Human genetic studies have linked polymorphisms in the GABRA2 (encoding the GABA-A a2-subunit) gene to alcoholism (Edenberg et al., 2004;Soyka et al., 2008). However, the precise behavioral and neurochemical mechanism(s) for this linkage remain unclear. For example, the available evidence suggests that the GABRA2 risk allele reduces a2-subunit expression (Haughey et al., 2008), and may modulate nsk for alcoholism through alterations in the behavioral correlates impulsivity (Dick et al., 2006) and trait anxiety (Enoch et al. 2006). However, due to the complexities of studying humans, including the inability to control conditions or access the brain, the development of good animal models will be necessary to more effectively elucidate the behavioral and neurochemical mechanisms underlying the effects of the GABRA2 nsk allele.The goal of the current proposal is to investigate the mechanisms by which Gabra2 affects alcohol intake/preference, impulsive choice, and anxiety-like behavior in two different high drinking/alcohol preferring mouse populations, the C57BL/6J (B6) inbred and the high alcohol preferring (HAP2) selectively bred mouse strains/lines. A lentiviral vector-mediated delivery approach will be used to reduce (knockdown) GABA-A a2- subunit expression in several mouse brain structures believed important in the modulation of alcohol intake/preference (posterior ventral tegmental area or pVTA;nucleus accumbens shell or NACsh), impulsive choice (orbitofrontal cortex or OFC), and anxiety-like behavior (amygdala or AMY). The hypothesis is that knockdown of a2 in each of these structures will reduce alcohol intake/preference in B6 and HAP2 mice. However, the hypothesis is that the effects of a2 knockdown on the presumed impulsivity and anxiety behavioral correlates will be site-specific, with only OFC knockdown reducing impulsivity, and only AMY knockdown reducing anxiety-like behavior. Such results would further implicate altered expression of a2 as the neurochemical mechanism, and the behavioral correlates impulsivity and anxiety as the behavioral mechanisms, by which the GABRA2 genotype influences alcoholism risk.

Public Health Relevance

The proposed studies will further elucidate the behavioral and neurochemical mechanisms underlying the the effects of the GABRA2 alcoholism risk genotype in humans. Such knowledge will positively impact the search for new prevention and drug treatment strategies for alcoholism.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Comprehensive Center (P60)
Project #
Application #
Study Section
Special Emphasis Panel (ZAA1-GG)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Indiana University-Purdue University at Indianapolis
United States
Zip Code
O'Tousa, David S; Warnock, Kaitlin T; Matson, Liana M et al. (2015) Triple monoamine uptake inhibitors demonstrate a pharmacologic association between excessive drinking and impulsivity in high-alcohol-preferring (HAP) mice. Addict Biol 20:236-47
Oberlin, Brandon G; Dzemidzic, Mario; Tran, Stella M et al. (2015) Beer self-administration provokes lateralized nucleus accumbens dopamine release in male heavy drinkers. Psychopharmacology (Berl) 232:861-70
Muralidharan, Pooja; Sarmah, Swapnalee; Marrs, James A (2015) Zebrafish retinal defects induced by ethanol exposure are rescued by retinoic acid and folic acid supplement. Alcohol 49:149-63
Guillot, Casey R; Fanning, Jennifer R; Liang, Tiebing et al. (2015) COMT Associations with Disordered Gambling and Drinking Measures. J Gambl Stud 31:513-24
Azarov, Alexey V; Woodward, Donald J (2014) Early ethanol and water consumption: accumulating experience differentially regulates drinking pattern and bout parameters in male alcohol preferring (P) vs. Wistar and Sprague Dawley rats. Physiol Behav 123:20-32
Montane Jaime, Lazara Karelia; Shafe, Samuel; Liang, Tiebing et al. (2014) Subjective response to alcohol and ADH polymorphisms in a select sample of young adult male East Indians and Africans in Trinidad and Tobago. J Stud Alcohol Drugs 75:827-38
Beckwith, S Wesley; Czachowski, Cristine L (2014) Increased delay discounting tracks with a high ethanol-seeking phenotype and subsequent ethanol seeking but not consumption. Alcohol Clin Exp Res 38:2607-14
Kasten, Chelsea R; Boehm 2nd, Stephen L (2014) Intra-nucleus accumbens shell injections of R(+)- and S(-)-baclofen bidirectionally alter binge-like ethanol, but not saccharin, intake in C57Bl/6J mice. Behav Brain Res 272:238-47
Toalston, Jamie E; Deehan Jr, Gerald A; Hauser, Sheketha R et al. (2014) Reinforcing properties and neurochemical response of ethanol within the posterior ventral tegmental area are enhanced in adulthood by periadolescent ethanol consumption. J Pharmacol Exp Ther 351:317-26
Hoffman, P L; Saba, L M; Flink, S et al. (2014) Genetics of gene expression characterizes response to selective breeding for alcohol preference. Genes Brain Behav 13:743-57

Showing the most recent 10 out of 124 publications