GABRA2 and the Pharmacokinetics of Risk for Alcoholism Hypothesis: An individual's genotype at the GABRA2 gene influences the human brain's initial and adaptive responses to alcohol. This genotypic effect is modulated by a family history of alcoholism, and together these effects contribute to a differential risk for alcoholism. The long term goal of this project is to elucidate factors related to the brain's response to alcohol that place some individuals at greater risk for alcoholism and alcohol-related problems. In the future, assays could be developed to identify high-risk individuals and interventions could be initiated earlier to decrease the risk of future alcohol dependence. In the current grant cycle, our methods for prescribing the time-course of breath alcohol concentration (BrAC) were applied to detect an association between a family history of alcohol dependence and (a) changes in the brain's response to alcohol following a week of abstinence, and (b) brain sensitivity to the rate of change of alcohol exposure. Recently, GABRA2 genotype has been shown to be a risk factor for alcohol dependence, and research suggests a GABRA2 effect in the brain's response to alcohol. Thus, we propose to employ BrAC """"""""clamping"""""""" methods to study the effects of variation in GABRA2 on the brain's responses to alcohol in the context of a family history of alcoholism and other factors associated with greater risk for alcoholism. BrAC clamping eliminates the experimental variance associated with oral alcohol administration and achieves the same, constant brain exposure for all subjects. We will use the clamping method to examine the brain's electrophysiological, eye-movement, behavioral, and subjective responses to alcohol as potential alcohol-related endophenotypes of risk. To explore a possible mechanism of genetic influence, we will employ fMRI in the same subjects to examine the effect of GABRA2 genotype and a family history of alcoholism on frontal lobe activity during 2 motor disinhibition tasks while alcohol exposure is clamped. We will initiate longitudinal, periodic assessment of all subjects for symptoms of alcohol use disorders in order to eventually validate the association of genotype with alcohol-related endophenotypes of risk. Overall, we expect that the influences of the GABRA2 high-risk genotype on responses to alcohol will be more apparent in subjects with a positive family history of alcoholism, and will accelerate the onset of alcohol-related problems.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Comprehensive Center (P60)
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Indiana University-Purdue University at Indianapolis
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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

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