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
Wardell, Jeffrey D; Ramchandani, Vijay A; Hendershot, Christian S (2016) Drinking Motives Predict Subjective Effects of Alcohol and Alcohol Wanting and Liking During Laboratory Alcohol Administration: A Mediated Pathway Analysis. Alcohol Clin Exp Res 40:2190-2198
McClintick, Jeanette N; McBride, William J; Bell, Richard L et al. (2016) Gene Expression Changes in Glutamate and GABA-A Receptors, Neuropeptides, Ion Channels, and Cholesterol Synthesis in the Periaqueductal Gray Following Binge-Like Alcohol Drinking by Adolescent Alcohol-Preferring (P) Rats. Alcohol Clin Exp Res 40:955-68
Yoder, Karmen K; Albrecht, Daniel S; Dzemidzic, Mario et al. (2016) Differences in IV alcohol-induced dopamine release in the ventral striatum of social drinkers and nontreatment-seeking alcoholics. Drug Alcohol Depend 160:163-9
Bell, R L; Hauser, S; Rodd, Z A et al. (2016) A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction. Int Rev Neurobiol 126:179-261
Sari, Youssef; Toalston, Jamie E; Rao, P S S et al. (2016) Effects of ceftriaxone on ethanol, nicotine or sucrose intake by alcohol-preferring (P) rats and its association with GLT-1 expression. Neuroscience 326:117-25
Ding, Zheng-Ming; Ingraham, Cynthia M; Rodd, Zachary A et al. (2016) Alcohol drinking increases the dopamine-stimulating effects of ethanol and reduces D2 auto-receptor and group II metabotropic glutamate receptor function within the posterior ventral tegmental area of alcohol preferring (P) rats. Neuropharmacology 109:41-8
O'Tousa, David S; Grahame, Nicholas J (2016) Long-Term Alcohol Drinking Reduces the Efficacy of Forced Abstinence and Conditioned Taste Aversion in Crossed High-Alcohol-Preferring Mice. Alcohol Clin Exp Res 40:1577-85
King, Andrea C; Hasin, Deborah; O'Connor, Sean J et al. (2016) A Prospective 5-Year Re-examination of Alcohol Response in Heavy Drinkers Progressing in Alcohol Use Disorder. Biol Psychiatry 79:489-98
Beckwith, Steven Wesley; Czachowski, Cristine Lynn (2016) Alcohol-Preferring P Rats Exhibit Elevated Motor Impulsivity Concomitant with Operant Responding and Self-Administration of Alcohol. Alcohol Clin Exp Res 40:1100-10
Qiu, Bin; Bell, Richard L; Cao, Yong et al. (2016) Npy deletion in an alcohol non-preferring rat model elicits differential effects on alcohol consumption and body weight. J Genet Genomics 43:421-30

Showing the most recent 10 out of 267 publications