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.

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National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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Special Emphasis Panel (ZRG4-ALTX-3 (01))
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Oregon Health and Science University
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Kozell, Laura B; Denmark, Deaunne L; Walter, Nicole A R et al. (2018) Distinct Roles for Two Chromosome 1 Loci in Ethanol Withdrawal, Consumption, and Conditioned Place Preference. Front Genet 9:323
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; 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
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
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
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
Buck, K J; Walter, N A R; Denmark, D L (2014) Genetic variability of respiratory complex abundance, organization and activity in mouse brain. Genes Brain Behav 13:135-43
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

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