG4-ALTX-3 (01))
Project Start
1997-08-01
Project End
2002-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

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

  Publications

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
Tipps, Megan E; Buck, Kari J (2015) GIRK Channels: A Potential Link Between Learning and Addiction. Int Rev Neurobiol 123:239-77
López-Jiménez, Alejandro; Walter, Nicole A R; Giné, Elena et al. (2013) A spontaneous deletion of ?-synuclein is associated with an increase in CB1 mRNA transcript and receptor expression in the hippocampus and amygdala: effects on alcohol consumption. Synapse 67:280-9
Iancu, Ovidiu D; Kawane, Sunita; Bottomly, Daniel et al. (2012) Utilizing RNA-Seq data for de novo coexpression network inference. Bioinformatics 28:1592-7
Laderas, Ted G; Walter, Nicole A R; Mooney, Michael et al. (2011) Computational detection of alternative exon usage. Front Neurosci 5:69
Bottomly, Daniel; Walter, Nicole A R; Hunter, Jessica Ezzell et al. (2011) Evaluating gene expression in C57BL/6J and DBA/2J mouse striatum using RNA-Seq and microarrays. PLoS One 6:e17820
Chen, Gang; Kozell, Laura B; Buck, Kari J (2011) Substantia nigra pars reticulata is crucially involved in barbiturate and ethanol withdrawal in mice. Behav Brain Res 218:152-7
Chen, Gang; Cuzon Carlson, Verginia C; Wang, Jun et al. (2011) Striatal involvement in human alcoholism and alcohol consumption, and withdrawal in animal models. Alcohol Clin Exp Res 35:1739-48
Milner, Lauren C; Buck, Kari J (2010) Identifying quantitative trait loci (QTLs) and genes (QTGs) for alcohol-related phenotypes in mice. Int Rev Neurobiol 91:173-204
Ehlers, Cindy L; Walter, Nicole A R; Dick, Danielle M et al. (2010) A comparison of selected quantitative trait loci associated with alcohol use phenotypes in humans and mouse models. Addict Biol 15:185-99

Showing the most recent 10 out of 18 publications